Dr James Schaller
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MULTIPLE SCLEROSIS AND ANTIBIOTICS

It is very surprising that even the conservative textbook by Reik on neurology and Lyme disease, discusses that this spiral shaped bacteria can cause massive damage to the brain, and sometimes quickly. This damage which occurs soon after a bite or many years later, does not even address the help Lyme disease gets from other co-infections common in ticks like Bartonella and Babesia.

I recently heard of a young woman who is slowly dying and is now having uncontrolled seizures, fibromyalgia and an inability to walk. She has had massive work ups, and she has not even been given a poor diagnosis. They found Lyme in her spinal fluid!


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Combined treatment with atorvastatin and minocycline suppresses severity of EAE.

Luccarini I, Ballerini C, Biagioli T, Biamonte F, Bellucci A, Rosi MC, Grossi C, Massacesi L, Casamenti F.

Department of Pharmacology, University of Florence, Viale Pieraccini n. 6, Florence, Italy.

Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). An approach to improve MS treatment is to identify a rational combination of new medications or existing therapies that impact different aspects of the disease process. Statins are effective in the treatment of MS animal models and are promising candidates for future treatment. Minocycline ameliorates clinical severity of experimental autoimmune encephalomyelitis (EAE) and exhibits several anti-inflammatory and neuroprotective activities. In this study, we tested whether the combination of these two drugs could produce beneficial effects in EAE mice immunized with myelin oligodendrocyte protein (MOG). Our findings show that combined treatment, compared to using the medications alone, resulted in a significant reduction in disease severity, in both the acute and chronic phases of the disease, along with attenuation of inflammation, demyelination and axonal loss. Stereological analysis revealed that the combined treatment significantly guarded against neuroinflammation and neurodegeneration. Moreover, a significant suppression of anti-MOG antibody production in animals treated with the two medications was found. In conclusion, our findings prove that this combination of drugs is neuroprotective and suppresses the severity of EAE. Furthermore, this pharmacological approach appears to be promising as a future therapeutic strategy to control MS.

Publication Types:
PMID: 18346732 [PubMed - indexed for MEDLINE]

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Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat.

KrŠmer S, Wang-Rosenke Y, Scholl V, Binder E, Loof T, Khadzhynov D, Kawachi H, Shimizu F, Diekmann F, Budde K, Neumayer HH, Peters H.

Department of Nephrology and Center for Cardiovascular Research, CharitŽ UniversitŠtsmedizin Berlin, CharitŽ Campus Mitte, Humboldt University, Berlin, Germany.

Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg.kg(-1).body wt(-1)) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. Kruskal-Wallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (-38%), systolic blood pressure (-16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (-61 and -24%), transforming growth factor-beta1 overexpression (-41 and -47%), collagen I deposition (-53 and -65%), cell proliferation (-90 and -76%), and leukocyte number (macrophages -52 and -53%; lymphocytes -58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine -0.68 mg/dl, urea -66.7 mg/day, and creatinine clearance +0.13 ml.min(-1).100 g body wt(-1)). In conclusion, low-dose mTOR inhibition by rapamycin limits the progressive course of anti-thy1-induced renal disease toward chronic glomerulosclerosis, tubulointerstitial fibrosis, and renal insufficiency. Renoprotection by rapamycin involved significant beneficial effects on multiple key pathways in the progression of chronic renal disease, i.e., proteinuria, extracellular matrix accumulation, renal cell proliferation, and inflammatory cell infiltration.

Publication Types:
PMID: 18094032 [PubMed - indexed for MEDLINE]

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Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial.

Minagar A, Alexander JS, Schwendimann RN, Kelley RE, Gonzalez-Toledo E, Jimenez JJ, Mauro L, Jy W, Smith SJ.

Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. aminag@lsuhsc.edu

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of combination therapy with intramuscular interferon beta-1a and oral doxycycline, a potent inhibitor of matrix metalloproteinases, in patients with relapsing-remitting multiple sclerosis (RRMS) having breakthrough disease activity. DESIGN: Open-label, 7-month trial. SETTING: Louisiana State University Health Sciences Center, Shreveport. PATIENTS: Fifteen patients with RRMS taking interferon beta-1a with breakthrough disease activity took doxycycline for 4 months. Patients underwent monthly neurologic examination, magnetic resonance imaging of the brain using triple-dose gadolinium, and safety blood work. INTERVENTIONS: Ongoing treatment with intramuscular interferon beta-1a plus oral doxycycline, 100 mg daily, for 4 months. MAIN OUTCOME MEASURES: The primary end point was gadolinium-enhancing lesion number change, and the secondary end points were relapse rates, safety and tolerability of the combination of interferon beta-1a and doxycycline in patients with MS, Expanded Disability Status Scale score, serum matrix metalloproteinase-9 levels, and transendothelial migration of monocytes exposed to serum from patients with RRMS. RESULTS: Combination of doxycycline and interferon beta-1a treatment resulted in reductions in contrast-enhancing lesion numbers and posttreatment Expanded Disability Status Scale values (P < .001 for both). Only 1 patient relapsed. Multivariate analyses indicated correlations between decreased serum matrix metalloproteinase-9 levels and enhancing lesion activity reduction. Transendothelial migration of monocytes incubated with serum from patients with RRMS undergoing combination therapy was suppressed. Adverse effects were mild; no adverse synergistic effects of combination therapy or unexpected adverse events were reported. CONCLUSIONS: Combination of intramuscular interferon beta-1a and oral doxycycline treatment was effective, safe, and well tolerated. Controlled clinical trials in larger cohorts of patients with MS are needed to evaluate the efficacy and tolerability of this combination. Trial Registration clinicaltrials.gov Identifier: NCT00246324

Publication Types:
PMID: 18071030 [PubMed - indexed for MEDLINE]

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Doxycycline in autoimmune central nervous system disorders in children: an in vitro study.

Anlar B, Senbil N, GŸven A.

Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Tetracyclines have antiinflammatory properties. To test the in vitro effect of doxycycline in autoimmune neurological disorders of childhood, peripheral blood lymphocytes from multiple sclerosis (n=11), acute disseminated encephalomyelitis (n=12), and control patients (epilepsy and headache, n=12), all aged 5-17, were examined for proliferation, migration, and apoptosis after culture with doxycycline, concanavalin A and myelin basic protein for 48 hours. Doxycycline increased proliferation in the control group, and less in the multiple sclerosis group but not in the acute disseminated encephalomyelitis group (p<0.03). It increased apoptosis in multiple sclerosis patients (p<0.02). According to this preliminary study, doxycycline might have immunomodulatory effects in children, justifying future studies with larger and more homogeneous patient groups.

Publication Types:
PMID: 17990580 [PubMed - indexed for MEDLINE]

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Systemic infections in multiple sclerosis and experimental autoimmune encephalomyelitis.

Tauber SC, Nau R, Gerber J.

Department of Neurology, Georg-August-University, Gšttingen, Germany.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It has been suggested that viral and bacterial infections contribute to the pathogenesis of MS. This review will give an overview about the influence of viral and bacterial infections on MS and experimental autoimmune encephalomyelitis (EAE). It will focus on bacterial infections and will also emphasise therapeutic consequences such as the impact of antibiotic treatment on the course of EAE. In summary, a growing body of evidence suggests that systemic infections are a risk factor for the initiation of autoimmune processes including the induction of acute events in MS. Experimental and clinical data strongly suggest early treatment of bacterial infections in MS patients to avoid aggravation and relapse.

Publication Types:
PMID: 17922308 [PubMed - indexed for MEDLINE]

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Hygiene, microbial diversity and immune regulation.

Guarner F.

Digestive System Research Unit, Ciberehd, University Hospital Vall d'Hebron, Barcelona, Spain. fguarner@vhebron.net

PURPOSE OF REVIEW: Sanitation, antibiotics and vaccines have done more to extend life expectancy than any other medical innovation. Concern exists, however, about the link between hygiene and increased incidence of immune-mediated disorders. RECENT FINDINGS: Studies confirm higher prevalence of asthma and allergic diseases in urban areas and developed countries rather than rural areas and developing countries. There is an inverse association between family size and disease. The debate over whether infection precipitates or prevents immune dysregulation remains a contentious one. Our knowledge about the microbial composition of the intestinal ecosystem is expanding rapidly with the introduction of molecular techniques. Differences in gut bacteria between health and atopy or inflammatory bowel disease are repeatedly reported. Recent data in inflammatory bowel disease suggest reduced species diversity and temporal instability of the gut microecosystem. The gut is a major site for induction of regulatory T cells, which secrete immunosuppressive cytokines. Not only infections, but also some commensals induce regulatory pathways, which seem to be functionally deficient in multiple sclerosis, allergies and inflammatory bowel disease. SUMMARY: Changes in lifestyle leading to decreased exposure to certain nonpathogenic species that are important for the development of immunoregulatory mechanisms are probably associated with increased incidence of some immune-mediated diseases, such as allergies and inflammatory bowel disease.

Publication Types:
PMID: 17906445 [PubMed - indexed for MEDLINE]

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Comment on:
Antimicrobial treatment of multiple sclerosis.

Stratton CW, Wheldon DB.

Publication Types:
PMID: 17882356 [PubMed - indexed for MEDLINE]

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Gangrenous, hemorrhagic, bullous cellulitis associated with pseudomonas aeruginosa in a patient with Waldenstršm's macroglobulinemia.

Falagas ME, Pappas VD, Michalopoulos A.

Alfa Institute of Biomedical Sciences, 9 Neapoleos Street, Marousi, 151 23, Athens, Greece. m.falagas@aibs.gr

BACKGROUND: Patients with Waldenstršm's macroglobulinemia may manifest several types of skin lesions. We present our experience with a patient with the disease that adds to the literature on the topic. CASE DESCRIPTION: A 57-year-old man with history of multiple sclerosis and Waldenstršm's macroglobulinemia was admitted to the intensive care unit in shock. His family members reported that the patient had complained of fever and the gradual development of gangrenous, hemorrhagic, bullous cellulitis lesions on the abdomen and lower extremities for 7 days prior to his admission to the hospital. Pseudomonas aeruginosa was isolated from fluid specimens collected from the cutaneous lesions. Appropriate antimicrobial treatment including continuous intravenous administration of meropenem (6 g every 24 h) led to the cure of the infection. CONCLUSIONS: We postulate that the underlying Waldenstršm's macroglobulinemia contributed to the pathophysiology of the development of the rare skin manifestations of the infection observed in our patient.

Publication Types:
PMID: 17721738 [PubMed - indexed for MEDLINE]

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Tuberous sclerosis complex: advances in diagnosis, genetics, and management.

Schwartz RA, Fern‡ndez G, Kotulska K, Jozwiak S.

Department of Dermatology, New Jersey Medical School, Newark, NJ 07103, USA. roschwar@cal.berkeley.edu

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, heart, kidneys, liver, and lungs. Two-thirds of patients represent sporadic mutations. The classic triad is seizures, mental retardation, and cutaneous angiofibromas. However, the full triad occurs in only 29% of patients; 6% of them lack all three of them. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16. This article highlights the most recent significant advances in the diagnosis and genetics of TSC, along with a discussion on the limitations and the usefulness of the revised 1998 clinical criteria for the tuberous sclerosis complex. The "ash leaf" macule often comes in other shapes, such as round; most are polygonal, usually 0.5 cm to 2.0 cm in diameter, resembling a thumbprint. Since the death of its describer, Thomas Fitzpatrick, we call each a "Fitzpatrick patch." Special attention is paid in this work to TSC treatment options, including therapeutic trials with rapamycin, also known as sirolimus. LEARNING OBJECTIVE: After completing this learning activity, participants should familiar with tuberous sclerosis complex, its cutaneous signs and systemic findings stratified by patient age, its genetics, and the potential for meaningful therapeutic intervention.

Publication Types:
PMID: 17637444 [PubMed - indexed for MEDLINE]

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Neuroprotective interventions targeting detrimental host immune responses protect mice from fatal alphavirus encephalitis.

Irani DN, Prow NA.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. dirani@jhmi.edu

Systemic treatment with the tetracycline derivative, minocycline, attenuates neurologic deficits in animal models of amyotrophic lateral sclerosis, hypoxic-ischemic brain injury, and multiple sclerosis. Inhibition of microglial activation within the CNS is 1 mechanism proposed to underlie the beneficial effects of the drug in these systems. Given the widening scope of acute viral encephalitis caused by mosquito-borne pathogens, we investigated the therapeutic effects of minocycline in a murine model of fatal alphavirus encephalomyelitis in which widespread microglial activation is known to occur. We found that minocycline conferred significant protection against both paralysis and death, even when started after viral challenge and despite having no effect on CNS virus replication or spread. Further studies demonstrated that minocycline inhibited early virus-induced microglial activation and that diminished CNS production of the inflammatory mediator, interleukin (IL)-1beta, contributed to its protective effect. Therapeutic blockade of IL-1 receptors also conferred significant protection in our model, validating the importance of the IL-1 pathway in disease pathogenesis. We propose that interventions targeting detrimental host immune responses arising from activated microglia may be of benefit in humans with acute viral encephalitis caused by related mosquito-borne pathogens. Such treatments could conceivably act through neuroprotective rather than antiviral mechanisms to generate these clinical effects.

Publication Types:
PMID: 17549013 [PubMed - indexed for MEDLINE]

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The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention.

Sheldon AL, Robinson MB.

Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104-4318, United States.

Extracellular concentrations of the predominant excitatory neurotransmitter, glutamate, and related excitatory amino acids are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in cell death. The latter phenomenon is known as 'excitotoxicity' and has been associated with a wide range of acute and chronic neurodegenerative disorders, as well as disorders that result in the loss of non-neural cells such as oligodendroglia in multiple sclerosis. Unfortunately clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with untoward side effects or little clinical benefit. In the mammalian CNS, the extracellular concentrations of glutamate are controlled by two types of transporters; these include a family of Na(+)-dependent transporters and a cystine-glutamate exchange process, referred to as system X(c)(-). In this review, we will focus primarily on the Na(+)-dependent transporters. A brief introduction to glutamate as a neurotransmitter will be followed by an overview of the properties of these transporters, including a summary of the presumed physiologic mechanisms that regulate these transporters. Many studies have provided compelling evidence that impairing the function of these transporters can increase the sensitivity of tissue to deleterious effects of aberrant activation of glutamate receptors. Over the last decade, it has become clear that many neurodegenerative disorders are associated with a change in localization and/or expression of some of the subtypes of these transporters. This would suggest that therapies directed toward enhancing transporter expression might be beneficial. However, there is also evidence that glutamate transporters might increase the susceptibility of tissue to the consequences of insults that result in a collapse of the electrochemical gradients required for normal function such as stroke. In spite of the potential adverse effects of upregulation of glutamate transporters, there is recent evidence that upregulation of one of the glutamate transporters, GLT-1 (also called EAAT2), with beta-lactam antibiotics attenuates the damage observed in models of both acute and chronic neurodegenerative disorders. While it seems somewhat unlikely that antibiotics specifically target GLT-1 expression, these studies identify a potential strategy to limit excitotoxicity. If successful, this type of approach could have widespread utility given the large number of neurodegenerative diseases associated with decreases in transporter expression and excitotoxicity. However, given the massive effort directed at developing glutamate receptor agents during the 1990s and the relatively modest advances to date, one wonders if we will maintain the patience needed to carefully understand the glutamatergic system so that it will be successfully targeted in the future.

Publication Types:
PMID: 17517448 [PubMed - indexed for MEDLINE]

PMCID: PMC2075474 [Available on 11/01/08]


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Microglial activation and its implications in the brain diseases.

Dheen ST, Kaur C, Ling EA.

Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore 117597.

An inflammatory process in the central nervous system (CNS) is believed to play an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, prion diseases, multiple sclerosis and HIV-dementia. The inflammatory response is mediated by the activated microglia, the resident immune cells of the CNS, which normally respond to neuronal damage and remove the damaged cells by phagocytosis. Activation of microglia is a hallmark of brain pathology. However, it remains controversial whether microglial cells have beneficial or detrimental functions in various neuropathological conditions. The chronic activation of microglia may in turn cause neuronal damage through the release of potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. Therefore, suppression of microglia-mediated inflammation has been considered as an important strategy in neurodegenerative disease therapy. Several anti-inflammatory drugs of various chemical ingredients have been shown to repress the microglial activation and to exert neuroprotective effects in the CNS following different types of injuries. However, the molecular mechanisms by which these effects occur remain unclear. In recent years, several research groups including ours have attempted to explain the potential mechanisms and signaling pathways for the repressive effect of various drugs, on activation of microglial cells in CNS injury. We provide here a comprehensive review of recent findings of mechanisms and signaling pathways by which microglial cells are activated in CNS inflammatory diseases. This review article further summarizes the role of microglial cells in neurodegenerative diseases and various forms of potential therapeutic options to inhibit the microglial activation which amplifies the inflammation-related neuronal injury in neurodegenerative diseases.

Publication Types:
PMID: 17504139 [PubMed - indexed for MEDLINE]

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Novel oral agents for multiple sclerosis.

Burton JM, O'Connor P.

Multiple Sclerosis Clinic, Division of Neurology, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. burtonj@smh.toronto.on.ca

In 1993, interferon beta-1b, the first clinically proven disease-modifying agent for multiple sclerosis, was approved, with several comparable agents following close behind. These agents have been beneficial in reducing relapse events and MRI lesions, but all require parenteral administration, leading some otherwise eligible patients to decline such therapies. Oral agents have been studied for decades with mixed results, but a small number of medications currently being tested in phase II/III clinical trials have shown promise in efficacy and tolerability. This review assesses the results of the more thoroughly studied of these agents, some of which may soon be approved for use in multiple sclerosis.

Publication Types:
PMID: 17488588 [PubMed - indexed for MEDLINE]

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The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study.

Zabad RK, Metz LM, Todoruk TR, Zhang Y, Mitchell JR, Yeung M, Patry DG, Bell RB, Yong VW.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

Minocycline has immunomodulatory and neuroprotective activities in vitro and in an animal model of multiple sclerosis (MS). We have previously reported that minocycline decreased gadolinium-enhancing activity over six months in a small trial of patients with active relapsing-remitting MS (RRMS). Here we report the impact of oral minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in this cohort over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment annualized relapse rate (1.3/year pre-enrolment; 1.2/year during a three-month baseline period) prior to treatment, no relapses occurred between months 6 and 24. Also, despite very active MRI activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of the p40 subunit of interleukin (IL)-12, which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1. The activity of matrix metalloproteinase-9 was decreased by treatment. Thus, clinical and MRI outcomes are supported by systemic immunological changes and call for further investigation of minocycline in MS.

Publication Types:
PMID: 17463074 [PubMed - indexed for MEDLINE]

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Comment in:
Rapamycin enriches for CD4(+) CD25(+) CD27(+) Foxp3(+) regulatory T cells in ex vivo-expanded CD25-enriched products from healthy donors and patients with multiple sclerosis.

Keever-Taylor CA, Browning MB, Johnson BD, Truitt RL, Bredeson CN, Behn B, Tsao A.

Department of Medicine/Division of Neoplastic Diseases and Related Disorders, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. ckeever@mcw.edu

BACKGROUND: CD4(+) CD25(bright+) regulatory T cells (Treg) can be expanded to clinical doses using CD3/CD28 Ab-coated beads plus IL-2. However, this method requires high purity of the starting population to prevent overgrowth by non-regulatory T cells. Rapamycin, an agent that inhibits T-cell proliferation but selectively spares Treg, may be a means to expand Treg from less pure CD25-enriched cells. METHODS: CD25-enriched cells were prepared by a single-step immunomagnetic-selection using anti-CD25 microbeads. The cells were activated with a single addition of anti-CD3/CD28 beads and expanded in ex vivo 15-5% HS and autologous CD4(+) CD25(-) feeder cells,+/-rapamycin (0.01-20 ng/mL). IL-2 was added on day 3. Cells were rested for 2 days in ex vivo 15-5% HS and tested for phenotype, intracellular Foxp3 protein and suppressor activity. RESULTS: In the absence of rapamycin, CD25-enriched fractions expanded >17 000-fold by 21 days. Although suppressor activity was detected to day 14, it declined significantly by 21 days as non-regulatory cells expanded. The addition of rapamycin inhibited expansion of non-regulatory T cells at doses > or =1 ng/mL while increasing suppressor activity and the percentage of CD4(+) CD25(+) CD27(+) Foxp3(+) cells. Rapamycin did not enrich for Foxp3(+) cells in expanded cultures of CD4(+) CD25(-) cells. Treg were also readily expanded in cultures of CD25-enriched cells obtained from patients with multiple sclerosis in the presence of rapamycin. DISCUSSION: The addition of 1-20 ng/mL rapamycin to CD25-enriched cultures increased the purity of cells with the phenotype and function of Treg. This approach may alleviate the need for rigorous enrichment of Treg prior to activation and expansion for potential clinical use.

Publication Types:
PMID: 17453966 [PubMed - indexed for MEDLINE]

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Comment on:
Manipulating regulatory T cells.

Barrett AJ.

Stem Cell Allotrransplantation Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, Maryland 20892, USA. barrettjj@mail.nih.gov

Publication Types:
PMID: 17453962 [PubMed - indexed for MEDLINE]

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Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation.

Maier K, Merkler D, Gerber J, Taheri N, Kuhnert AV, Williams SK, Neusch C, BŠhr M, Diem R.

Neurologische UniversitŠtsklinik, Robert-Koch-Strasse 40, D-37075 Gšttingen, Germany. kmaier@gwdg.de

Axonal destruction and neuronal loss occur early during multiple sclerosis, an autoimmune inflammatory CNS disease that frequently manifests with acute optic neuritis. Available therapies mainly target the inflammatory component of the disease but fail to prevent neurodegeneration. To investigate the effect of minocycline on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, we used a rat model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis. Optic neuritis in this model was diagnosed by recording visual evoked potentials and RGC function was monitored by measuring electroretinograms. Functional and histopathological data of RGCs and optic nerves revealed neuronal and axonal protection when minocycline treatment was started on the day of immunization. Furthermore, we demonstrate that minocycline-induced neuroprotection is related to a direct antagonism of multiple mechanisms leading to neuronal cell death such as the induction of anti-apoptotic intracellular signalling pathways and a decrease in glutamate excitotoxicity. From these observations, we conclude that minocycline exerts neuroprotective effects independent of its anti-inflammatory properties. This hypothesis was confirmed in a non-inflammatory disease model leading to degeneration of RGCs, the surgical transection of the optic nerve.

Publication Types:
PMID: 17239606 [PubMed - indexed for MEDLINE]

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Comment in:
Long-term antibiotic treatment with roxithromycin in patients with multiple sclerosis.

Woessner R, Grauer MT, Frese A, Bethke F, Ginger T, Hans A, Treib J.

Dept. of Neurology, Westpfalz Medical Center, 67655, Kaiserslautern, Germany.

BACKGROUND: There are conflicting results concerning an association between Chlamydia pneumoniae and MS (multiple sclerosis). In the present study, we investigated a possible therapeutic option with antibiotics. PATIENTS AND METHODS: In our randomized, placebo-controlled double-blind study, 28 patients with the confirmed diagnosis of MS [61% relapsing-remitting MS (RR-MS), 32% secondary chronic-progressive MS (SP-MS) and 7% primary chronic progressive MS (PP-MS)] were treated over a time period of 12 months with three cycles of a 6-week oral antibiotic therapy with roxithromycin (300 mg per day) or placebo. RESULTS: No significant differences were observed in patients with RR-MS regarding the expanded disability status scale (EDSS) and the relapse rate when comparing treatment with roxithromycin and placebo. CONCLUSION: Our study shows that the patients with MS do not profit from a long-term antibiotic treatment with roxithromycin compared to placebo treatment. A causative connection between bacterial infections with C. pneumonia and MS therefore does seem very unlikely.

Publication Types:
PMID: 17180590 [PubMed - indexed for MEDLINE]

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Comment on:
Antibiotic treatment of diseases without an evident infectious etiology.

Ruef C.

Publication Types:
PMID: 17180581 [PubMed - indexed for MEDLINE]

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Dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) as regulators of T cell function and targets of immunotherapy in CNS inflammation.

Reinhold D, Biton A, Pieper S, Lendeckel U, Faust J, Neubert K, Bank U, TŠger M, Ansorge S, Brocke S.

Institute of Immunology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. dirk.reinhold@medizin.uni-magdeburg.de <dirk.reinhold@medizin.uni-magdeburg.de>

The ectoenzymes dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) have been implicated in the regulation of T cell activation and function. Both DP IV and APN serve as targets of efficient enzymatic inhibitors which induce autocrine production of TGF-beta1 and subsequent suppression of T cell proliferation and cytokine release. Here, we tested the hypothesis that the simultaneous inhibition of DP IV and APN enzymatic activity on leukocytes potentiates the anti-inflammatory effect of single DP IV or APN inhibitors. Our data show that the combined application of DP IV and APN inhibitors increased suppression of DNA synthesis in human peripheral blood mononuclear cells and isolated T cells in vitro when compared to the use of a single ectopeptidase inhibitor. Moreover, the combined action of DP IV and APN inhibitors markedly increased TGF-beta1 production associated with the observed immunosuppressive effects. In vivo, targeting DP IV and APN provided a potent therapeutic approach for the treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Taken together, our study suggests that combined DP IV and APN inhibition on pathogenic T cells represents a novel and efficient therapy for autoimmune disease of the central nervous system by a mechanism that involves an active TGF-beta1-mediated anti-inflammatory effect at the site of pathology.

Publication Types:
PMID: 17161346 [PubMed - indexed for MEDLINE]

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A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model.

Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, Hinterding K, Nuesslein-Hildesheim B, Tuntland T, Lefebvre S, Liu Y, Gao W, Chu A, Brinkmann V, Bruns C, Streiff M, Cannet C, Cooke N, Gray N.

Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.

FTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P(1)-dependent phenomena. Oral administration of AUY954 induces a profound and reversible reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation.

PMID: 17114004 [PubMed - indexed for MEDLINE]

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Comment on:
Re: "antibiotic use and risk of multiple sclerosis".

Parratt JD, O'Riordan JI, Swingler RJ, Parratt D.

Publication Types:
PMID: 17095537 [PubMed - indexed for MEDLINE]

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Minocycline delays but does not attenuate the course of experimental autoimmune encephalomyelitis in Streptococcus pneumoniae-infected mice.

Herrmann I, Kellert M, Spreer A, Gerber J, Eiffert H, Prinz M, Nau R.

Department of Neurology, Georg August University, D-37075 Gšttingen, Germany.

OBJECTIVES: Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), can be aggravated by a mild Streptococcus pneumoniae infection. This study was performed to assess whether treatment with antibiotics inhibiting bacterial protein synthesis reduces the detrimental effect of infection on the course of EAE. METHODS: In vitro, release of proinflammatory pneumococcal products was studied by enzyme immunoassay and western blot. Seven days after induction of EAE (prior to the onset of symptoms) mice were infected intraperitoneally with S. pneumoniae and treated either with the inhibitors of bacterial protein synthesis minocycline or rifampicin, or with the beta-lactam ceftriaxone. RESULTS: During bacterial killing in vitro, minocycline and rifampicin released lower quantities of proinflammatory bacterial products from S. pneumoniae than ceftriaxone. Mice treated with minocycline developed symptoms of EAE 1 day later than mice treated with ceftriaxone. Neither minocycline nor rifampicin therapy, however, reduced the severity of EAE in comparison with ceftriaxone treatment. CONCLUSIONS: Although statistically significant (P = 0.04), a delay of 1 day in the onset of symptoms of EAE after minocycline treatment is of minor clinical relevance. These data do not support the hypothesis of superiority of a bacterial protein synthesis inhibitor over a beta-lactam antibiotic for the treatment of concomitant infections during the latent phase of EAE or MS.

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PMID: 17079237 [PubMed - indexed for MEDLINE]

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Comment in:
TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.

Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL.

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.

Publication Types:
PMID: 16959574 [PubMed - indexed for MEDLINE]

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Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies.

Witzig TE, Kaufmann SH.

Mayo Clinic, Stabile 628, 200 First Street SW, Rochester, MN 55905, USA. witzig@mayo.edu

The phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Key components of the pathway are the lipid kinase PI3-K, the small guanosine triphosphate-binding protein Rheb, and the protein kinases Akt and mTOR. Important natural inhibitors of the pathway include the lipid phosphatase PTEN and the tuberous sclerosis complex. Several components of this pathway are targeted by investigational antineoplastic agents. Rapamycin (sirolimus), the prototypic mTOR inhibitor, exhibits activity in acute myeloid leukemia. Three rapamycin analogs, temsirolimus, everolimus, and AP23573, are in clinical trials for various hematologic malignancies. Temsirolimus has produced a 38% overall response rate in relapsed mantle cell lymphoma, and AP23573 has demonstrated activity in acute leukemia. Everolimus is undergoing clinical testing in lymphoma (Hodgkin and non-Hodgkin) and multiple myeloma. In addition, perifosine, an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models, is being examined in relapsed multiple myeloma. Based on results obtained to date, it appears that inhibitors of the PI3-K/mTOR pathway hold promise as single agents and in combination for hematologic malignancies.

Publication Types:
PMID: 16916489 [PubMed - indexed for MEDLINE]

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Recurrent optic neuritis associated with Chlamydia pneumoniae infection of the central nervous system.

Pohl D, Rostasy K, Gieffers J, Maass M, Hanefeld F.

Department of Paediatrics and Paediatric Neurology, Georg August University Gšttingen, Germany.

It has been suggested that Chlamydia pneumoniae (C. pneumoniae) is involved in the pathogenesis of diverse diseases of the central nervous system (CNS), including multiple sclerosis. We report the case of a 12-year-old male with isolated recurrent optic neuritis and an associated CNS infection with C. pneumoniae. The patient presented with three attacks of optic neuritis within 5 months. A positive polymerase chain reaction for C. pneumoniae in the cerebrospinal fluid led to the diagnosis of a CNS infection with C. pneumoniae. After treatment with the antibiotic rifampicin, he experienced no further attacks during the follow-up period of 6 years. These findings suggest the possibility of a C. pneumoniae infection as a contributing factor or even causative event for the development of optic neuritis.

Publication Types:
PMID: 16904026 [PubMed - indexed for MEDLINE]

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Combination of a rapamycin analog (CCI-779) and interferon-gamma is more effective than single agents in treating a mouse model of tuberous sclerosis complex.

Lee L, Sudentas P, Dabora SL.

Hematology Division, Department of Medicine, Brigham and Women's Hospital, Karp Family Research Laboratories, Boston, MA 02115, USA.

Tuberous sclerosis complex (TSC) is a familial tumor syndrome characterized by the development of hamartomas in the brain, heart, kidney, and skin. Disease-causing mutations in the TSC1 or TSC2 gene result in constitutive activation of the highly conserved mTOR signal transduction pathway, which regulates cell growth, proliferation, and metabolism. The mTOR inhibitor, rapamycin (sirolimus), reduces disease severity in rodent models of TSC, and is currently in phase II clinical trials. The cytokine interferon-gamma (IFN-gamma) is another potential therapeutic agent for TSC. A high-expressing IFN-gamma allele is associated with a lower frequency of kidney tumors in TSC patients, and treatment with exogenous IFN-gamma reduces the severity of TSC-related disease in mouse models. Here, we examine the effects of treating tumor-bearing nude mice with a combination of a rapamycin analog (CCI-779) and IFN-gamma. We observed that combination therapy was more effective than single agent therapy in reducing tumor growth and improving survival in this mouse model of TSC. Immunoblot and immunohistochemical analyses showed that tumors treated with CCI-779 plus IFN-gamma had decreased cell proliferation and increased cell death in comparison with untreated tumors or tumors treated with either agent alone. We also observed that CCI-779 resistance could develop with prolonged treatment. Taken together, our results show that targeting multiple cellular pathways is an effective strategy for treating TSC-related tumors, and underscore the importance of investigating combination therapy in future clinical trials for patients with TSC. (c) 2006 Wiley-Liss, Inc.

Publication Types:
PMID: 16845661 [PubMed - indexed for MEDLINE]

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Familial malignant osteopetrosis in children: a case report.

Gomes MF, Rangel DC, Starling CC, Goulart MG.

Department of Biosciences and Oral Diagnosis, S‹o Jose dos Campos Dental School, Sao Paulo State University-UNESP, Brazil. mfgomes@fosjc.unesp.br

The clinical, radiological, pathological and laboratory findings of two brothers with autosomal recessive malignant osteopetrosis are presented. Our findings are similar to characteristics previously reported in the literature about patients with osteopetrosis. The 6-year-old male patient was pale and had petechiae on his arms and legs. He also had macrocephalia, splenomegaly, severe pancytopenia, genu valgus, hypocalcemia, amaurosis, cessation of physical development, generalized bone sclerosis and recurrent infections with a history of multiple incidences of acute otitis media. Generalized bone sclerosis and irregular sclerosis of the maxilla and mandible were seen on radiographs. The oral mucosa was apparently normal but permanent tooth eruption was delayed although there was early loss of deciduous teeth. The recommended treatment was blood transfusion and therapy with antibiotics when necessary; a bone marrow transplant was not possible due to lack of a compatible donor.

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PMID: 16774187 [PubMed - indexed for MEDLINE]

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The atypical pneumonias: clinical diagnosis and importance.

Cunha BA.

Infectious Disease Division, Winthrop-University Hospital, Mineola, New York 11501, USA.

The most common atypical pneumonias are caused by three zoonotic pathogens, Chlamydia psittaci (psittacosis), Francisella tularensis (tularemia), and Coxiella burnetii (Q fever), and three nonzoonotic pathogens, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella. These atypical agents, unlike the typical pathogens, often cause extrapulmonary manifestations. Atypical CAPs are systemic infectious diseases with a pulmonary component and may be differentiated clinically from typical CAPs by the pattern of extrapulmonary organ involvement which is characteristic for each atypical CAP. Zoonotic pneumonias may be eliminated from diagnostic consideration with a negative contact history. The commonest clinical problem is to differentiate legionnaire's disease from typical CAP as well as from C. pneumoniae or M. pneumonia infection. Legionella is the most important atypical pathogen in terms of severity. It may be clinically differentiated from typical CAP and other atypical pathogens by the use of a weighted point system of syndromic diagnosis based on the characteristic pattern of extrapulmonary features. Because legionnaire's disease often presents as severe CAP, a presumptive diagnosis of Legionella should prompt specific testing and empirical anti-Legionella therapy such as the Winthrop-University Hospital Infectious Disease Division's weighted point score system. Most atypical pathogens are difficult or dangerous to isolate and a definitive laboratory diagnosis is usually based on indirect, i.e., direct flourescent antibody (DFA), indirect flourescent antibody (IFA). Atypical CAP is virtually always monomicrobial; increased IFA IgG tests indicate past exposure and not concurrent infection. Anti-Legionella antibiotics include macrolides, doxycycline, rifampin, quinolones, and telithromycin. The drugs with the highest level of anti-Legionella activity are quinolones and telithromycin. Therapy is usually continued for 2 weeks if potent anti-Legionella drugs are used. In adults, M. pneumoniae and C. pneumoniae may exacerbate or cause asthma. The importance of the atypical pneumonias is not related to their frequency (approximately 15% of CAPs), but to difficulties in their diagnosis, and their nonresponsiveness to beta-lactam therapy. Because of the potential role of C. pneumoniae in coronary artery disease and multiple sclerosis (MS), and the role of M. pneumoniae and C. pneumoniae in causing or exacerbating asthma, atypical CAPs also have public health importance.

Publication Types:
PMID: 16669925 [PubMed - indexed for MEDLINE]

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Comment in:
Antibiotic use and risk of multiple sclerosis.

Alonso A, Jick SS, Jick H, Hern‡n MA.

Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. aalogut@alumni.unav.es

Some reports suggest that bacteria, including Chlamydophila pneumoniae, could be involved in the etiology of multiple sclerosis. If that is true, persons who used antibiotics active against these bacteria, compared with nonusers, might be at lower risk of multiple sclerosis. Using a 1993-2000 case-control study nested in the United Kingdom-based General Practice Research Database cohort, the authors identified 163 multiple sclerosis cases who were followed up for at least 3 years before their first symptoms (the index date). Up to 10 controls matched to the cases by age, sex, general practice, and time in the cohort were selected. Exposure to antibiotics was assessed through computerized medical records. Overall antibiotic use or use of antibiotics against C. pneumoniae was not associated with multiple sclerosis risk. However, use of penicillins in the 3 years before the index date decreased the risk of developing a first attack of multiple sclerosis (odds ratio=0.5, 95% confidence interval: 0.3, 0.9 for those who used penicillins for >or=15 days compared with no use). In conclusion, use of antibiotics active against C. pneumoniae was not associated with a decreased risk of short-term multiple sclerosis. The observed lower risk of multiple sclerosis for penicillin users needs to be confirmed in other populations.

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PMID: 16597708 [PubMed - indexed for MEDLINE]

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Comment on:
Futility studies: spending a little to save a lot.

Schwid SR, Cutter GR.

Publication Types:
PMID: 16534098 [PubMed - indexed for MEDLINE]

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Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.

Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, Dinopoulos A, Thomas G, Crone KR.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA. david.franz@cchmc.org

OBJECTIVE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in multiple organs. Five to 15% of affected individuals display subependymal giant cell astrocytomas, which can lead to substantial neurological and postoperative morbidity due to the production of hydrocephalus, mass effect, and their typical location adjacent to the foramen of Monro. We sought to see whether therapy with oral rapamycin could affect growth or induce regression in astrocytomas associated with TSC. METHODS: Five subjects with clinically definite TSC and either subependymal giant cell astrocytomas (n = 4) or a pilocytic astrocytoma (n = 1) were treated with oral rapamycin at standard immunosuppressive doses (serum levels 5-15 ng/ml) from 2.5 to 20 months. All lesions demonstrated growth on serial neuroimaging studies. Magnetic resonance imaging scans were performed before and at regular intervals following initiation of therapy. RESULTS: All lesions exhibited regression and, in one case, necrosis. Interruption of therapy resulted in regrowth of subependymal giant cell astrocytomas in one patient. Resumption of therapy resulted in further regression. Treatment was well tolerated. INTERPRETATION: Oral rapamycin therapy can induce regression of astrocytomas associated with TSC and may offer an alternative to operative therapy of these lesions.

Publication Types:
PMID: 16453317 [PubMed - indexed for MEDLINE]

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cAMP cascade (PKA, Epac, adenylyl cyclase, Gi, and phosphodiesterases) regulates myelin phagocytosis mediated by complement receptor-3 and scavenger receptor-AI/II in microglia and macrophages.

Makranz C, Cohen G, Reichert F, Kodama T, Rotshenker S.

Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical Schooland the Eric Roland Center for Neurodegenerative Diseases, Jerusalem, Israel.

The removal by phagocytosis of degenerated myelin is central for repair in Wallerian degeneration that follows traumatic injury to axons and in autoimmune demyelinating diseases (e.g., multiple sclerosis). We tested for roles played by the cAMP cascade in the regulation of myelin phagocytosis mediated by complement receptor-3 (CR3/MAC-1) and scavenger receptor-AI/II (SRAI/II) separately and combined in mouse microglia and macrophages. Components of the cAMP cascade tested are cAMP, adenylyl cyclase (AC), Gi, protein kinase A (PKA), exchange protein directly activated by cAMP (Epac), and phosphodiesterases (PDE). PKA inhibitors H-89 and PKI(14-22) amide inhibited phagocytosis at normal operating cAMP levels (i.e., those occurring in the absence of reagents that alter cAMP levels), suggesting activation of phagocytosis through PKA at normal cAMP levels. Phagocytosis was inhibited by reagents that elevate endogenous cAMP levels to above normal: Gi-inhibitor Pertussis toxin (PTX), AC activator Forskolin, and PDE inhibitors IBMX and Rolipram. Phagocytosis was inhibited also by cAMP analogues whose addition mimics abnormal elevations in endogenous cAMP levels: nonselective 8-bromo-cAMP, PKA-specific 6-Benz-cAMP, and Epac-specific 8-CPT-2'-O-Me-cAMP, suggesting that abnormal high cAMP levels inhibit phagocytosis through PKA and Epac. Altogether, observations suggest a dual role for cAMP and PKA in phagocytosis: activation at normal cAMP levels and inhibition at higher. Furthermore, a balance between Gi-controlled cAMP production by AC and cAMP degradation by PDE maintains normal operating cAMP levels that enable efficient phagocytosis.

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PMID: 16345030 [PubMed - indexed for MEDLINE]

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Delivery of Chlamydia vaccines.

Igietseme J, Eko F, He Q, Bandea C, Lubitz W, Garcia-Sastre A, Black C.

National Center for Infectious Disease/CDC, Atlanta, GA 30333, USA. jigietseme@cdc.gov

The plethora of ocular, genital and respiratory diseases of Chlamydia, including nongonococcal urethritis, cervicitis pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, conjunctivitis, blinding trachoma and interstitial pneumonia, and chronic diseases that may include atherosclerosis, multiple sclerosis, adult onset asthma and Alzheimer's disease, still pose a considerable public health challenge to many nations. Although antibiotics are effective against Chlamydia when effectively diagnosed, asymptomatic infections are rampart, making clinical presentation of complications often the first evidence of an infection. Consequently, the current medical opinion is that an effective prophylactic vaccine would constitute the best approach to protect the human population from the most severe consequences of these infections. Clinical and experimental studies have demonstration that Chlamydia immunity in animals and humans is mediated by T cells and a complementary antibody response, and the completion of the genome sequencing of several isolates of Chlamydia is broadening our knowledge of the immunogenic antigens with potential vaccine value. Thus, major advances have been made in defining the essential elements of a potentially effective subunit vaccine design and parameters for evaluation. However, the challenge to develop effective delivery systems and human compatible adjuvants that would boost the immune response to achieve long-lasting protective immunity remains an elusive objective in chlamydial vaccine research. In response to evolving molecular and cellular technologies and novel vaccinology approaches, considerable progress is being made in the construction of novel delivery systems, such as DNA and plasmid expression systems, viral vectors, living and nonliving bacterial delivery systems, the use of chemical adjuvants, lipoprotein constructs and the codelivery of vaccines and specific immuno-modulatory biological agonists targeting receptors for chemokines, Toll-like receptors, and costimulatory molecules. The application of these novel delivery strategies to Chlamydia vaccine design could culminate in timely achievement of an efficacious vaccine.

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PMID: 16296774 [PubMed - indexed for MEDLINE]

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Cerebrospinal fluid proteomic analysis reveals dysregulation of methionine aminopeptidase-2 expression in human and mouse neurofibromatosis 1-associated glioma.

Dasgupta B, Yi Y, Hegedus B, Weber JD, Gutmann DH.

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Individuals affected with the neurofibromatosis 1 (NF1) tumor predisposition syndrome are prone to the development of multiple nervous system tumors, including optic pathway gliomas (OPG). The NF1 tumor suppressor gene product, neurofibromin, functions as a Ras GTPase-activating protein, and has been proposed to regulate cell growth by inhibiting Ras activity. Recent studies from our laboratory have shown that neurofibromin also regulates the mammalian target of rapamycin activity in a Ras-dependent fashion, and that the rapamycin-mediated mammalian target of rapamycin inhibition ameliorates the Nf1-/- astrocyte growth advantage. Moreover, Nf1-deficient astrocytes exhibit increased protein translation. As part of a larger effort to identify protein markers for NF1-associated astrocytomas that could be exploited for therapeutic drug design, we did an objective proteomic analysis of the cerebrospinal fluid from genetically engineered Nf1 mice with optic glioma. One of the proteins found to be increased in the cerebrospinal fluid of OPG-bearing mice was the eukaryotic initiation factor-2alpha binding protein, methionine aminopeptidase 2 (MetAP2). In this study, we show that Nf1 mouse OPGs and NF1-associated human astrocytic tumors, but not sporadic pilocytic or other low-grade astrocytomas, specifically expressed high levels of MetAP2. In addition, we show that Nf1-deficient astrocytes overexpress MetAP2 in vitro and in vivo, and that treatment with the MetAP2 inhibitor fumagillin significantly reduces Nf1-/- astrocyte proliferation in vitro. These observations suggest that MetAP2 is regulated by neurofibromin, and that MetAP2 inhibitors could be potentially employed to treat NF1-associated tumor proliferation.

Publication Types:
PMID: 16267007 [PubMed - indexed for MEDLINE]

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Optic neuritis with concurrent etanercept and isoniazid therapy.

Noguera-Pons R, Borr‡s-Blasco J, Romero-Crespo I, Ant—n-Torres R, Navarro-Ruiz A, Gonz‡lez-Ferrandez JA.

Rheumatology Section, Hospital General Universitario de Elche, Alicante, Spain.

OBJECTIVE: To report a case of optic neuritis associated with concurrent etanercept and isoniazid therapy. CASE SUMMARY: A 55-year-old man diagnosed as having rheumatoid arthritis had received treatment with nonsteroidal antiinflammatory drugs, sulfasalazine, oral methotrexate, leflunomide, and deflazacort. Four months prior to admission, he had a Disease Activity Score of 6.06; treatment with etanercept was considered. Three months prior to admission, because of evidence of latent tuberculosis, isoniazid 300 mg once daily and pyridoxine 50 mg once daily were prescribed. Treatment with subcutaneous etanercept 25 mg twice weekly was started 5 days after isoniazid was initiated. Two weeks prior to admission, the patient developed blurred vision in his left eye. Ten days later, his vision worsened and he was hospitalized. The visual acuity in both eyes was 0.7, and a campimetric examination was compatible with optic neuritis. Magnetic resonance imaging of the brain revealed lesions suggesting demyelinating lesions. The clinical course was consistent with bilateral optic neuritis. Etanercept was stopped, and isoniazid was replaced with rifampin 600 mg once daily. The patient was treated with intravenous methylprednisolone hemisuccinate 1 g/day for 5 days followed by oral prednisolone, resulting in a minor subjective improvement in left eye visual acuity. He then received oral prednisone for 3 weeks, slowly tapering to discontinuation. DISCUSSION: No physiologic factors could have predisposed this patient to develop optic neuritis. He was not diagnosed with a demyelinating disease or underlying systemic condition. The optic neuritis was unlikely to be an early manifestation of multiple sclerosis based on the clinical course and the negative results of the imaging tests. Furthermore, there was a close temporal correlation between the drug exposure and the onset of symptoms. After discontinuation of etanercept and isoniazid therapy, the patient's general condition improved. Use of the Naranjo probability scale indicated a possible relationship between optic neuritis and combined etanercept-isoniazid therapy. CONCLUSIONS: Patients initiated on etanercept and isoniazid should be closely monitored for the development of adverse neurologic signs and effects. If optic neuritis is determined, etanercept and isoniazid should be discontinued immediately.

Publication Types:
PMID: 16264061 [PubMed - indexed for MEDLINE]

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Neuralgia and demyelinating plaques: MS or lyme disease?

Savely G.

South Austin Family Practice Clinic, Austin, Texas, USA.

Publication Types:
PMID: 16152811 [PubMed - indexed for MEDLINE]

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Effective combination of minocycline and interferon-beta in a model of multiple sclerosis.

Giuliani F, Fu SA, Metz LM, Yong VW.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

The objective of the current study was to investigate whether minocycline improves the effect of an existing multiple sclerosis (MS) medication, interferon-beta, on experimental autoimmune encephalomyelitis (EAE) in mice. When used at sub-optimal doses, neither medication affected EAE but their combination at these doses led to the significant alleviation of EAE disease severity scores and histological outcomes. In culture, the toxicity of T cells to neurons was alleviated by their prior exposure to minocycline or interferon-beta and their combination further attenuated neuronal death. Collectively, these results suggest the utility of the combination of minocycline and interferon-beta in MS.

Publication Types:
PMID: 15958276 [PubMed - indexed for MEDLINE]

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Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS.

Sriram S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS.

Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. subramaniam.sriram@vanderbilt.edu

This trial examined the safety and possible MRI and clinical effects of anti-chlamydial antibiotic therapy in relapsing-remitting MS (RRMS). Newly diagnosed MS patients were selected to participate if they showed Chlamydia pneumoniae gene in their CSF and had one or more enhancing lesions on brain magnetic resonance imaging (MRI). After a 4-month run in phase of monthly MRI, patients were randomized to receive rifampin (300 mg twice daily) and azithromycin (500 mg every other day) for 6 months or placebo (PBO). Patients then had monthly MRI on therapy and two additional scans on months 12 and 14. Lumbar punctures were repeated between months 7 and 8 and within 2 weeks of termination of the study. Data on 4 patients on treatment and 4 on PBO were available for analysis. The primary outcome measure of showing a beneficial effect on enhancing lesions was not met. However, there was a significant difference in brain parenchymal fraction loss favoring those patient receiving antibiotics compared with PBO (p< or =0.02). Three of the four patients on antibiotic therapy cleared the organism from the CSF by month 12; in the PBO group one patient cleared the organism. The reduction in atrophy in patients receiving antibiotics must be viewed with caution, due to the small number of patients studied.

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PMID: 15935383 [PubMed - indexed for MEDLINE]

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Cervical stump necrosis and septic shock after laparoscopic supracervical hysterectomy.

Huang JY, Ziegler C, Tulandi T.

Department of Obstetrics and Gynecology, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

The decision to retain or remove the cervix when performing laparoscopic hysterectomy remains a topic of debate. A 38-year-old woman with multiple sclerosis underwent laparoscopic supracervical hysterectomy (LASH) for menometrorrhagia. Two weeks later, she was seen at our institution with septic shock. She underwent an exploratory laparotomy and was found to have cervical stump necrosis and peritonitis. Trachelectomy was performed. The postoperative course was prolonged by persistent fever, pleural effusion, and abscess collections. Although rare, cervical stump necrosis is a possible complication of LASH.

Publication Types:
PMID: 15904622 [PubMed - indexed for MEDLINE]

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Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction.

Giuliani F, Hader W, Yong VW.

Department of Clinical Neurosciences, University of Calgary, Alberta, Canada.

Minocycline, a tetracycline with anti-inflammatory properties, has been reported to down-regulate the activity of microglia, whose activation occurs in inflammatory and degenerative diseases of the central nervous system, such as multiple sclerosis and Alzheimer's disease. In these disorders, a T cell component is also evident, and we have demonstrated previously that the interaction of activated T cells with microglia led to the substantial increase in tumor necrosis factor alpha (TNF-alpha) levels. Here, we report that minocycline decreases TNF-alpha levels produced in human T cell-microglia interaction. This effect is mediated by a direct action of minocycline on the activated T cells and on microglia, which resulted in the decreased ability of T cells to contact microglia. In correspondence, minocycline decreased the expression on T cells of the CD40 ligand (CD40L), a key molecule regulating the contact-mediated interaction of T cells with microglia. These results demonstrate that the mechanism of action of minocycline involves not only microglia but also T cells and their subsequent activation of microglia. The capacity of minocycline to down-regulate CD40L on T cells may provide a new means to target the CD40-CD40L pathway, which regulates several inflammatory processes.

Publication Types:
PMID: 15817702 [PubMed - indexed for MEDLINE]

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Discovery of structurally diverse natural product antagonists of chemokine receptor CXCR3.

Ondeykal JG, Herath KB, Jayasuriya H, Polishook JD, Bills GF, Dombrowski AW, Mojena M, Koch G, DiSalvo J, DeMartino J, Guan Z, Nanakorn W, Morenberg CM, Balick MJ, Stevenson DW, Slattery M, Borris RP, Singh SB.

Merck Research Laboratories, Rahway, NJ, USA. john_ondeyka@merck.com

The chemokines (CXCL9, CXCL10 and CXCL11) and associated CXCR3 receptor are expressed during the inflammatory process from multiple sclerosis, atherosclerosis or organ transplantation resulting in the recruitment of lymphocytes leading to tissue damage. It is hypothesized that blocking of the ligand/CXCR3 receptor interaction has potential to provide opportunity for development of agents that would block tissue rejection. In this paper, four classes of natural product inhibitors (IC50 ranging 0.1-41 microM) have been described that block the CXCR3 receptor interaction of IP-10 ligand. These include a cyclic thiopeptide (duramycin), polyketide glycosides (roselipins), steroidal glycosides (hypoglausin A and dioscin) and a novel alkyl pyridinium alkaloid that were isolated by bioassay-guided fractionation of the organic extracts derived from actinomycete, fungal, plant and marine sources and discovered using 125I IP-10/CXCR3 binding assay. Duramycin was the most potent with an IC50 of 0.1 microM. Roselipins 2A, 2B and 1A showed IC50 values of 14.6, 23.5, and 41 microM, respectively. Diosgenin glycosides dioscin, hypoglaucin A and kallstroemin D exhibited IC50 values of 2.1, 0.47 and 3 microM, respectively. A novel cyclic 3-alkyl pyridinium salt isolated from a sponge displayed a binding IC50 of 0.67 microM.

PMID: 15789559 [PubMed - indexed for MEDLINE]

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[Percutaneous endoscopic gastrostomy in patients with neurological diseases. Results of a prospective multicenter and international study]

[Article in Spanish]

Zalar AE, GuŽdon C, Piskorz EL, S‡nchez Basso A, DucrottŽ P.

Divisi—n de Gastroenterolog’a, Hospital "Juan A. Fern‡ndez" del GCBA, Buenos Aires, Argentina. azalar@intramed.net.ar

AIM: To determine prospectively the long-term evolution of patients with neurological diseases after insertion of percutaneous endoscopic gastrostomy (PEG). METHODS: 109 PEG were performed in 99 consecutive patients (49 females, 50 males), mean age 75 years (range: 20-97 years) as an alternative to a nasogastric tube. Patients were enterally fed because of chronic neurological swallowing difficulties: cerebrovascular disease 38, dementia 27, disordered swallowing mechanisms in elderly patients 10, motor neurona disease and multiple sclerosis 10, neuro-surgical disease 6, Parkinson's disease 3, brain tumor 3, neo-natal encephalopathy 1, HIV encephalopathy 1. The procedure took place in a dedicated endoscopy room. In all cases, prophylatic antibiotics were given and the PEG tube was inserted by the "pull" technique. RESULTS: PEG insertion was technically succesful in all cases. After PEG insertion, all patients were subsequently discharged to local nursing home facilities. 85/99 patients were long-term followed-up on an outpatient basis, 25% of them were followed for more than a year. The mean follow-up time was 3 months (range: 1-24 months). The most frequent complication were minor: local wound infection 6, ostomy leakage 8, silicon degradation 16, leading to the removal of the PEG and the placement of a new PEG tubes in 10 cases. Two major complications were observed : one gastric perforation and death 2 months after the PEG placement and one gastrocolic fistula. No aspiration pneumonia was reported. In one patient, PEG was removed after recuperation of a normal swallowing. All patients had a nutritional improvement. A total of 11 deaths occurred during the follow-up, related to the neurological disorder in 10/11 cases. Nursing home team, patient's physicians and patient's families found PEG manipulations easier than naso-gastric tube. CONCLUSION: Our study suggests that PEG is a method of choice for enteral feeding of patients with chronic neurological disorders. PEG is well-tolerated, leading to an improvement in nutritional status and offering good facilities for home nursing.

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PMID: 15742927 [PubMed - indexed for MEDLINE]

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Griseofulvin: a novel addition to anti-multiple sclerosis ammunition?

Namazi MR.

Publication Types:
PMID: 15732274 [PubMed - indexed for MEDLINE]

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[The treatment of skin ulcers in patients with systemic sclerosis]

[Article in Italian]

Fiori G, Amanzi L, Moggi Pignone A, Braschi F, Matucci-Cerinic M.

Universitˆ degli studi di Firenze, Medicina Interna I e II, Sezione di Reumatologia, 50139 Firenze. ginevrafiori@hotmail.com

Systemic Sclerosis (Ssc) is a complex disease of the connective tissue, characterized by progressive thickening and fibrosis of the skin and the internal organs and by diffused damage of the microvascular system. The fibrosis ones of the skin associated to the characteristic vascular alterations lead to the genesis of ulcers, more or less extended, often multiple, peripheral localization, chronic course, painful, able to influence patient's quality of life. Indeed, immunity reactivity, the thinning and the loss of elasticity of the skin, the peripheral neurological damage and the eventual drug assumption that can reduce regenerative/reparative abilities, can easily make an ulcer chronic and become infected complicating still more the patient disease, rendering more difficult the cure often, ulcer evolves to gangrene, and in some cases, in amputation too. For all these reasons, we have begun to study ulcers therapy (local and systemic), considering this activity it leave integrating of the charitable distance of the sclerodermic patient, putting to point on strategy both diagnostic and therapeutic, but above all with the primary scope, if possible, is to prevent ulcers, in contrary case, to alleviate the pain and to render the quality of the life of the patient better.

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PMID: 15643477 [PubMed - indexed for MEDLINE]

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Other therapy options and future strategies for treating patients with multiple sclerosis.

Rizvi SA, Bashir K.

Department of Clinical Neurosciences, Brown University School of Medicine, 2 Dudley Street, Suite 555, Providence, Rhode Island 02905, USA. srizvi@lifespan.org

Research into therapy for multiple sclerosis (MS) is occurring at a rapid pace, and current treatment options approved by the FDA specifically target the inflammatory phase of MS. However, drugs that are not FDA-approved are routinely used to treat MS. One example is corticosteroids, which are commonly used to treat acute relapses. Other drugs that are commonly used to treat patients who do not respond to the FDA-approved agents include the following: methotrexate, azathioprine, cyclophosphamide, and pulse steroids. Drugs being studied as possible therapeutic agents include the statins, mycophenolate mofetil, various monoclonal antibodies (e.g., alemtuzumab, daclzumab, natalizumab, and rituximab), antibiotics and antivirals, and the pregnancy hormone estriol. Disease modifying agents (DMAs) that promote remyelination would be beneficial for preventing long-term disability, and such agents are also under active investigation (e.g., IV immunoglobulin G and stem cell transplantation). Combination therapy with DMAs with different mechanisms of action may be advantageous in the future for providing optimal treatment that both delays the progression of disability and promotes repair and remyelination.

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PMID: 15623671 [PubMed - indexed for MEDLINE]

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Chronic Lyme borreliosis at the root of multiple sclerosis--is a cure with antibiotics attainable?

Fritzsche M.

Clinic for Internal and Geographical Medicine, Soodstrasse 13, 8134 Adliswil, Switzerland. markus.fritzsche@gmx.ch

Apart from its devastating impact on individuals and their families, multiple sclerosis (MS) creates a huge economic burden for society by mainly afflicting young adults in their most productive years. Although effective strategies for symptom management and disease modifying therapies have evolved, there exists no curative treatment yet. Worldwide, MS prevalence parallels the distribution of the Lyme disease pathogen Borrelia (B.) burgdorferi, and in America and Europe, the birth excesses of those individuals who later in life develop MS exactly mirror the seasonal distributions of Borrelia transmitting Ixodes ticks. In addition to known acute infections, no other disease exhibits equally marked epidemiological clusters by season and locality, nurturing the hope that prevention might ultimately be attainable. As minocycline, tinidazole and hydroxychloroquine are reportedly capable of destroying both the spirochaetal and cystic L-form of B. burgdorferi found in MS brains, there emerges also new hope for those already afflicted. The immunomodulating anti-inflammatory potential of minocycline and hydroxychloroquine may furthermore reduce the Jarisch Herxheimer reaction triggered by decaying Borrelia at treatment initiation. Even in those cases unrelated to B. burgdorferi, minocycline is known for its beneficial effect on several factors considered to be detrimental in MS. Patients receiving a combination of these pharmaceuticals are thus expected to be cured or to have a longer period of remission compared to untreated controls. Although the goal of this rational, cost-effective and potentially curative treatment seems simple enough, the importance of a scientifically sound approach cannot be overemphasised. A randomised, prospective, double blinded trial is necessary in patients from B. burgdorferi endemic areas with established MS and/or Borrelia L-forms in their cerebrospinal fluid, and to yield reasonable significance within due time, the groups must be large enough and preferably taken together in a multi-centre study.

PMID: 15617845 [PubMed - indexed for MEDLINE]

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The potential of minocycline for neuroprotection in human neurologic disease.

Zemke D, Majid A.

Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan 48824, USA.

Minocycline is a member of the tetracycline class of molecules with broad-spectrum antibiotic activity. The unique properties of minocycline result in increased tissue distribution when compared with the other tetracyclines. Of particular interest is the ability of minocycline to diffuse into the central nervous system at clinically effective levels. Aside from its antimicrobial properties, minocycline has been found to have beneficial effects on inflammation, microglial activation, matrix metalloproteinases, nitric oxide production, and apoptotic cell death. Concordantly, minocycline has been found to have neuroprotective effects in animal models of a number of diseases including stroke, multiple sclerosis, and Parkinson disease. The proven safety of minocycline over decades of use as an antibiotic suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.

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PMID: 15613934 [PubMed - indexed for MEDLINE]

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The relentless therapeutic imperative.

Paul C.

Department of Preventive and Social Medicine, University of Otago Medical School, Dunedin, New Zealand. charlotte.paul@stonebow.otago.ac.nz

PMID: 15604183 [PubMed - indexed for MEDLINE]

PMCID: PMC535978


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Additive effect of the combination of glatiramer acetate and minocycline in a model of MS.

Giuliani F, Metz LM, Wilson T, Fan Y, Bar-Or A, Yong VW.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

There have been significant advances in the treatment of multiple sclerosis (MS) in recent years, but further improvement in therapy is required as not all patients have responded optimally. An approach to enhancing MS treatment is to combine drugs that impact on different aspects of the disease process. We have described that the tetracycline derivative, minocycline, attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a model of MS. Here, we have evaluated the combination of minocycline and glatiramer acetate (GA), a current therapy in MS, on the course of EAE in mice. This combination resulted in a significant reduction of disease severity and disease burden with attenuation of the inflammation, axonal loss and demyelination.

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PMID: 15589056 [PubMed - indexed for MEDLINE]

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Temsirolimus: CCI 779, CCI-779, cell cycle inhibitor-779.

[No authors listed]

Wyeth (formerly American Home Products) is developing temsirolimus [Cell cycle inhibitor-779, CCI 779], an ester analogue of sirolimus, for the treatment of cancer, multiple sclerosis and rheumatoid arthritis. Temsirolimus binds to the cytosolic protein, FKBP, which subsequently inhibits mTOR (mammalian target of rapamycin). Inhibition of mTOR blocks a number of signal transduction pathways that suppress translation of several key proteins regulating the cell cycle. These effects lead to a cell cycle block at the G1 phase.In animal models of human cancers, temsirolimus inhibited the growth of a diverse range of cancer types even when an intermittent dosing schedule was used. The compound also appears to have potential for the blockade of inflammatory responses associated with autoimmune and rheumatic diseases by inhibiting T-cell proliferation.On 11 March 2002, American Home Products changed its name and the name of its subsidiary Wyeth-Ayerst to Wyeth.During the first half of 2004, Wyeth initiated ongoing recruitment into a US phase III trial comparing orally administered temsirolimus plus letrozole versus letrozole alone as first-line treatment among approximately 1200 postmenopausal women with advanced breast cancer. The multicentre, randomised, double-blind, placebo-controlled trial is estimated to last 34 months. All subjects will have the option of participating in the long-term follow-up phase of the trial that involves follow-up every 3 months until disease progression; the primary endpoint is overall progression-free survival.In August 2004, the US FDA granted temsirolimus fast-track status for the first-line treatment of poor-prognosis patients with advanced renal cell carcinoma. Previously in March 2002, temsirolimus received fast-track status from the FDA for the treatment of renal cell carcinoma in patients who failed to respond to interleukin-2 treatment. Wyeth intends to file a NDA for temsirolimus for this indication by 2006. Researchers from Wyeth presented the findings from a preclinical study of temsirolimus at the 67th Annual Scientific Meeting of the American College of Rheumatology and the 38th Annual Meeting Association of Rheumatology Health Professionals (ACR/ARHP-2003) [Orlando, FL, USA; October 2003]. The aim of this study was to determine the effect of temsirolimus on lymphocyte proliferation and cytokine production. Since lymphocytes and cytokines are significantly involved in the pathogenesis of rheumatoid arthritis, temsirolimus could have disease-modifying antirheumatic drug (DMARD) activity against rheumatoid arthritis via the inhibition of these factors.According to Wyeth's investor presentation in June 2004, the patent covering temsirolimus is due for expiry in 2014.

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PMID: 15563243 [PubMed - indexed for MEDLINE]

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The promise of minocycline in neurology.

Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. vyong@ucalgary.ca

The capacity of minocycline to alleviate disease for several neurological disorders in animals is increasingly being recognised. Indeed, that one drug alone can attenuate the severity of disease in stroke, multiple sclerosis, spinal-cord injury, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis is astounding. In this review, we describe the evidence for the efficacy of minocycline in several animal models of neurological disease, discuss the mechanisms by which minocycline affects a range of neurological diseases with diverse causes, and introduce the emerging investigation of minocycline in clinical neurology. The encouraging results of minocycline in experimental neurology bode well for its therapeutic use in human neurological diseases.

Publication Types:
PMID: 15556807 [PubMed - indexed for MEDLINE]

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Staphylococcus aureus IsdG and IsdI, heme-degrading enzymes with structural similarity to monooxygenases.

Wu R, Skaar EP, Zhang R, Joachimiak G, Gornicki P, Schneewind O, Joachimiak A.

Structural Biology Center and Midwest Center for Structural Genomics, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA.

Heme-degrading enzymes are involved in human diseases ranging from stroke, cancer, and multiple sclerosis to infectious diseases such as malaria, diphtheria, and meningitis. All mammalian and microbial enzymes identified to date are members of the heme oxygenase superfamily and assume similar monomeric structures with an all alpha-helical fold. Here we describe the crystal structures of IsdG and IsdI, two heme-degrading enzymes from Staphylococcus aureus. The structures of both enzymes resemble the ferredoxin-like fold and form a beta-barrel at the dimer interface. Two large pockets found on the outside of the barrel contain the putative active sites. Sequence homologs of IsdG and IsdI were identified in multiple Gram-positive pathogens. Substitution of conserved IsdG amino acid residues either reduced or abolished heme degradation, suggesting a common catalytic mechanism. This mechanism of IsdG-mediated heme degradation may be similar to that of the structurally related monooxygenases, enzymes involved in the synthesis of antibiotics in Streptomyces. Our results imply the evolutionary adaptation of microbial enzymes to unique environments.

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PMID: 15520015 [PubMed - indexed for MEDLINE]

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Comment in:
Comment on:
Lyme borreliosis: perspective of a scientist-patient.

Hamlen R.

rhamlen@iximd.com <rhamlen@iximd.com>

Publication Types:
PMID: 15451481 [PubMed - indexed for MEDLINE]

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Trypanosoma cruzi trans-sialidase as a new therapeutic tool in the treatment of chronic inflammatory diseases: possible action against mycoplasma and chlamydia.

de Lourdes Higuchi M.

Pathology Laboratory, Heart Institute (InCor) of Clinical Hospital, School of Medicine of S‹o Paulo University, Av. Dr Eneas de Carvalho Aguiar 44, 05403-000 S‹o Paulo, SP, Brazil. anplourdes@incor.usp.br

The present paper proposes a new therapy using Trypanosoma cruzi trans-sialidase to treat diseases with unclear pathogenesis that present in common chronic inflammation and fibrosis. This hypothesis is based on recent findings that co-infection with mycoplasma and chlamydia is present in many of these diseases and that this enzyme was capable to eliminate or decrease the co-infection from the host. We identified that mycoplasmas and chlamydias are present in atherosclerosis, aortic valve stenosis, dilated cardiomyopathy, chronic chagasic myocarditis and cancer. We hypothetized that mycoplasmal infection may induce immunodepression in the host, favoring proliferation of pre-existent chlamydial infection and that elimination of mycoplasma would lead to improvement of the immune system resistance and the control of chlamydial proliferation. Mycoplasma has a particular parasitic relationship with host cells, involving strong adherence of their membranes, making it extremely difficult to eradicate mycoplasmal infection from the host. A new therapeutic approach is suggested using one or more agents that prevent or inhibit the adherence of mycoplasma to host cell membranes by removing sialic acid residues and preventing oxidation of the cells. The use of a neuraminidase enzyme, particularly the T. cruzi trans-sialidase enzyme, associated with treatment using anti-oxidating agents is proposed. Preliminary experimental animal and laboratory tests showed good results. The proposal that trans-sialidase from T. cruzi is efficient in combating co-infection of mycoplasma and chlamydia is based, at least in part, on the observation that chagasic patients suffering from T. cruzi infection present less mycoplasma and chlamydia infection in their tissues. Also, a lower incidence of the diseases above described to be related to mycoplasma infection is observed in chagasic patients. It is also hypothesized that co-infection with mycoplasma and chlamydia may induce oxidation of the host cells. Anti-oxidants such as those present in plant extracts may also be used in the treatment. Other diseases such as chronic hepatitis, glomerulonephritis, Multiple Sclerosis, Alzheimer's Syndrome and idiopathic encephalitis are other examples of chronic diseases where mycoplasma and chlamydia might be present, as they have the characteristics of unknown etiology, persistent chronic inflammation and fibrosis. Copyright 2004 Elsevier Ltd.

PMID: 15325005 [PubMed - indexed for MEDLINE]

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[Six years evaluation of Clostridium difficile associated diarrhea]

[Article in Turkish]

Ercis S, Ergin A, Haselik G.

Hacettepe Universitesi Tip FakŸltesi, Mikrobiyoloji ve Klinik Mikrobiyoloji Anabilim Dali, Ankara.

This study was aimed to detect the presence of Clostridium difficile toxin in the stool samples of patients with antibiotic-associated diarrhea or pseudomembranous colitis, and to relate its presence with the clinical findings of the patients. Between January 1997-April 2003, a total of 726 stool samples were investigated for C. difficile toxin A and/or B by enzyme immunoassay. Of them, 68 (9.4%) were found positive for C. difficile toxin (62 were toxin A, 6 were toxin B). C. difficile associated diarrhea were found to be related mostly with the use of beta-lactam/beta-lactamase inhibitor combinations (32/68), followed by aminoglycosides (12/68), and cephalosporins (8/68). The ages of the patients were between 1-86 years old (mean: 43.3 years), and 36 (52.9%) of them had an underlying conditions. Chronic obstructive pulmonary disease and chronic renal failure were the underlying disease in 18, malignancy in 11, and others (diabetes, hepatitis, transplantation, multiple sclerosis) in 7 of the patients. In conclusion, toxin detection and knowledge of the risk factors are the beneficial guidelines for the diagnosis of C. difficile associated diarrhea in the routine setting.

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PMID: 15293901 [PubMed - indexed for MEDLINE]

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Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis.

Metz LM, Zhang Y, Yeung M, Patry DG, Bell RB, Stoian CA, Yong VW, Patten SB, Duquette P, Antel JP, Mitchell JR.

Publication Types:
PMID: 15122721 [PubMed - indexed for MEDLINE]

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[Infectious endocarditis in a patient with multiple sclerosis--case report]

[Article in Polish]

Prystupa A, Mosiewicz J.

Katedry i Kliniki Chor—b Wewnetrznych Akademii Medycznej w Lublinie. zawada@eskulap.am.lublin.pl

Multiple sclerosis is chronic demyelination disease associated with complex immunological disorders, resulting in increased susceptibility to different infections. A case of woman, aged 40 with multiple sclerosis who was admitted to the Internal Medicine Ward because of severe general state, fever of seven-day duration and systolic murmur in apex area is discussed in this paper. Clinical status and performed diagnostics, among others; echocardiography, blood cultures, abdominal ultrasonography, allowed to diagnose infective endocarditis caused by Enterococcus faecalis. Antibiotics as follows: augmentin, cefuroxim, cefotaxim and vancomycin were administered parenterally. As a result of the treatment normalization of temperature and complete recovery were obtained.

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PMID: 15058172 [PubMed - indexed for MEDLINE]

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Aeromonas hydrophila and aspiration pneumonia: a diverse presentation.

Mukhopadhyay C, Bhargava A, Ayyagari A.

Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.

Although there are ever increasing reports of extraintestinal human infections caused by Aeromonads, in both immunocompromised and immunocompetent patients, respiratory tract infections remain uncommon. We describe a case of aspiration pneumonia in an immunocompetent patient with multiple sclerosis, caused by a community acquired, multidrug resistant strain of Aeromonas hydrophila sensitive only to meropenem. The case highlights the clinical significance of Aeromonas hydrophila as a respiratory pathogen, as well as the community origin of multidrug resistance and the utility of newer carbapenems in such cases.

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PMID: 14703621 [PubMed - indexed for MEDLINE]

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TSC2 regulates VEGF through mTOR-dependent and -independent pathways.

Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG Jr.

Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.

Inactivation of the TSC2 tumor suppressor protein causes tuberous sclerosis complex (TSC), a disease characterized by highly vascular tumors. TSC2 has multiple functions including inhibition of mTOR (mammalian target of Rapamycin). We found that TSC2 regulates VEGF through mTOR-dependent and -independent pathways. TSC2 loss results in the accumulation of HIF-1alpha and increased expression of HIF-responsive genes including VEGF. Wild-type TSC2, but not a disease-associated TSC2 mutant, downregulates HIF. Rapamycin normalizes HIF levels in TSC2(-/-) cells, indicating that TSC2 regulates HIF by inhibiting mTOR. In contrast, Rapamycin only partially downregulates VEGF in this setting, implying an mTOR-independent link between TSC2 loss and VEGF. This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells.

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PMID: 12957289 [PubMed - indexed for MEDLINE]

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New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF).

Kleine TO, Zwerenz P, Zšfel P, Shiratori K.

Neurochemistry Department, Centre of Nervous Diseases, Clinicum of the University, D-35033 Marburg, Germany.

Five new markers (tumor necrosis factor TNF-alpha, interleukin IL-1 beta, IL-6, IL-8, lipopolysaccharide binding protein (LBP)) and 11 old classical markers were evaluated in 180 cerebrospinal fluid (CSF) and serum pairs to discriminate acute bacterial meningitis (BM) on admission from aseptic (viral) meningitis (AM), bacterial meningitis treated with antibiotics (TM) from AM, and AM from multiple sclerosis (MS). Statistical tests were computed which classified correctly > or =90% of the patients with BM, TM, AM at a sum minimum of false positive plus false negative results, and which reached additionally > or =90% sensitivity and specificity. To discriminate BM from AM, CSF IL-6 test > or =500 ng/l and CSF IL-1 beta test > or =8 ng/l besides CSF lactate test > or =3.5mM/l and CSF granulocyte test > or =150 M/l were revealed. CSF lactate test > or =3.2 mmol/l discriminated TM from AM. CSF leukocyte test > or =35 M/l discriminated AM from MS. Tests with the new markers were more laborious, expensive, and time consuming compared to CSF lactate test. Test candidates, detecting > or =80% of patients with > or =80% sensitivity and specificity, were evaluated with CSF TNF-alpha, IL-8 and LBP, serum IL-6, CSF leukocytes, lymphocytes and monocytes, Qglucose, CSF total protein, albumin, and Qalbumin. All tests should be reviewed in context of clinical findings to diagnose BM reliably.

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PMID: 12909299 [PubMed - indexed for MEDLINE]

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Transcription factor expression and cellular redox in immature oligodendrocyte cell death: effect of Bcl-2.

FitzGerald UF, Gilbey T, Brodie S, Barnett SC.

Department of Neurology and Department of Medical Oncology, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland.

Multiple sclerosis (MS) is characterized by the progressive damage or loss of oligodendrocytes. In an effort to better understand the causes of oligodendrocyte destruction in MS plaques, we treated immature oligodendrocytes with glucose oxidase, ceramide, or brefeldin A. These treatments model the different mechanisms by which oligodendrocytes are thought to die. We report that the AP-1 and Egr-1 transcription factors are induced within an hour of treatment. Of the AP-1 proteins studied, c-Jun was expressed at the highest level, followed by JunD, c-Fos, and Fra-2, although different treatments induced slightly different levels of expression. Bcl-2 overexpression protects against all treatments, to differing degrees. Although Bcl-2 did not have a dramatic effect on AP-1 or Egr-1 induction within the first 3 h, it caused a lowering of steady-state redox levels with a concomitant increase in cellular glutathione. We propose that the lowering of cellular redox and the upregulation of glutathione are responsible in part for the protective properties of Bcl-2.

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PMID: 12727447 [PubMed - indexed for MEDLINE]

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Aggressive conservative treatment of esophageal perforations in children.

Martinez L, Rivas S, Hern‡ndez F, Avila LF, Lassaletta L, Murcia J, Olivares P, Queiz‡n A, Fernandez A, L—pez-Santamar’a M, Tovar JA.

Department of Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain.

BACKGROUND/PURPOSE: In contrast with adult patients in whom surgical closure of the defect is preferred, nonoperative treatment has been the usual approach for esophageal perforation (EP) in children. This report aims to assess whether this strategy stands the passage of time. METHODS: We reviewed retrospectively the charts of 17 patients aged 5.3 +/- 0.9 years (mean +/- SD) treated at our institution for EP between 1991 and 2001. RESULTS: Nineteen episodes of EP were caused by stricture dilation in 9 cases, foreign body extraction in 3, and blunt trauma and sclerosis of varices in 2 cases each. The remaining child had multiple gastrointestinal perforations in the course of chemotherapy for leukemia. Vigorous treatment, consisting of nasopharyngeal aspiration, wide spectrum antibiotics, prompt drainage of effusions and either parenteral or infraesophageal nutritition, was implemented immediately after diagnosis. Perforations were closed without direct surgery in 18 of 19 episodes (16 of 17 children). One or more pleural drains were inserted in 12 cases, and pericardial drainage was required once. Seven gastrostomies, 2 jejunostomies, and one esophagostomy were performed. Several major abdominal operations were necessary to repair concomitant lesions in a child who sustained severe blunt abdominal trauma and in the patient with leukemic perforations. All patients survived, and all recovered esophageal function. However, 2 with intractable lye strictures ultimately required esophageal replacement. The only patient in whom a direct approach for esophageal necrosis due to variceal endosclerosis was unavoidable, lost her organ and had a retrosternal colonic interposition after a successful portosystemic shunt. Excluding patients with other concomitant lesions and the patient who underwent surgery, median length of stay was 11 days (range, 6 to 47). CONCLUSIONS: Prompt and aggressive nonoperative treatment of esophageal perforations in children allows survival with conservation of the organ in most cases and remains, in the authors' hands, the first therapeutic choice at this age. Copyright 2003 Elsevier Inc. All rights reserved.

PMID: 12720170 [PubMed - indexed for MEDLINE]

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Thalidomide for erythema nodosum leprosum and other applications.

Okafor MC.

Department of Pharmacy Practice, University of California, San Francisco, USA.

Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.

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PMID: 12680478 [PubMed - indexed for MEDLINE]

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Comment in:
Efficient three-drug cocktail for disease induced by mutant superoxide dismutase.

Kriz J, Gowing G, Julien JP.

Centre for Research in Neurosciences, McGill University, Research Institute of the McGill University Health Centre, MontrŽal, QuŽbec H3G 1A4, Canada.

There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.

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PMID: 12666110 [PubMed - indexed for MEDLINE]

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Correlation of mollicutes and their viruses with multiple sclerosis and other demyelinating diseases.

Brown JS Jr.

McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249, USA. jbrown2185@aol.com

To identify infectious diseases likely involved in MS, the author previously correlated the geographical distribution of MS with the global distribution of tick-borne diseases. Tick-borne infectious agents include mollicutes or mycoplasmas. The current paper reviews evidence that mollicutes, especially spiroplasmas, or their viruses could be the initial exposure that causes MS. Mollicute infections, including the effects of their toxins, can be treated or prevented with gold salts or tetracyclines. If further research recommended by this review finds a role of mycoplasmas in MS, treatment of MS with gold with tetracycline should be evaluated.

PMID: 12606251 [PubMed - indexed for MEDLINE]

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Acute disseminated encephalomyelitis: recognition in the hands of general paediatricians.

Stonehouse M, Gupte G, Wassmer E, Whitehouse WP.

Department of Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK.

Acute disseminated encephalomyelitis will often present to the general paediatrician as an acute polysymptomatic encephalopathy, and initially the diagnosis may not be clear. A brain MRI scan is essential in establishing the diagnosis and so enabling appropriate advice and treatment to be given. Multicentre clinical audit of outcome and controlled therapeutic trials are needed to secure an evidence base for current practice.

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PMID: 12538312 [PubMed - indexed for MEDLINE]

PMCID: PMC1719460


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Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants.

White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, Masaki K, Launer L, Markesbery WR.

Kuakini Medical Center, 846 S Hotel Street, Honolulu, HI 96813, USA. White@phri.Hawaii-health.com

Clinicopathologic data from 285 autopsies were analyzed. The decedents were long-standing participants in the Honolulu-Asia Aging Study, a prospective epidemiologic investigation of stroke, neurodegenerative diseases, and aging. We assessed the prevalence at death of four primary neuropathologic processes using specific microscopic lesions as indicators. An algorithm was developed to assign each decedent to one of six subsets, corresponding to pathologic dominance by microvascular lesions (14% of decedents), Alzheimer lesions (12%), hippocampal sclerosis (5%), cortical Lewy bodies (5%), codominance by two or more primary processes (9%), or without a dominant pathologic process recognized (55%). Definite or probable dementia had been identified in 118 of the decedents. The proportions of men in each subset identified as demented were (in the same order) 57%, 53%, 79%, 57%, 76%, and 25%. In this autopsied panel of older Japanese-American men, the importance of microvascular lesions as a likely explanation for dementia was nearly equal to that of Alzheimer lesions. The cerebrovascular lesion type most essentially and inclusively related to dementia was multiple microinfarction.

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PMID: 12480729 [PubMed - indexed for MEDLINE]

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Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors.

Kenerson HL, Aicher LD, True LD, Yeung RS.

Department of Surgery, University of Washington, Seattle 98195, USA.

Disruption of the TSC1 or TSC2 gene leads to the development of tumors in multiple organs, most commonly affecting the kidney, brain, lung, and heart. Recent genetic and biochemical studies have identified a role for the tuberous sclerosis gene products in phosphoinositide 3-kinase signaling. On growth factor stimulation, tuberin, the TSC2 protein, is phosphorylated by Akt, thereby releasing its inhibitory effects on p70S6K. Here we demonstrate that primary tumors from tuberous sclerosis complex (TSC) patients and the Eker rat model of TSC expressed elevated levels of phosphorylated mammalian target of rapamycin (mTOR) and its effectors: p70S6K, S6 ribosomal protein, 4E-BP1, and eIF4G. In the Eker rat, short-term inhibition of mTOR by rapamycin was associated with a significant tumor response, including induction of apoptosis and reduction in cell proliferation. Surprisingly, these changes were not accompanied by significant alteration in cyclin D1 and p27 levels. Our data provide in vivo evidence that the mTOR pathway is aberrantly activated in TSC renal pathology and that treatment with rapamycin appears effective in the preclinical setting.

Publication Types:
PMID: 12384518 [PubMed - indexed for MEDLINE]

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Identification of new therapeutic targets for prevention of CNS inflammation.

Owens T.

Neuroimmunology Unit, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4. trevor.owens@mcgill.ca

Multiple sclerosis (MS) is a disease of complex pathologies, which involves infiltration by CD4(+) and CD8(+) T cells of and response within the central nervous system. Expression in the CNS of cytokines, reactive nitrogen species and costimulator molecules have all been described in MS. Notably, the cytokines IFN-gamma and TNF are strongly expressed. Microglial cells in the CNS express costimulator molecules and it is assumed that they play a role in directing or inducing the T cell response. Transgenic experiments have tested the effects of overexpression of these molecules in mice and have shown that TNF has multiple effects in the CNS. These range from pro-inflammatory effects of soluble TNF signalling through one of its receptors TNF-RI, to protective/regenerative effects of membrane-associated TNF signalling through the other receptor, TNF-RII. Although IFN-gamma induces nitric oxide production via the enzyme inducible nitric oxide synthase, which is immunosuppressive, IFN-gamma is predominantly pro-inflammatory. In CNS disease in mice that involves CD8(+) T cells, IFN-gamma blockade is protective. Finally, microglial expression of the costimulator ligand B7.2 induces demyelinating pathology. Animal experiments therefore point to IFN-gamma and costimulatory microglia as logical targets of therapy for MS. IFN-gamma represents a more accessible target and should therefore be pursued at the earliest opportunity.

Publication Types:
PMID: 12223081 [PubMed - indexed for MEDLINE]

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Acute disseminated encephalomyelitis in children.

Murthy SN, Faden HS, Cohen ME, Bakshi R.

Department of Neurology, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York, USA.

OBJECTIVE: To describe the epidemiologic, clinical, neuroimaging, and laboratory features; treatment; and outcome in a cohort of children with acute disseminated encephalomyelitis (ADEM). METHODS: A 6-year retrospective chart review of children with the diagnosis of ADEM was conducted. RESULTS: Eighteen cases were identified. Sixteen patients (88%) presented in either winter or spring. Thirteen children (72%) had a recent upper respiratory tract illness. Patients presented most often with motor deficits (77%) and secondly with altered consciousness (45%). Spinal fluid abnormalities occurred in 70%. Despite rigorous microbiologic testing, a definite microbiologic diagnosis was established only in 1 child with Epstein-Barr virus disease and probable or possible diagnoses in 3 children with Bartonella henselae, Mycoplasma pneumoniae, or rotavirus disease. Brain magnetic resonance imaging identified lesions in the cerebral cortex in 80%, in subcortical white matter in 93%, in periventricular white matter in 60%, in deep gray matter in 47%, and in brainstem in 47% of patients. Eleven patients (61%) were treated with corticosteroids, and 2 were treated with intravenous immunoglobulins. All patients survived. Three patients (17%) had long-term neurologic sequelae. CONCLUSIONS: Epidemiologic evidence from this study suggests an infectious cause for ADEM. The agent is most likely a difficult-to-diagnose winter/spring respiratory virus. Magnetic resonance imaging was the neuroimaging study of choice for establishing the diagnosis and for following the course of the disease. Prognosis for survival and outcome was excellent. Recurrent episodes of ADEM must be differentiated from multiple sclerosis.

PMID: 12165620 [PubMed - indexed for MEDLINE]

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Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis.

Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW.

Department of Clinical Neurosciences, University of Calgary, Canada.

Multiple sclerosis is characterized by the infiltration of leukocytes into the CNS. As matrix metalloproteinases (MMPs) facilitate the passage of leukocytes across matrix barriers, we tested the hypothesis that targeting MMPs could attenuate neuro-inflammation. We report that minocycline, a widely used generic drug with a good safety record, inhibited MMP activity, reduced production of MMP-9 and decreased the transmigration of T lymphocytes across a fibronectin matrix barrier. In addition, minocycline was efficacious against both mild and severe experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis. When severe EAE was produced, minocycline pre-treatment delayed the course of the disease: when maximal disease activity occurred in vehicle-treated EAE mice, minocycline animals were relatively normal and had minimal signs of inflammation and demyelination in the CNS. When tested in mice afflicted with mild EAE, minocycline attenuated the clinical severity of disease throughout the course of treatment. These results indicate that minocycline may constitute a safe and inexpensive therapy for multiple sclerosis.

Publication Types:
PMID: 12023318 [PubMed - indexed for MEDLINE]

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[Ewing's sarcoma of the ethmoid bone. Case report]

[Article in French]

Velche-Haag B, Proust F, Laquerrire A, Dehesdin D, FrŽger P.

Service d'ORL, Hospital Charles Nicolle, CHU de Rouen, avenue de Germont, 76032 Rouen Cedex, France.

Ewing's sarcoma is rarely located at the base of the skull. We report a case of ethmoid Ewing's sarcoma. Diagnosis was established on microscopic examination. A complete surgical resection was performed, followed by cranial base reconstruction. During the postoperative period, a combined course of chemotherapy and radiotherapy was performed. We also present a review of the literature.

Publication Types:
PMID: 11972147 [PubMed - indexed for MEDLINE]

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Comment in:
Inhibition of autoimmune encephalomyelitis by a tetracycline.

Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID.

Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA.

We have explored the use of minocycline, a tetracycline with antiinflammatory properties, to treat chronic relapsing-remitting experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Therapeutic treatment with minocycline dramatically suppresses ongoing disease activity and limits disease progression. Disease suppression is associated with immune deviation in the periphery and with suppression of the inflammatory cascade in the central nervous system. This association is demonstrated by inhibition of microglial activation and metalloproteinase-2 expression, which results in a concomitant decrease in inflammation and demyelination. As an established antiinflammatory drug with neuroprotective properties, minocycline may provide a novel therapeutic agent for relapsing-remitting multiple sclerosis.

Publication Types:
PMID: 11835378 [PubMed - indexed for MEDLINE]

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Thalidomide: new indications?

Combe B.

Rheumatology Federation, H™pital Lapeyronie, Montpellier, France. combe@montp.inserm.fr

Thalidomide, which was developed as a nonbarbiturate sedative agent, was taken off the market in 1961 after it was linked to a spate of major birth defects. Gradually, thalidomide was reintroduced for the treatment of a few skin diseases including leprous erythema nodosum, severe mucosal ulcers (e.g., associated with HIV infection or Behet's disease), lymphocytic skin infiltrations, cutaneous lupus erythematosus, and chronic graft-versus-host disease. Recent reports of original pharmacological properties including modulation of cytokine production (mainly reduced TNF-alpha production) and inhibition of angiogenesis have led to the suggestion that thalidomide may be useful in some inflammatory and neoplastic conditions. Several open-label studies and case reports have described the effects of thalidomide in Crohn's disease, rheumatoid arthritis, ankylosing spondylarthritis, systemic sclerosis, and a few other systemic disorders. In these indications, minor but dose-limiting side effects were apparently common. Thalidomide analogs with better acceptability profiles are under evaluation. The anti-angiogenic effects of thalidomide may make this compound valuable as single-drug therapy or as an adjunct to chemotherapy in patients with cancer, particularly those with metastases or multiple myeloma. This possibility requires further evaluation.

Publication Types:
PMID: 11809002 [PubMed - indexed for MEDLINE]

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Optic neuritis with transient total blindness during lactation(1).

Retzloff MG, Kobylarz EJ, Eaton C.

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. mretzloff@partners.org

BACKGROUND: Lactation-induced blindness is a rare but devastating puerperal complication. There are few reported cases and no consistent associated disease processes historically identified. This case illustrates lactation-associated optic neuritis as an early identifier of multiple sclerosis. CASE: A nulliparous woman underwent a term vaginal delivery complicated only by chorioamnionitis. She was treated with intravenous antibiotics, which included spontaneous bacterial endocarditis prophylaxis. Her postpartum course was uncomplicated, and she was discharged on postpartum day 2 with her infant. She was readmitted on postpartum day 16 completely blind. Evaluation revealed bilateral optic neuritis. Symptoms were initiated and exacerbated during nursing. Transitory waxing and waning of her visual deficits were noted after aggressive steroid therapy and discontinuing nursing. The patient was subsequently diagnosed with multiple sclerosis of relapsing-remitting type. CONCLUSION: Multiple sclerosis must be considered as an etiology for acute puerperal lactation-associated blindness when there is no clear anatomic or infectious cause.

Publication Types:
PMID: 11704195 [PubMed - indexed for MEDLINE]

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Perinephric abscesses in the neurologically impaired.

Deck AJ, Yang CC.

Section of Urology, Veterans Affairs-Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108, USA.

STUDY DESIGN: Retrospective chart review. OBJECTIVES: To document the occurrence and management of large perinephric abscesses in neurologically impaired patients at high risk for this infectious complication. SETTING: US Veterans Affairs hospital. METHODS: The records, radiographs, operative findings and outcomes of all patients who presented with perinephric abscesses evident on physical exam within the last 5 years were reviewed. RESULTS: Four patients presented with large perinephric abscesses evident on physical examination. All had severe neurologic impairment with high sensory levels; three had spinal cord injuries, one had advanced multiple sclerosis. All had neurogenic bladders and recurrent urinary tract infections. The diagnosis was made through a combination of history, physical examination and computed tomography (CT) examination. All were found to have upper tract obstruction. All were managed with immediate abscess drainage and three had elective nephrectomy once the infection had resolved. No patients died of their perinephric abscess. CONCLUSIONS: These four cases illustrate that although advances in antibiotics, imaging and percutaneous management have improved the speed of diagnosis and reduced the mortality in patients with perinephric abscesses, the neurologically impaired population continues to remain at significant risk for the development and the delayed diagnosis of these morbid renal infections.

Publication Types:
PMID: 11571659 [PubMed - indexed for MEDLINE]

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[Bacteremia due to Providencia rettgeri]

[Article in Spanish]

Goenaga MA, Mar’a Mor‡n J, Carrera JA, Garde C, Millet M.

Publication Types:
PMID: 11440672 [PubMed - indexed for MEDLINE]

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Sodium fusidate (fusidin) ameliorates the course of monophasic experimental allergic encephalomyelitis in the Lewis rat.

Di Marco R, Puglisi G, Papaccio G, Nicoletti A, Patti F, Reggio A, Bendtzen K, Nicoletti F.

Department of Microbiological and Gynaecological Sciences, University of Catania, Catania, Italy.

We have evaluated the effect of the immunosuppressant sodium fusidate (fusidin) on the course of acute monophasic experimental encephalomyelitis (EAE) in male Lewis rats. Prophylactic treatment with fusidin, 80 or 120 mg/kg bd wt., markedly ameliorated the course of the disease in rats immunized with myelin basic proteins in complete Freund's adjuvant, entailing delayed onset of symptoms, lower clinical scores and more rapid recovery than PBS-treated control rats. The fusidin-treated, immunized rats exhibited milder mononuclear cell infiltration of brains and spinal cords than control animals. These data provide further evidence for the anti-inflammatory effect of fusidin and suggest that this drug may be valuable for the treatment of human multiple sclerosis.

PMID: 11424629 [PubMed - indexed for MEDLINE]

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Neurology was there in the 1930s.

Satran R.

Department of Neurology, University of Rochester Medical School, Rochester, NY 14642, USA.

Publication Types:
PMID: 11405821 [PubMed - indexed for MEDLINE]

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[Chlamydia infections in neurology]

[Article in German]

Woessner R, Treib J.

Neurologische Klinik, Westpfalz-Klinikum Kaiserslautern. r.woessner@gmx.de

Publication Types:
PMID: 11233885 [PubMed - indexed for MEDLINE]

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A novel doxycycline inducible autoregulatory plasmid which displays "on"/"off" regulation suited to gene therapy applications.

Gould DJ, Berenstein M, Dreja H, Ledda F, Podhajcer OL, Chernajovsky Y.

Bone and Joint Research Unit, St. Bartholomew's and Royal London School of Medicine and Dentistry, Charterhouse Square, Queen Mary, University of London, London ECIM 6BQ, UK.

The development of transcriptionally controlled systems which function in eukaryotic cells are important for achieving regulated gene expression in gene therapy. In this study we combined the components of the tetracycline-inducible system in self-contained retroviral and plasmid vectors. Regulated reporter gene expression from the autoregulatory plasmid pGTRTL in response to doxycycline (Dox) induction surpasses the expression observed from other self-contained retroviral and plasmid vectors. Induction kinetics and expression levels of luciferase and the therapeutic molecule, truncated soluble complement receptor 1 (sCR1) were characterised in a mouse fibroblast and a human neuroblastoma cell line. The regulatory characteristics of the plasmids were shown to be optimal for gene therapy applications, as there was a rapid reduction in expression levels following removal of Dox. Co-transfection of cells with an autoregulatory plasmid and a Dox inducible enhanced green fluorescent protein (EGFP) plasmid demonstrated the feasibility of using this plasmid combination to achieve parallel regulation of two genes of interest in a single cell under the control of Dox. These novel autoregulatory plasmids display the requirements for gene therapy applications in chronic conditions which are remitting/relapsing such as rheumatoid arthritis or multiple sclerosis, where novel protein therapeutics and combination therapies are needed. Gene Therapy (2000) 7, 2061-2070.

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PMID: 11223986 [PubMed - indexed for MEDLINE]

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Erratum in:
  • JAMA 2001 Apr 18;285(15):1964.

Not so fast: research on infectious links to MS questioned.

Vastag B.

Publication Types:
PMID: 11176824 [PubMed - indexed for MEDLINE]

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[Paraplegia episodes revealing tuberculous myelitis]

[Article in French]

Douay X, de Seze J, Stojkovic T, Gauvrit JY, Savage C, Pruvo JP, Vermersch P.

Clinique Neurologique, H™pital Roger Salengro, CHRU de Lille.

A 38 year-old woman, without previous medical history, presented, since 1993, several paraplegic fits carrying herself progressively through to a severe paraplegia. Diagnoses successively proposed were spinal cord compressions by slipped discs, spinal cord infarct and multiple sclerosis. In November 1998, the patient presented back pain and fever. Spinal cord magnetic resonance imaging (MRI) revealed a mildly enlarged dorsal cord with signal abnormalities. The lesions were isointense on T1-weighted images, hyperintense on T2-weighted images and showed a ringlike contrast enhancement. A lumbar puncture showed a trouble cerebrospinal fluid (CSF) with leucocytes 600/mm(3) (85 p.100 polynuclear), protein 6.7 g/l, glucose 0.26 g/l, chloride 109 mmol/l. The patient was first treated with parenteral unspecific antibiotherapy. Microbiological studies of blood and CSF were negative. CSF examination with polymerase chain reaction (PCR) was positive for Mycobacterium tuberculosis. Clinical (pain and fever) symptoms and CSF abnormalities decreased after antituberculous treatment. However, paraparesis remain severe. Spinal tuberculous localizations often lead to diagnostic and therapeutic errors. Improvement of spinal cord MRI sequences and using of PCR technics in CSF would contribute to reduce these difficulties.

Publication Types:
PMID: 10891803 [PubMed - indexed for MEDLINE]

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Pseudomonas aeruginosa infection in an intrathecal baclofen pump: successful treatment with adjunct intra-reservoir gentamicin.

Galloway A, Falope FZ.

Public Health Laboratory, Newcastle General Hospital, Newcastle upon Tyne, UK.

OBJECTIVE: To describe the use of intra-reservoir gentamicin for the treatment of a Pseudomonas aeruginosa infected baclofen pump. SETTING: Regional Spinal Injuries Centre, Hexham, Northumberland, England. SUBJECT: Male patient aged 32 years with progressive multiple sclerosis and severe bilateral spasticity. RESULTS: Intra-reservoir gentamicin proved successful in treating infection with Pseudomonas aeruginosa. CONCLUSION: Intra-reservoir gentamicin may be successful in treating pump infection with Pseudomonas aeruginosa without the need for pump removal.

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PMID: 10762189 [PubMed - indexed for MEDLINE]

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Comment on:
The immunoregulatory abilities of polymorphonuclear neutrophils in multiple sclerosis.

Mayer M.

Publication Types:
PMID: 10704082 [PubMed - indexed for MEDLINE]

PMCID: PMC1781808


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Sodium fusidate in steroid resistant relapses of multiple sclerosis.

Nicoletti F, Patti F, Nicoletti A, L'Espiscopo MR, DiMarco R, Bendtzen K, Reggio A.

Publication Types:
PMID: 10644161 [PubMed - indexed for MEDLINE]

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Comment in:
Failure to detect Chlamydia pneumoniae in the central nervous system of patients with MS.

Boman J, Roblin PM, Sundstršm P, Sandstršm M, Hammerschlag MR.

Department of Virology, UmeΠUniversity, Sweden.

PMID: 10636169 [PubMed - indexed for MEDLINE]

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Inhibition of TNF-alpha synthesis with thalidomide for prevention of acute exacerbations and altering the natural history of multiple sclerosis.

Sastry PS.

Leukaemia/Myeloma Unit, Royal Marsden Hospital, Sutton, Surrey, UK.

Multiple sclerosis (MS) is a common neurological disorder which has a relapsing/remitting course and is presently incurable. A variety of agents have been tried to prevent excerbations and alter the natural history of the disease. Tumor necrosis factor-alpha (TNF-alpha) has been implicated as the most important cytokine in the pathogenesis of MS. There is evidence that thalidomide is an agent which blocks production of TNF-alpha by a mechanism different from other agents. Hence it is hypothesized that using thalidomide as therapy would prevent acute exacerbations of MS as well as alter its natural history.

PMID: 10499831 [PubMed - indexed for MEDLINE]

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Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in a patient with multiple sclerosis.

Kšhler LD, Mšhrenschlager M, Worret WI, Ring J.

Publication Types:
PMID: 10449965 [PubMed - indexed for MEDLINE]

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Long-term open-trial of mizoribine with prednisolone in 24 patients with multiple sclerosis: safety, clinical and magnetic resonance imaging outcome.

Saida K, Zhigang Z, Ozawa K, Konishi T, Saida T.

Department of Neurology, Nishinara National Hospital, Nara.

OBJECT: Mizoribine (MZR), imidazole nucleotide, inhibits purine synthesis and helper T cell functions. It is used as an immunosuppressant in chronic rheumatic arthritis in Japan. Twenty-four patients with relapsing-remitting and chronic progressive multiple sclerosis (MS) were studied for the long-term effects of MZR over 8 years. METHODS: Average daily MZR doses of 200 mg along with prednisolone (PSL) were administered in the patients studied. Ten of 24 patients were treated for more than 5 years. RESULTS: The mean relapse rate per year at entry (1.50 +/- 0.24, mean +/- SE, n = 22) decreased [0.46 +/- 0.24 (n = 19)] after two years. In 70% of the patients, the disability did not worsen. Eleven of 18 patients showed a mild decrease of the total lesion size in magnetic resonance imaging (MRI). CONCLUSION: MZR was well tolerated and could be used for long-term in MS as an adjunctive immunosuppressant to PSL, and the PSL doses could be decreased. A further randomized controlled trial with PSL is necessary.

Publication Types:
PMID: 10440499 [PubMed - indexed for MEDLINE]

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[Asymptomatic pneumatosis cystoides intestinalis in a patient with systemic lupus erythematosus]

[Article in Japanese]

Hiraishi T, Tokuda M, Mitsunaka H, Dobashi H, Takahara J.

First Department of Internal Medicine, Kagawa Medical University.

Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by the presence of gas-filled cysts in the submucosa or subserosa of gastrointestinal tract. PCI has been widely recognized as a late manifestation of systemic sclerosis but seldom reported to take place in patients with systemic lupus erythematosus (SLE). We reported here a 13-year-old female who had been diagnosed to have SLE based on the following findings; malar rash, discoid erythema, proteinuria, positive antinuclear antibody and anti-DNA antibody. She had been treated with various immunosuppressive drugs including pulse use of corticosteroid, cyclophosphamide and cyclosporin A. She was referred to our hospital because of proteinuria and numbness on her right fifth toe, refractory to above treatment. On admission, the activity of her disease was already low and she had no abdominal symptoms. Plain X-ray film showed multiple round translucencies along the wall of the ascending and transverse colon. Colonoscopy revealed multiple firm-walled cysts distributing in the terminal ileum as well. A diagnosis of PCI was made and she was successfully treated with oral antibiotics and laxatives. The association of PCI with SLE is reviewed briefly.

Publication Types:
PMID: 10434754 [PubMed - indexed for MEDLINE]

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Expression of green fluorescent protein in oligodendrocytes in a time- and level-controllable fashion with a tetracycline-regulated system.

Huang CJ, Spinella F, Nazarian R, Lee MM, Dopp JM, de Vellis J.

Departments of Neurobiology and Psychiatry, Brain Research Institute, Mental Retardation Research Center, UCLA School of Medicine, Los Angeles, California 90024, USA.

Developments in transgenic technology have greatly enhanced our ability to understand the functions of various genes in animal models and relevant human diseases. The tetracycline (tet)-regulated transactivation system for inducing gene expression allowed us to control the expression of exogenous genes in a temporal and quantitative way. The ability to manipulate a cell-specific promoter enabled us to express one particular protein in a single type of cell. The combination of a tetracycline system and a tissue-specific promoter has led us to the development of an innovative gene expression system, which is able to express genes in a cell type-specific and time- and level-controllable fashion. An oligodendrocyte-specific myelin basic protein (MBP) gene promoter controls the reversed tet-inducible transactivator. The green fluorescent protein (GFP) gene was placed under the control of the human cytomegalovirus (CMV) basic promoter in tandem with seven tet-responsive elements (TRE), binding sites for the activated transactivator. Upon the addition of doxycycline (DOX, a tetracycline derivative), tet transactivators became activated and bound to one or more TRE, leading to the activation of the CMV promoter and the expression of GFP in oligodendrocytes. We have successfully expressed GFP and luciferase at high levels in oligodendrocytes in a time- and dose-dependent fashion. In the absence of DOX, there was almost no GFP expression in oligodendroglial cultures. Graded levels of GFP expression were observed after induction with DOX (0.5 to 12.5 microg/ml). Our data indicate that this inducible gene expression system is useful for the study of gene function in vivo and for the development of transgenic animal models relevant to human diseases such as multiple sclerosis.

Publication Types:
PMID: 10203578 [PubMed - indexed for MEDLINE]

PMCID: PMC2230417


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Doxycycline sclerosis of benign lymphoepithelial cysts in patients infected with HIV.

Lustig LR, Lee KC, Murr A, Deschler D, Kingdom T.

Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco 94143-0342, USA.

Benign lymphoepithelial cysts (BLCs) are a widely recognized cause of parotid gland swelling in HIV-infected patients. Although they are neither invasive nor associated with malignant degeneration, BLCs can become large and disfiguring. Multiple modalities have been used to control these cysts, but no ideal treatment has been identified. The current study examines the efficacy of doxycycline as a BLC sclerosant in eight patients, and nine BLCs (bilateral BLC in one patient). Follow-up ranged from 12 to 17 months in all cases. Doxycycline sclerosis controlled further cyst growth in 100% of cases with no serious complications. The BLCs became negligible or unnoticeable in two patients, and in six patients (seven BLCs) the cyst became fibrosed and showed no evidence of further growth over the follow-up period. Although further studies are needed to determine the long-term efficacy of this treatment modality, doxycycline sclerosis appears to offer a simple, safe, cost-effective, office-based therapeutic option for the treatment of BLCs in patients infected with HIV.

PMID: 9707244 [PubMed - indexed for MEDLINE]

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Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis.

Dubois B, D'Hooghe MB, De Lepeleire K, Ketelaer P, Opdenakker G, Carton H.

Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Belgium.

The serine proteinase tissue-type plasminogen activator (t-PA) and the metalloproteinase gelatinase B (MMP-9) have recently been demonstrated in MS lesions. Both enzymes are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in vitro experiments to inhibit gelatinase B. The combination of peroral D-penicillamine plus metacycline was evaluated in a double-blind placebo-controlled way in two groups of 10 patients suffering from secondary progressive multiple sclerosis. The major objectives of this pilot trial were to examine the safety of this combination and the possibility of blinding, while the effect on disease progression was considered as a secondary endpoint. Over a follow-up period of 1 year and in this selected patient group, there was no significant improvement in the Expanded Disability Status Scale score (EDSS) as compared with that of the placebo-control group. Toxicity was too high to consider additional trials with this combination of metalloproteinase inhibitors. Although peroral treatment is by most MS patients acknowledged as a major improvement in treatment compliance, one has to await the development of more selective and efficacious protease inhibitors than those used in the combination therapy described here.

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PMID: 9599337 [PubMed - indexed for MEDLINE]

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Comment in:
An outcome analysis of 100 women after explantation of silicone gel breast implants.

Peters W, Smith D, Fornasier V, Lugowski S, Ibanez D.

Division of Plastic Surgery, University of Toronto, Ontario, Canada.

A prospective outcome analysis was conducted on 100 consecutive women who requested explantation of their silicone gel breast implants from January 6, 1992 (the moratorium), through 1995. Eighteen patients were referred by rheumatologists with a diagnosis of autoimmune or rheumatic disease. Six had autoimmune disease (systemic lupus, 2 patients; rheumatoid arthritis, 2 patients; multiple sclerosis, 1 patient; and Raynaud's disease, 1 patient). Twelve had rheumatic disease (fibromyalgia, 10 patients; inflammatory arthritis, 2 patients). All of these 18 patients had developed symptoms of their disease after they had received implants. All 100 patients were extensively evaluated pre- and postoperatively by interviews, clinical assessment, and by assay of the following laboratory tests: rheumatoid factor, ESR, ANA, and anti-Ro/SSA, -La/SSP, -Sm, -RNP, -double-stranded deoxyribonucleic acid, -Scl-70, -centromere, and -cardiolipin. Patients were also evaluated by a questionnaire that was sent at a mean time of 2.7 years postexplantation (range, 1-5 years), which had a 75% response rate. Reasons for implants were augmentation, 75%; lifting, 11%; reconstruction, 12%; and congenital aplasia, 2%. The mean age at first implant was 28.9 years (range, 13-55 years) and at explantation was 41.5 years (range, 25-65 years). The mean duration of implantation was 12.0 years (range, 1-27 years). Thirty-six percent of the patients had undergone at least one closed capsulotomy and 54% at least one open capsulotomy. The mean reasons for explantation were suspected silicone-related health problems, 76%; suspected rupture, 59%; breast firmness, 36%; breast pain, 36%; and musculoskeletal pain, 23%. Before explantation 75% of the questionnaire respondees had lost some sensitivity in their nipples following their breast augmentation. In 36% of those 75 patients, that loss was almost complete. Loss of sensitivity was related to capsular contracture and to pain (p < 0.05). Following explantation there was significant improvement in nipple sensitivity in 38% of breasts in the 75 respondees. A total of 186 implants were removed. Fifty-seven percent had failed by rupturing or leaking. Only 3.2% demonstrated extravasation extracapsularly. Twenty-five percent of the capsules were calcified, demonstrating visible plaques of calcification on their inner surface. Forty-two percent were colonized by bacteria. The prevalence of class III-IV capsular contracture was 61% and it was related to implant location, duration in situ, and capsular calcification (p < 0.05), but not to capsular colonization or implant integrity (p > 0.05). Only 43 of the 100 patients elected to have saline implants inserted. Of the others, 56% felt that the shell of the saline implant could be associated with medical problems. The others felt that breast size was of minor importance to them at this time. There were few complications from the explantation procedure. Two "masses" were discovered-one was an occult carcinoma, the other a galactocele. There was one wound infection, which responded to antibiotics. Three patients developed decreased sensitivity and 3 developed increased breast pain. From the patient questionnaires, in those women who did not have saline implants inserted, 15% felt that their breast appearance was improved after explantation, 36% were "pleased," 33% were disappointed, and 13% felt "mutilated". In women who did have saline implants inserted, 18% felt that their breast appearance was now improved, 60% were "pleased," and 14% were disappointed, mainly because of wrinkling. At a mean time of 2.7 years (range, 1-5 years) after explantation, 45% of the 75 questionnaire respondees felt that their implants had caused permanent health problems and 56% felt that they had not been given adequate informed consent by their original surgeon (particularly regarding implant rupture and a possible relationship to medical disease). (ABSTRACT TRUNCATED)

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PMID: 9229086 [PubMed - indexed for MEDLINE]

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How safe is oral isotretinoin?

Meigel WN.

Department of Dermatology, Allgemeines Krankenhaus St. Georg, Hamburg, Germany.

Since oral isotretinoin (Roaccutane/Accutane) is the only therapy to address all major acne causes, it remains the most effective antiacne therapy available. Due to this unique efficacy and its potential side effects that are predictable and can be managed easily and effectively, it is widely used also in acne patients suffering from serious systemic diseases. As the primary mechanism of action of oral isotretinoin is suppression of sebaceous gland activity, mucocutaneous side effects such as dry lips, nasal passages and eyes are predictable. Pretreatment counseling and concomitant use of moisturizing agents usually manage these side effects effectively; in unusual cases of particularly poor tolerability, dose adjustments suffice. Severe side effects are rare, the most common being aches and pains requiring no therapy, aspirin or paracetamol. As with other retinoids, reliable contraception is mandatory for women of childbearing potential. Acne patients with serious concomitant systemic disease, such as insulin-dependent diabetes, epilepsy or spina bifida, transplant patients, patients with renal failure, multiple sclerosis motor neuron disease and other can also safe be treated with a standard cumulative dose of 120 mg/kg per treatment course.

Publication Types:
PMID: 9310742 [PubMed - indexed for MEDLINE]

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Multiple sclerosis: management in Dutch general practice.

Donker GA, Foets M, Spreeuwenberg P.

NIVEL, Dutch National Survey of General Practice, Utrecht, The Netherlands.

BACKGROUND AND OBJECTIVES: A descriptive study on 118 MS patients in general practice, to describe the family physician's role in diagnosis, treatment and follow-up of patients. METHOD: Random sample of 103 general practices (161 family physicians) throughout The Netherlands with a total list of 335,000 patients. RESULTS: MS patients had on average 5.7 encounters with general practice in 3 months compared to 2.3 in all other patients (P < 0.001). Home visits counted for 38.7% of all family physician's encounters in MS patients compared to 16.6% in all other patients (P < 0.01). The average encounter lasted 12.9 minutes per MS patient compared to 7.8 in all other patients (P < 0.01). Counselling by the family physician took place in all new patients and in 53% of known patients. Follow-up appointments were made with all new patients and 65.9% of all MS patients. Fifteen patients (12.7%) were newly referred to a specialist and 28 patients (24%) were still treated by specialists. No medication was prescribed to almost 40% of patients. Vitamin B, benzodiazepines, laxatives, antibiotics for treatment of urinary tract infections and muscle relaxants are the most frequently prescribed drugs. The average dose of vitamin B complex was 1.94 times the defined daily dose. CONCLUSIONS: The family physician spends more time than average on MS patients, carries out more home visits and takes care of treatment of symptoms and complications of MS. Counselling and follow-up of patients takes an important place in family physician's management of MS. Vitamin B complex is being prescribed (too) frequently in a (too) high dose.

PMID: 8902512 [PubMed - indexed for MEDLINE]

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Drug therapy in multiple sclerosis: a study of Nova Scotia senior citizens.

Sketris IS, Brown M, Murray TJ, Fisk JD, McLean K.

College of Pharmacy, Dalhousie University, Halifax, Nova Scotia, Canada.

We conducted a study to determine the types and costs of drugs used by Nova Scotia senior citizens with multiple sclerosis (MS) compared with the types and costs of drugs used by all senior citizens in Nova Scotia. Administrative claims databases from the Nova Scotia Seniors Pharmacare program for persons aged 65 years or older were linked to the Dalhousie Multiple Sclerosis Research Unit (DMSRU) clinical database (1980-1994). Analyses compared persons with MS aged 65 years or older who attended the DMSRU at least once with the general population of senior citizens. Not all persons with MS attended the DMSRU. In aggregate, Pharmacare costs in 1993-1994 for patients with MS aged 65 years or older (N = 52) were $975.00 Canadian per capita compared with $590.00 Canadian for all senior citizens in Nova Scotia (N = 108,646). Thus average drug costs for the senior citizens with MS were 65% greater than those for all senior citizens covered by Nova Scotia's comprehensive, publicly funded Pharmacare program. Compared with other senior citizens, those with MS more frequently received alpha-blockers, anticholinergics, cholinergics, tricyclic antidepressants, anticonvulsants, antifatigue agents, antispasticity agents, and antibiotics for bladder infections.

Publication Types:
PMID: 8733991 [PubMed - indexed for MEDLINE]

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[Fine needle puncture--method of treatment in nodular pathology of the thyroid]

[Article in French]

Zbranca E, Mogos V, Vulpoi C, Bostaca T, Rusu M, Nisfoeanu G, Galesanu C, Nestor C, Natasa Macovei G.

Service d'Endocrinologie, UniversitŽ de MŽdecine et Pharmacie Gr. T. Popa, Iasi Roumanie.

Fine needle biopsy (FNB) has been used as a therapeutic method in different nodular lesions of the thyroid. Between 1989-1995, 295 subjects with thyroid cysts, 235 women and 60 men have been treated by FNB. The treatment of cysts was performed by: one or multiple aspirations in 207 cases, sclerosis by injection with tetracycline in 77 cases and by ethanol washing in 11 cases. 263 (89.11%) cases have been cured and we have lost track of 32 cases in the survey. Of the 207 cases treated by aspiration, 177 (86.5%) have been cured after one or more aspirations. Of the 77 cases treated by injections with tetracycline, 75 (97.26%) displayed sclerosis after one or more injections. All 11 cases treated by ethanol washing method displayed sclerosis. Between 1993-1995 we used percutaneous ethanol injection (PE1) in 6 cases, as an alternative to the classic treatment, in order to induce necrosis of toxic adenoma. After 1 to 9 injections all cases were cured, with the appearance of the entire image of the gland on the scintigram. In 4 cases of cold nodules with benign cytology PEI, induced a significant decrease of volume appreciated by sonography.

Publication Types:
PMID: 8991108 [PubMed - indexed for MEDLINE]

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Role of bacterial infection in exacerbation of multiple sclerosis.

Rapp NS, Gilroy J, Lerner AM.

Department of Physical Medicine and Rehabilitation, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

One hundred consecutive patients admitted to the hospital with a diagnosis of exacerbation of multiple sclerosis were evaluated for an infectious process. All patients received a complete blood count, urinalysis, urine culture with susceptibility studies, blood cultures, and a chest x-ray at the time of admission. A control group of 55 patients carrying the diagnosis of multiple sclerosis but without symptoms of neurologic decline were also studied. Thirty-five percent of patients experiencing exacerbation of their disease were identified as having a significant bacterial infection compared with 11% in the control group with quiescent disease. These results were significant with a P value of < 0.001. When presumptive viral and bacterial infections diagnosed before admission were included, almost 50% of patients could have had an exacerbation of their disease in response to an infectious process. Bacterial infection might well play a role in precipitating relapse in multiple sclerosis as well as influencing treatment.

Publication Types:
PMID: 8534384 [PubMed - indexed for MEDLINE]

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Effect of repeated treatments with cladribine (2-chlorodeoxyadenosine) on blood counts in multiple sclerosis patients.

Grieb P, Stelmasiak Z, Solski J, Nowicki J, Jakubowska B, Ryba M.

Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

We report the results of blood morphology monitoring of 11 remitting-relapsing multiple sclerosis patients who received repeated treatments with cladribine (2-chlorodeoxyadenosine). The drug was given once, daily, subcutaneously (5 mg) or orally (10 mg) for 5 consecutive days, as 6 monthly courses followed by one or two additional courses at 3 or 6 month intervals. The treatments were well tolerated, although many patients suffered from incidental upper respiratory tract infections, most of which occurred during the last 6 months of the observation period. One patient had recurrent infections, including an episode of urosepsis. All infections responded to standard therapy with antibiotics. Progressive lymphocyte reduction to 1000/microliters on average, and clear, but clinically insignificant drop in thrombocytes, was observed. Granulocyte counts were sometimes markedly elevated. A few patients developed macrocytosis, but none required transfusion. With our dosing and schedule, cladribine seems relatively safe in multiple sclerosis patients.

PMID: 8744654 [PubMed - indexed for MEDLINE]

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The efficacy of percutaneous tetracycline instillation for sclerosis of recurrent thyroid cysts: a multivariate analysis.

Rajatanavin R, Chailurkit L, Chiemchanya S.

Department of Medicine and Pathology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

A dichotomy exists in the literature concerning the efficacy of sclerosing agent tetracycline hydrochloride for treatment of thyroid cysts. However, the studies vary in patient selection and none employed a statistical method for simultaneous analysis of multiple factors that might affect the outcome of therapy. We, therefore, studied the efficacy of percutaneous instillation of tetracycline for eradication of recurrent thyroid cysts, using a multivariate analysis. Thirty-seven patients with recurrent, cytologically benign thyroid cysts (not cured after 3 aspirations) were studied. Twenty-three patients were given tetracycline instillations [100 mg/ml, range (R): 1-4 ml]. The remainder underwent only repeated needle aspiration. They were followed for 33 +/- 12 (SD) months, R: 12-58 months. Cure was achieved in 21 out of 23 cases after tetracycline instillation within 2 +/- 1.7 months (R: 1-6 months) and in 12 out of 14 cases after aspiration alone within 9.9 +/- 11.3 months (R: 1-43 months, 4-10 aspirations). Multivariate survival analysis using the Cox proportional-hazards regression model demonstrated significantly shorter time interval before cure in the group with tetracycline instillation (p = 0.001). The volume, color or duration of cysts and levothyroxine (L-T4) treatment did not appear to influence the outcome of therapy. After initial cure by tetracycline instillation, 5 cases had relapse. Three were later cured by reinstillation of tetracycline or by repeated aspirations (R: 1-3 times). Complications of tetracycline instillation included brief episode of neck pain and development of a foreign body granuloma in a single patient. In conclusion, tetracycline instillation is a quick and effective procedure for treating recurrent thyroid cysts.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
PMID: 8006332 [PubMed - indexed for MEDLINE]

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Rapamycin, a potential disease-modifying antiarthritic drug.

Carlson RP, Hartman DA, Tomchek LA, Walter TL, Lugay JR, Calhoun W, Sehgal SN, Chang JY.

Wyeth-Ayerst Research, Princeton, New Jersey.

Rapamycin (RAPA), a potent immunosuppressive agent that prevents organ graft rejection in animal models of transplantation, possesses a mechanism of action different than that of cyclosporin A and FK-506. In this study, the pharmacological activity of RAPA in a variety of immune and inflammatory models was assessed in order to define better its potential utility as an antiarthritic agent. RAPA inhibited T cell-mediated inflammation in mouse methylated bovine serum albumin-induced delayed-type hypersensitivity (ED40 = 4.7 mg/kg p.o.) and produced oral ED50 of 2.0 mg/kg against developing adjuvant arthritis in rats (3-day dosing schedule) and 9.5 mg/kg in established adjuvant arthritis in rats (daily dosing schedule). In both models of adjuvant arthritis, effects of RAPA were maintained even after cessation of drug dosing. In contrast, after discontinuation of cyclosporin A (5- and 10-mg/kg doses), disease activity returned. RAPA was also effective in another T cell-mediated model, experimental allergic encephalomyelitis (ED50 approximately 5 mg/kg p.o.). At higher doses, RAPA significantly inhibited carrageenan paw edema in rats, a model of acute inflammation (ED40, 56 mg/kg p.o.), without increasing serum corticosterone levels. In this model, doses approximately 10 to 20 times greater than active doses in T cell-mediated models were required. RAPA at 1 to 50 microM did not inhibit in vitro human synovial phospholipase A2 or 5-lipoxygenase and cyclo-oxygenase activity in the human blood leukocyte assay. The total profile of RAPA suggests that it may be effective in the treatment of rheumatoid arthritis, multiple sclerosis and other autoimmune diseases.

PMID: 8355184 [PubMed - indexed for MEDLINE]

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[Acute bilateral amaurosis caused by autoimmune optic nerve neuritis]

[Article in German]

JŸnemann A, Naumann GO.

Augenklinik mit Poliklinik, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg.

BACKGROUND: The bilateral simultaneous optic neuritis is rarely associated with multiple sclerosis. Diagnosis and prognosis have to be dealt with independently. PATIENT: A 45-year-old woman presented with an acute bilateral simultaneous amaurosis which developed within one day with bilateral papilledema. Initially there were positive antinuclear and anticytoplasmatic antibodies and antibodies against heart and skeletal muscles. The serum titer was elevated for immunoglobulin A, lowered for complement factors C3 and C4. Antigens for polio-virus type 3 and coxsackievirus type B5 and B3 were borderline positive. An oncologic, toxic or vascular cause of the neuritis was unlikely. THERAPY AND COURSE: The amaurosis lasted for 4 days. Vision improved gradually under a combined therapy with steroids, antibiotics and virostatics. Nineteen months later the vision was 20/25 OD and 20/200 OS. CONCLUSION: The acute bilateral neuritis was probably of autoimmunological origin. Under combined antiinfectious and steroidal therapy vision improved more than expected.

Publication Types:
PMID: 8377428 [PubMed - indexed for MEDLINE]

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Substance P stimulates IL-1 production by astrocytes via intracellular calcium.

Martin FC, Charles AC, Sanderson MJ, Merrill JE.

Department of Neurology, Reed Neurological Research Center, UCLA School of Medicine 90024.

There is increasing evidence that local substance P (SP) exacerbates peripheral inflammations, partly by stimulating production of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha). SP may play similar roles in certain central nervous system inflammations. Multiple sclerosis plaques, for example, form around veins which are innervated by unmyelinated SP-containing fibers, and astrocytes in multiple sclerosis plaques stain for SP. We tested whether SP could stimulate IL-1 and TNF alpha production by cultured astrocytes and whether calcium was the second messenger in this process. We found that both SP and the calcium ionophore A23187 raised intracellular calcium ([Ca2+]i) and stimulated IL-1 production in astrocytes. SP also nonsignificantly increased TNF alpha production by astrocytes. Treatment with dibromo BAPTA/AM, an intracellular calcium buffer, blocked SP-induced IL-1 production. These findings indicate that SP induces IL-1 production by astrocytes and uses calcium as a second messenger. Our results indicate local SP may play a role in multiple sclerosis and certain other central nervous system inflammations.

Publication Types:
PMID: 1283556 [PubMed - indexed for MEDLINE]

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[A 14-year-old with pulmonary hamartomatous lymphangiomyomatosis associated with bilateral pneumothoraces]

[Article in Japanese]

Sakamoto A, Miyazaki T, Komori K, Taketomi K, Tobinaga K, Kishikawa M, Kohno S, Hara K.

Department of Internal Medicine, Isahaya Insurance General Hospital, Japan.

A 14-year-old girl was admitted because of cough, chest pain and hemosputum. Chest roentgenogram on admission showed a pneumothorax and a cavitary lesion with niveau formation in the right lung and cystic lesions in the bilateral lung fields. After bed rest and intravenous administration of antibiotics for two weeks, the right lung inflated well and the niveau formation disappeared, and the patient was discharged. One week later, she was readmitted with sudden-onset severe dyspnea, caused by bilateral pneumothoraces. Emergency tube thoracostomy and wedge resection of the bullous lesion was performed. Macroscopically, multiple small cystic changes were seen on the surface of the right lung. Histological examination revealed nodular proliferations of smooth muscle cells in the interstitium and vessel walls in the lung, which contained slit-like lymphatic channels. The diagnosis of pulmonary lymphangiomyomatosis was made. In this case, we could not measure receptors for estrogen and progesterone. Recently, hormonal therapy and oophorectomy have been reported as being useful. Tamoxifen (Norvadex) was therefore initiated, and the patient has remained well with slight dyspnea on exertion. There has been no recurrence of pneumothorax. Lymphangiomyomatosis is a rare disease of unknown etiology which occurs exclusively in women, mostly in those of reproductive age. We report a 14-year-old female patient with lymphangiomyomatosis associated with repeated pneumothorax, who had been under treatment for epilepsy. We believe this case to be of importance because of the long discussed relation between pulmonary lymphangiomyomatosis and tuberous sclerosis.

Publication Types:
PMID: 1434226 [PubMed - indexed for MEDLINE]

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Syndrome of inappropriate secretion of antidiuretic hormone associated with multiple sclerosis.

Sakai N, Miyajima H, Shimizu T, Arai K.

First Department of Medicine, Hamamatsu University School of Medicine, Japan.

A 63-year-old man who developed episodes of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) twice in the course of multiple sclerosis (MS) is reported. SIADH in this patient occurred only during the administration of antibiotics (sulbactam/cefoperazone, SBT/CPZ). At autopsy, demyelinating lesions in the optic nerves, cervical and thoracic spinal cord, and areas adjacent to the lateral ventricles were observed. Destruction and loss of neuronal cells were found in the supraoptic nuclei. Lymphocytic infiltration was observed in the area adjacent to the supraoptic nuclei. Destruction and swelling of axons and reactive astrocytic gliosis were observed in the hypothalamus. SIADH associated with MS is rare and the histological findings in such a case have not yet been reported. It is suggested that the development of SIADH in MS may be related to the damage in the supraoptic nuclei of the hypothalamus.

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PMID: 1633348 [PubMed - indexed for MEDLINE]

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Comment in:
Relapsing transverse myelitis.

Tippett DS, Fishman PS, Panitch HS.

Department of Neurology, University of Maryland School of Medicine, Baltimore 21201.

Acute transverse myelitis is a monophasic disorder, the recurrence of which raises the question of multiple sclerosis (MS) or other multifocal CNS disease. We now report three patients with a previously undescribed syndrome of relapsing isolated acute transverse myelitis. Each had two to five attacks over periods of 3 to 8 years, characterized by ascending paresthesias, urinary retention, sensory loss with a thoracic or cervical level, paraparesis, hyperreflexia, and bilateral Babinski signs. MRI demonstrated areas of increased signal intensity on T2- and proton density-weighted scans and decreased signal intensity on T1-weighed scans of the cervical or thoracic spinal cord consistent with an inflammatory or demyelinating process. All patients had normal complete myelograms, oligoclonal IgG bands were consistently absent from the cerebrospinal fluid, cranial MRIs were normal, and there was no other clinical or laboratory evidence of MS, collagen-vascular disease, or active viral infection. They were treated with high doses of intravenous corticosteroids, stabilized between episodes, and had partial or complete recovery. The recognition of these three patients at a single medical center in a 1-year period suggests that relapses of acute transverse myelitis may not be rare.

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PMID: 2027486 [PubMed - indexed for MEDLINE]

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[Current therapy of multiple sclerosis: value of cyclosporin A and FK 506]

[Article in German]

Hohlfeld R.

Neurologische Klinik, Ludwig-Maximilians-UniversitŠt MŸnchen.

Publication Types:
PMID: 1709725 [PubMed - indexed for MEDLINE]

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[Maxillary cyst of dental origin with uncommon ocular complication]

[Article in French]

Philippe J, Philippe HJ, Ghazi I, Desvaux P, Molho M, Outin H.

Service d'Ophtalmologie, CHI Poissy.

A 23-year-old woman was referred for decreased vision and central scotoma. Fundus examination disclosed unilateral acute oedematous optic neuritis. A nasolabial cyst was diagnosed, probably of dental origin, because numerous apical granuloma were noticed. The abscess did not produce any fistula which explained the absence of clinical and radiological dental sinusitis. Treatment included excision of the nasolabial cyst and systemic antibiotics. The prognosis was excellent with recovery of a normal visual acuity and normal fundus appearance. There was no evidence of any recurrent episode. The nasolabial cyst was the cause likely of the neuritis. Nevertheless, multiple sclerosis must be considered. Only long-term absence of neurological signs could prove that the maxillary lesion was directly responsible for the optic disorder.

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PMID: 2050961 [PubMed - indexed for MEDLINE]

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Primary sclerosing cholangitis.

Lillemoe KD, Pitt HA, Cameron JL.

Department of Surgery, Johns Hopkins University, Baltimore, Maryland.

Primary sclerosing cholangitis is a rare disease of unknown etiology. Sclerosis of the bile ducts may actually be the final result of multiple factors such as autoimmune, bacterial, congenital, drug, or viral injury. The most commonly associated diseases are ulcerative colitis and chronic pancreatitis. Except in the earliest stages of the disease, liver histologic findings are not specific. Most patients present with jaundice, pain, and pruritus, although an increasing number of asymptomatic patients with inflammatory bowel disease and abnormal liver function are being identified. Cholangiography is key to the diagnosis and is usually pathognomonic except in the unusual case where primary sclerosing cholangitis is confused with cholangiocarcinoma. Many forms of medical therapy have been tried, including antibiotics, azathioprine, cholestyramine, colchicine, cyclosporine, D-penicillamine, steroids, and ursodeoxycholic acid. To date, none of these medications has been proved to alter the course of this disease. Recent reports of ursodeoxycholic acid trials have been encouraging, but long-term results of ongoing randomized trials have yet to be published. In recent years, balloon dilatation of biliary strictures has been accomplished via endoscopic and percutaneous transhepatic approaches. However, in patients with primary sclerosing cholangitis, these nonoperative manipulations must be done repeatedly, may entail multiple general anesthetics, and are difficult to perform. We believe that a direct surgical approach to the biliary tree with long-term transhepatic stenting is indicated in selected patients with severe hilar or extrahepatic stricturing, persistent jaundice or recurrent cholangitis, and no evidence of cirrhosis. Hepatic transplantation should be reserved for patients with primary sclerosing cholangitis who have well-established cirrhosis and have not responded to other therapeutic measures.

Publication Types:
PMID: 2247821 [PubMed - indexed for MEDLINE]

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Induction and regulation of interleukin-6 gene expression in rat astrocytes.

Benveniste EN, Sparacio SM, Norris JG, Grenett HE, Fuller GM.

Department of Neurology, University of Alabama, Birmingham 35294.

Cells that produce interleukin-6 (IL-6) require the presence of signaling molecules since this cytokine is not normally constitutively expressed. It is now established that astrocytes produce IL-6; however, the precise inducing molecules and the kinetics of their action have not yet been clearly identified. In the current study, we show that either interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) exert a strong inducing signal for IL-6 in primary rat astrocytes. When the two cytokines are added together the response is synergistic, suggesting that each cytokine may induce IL-6 gene expression by different pathways. Interferon-gamma (IFN-gamma) does not affect IL-6 expression although if it is added in conjunction with IL-1 beta, an augmented induction of IL-6 occurs. In addition to the cytokines, bacterial lipopolysaccharide (LPS) and the calcium ionophore, A23187, induce IL-6 expression. IL-6 expression can be blocked by the glucocorticoid analogue, dexamethasone. IL-6 induction by LPS/Ca2+ ionophore is more sensitive to the suppressive effects of dexamethasone than is IL-6 induction by TNF-alpha/IL-1 beta. Cycloheximide (CHX), an inhibitor of protein synthesis, markedly increased levels of IL-6 mRNA in both unstimulated and stimulated astrocytes, indicating that ongoing protein synthesis is not required for astrocyte IL-6 gene expression. We propose that astrocyte-produced IL-6 may have a role in augmenting intracerebral immune responses in neurological diseases such as multiple sclerosis (MS), AIDS dementia complex (ADC), and viral infections. These diseases are characterized by infiltration of lymphoid and mononuclear cells into the central nervous system (CNS), and intrathecal production of immunoglobulins. IL-6 may act to promote terminal differentiation of B cells in the CNS, leading to immunoglobulin synthesis.

Publication Types:
PMID: 2121800 [PubMed - indexed for MEDLINE]

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[The effect of thrombocytes on the inhibition of granulocyte adherence induced by the ionophore A 23187 in multiple sclerosis]

[Article in Czech]

Mayer M.

Ustav klinickŽ a experiment‡ln’ neurologie Univerzity PalackŽho, Olomouc.

In patients with disseminated sclerosis and in a control group inhibition of granulocyte adherence was investigated after stimulation with the ionophore A23187 and the effect of autologous thrombocytes on this reactivity was investigated. The granulocyte adherence was not markedly influenced in the described experimental set-up by the ionophore alone not by incubation with thrombocytes alone. The ionophoretic stimulation of granulocytes incubated with thrombocytes caused marked inhibition of leucocyte adherence in healthy controls and to a significantly smaller extent in patients with multiple sclerosis without corticosteroid treatment. In patients treated with corticosteroids this response was not observed. The results suggest a change of membrane properties, dependent on thrombocytes, in the early stage of non-specific granulocyte activation in patients with multiple sclerosis.

Publication Types:
PMID: 2115399 [PubMed - indexed for MEDLINE]

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[Effects of novel immunosuppressant FK 506 in acute experimental allergic encephalomyelitis]

[Article in Japanese]

Deguchi K, Takeuchi H, Miki H, Yamada A, Touge T, Terada S, Nishioka M.

Department of Internal Medicine, Kagawa Medical School, Japan.

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease. It is widely used as an animal model of multiple sclerosis (MS). We studied the prophylactic effects of FK 506 electrophysiologically and immunohistochemically in acute EAE. Female Lewis rats were sensitized with guinea pig spinal cord in complete Freund's adjuvant. FK 506 suspended in distilled water was orally administered at 1.0, 3.2, 5.0 or 10.0 mg/kg per day for 12 successive days starting from the day of sensitization. A placebo was used as the control. Administration of FK 506 at doses of 3.2 mg/kg per day and over significantly delayed the onset of clinical signs. However, the FK 506 group showed a relapse or a chronic state following the onset of EAE. We made a time course recording of cortical somatosensory evoked potential (cortical SEP: P 15). P 15 latency in the placebo group was significantly delayed in accordance with the clinical signs and showed immediate improvement upon recovery. Prolongation of P 15 latency in the FK 506 group also occurred concomitantly with the clinical signs, but the delay continued after the loss of symptoms as well. After the onset of EAE, the infiltrating lymphocyte subset was examined by the avidin-biotin peroxidase complex (ABC) method in the lumbar spinal cord. In the placebo group, the number of OX3+ (Ia) cells and the W 3 25+: OX8+ (helper/inducer T: suppressor/cytotoxic T) ratio clearly reflected the development and remission of EAE. In the FK 506 group, however, increases in OX8+ lymphocytes were observed irrespective of clinical sign fluctuation, and there were corresponding decreases in the W 3/25+: OX8+ ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

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PMID: 1697182 [PubMed - indexed for MEDLINE]

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Successful treatment of acquired pendular elliptical nystagmus in multiple sclerosis with isoniazid and base-out prisms.

Traccis S, Rosati G, Monaco MF, Aiello I, Agnetti V.

Neurological Clinic, Sassari University, Italy.

We treated 3 multiple sclerosis patients who had pendular nystagmus with isoniazid (800 to 1,000 mg/d). Isoniazid abolished the nystagmus and relieved oscillopsia in 2 patients but was ineffective in the 3rd in whom the nystagmus was damped with convergence and vision improved with converging (base-out) prisms.

Publication Types:
PMID: 2314593 [PubMed - indexed for MEDLINE]

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Mononuclear leucocytes, granulocytes and thrombocytes in the calcium ionophore-induced leucocyte adherence inhibition in multiple sclerosis patients and controls.

Mayer M.

Department of Neurology, Palacky University, Olomouc.

The calcium ionophore A23187-induced adherence inhibition of mononuclear leucocytes and granulocytes in multiple sclerosis patients and in controls was investigated. Furthermore, the role of thrombocytes in the ionophore-induced adherence inhibition of both the mononuclears and the granulocytes was evaluated. In the control group and in patients treated with corticosteroids the ionophore consistently induced the adherence inhibition of mononuclear leucocytes. In multiple sclerosis patients without corticosteroid treatment rather heterogenous results were obtained, which appears to reflect the fluctuation of the disease activity. Addition of thrombocytes to the mononuclear leucocyte suspension led to a decrease of leucocyte adherence in both multiple sclerosis groups regardless of the presence of the ionophore. The ionophore stimulation of granulocytes preincubated with the thrombocyte suspension resulted in an increase of the granulocyte nonadherence in healthy controls. An analogous response in multiple sclerosis patients without corticosteroid treatment was significantly less expressed and was not found in patients treated with corticosteroids. These results suggest a thrombocyte-dependent alteration of the membrane properties in the early phase of nonspecific granulocyte activation in patients with multiple sclerosis.

PMID: 2113495 [PubMed - indexed for MEDLINE]

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Splenic cysts: aspiration, sclerosis, or resection.

Moir C, Guttman F, Jequier S, Sonnino R, Youssef S.

Department of Surgery, McGill University, Montreal Children's Hospital, Quebec, Canada.

Percutaneous aspiration and tetracycline sclerosis is a safe but temporary therapy of large splenic cysts in children. Between 1985 and 1987, three girls with splenic cysts were seen. Their ages ranged from 5 to 14 years, and the cysts were from 8 to 16 cm in diameter. Despite their large size, all were asymptomatic and were discovered upon physical examination or ultrasound for unrelated conditions. All cysts were avascular by scan and had irregular crenated or smooth walls by ultrasound. Further investigation excluded infectious or parasitic causes. Each cyst was aspirated for diagnosis, and a pigtail catheter was inserted for drainage and sclerotherapy. All needle aspirations resulted in cyst collapse, but in one patient the pigtail catheter insertion was unsuccessful, and in the other two cases, multiple attempts of tetracycline sclerosis failed to obliterate the cysts. There were no other complications. Surgery for the recurrent splenic cysts was performed 3 months to 2 years following the percutaneous procedures. The two patients operated on with 3 months of aspiration underwent successful partial splenectomy and have normal splenic function by ultrasound scan, and absence of RBCs. The third patient had progression of the cystic disease throughout the spleen, and required splenectomy. Pathology confirmed multiseptate congenital mesothelial cysts in the first two patients and massive lymphangiomatosis in the third. In all three cases, percutaneous therapy was safe but did not result in long-term control. In one patient, the cystic disease progressed following sclerotherapy and may have influenced the need for complete splenectomy. Prior manipulation did not adversely affect the dissection and mobilization of the spleens.(ABSTRACT TRUNCATED AT 250 WORDS)

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PMID: 2754580 [PubMed - indexed for MEDLINE]

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Borrelia burgdorferi antibodies in multiple sclerosis patients.

Coyle PK.

Department of Neurology, SUNY, Stony Brook 11794.

Lyme disease is said to produce a late syndrome resembling multiple sclerosis. We analyzed serum antibodies to Borrelia burgdorferi in 100 patients referred for possible MS. All lived in an area endemic for Lyme disease. Only 1 of 89 definite MS patients and 2 of 11 non-MS patients were antibody positive. Infection with Borrelia burgdorferi is rare in MS, and Lyme disease is unlikely to play a significant role in the differential diagnosis of MS.

PMID: 2725867 [PubMed - indexed for MEDLINE]

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[Adherence of mononuclear leukocytes in multiple sclerosis: the effect of the calcium ionophore A 23187 and leukotrienes B4 and C4]

[Article in Czech]

Mayer M.

The author assessed the effect of leucotrienes B4 and C4 and the calcium ionophore A23187 on the adherent reactivity of mononuclear leucocytes in patients with multiple cerebrospinal sclerosis and in controls. The calcium ionophore A23187 in concentrations of 200 nmol/1 - 5 mumol/1 induced inhibition of leucocyte adherence, depending on the concentration used. This reactivity was, as compared with controls, significantly lower in patients with multiple sclerosis who did not take cortisoid preparations and in patients taking prednisone in doses up to 5 mg/day. In patients treated with higher prednisone doses (20-90 mg/day) the values of the non-adherence index reached values insignificantly higher than in controls. Leukotrienes B4 and C4 (1 nmol/1 - 100 nmol/1 stimulated leucocyte adherence in patients treated with higher corticoid doses, in the remaining patients and in controls they did not influence the leukocyte adherence. The results of the investigation provide evidence of abnormalities of the membrane properties of the mononuclear leucocytes in patients with multiple sclerosis and draw attention to the association of these changes with metabolic chains of arachidonic acid and with calcium ion homeostasis.

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PMID: 2545361 [PubMed - indexed for MEDLINE]

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Multiple sclerosis is a chronic central nervous system infection by a spirochetal agent.

Marshall V.

Animal Vaccine Laboratory, Council Bluffs, Iowa 51501.

Multiple Sclerosis (MS) is a chronic central nervous system (CNS) infection similar to Lyme Disease or Neurosyphilis in its latency period, pathogenesis, symptoms, histopathology and chronic CNS involvement. It does not have as yet a fully identified spirochetal etiological agent. Much research and clinical support for this hypothesis was published before 1954 and is based on silver staining of neural lesions, animal isolation of the etiologic agent and the characteristic symptoms and pathogenesis of the disease. If this hypothesis is correct, the disease should be treatable with antibacterial agents that penetrate the CNS (such as high dose antibiotics), diagnosible by specific immunological tests, and preventable by early treatment or by the use of vaccines in high risk populations.

PMID: 3357458 [PubMed - indexed for MEDLINE]

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Sclerosing cholangitis.

Lillemoe KD, Pitt HA, Cameron JL.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

PSC is an unusual disease of unknown etiology. In fact, sclerosis of the bile ducts may be the result of multiple factors, including autoimmune, bacterial, congenital, drug, or viral agents. The most commonly associated diseases are ulcerative colitis and chronic pancreatitis. Except for the earliest stages of the disease, liver histology is not specific. Most patients present with jaundice, pain, and pruritis, although an increasing number of asymptomatic patients with inflammatory bowel disease and abnormal liver function are being diagnosed. Cholangiography is the key to the diagnosis and is usually pathognomonic except in the unusual case where PSC is confused with cholangiocarcinoma. Multiple forms of medical therapy have been tried, including steroids, azothiaprine, D-penicillamine, colchicine, cholestyramine, and antibiotics. To date, however, none of these medications has altered the course of this disease. In recent years, balloon dilation of biliary strictures has been accomplished via endoscopic and percutaneous transhepatic approaches. However, in patients with PSC these nonoperative manipulations must be done repeatedly, may require multiple general anesthetics, and are difficult to perform. A direct surgical approach to the biliary tree with prolonged transhepatic stenting is indicated in patients with severe hilar or extrahepatic stricturing, persistent jaundice and/or recurrent cholangitis, and no evidence of cirrhosis. Hepatic transplantation should be reserved for patients with PSC who have well-established cirrhosis and in whom other therapeutic options have failed.

Publication Types:
PMID: 3318316 [PubMed - indexed for MEDLINE]

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Effect of calcium ionophore A23187 and of leukotrienes B4 and C4 on the adherence of mononuclear leucocytes in multiple sclerosis.

Mayer M.

Research Institute of Higher Nervous Activity, Palacky University, Olomoue.

The disturbances of the arachidonic acid metabolic cascade are supposed to play a significant part in some membrane alterations and in associated immunopathological changes in multiple sclerosis. Since the lipoxygenase derivatives of the arachidonic acid and the calcium ion influx were proved to participate in the mechanisms involved in the leucocyte adherence inhibition phenomenon, the effect of calcium ionophore A23187 and of leukotrienes B4 and C4 upon the adherence of mononuclear leucocytes of multiple sclerosis patients and of healthy controls was investigated in the present study using a modification of the leucocyte adherence inhibition assay. A23187, a potent stimulator of the arachidonic acid metabolism, induced the mononuclear leucocyte adherence inhibition in a dose-dependent manner. In multiple sclerosis patients without corticosteroid treatment and in those treated with lower prednison doses (up to 5 mg/day), the non-adherent response to A23187 stimulation was significantly lower than in the controls, whereas in multiple sclerosis patients treated with prednison doses varying from 20 to 90 mg/day the A23187-induced adherence inhibition reached non-significantly higher values compared to the controls. Leukotrienes B4 and C4 stimulated the adherence of the leucocytes in multiple sclerosis patients treated with higher prednison doses. Compared to controls, statistically significant differences were found using 1 nM and 100 nM LTC4. The findings obtained in this study with all probability reflect alterations of the membrane processes in multiple sclerosis leucocytes associated with calcium ion homeostasis and arachidonic acid metabolic cascade.

PMID: 2839380 [PubMed - indexed for MEDLINE]

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Multiple sclerosis: enigmas of etiology and management.

Johnson DP.

Publication Types:
PMID: 3427964 [PubMed - indexed for MEDLINE]

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Bacteriuria in multiple sclerosis: documentation by prospective cultures.

Wahlquist GI, Booss J.

PMID: 3322667 [PubMed - indexed for MEDLINE]

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[Amphoglucamine in the combined chemotherapy of viral diseases]

[Article in Russian]

Shneider MA, Golovkin VI, Chizhov NP, Shtil'bans EB.

Publication Types:
PMID: 3445592 [PubMed - indexed for MEDLINE]

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Leukotrienes B4 and C4 in MS.

Prosiegel M, Neu I, Wildfeuer A, Mehlber L, Mallinger J, Ruhenstroth-Bauer G.

Release of leukotriene B4 (LTB4) and leukotriene C4 (LTC4) from neutrophils and platelet-neutrophil suspensions in response to ionophore A23187 was measured in 12 multiple sclerosis (MS) patients and 8 healthy volunteers. LTC4 release from neutrophils, as well as from platelet-neutrophil suspensions, was significantly decreased in MS patients compared with the controls. There was no significant difference in the release of LTB4 between MS patients and controls. The findings suggest that permanent stimulation of platelets and neutrophils e.g., by encephalitogenic peptide leads to continuous LTC4 release with subsequent depletion of intracellular substrates serving as precursors for the formation of 5-lipoxygenase products. Since the target of microvascular actions of LTC4 are postcapillary venules, the release of this sulfidopeptide leukotriene might play a pathogenetic role in the formation of MS lesions.

PMID: 3039781 [PubMed - indexed for MEDLINE]

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Neurological manifestations and toxicities of the antituberculosis drugs. A review.

Holdiness MR.

The neurological manifestations and toxicities of 12 antituberculosis drugs [isoniazid, rifampicin (rifampin), ethambutol, p-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Their effects upon the central nervous system, cranial nerves, peripheral nerves and the neuromuscular junction are examined, and drug interactions of neurological concern are briefly discussed. Isoniazid is well known to increase the concentrations of gamma-aminobutyric acid in neural tissues. Although conflicting data have been published, isoniazid may play a limited future role in reducing the degree of adventitious movements noted in certain neurological diseases such as multiple sclerosis, spasmodic torticollis, and other segmental dystonic syndromes. With rifampicin neurological complications have been observed infrequently. Rifampicin penetrates into the CSF and has been shown to have useful activity against various micro-organisms in the CSF, including certain viruses; however, contrary to earlier suggestions, it appears to have no role in the treatment of subacute sclerosing panencephalitis. A number of studies have indicated that isoniazid is associated with a large number of accidental and intentional poisonings. The highest incidence has been observed with Southwestern American Indians in which this agent was involved in 7% of all suicide attempts and 19% of the suicide deaths. Degeneration of the optic chiasma and nerve is a well-known adverse effect of ethambutol; toxicity is manifested by impairment of visual acuity, marked loss of colour discrimination, constricted visual fields, and central and peripheral scotoma. Ototoxicity is a well known problem caused by streptomycin, kanamycin, capreomycin and viomycin. The use of streptomycin in pregnant mothers is associated with congenital deafness in newborns in certain cases. The aminoglycoside antibiotics are also associated with flaccid paralysis following neuromuscular blockade. Adverse reactions to cycloserine are mainly dose-related with neurological and psychiatric syndromes noted in up to 50% of patients. Recent data indicate that isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, kanamycin, ethionamide, and cycloserine appear in measurable quantities in the cerebrospinal fluid. Five of these compounds (isoniazid, rifampicin, ethambutol, kanamycin, cycloserine) pass to some degree through non-inflamed meninges. Other than discontinuation of the therapeutic regimen and general supportive measures, very few methods are described in the literature for treatment of acute intoxications with antituberculosis drugs.

Publication Types:
PMID: 3547005 [PubMed - indexed for MEDLINE]

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A controlled trial of isoniazid therapy for action tremor in multiple sclerosis.

Bozek CB, Kastrukoff LF, Wright JM, Perry TL, Larsen TA.

Ten patients with clinically definite multiple sclerosis (MS) and action tremor were treated with isoniazid (INH) in a double-blind single crossover trial. The daily dose of INH administered during the 4-week treatment phase of the trial was determined by acetylator phenotype with slow acetylators receiving 12 mg/kg per day and rapid acetylators 20 mg/kg per day. Six of eight patients who completed the trial showed clinical improvement in the postural (alternating) tremor while on INH but the degree was minimal in all cases. Results of tremograms indicated that improvement also occurred in the intentional (synchronous) component of three patients while on INH, but this did not achieve statistical significance. Cerebrospinal fluid (CSF) levels of gamma-aminobutyric acid (GABA) homocarnosine and ornithine were markedly elevated with INH therapy (providing evidence for substantial inhibition of GABA aminotransferase activity and increase in GABA in the CNS), but no correlation was found between the degree of GABA elevation in the CSF and the clinical response. Side effects were minimal and well tolerated. Although INH appears to have a limited therapeutic role, a trial is warranted in MS patients with postural tremor.

Publication Types:
PMID: 3546605 [PubMed - indexed for MEDLINE]

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The response to isoniazid of action tremor in multiple sclerosis and its assessment using polarised light goniometry.

Francis DA, Grundy D, Heron JR.

Isonicotinic acid hydrazide (isoniazid) was evaluated in five patients as a treatment for the control of severe cerebellar action tremor occurring in multiple sclerosis. Oral doses of isoniazid BPC were increased every 2 weeks from 300 mg to 1200 mg daily over an 8 week period. Four patients reported considerable symptomatic benefit at doses ranging from 600 mg to 900 mg daily. Polarised light goniometry demonstrated a two to three-fold reduction of tremor in these patients when standard methods of clinical assessment showed only marginal improvement.

PMID: 3958735 [PubMed - indexed for MEDLINE]

PMCID: PMC1028653


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[New aspects of therapy with standard immunoglobulin preparations]

[Article in German]

Briese V.

Both, in vitro and in vivo studies have shown that intravenous immunoglobulin administration in high doses is of usefulness in the therapy of bacterial infections because of synergistic effects with antibiotics. Unmodified, polyvalent immunoglobulin for intravenous administration is actually used for therapy in patients with severe generalized infections, in patients with autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP). ITP patients were treated with IgG i.v. 400 mg/kg KG. One can hope for practical purposes that IgG preparations administrated prophylactically decrease infectious complications in myelosuppressive phases during aggressive tumor therapy.

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PMID: 3811676 [PubMed - indexed for MEDLINE]

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Isoniazid for tremor in multiple sclerosis: a controlled trial.

Duquette P, Pleines J, du Souich P.

We evaluated the effects of isoniazid on tremor in 13 patients with MS. Patients were evaluated before treatment, after 1 month of therapy (1,000 mg daily), and 1 month after the last dose. Ten patients improved on at least one of three methods of evaluation. Transient side effects were common, possibly because there was a high percentage of "slow acetylators"; dosage was reduced by one-half in five patients. Improvement was mild and did not result in significant functional improvement.

Publication Types:
PMID: 3906430 [PubMed - indexed for MEDLINE]

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Isoniazid and action tremor in multiple sclerosis.

Hallett M.

Publication Types:
PMID: 4045495 [PubMed - indexed for MEDLINE]

PMCID: PMC1028508


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Controlled trial of isoniazid therapy for severe postural cerebellar tremor in multiple sclerosis.

Hallett M, Lindsey JW, Adelstein BD, Riley PO.

Six patients with severe postural cerebellar tremor were studied in a double-blind, placebo-controlled, crossover trial with isoniazid. Each phase of the study lasted 4 weeks, and in the isoniazid phase patients received an increasing dose up to 1200 mg/d. Patients were studied with self-rating scales, quantitative tremor recording, and blinded ratings of videotapes. All patients improved by at least one method, three improved by all methods, and four improved sufficiently to want to continue with the drug after the trial was finished. There is a definite, but limited, therapeutic role for isoniazid.

Publication Types:
PMID: 3895037 [PubMed - indexed for MEDLINE]

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Diagnosis of spirochetal meningitis by enzyme-linked immunosorbent assay and indirect immunofluorescence assay in serum and cerebrospinal fluid.

Stiernstedt GT, Granstršm M, Hederstedt B, Skšldenberg B.

The antibody response against a spirochetal strain isolated from Swedish Ixodes ricinus ticks was determined by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay of cerebrospinal fluid (CSF) and serum specimens from 45 patients with chronic meningitis. Samples of CSF, serum, or both from patients with various infections of the central nervous system, multiple sclerosis, syphilis, or infectious mononucleosis and from healthy individuals served as control samples. Probable spirochetal etiology could be demonstrated for 41 of 45 (91%) patients with clinical symptoms of chronic meningitis. Approximately 25% of the patients had significantly elevated titers of antibody to the spirochete in CSF but not in serum. The highest diagnostic sensitivity, 91%, was demonstrated by measurement of CSF antibodies and calculation of a spirochetal CSF titer index, which is the ratio of (ELISA titer in CSF/ELISA titer in serum) to (albumin in CSF/albumin in serum) and which also considers the degree of blood-CSF barrier damage. The highest specificity, 98%, was obtained by calculation of a CSF titer index. Patients with short duration of disease were especially prone to be antibody negative in serum but positive in CSF. Significant rise in serum antibody titers was seldom demonstrated in patients treated with antibiotics. It is concluded that measurement of CSF antibodies, especially by ELISA, is a highly sensitive and specific method for the immunological diagnosis of spirochetal meningitis.

Publication Types:
PMID: 3889049 [PubMed - indexed for MEDLINE]

PMCID: PMC271789


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Isoniazid and action tremor in multiple sclerosis.

Morrow J, McDowell H, Ritchie C, Patterson V.

Publication Types:
PMID: 3981201 [PubMed - indexed for MEDLINE]

PMCID: PMC1028268


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Multiple sclerosis. Current concepts in management.

Giesser B.

Multiple sclerosis is a chronic, often progressive disease of the central nervous system which can produce visual, sensory, motor, and genitourinary dysfunction. Although there is no cure, many disabling symptoms can be ameliorated. Baclofen is the treatment of choice for spasticity and is usually given in doses of 30 to 80 mg/day, although higher doses may be used. Bladder symptoms in multiple sclerosis generally fall into the categories of failure to store, failure to empty, and mixed types. Most patients can be managed after obtaining a urine culture and sensitivity and post-voiding residual. A variety of anticholinergic agents plus intermittent self-catheterisation is usually the most effective treatment for bladder dysfunction. Prevention of infection is accomplished by urinary acidifiers or low-dose antibiotics. There is no evidence that long term use of corticosteroids has a beneficial effect on the outcome of multiple sclerosis, although they appear to be useful in hastening the recovery time from an acute exacerbation. There are a number of experimental therapeutic agents which are used to modulate the immune response, which may prove to be of use in slowing or arresting the progression of multiple sclerosis.

Publication Types:
PMID: 2982564 [PubMed - indexed for MEDLINE]

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Elevation of gamma-aminobutyric acid in human brain may increase dopaminergic neuronal function.

Perry TL, Ito M, Jones K, Hansen S.

Studies in experimental animals have yielded conflicting findings as to the influence of gamma-aminobutyric acid (GABA) on the activity of nigrostriatal and mesolimbic dopaminergic neurons. We measured cerebrospinal fluid (CSF) concentrations of GABA and homovanillic acid (HVA) in 19 patients before and during treatment with isoniazid. CSF GABA concentrations increased markedly during isoniazid administration, presumably reflecting increases in brain GABA content. At the same time, HVA concentrations in CSF rose significantly. The net effect of elevating brain GABA content in humans appears to be to increase dopamine release from dopaminergic neurons.

Publication Types:
PMID: 6238245 [PubMed - indexed for MEDLINE]

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Free and conjugated GABA in human cerebrospinal fluid: effect of degenerative neurologic diseases and isoniazid.

Manyam BV, Tremblay RD.

gamma-Aminobutyric acid (GABA) was measured in CSF as such and following acid hydrolysis by the ion-exchange/fluorometric method. The conjugated GABA level was obtained by subtracting the free GABA level from the total GABA level. Results showed that at room temperature, while the free GABA level increased, the level of conjugated GABA decreased in a linear fashion during the first 24 h (r = -0.974; P less than 0.001). Aging and CSF conjugated GABA levels were inversely correlated (r = -0.613; P less than 0.05). Unlike free GABA levels, the levels of conjugated GABA were not altered in Huntington's disease, Parkinson's disease, cerebellar ataxias, dementias, epilepsy and multiple sclerosis compared to controls. In patients with Huntington's disease, on administration of isoniazid at 900 mg/day, along with pyridoxine at 100 mg/day, a 4-fold increase of both free (P less than 0.005) and conjugated GABA (P less than 0.0025) was seen. The results indicate that while total GABAergic peptides are not altered in several of the neurologic diseases studied, drugs such as isoniazid and/or pyridoxine can significantly elevate both free and conjugated GABA levels in human CSF.

Publication Types:
PMID: 6235893 [PubMed - indexed for MEDLINE]

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Pharmacologic trials in the treatment of cerebellar tremor.

Koller WC.

We studied the effect of long-term administration of propranolol hydrochloride and isoniazid and the acute action of ethyl alcohol on cerebellar tremor in patients with multiple sclerosis and primary cerebellar degeneration in a placebo-controlled double-blind crossover test. None of the drugs decreased the severity of either static or kinetic cerebellar tremors.

Publication Types:
PMID: 6365047 [PubMed - indexed for MEDLINE]

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INH in multiple sclerosis.

[No authors listed]

Publication Types:
PMID: 6537847 [PubMed - indexed for MEDLINE]

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[Immunosuppressive therapy]

[Article in German]

Schumacher K, Gross R.

Publication Types:
PMID: 6370894 [PubMed - indexed for MEDLINE]

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Treatment and prevention of myelin disorders: multiple sclerosis.

Abramsky O.

PMID: 6326915 [PubMed - indexed for MEDLINE]

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Treatment of action tremor in multiple sclerosis with isoniazid.

Sabra AF, Hallett M, Sudarsky L, Mullally W.

Four patients with disabling action tremor in the setting of MS were treated with isoniazid (800 to 1200 mg per day). All patients showed significant improvement of the tremor, allowing more functional use of their extremities. To the best of our knowledge, this is the only medical treatment for this type of tremor.

Publication Types:
PMID: 7201590 [PubMed - indexed for MEDLINE]

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[Acute relapses in multiple sclerosis. Emergency diagnosis and therapy]

[Article in German]

Hielscher H.

Publication Types:
PMID: 6258006 [PubMed - indexed for MEDLINE]

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Myelin basic protein treatment of experimental allergic encephalomyelitis in monkeys.

Alvord EC Jr, Shaw CM, Hruby S.

Treatment of experimental allergic encephalomyelitis (EAE) in two strains of monkeys with large amounts of myelin basic basic protein (BP) fails unless an adjunct is also used. In both strains the adjunct by itself is more effective than BP by itself, but in the one strain which could be investigated sufficiently, the combination can be made almost totally effective in reversing EAE. The adjunct varies with the strain of monkey, an antibiotic in Macaca mulatta and a steroid in Macaca fascicularis. Similar adjunctive treatments should be considered in the management of multiple sclerosis, for EAE remains one of the best studied models.

Publication Types:
PMID: 93874 [PubMed - indexed for MEDLINE]

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Appraisal of the PAM cell effect as a diagnostic test for multiple sclerosis.

Cohn H, Oger J, Sabouraud O, Ardouin M.

The selective reduction of PAM cell yield reported by Carp and associates in the presence of tissue from patients with multiple sclerosis (MS) has been attributed to replication in culture of a viral agent associated with MS (MSAA). We investigated the diagnostic potential of the PAM cell effect in MS and in optic neuritis (ON). Six serum and 7 CSF samples from 7 patients with MS, 3 serum and 3 CSF samples from 4 patients with idiopathic ON, and 4 sera from 4 patients with ON induced by ethambutal toxicity were tested. Blind counting showed no reduction in PAM cell yield in the MS group nor any significant difference between the two ON groups. Disturbing inconsistencies in PAM cell growth rates over time and between control flasks were demonstrated.

PMID: 727719 [PubMed - indexed for MEDLINE]

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[Cerebrospinal toxoplasmosis: detection, clinical course and therapy]

[Article in German]

Kaeser HE, Dietrich R, Kocher R.

With modern techniques (membrane marking by indirect immunofluorescence and identification by morphological criteria) Toxoplasma gondii can be reliably identified in the CSF. Identification of the causative agent confirms the diagnosis of toxoplasmosis of the meninges, the central nervous system and the nerve roots. Toxoplasma encephalomyelitis associated with meningoradiculitis has hitherto only rarely been described. Our own cases afford evidence of the fact that even in the most typical cases of multiple sclerosis this possibility must be considered. Fansidar (a combination of an ultralong-acting sulfonamide with pyrimethamine combined with spiramycine is recommended as the treatment of choice.

Publication Types:
PMID: 335505 [PubMed - indexed for MEDLINE]

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Acute necrotic myelopathy with pulmonary tuberculosis.

Hughes RA, Mair WG.

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PMID: 884483 [PubMed - indexed for MEDLINE]

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Ileal loop ureteroileostomy in patients with neurogenic bladder. Personal experience with 54 patients.

Kambouris AA, Allaben RD, Carpenter WS, Shumaker EJ.

(1) In a six year experience with ileal loops in patients with neurogenic bladder, 49% of the patients were paralyzed, 30% had multiple sclerosis, and 91% had recurrent or persistent urinary tract infection. Reflux, incontinence, retention, and bladder calculi were additional indications for supravesical urinary diversions. (2) All loops were performed in a similar manner, most of them placed retroperitoneally, and a vigorous program of postoperative care was followed. There were no postoperative deaths, and a moderate number of complications occurred in 51.8% of the patients. (3) The participation of the enterostomal therapist is the preparation of the patient and in the immediate and long-term stomal care has been invaluable and is strongly recommended.

PMID: 1251964 [PubMed - indexed for MEDLINE]

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[Problems about retrobulbar neuritis and its present status in Japan (author's transl)]

[Article in Japanese]

Suzuki Y.

Publication Types:
PMID: 1172359 [PubMed - indexed for MEDLINE]

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Meningitis caused by Streptococcus in adults.

Lerner PI.

Meningitis caused by Streptococcus is uncommon in adults. Otitis media, mastoiditis, sinusitis, or trauma has antedated most cases reported in the past. Data on 10 recent cases suggest changes in the current pathogenesis of streptococcal meningitis in adults and emphasize the importance of accurate streptococcal speciation. Endocarditis was present in five cases; trauma played a role in two others. Brain abscess, corticosteroids, alcoholic cirrhosis, and peritonitis secondary to chronic peritoneal dialysis were etiologic factors in five patients. Otitis media, mastoiditis, and sinusitis were conspicuously absent. Streptococcus agalctiae accounted for purulent meningitis in two postmenopausal women. Both strains of group B Streptococcus were bacitracin-sensitive and were thus mislabeled group A. Recognition of Streptococcus bovis spared two patients unnecessary aminoglycoside adminstration. Nine of the 10 patients survived, including a women with prosthetic mitral valve endocarditis and a man with a ruptured brain abscess. Differentiation of these streptococci from Streptococcus pneumoniae was seldon possible on the basis of the spinal fluid gram stain alone.

PMID: 1092775 [PubMed - indexed for MEDLINE]

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[Acute hemorrhagic encephalitis of Hurst. Clinical, electroencephalographic and anatomic presentation of a case from the literature and revue]

[Article in French]

de Crousaz PG, Deruaz JP, Despland PA, Berger JP.

Clinical and electroencephalographic evolution, as well as the neuropathology, are described in a 25 year old man with a Hurst's acute haemorrhagic leucoencephalitis. Lesions, unusually symmetrical, coexists with those, without vascular necrosis nor haemorrhages, of the perivenous encephalomyelitis. The aspecific onset, course and results of complementary investigations appear on reviewing 44 clinical observations in the literature. Histologic examination of affected white matter is the only was to assess the diagnosis. Two features that may have been previously neglected are outlined: the predilection for 20 to 40 years old males, while the adolescent male, the most susceptible to perivenous encephalomyelitis after specific fevers, is not affected by Hurst's disease. Multiple sclerosis or a prodromal meningo-encephalitis, clinically undetected, could be not rare. Therapeutic results of surgical decompression, hyperosmolar substances and massive doses of corticosteroids (3 survivals out of 10 cases diagnosed on biopsy) cannto be evaluated at the present time. By analogy with the simple and the hyperacute forms of EAE, the myelinotoxicity may result from sensitized lymphocytes alone in the perivenous encephalomyelitis, from an association of circulating antibodies and lymphocytes in Hurst's disease. Whether the immunoglobulins enchance the cellular myelinotoxicity or induce an immune complex disease upon a perivenous encephalomyelitis is still to be determined.

Publication Types:
PMID: 1153966 [PubMed - indexed for MEDLINE]

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Pulmonary infections complicating treatment of multiple sclerosis. Occurrence with administration of corticotropin or adrenal steroids.

Sexauer JM, Fekety FR Jr.

PMID: 4361390 [PubMed - indexed for MEDLINE]

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[Modern views on the treatment of multiple sclerosis]

[Article in Polish]

Sieniarski A.

Publication Types:
PMID: 4360561 [PubMed - indexed for MEDLINE]

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Followup on unsterile intermittent self-catheterization.

Lapides J, Diokno AC, Lowe BS, Kalish MD.

PMID: 4810761 [PubMed - indexed for MEDLINE]

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[Therapeutic problems in disseminated encephalomyelitis (multiple sclerosis)]

[Article in German]

Payk TR.

Publication Types:
PMID: 4573496 [PubMed - indexed for MEDLINE]

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Rifampicin and multiple sclerosis.

Rosenkranz HS.

PMID: 4118239 [PubMed - indexed for MEDLINE]

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[Pathology of the cochlear nuclei]

[Article in German]

Pirsig W.

PMID: 4637584 [PubMed - indexed for MEDLINE]

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Subacute demyelinating disease in an adult (diffuse-disseminated sclerosis).

Cancilla PA, Andrews JM, Rose AS.

PMID: 4328371 [PubMed - indexed for MEDLINE]

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[Immunodepressors in ophthalmology]

[Article in French]

Bonnet M.

Publication Types:
PMID: 4356770 [PubMed - indexed for MEDLINE]

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[Diagnostic accuracy in multiple sclerosis]

[Article in German]

Schunk W.

PMID: 5521430 [PubMed - indexed for MEDLINE]

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Rickettsial antibodies in multiple sclerosis.

Field EJ, Chambers M.

PMID: 4983591 [PubMed - indexed for MEDLINE]

PMCID: PMC1700902


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[Devic's syndrome of rheumatic etiology]

[Article in Polish]

Gaj T, Grendus-Tota B.

PMID: 5307948 [PubMed - indexed for MEDLINE]

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Infection of the hip as a complication of advanced neurologic disease.

Freehafer AA, Herndon CH.

PMID: 4893443 [PubMed - indexed for MEDLINE]

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[Vestibular symptoms in neurology]

[Article in German]

von Albert HH.

PMID: 5305742 [PubMed - indexed for MEDLINE]

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[American neurology for Swedish use]

[Article in Swedish]

Gilland O.

PMID: 4315962 [PubMed - indexed for MEDLINE]

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Systemic (cerebral) chromoblastomycosis: diagnosis during life, drug sensitivities, and treatment of a single case.

Summers DS.

PMID: 5690340 [PubMed - indexed for MEDLINE]

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[Contribution to the treatment of pernicious anemia and to the relationship between pernicious anemia and stomach cancer]

[Article in German]

Rall T.

PMID: 4886787 [PubMed - indexed for MEDLINE]

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[Experience with corticoid long-term therapy in multiple sclerosis]

[Article in German]

Muller E, Kostakopoulos M.

PMID: 5584097 [PubMed - indexed for MEDLINE]

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[On a case of neuromyelitis optica]

[Article in Italian]

Orzalesi N, Saba V.

PMID: 5985613 [PubMed - indexed for MEDLINE]

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[Leading symptom: vertigo from the point of view of the internist]

[Article in German]

Schrader A.

PMID: 6013875 [PubMed - indexed for MEDLINE]

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[Therapy of inflammatory diseases of the nervous system]

[Article in German]

Sayk J.

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PMID: 5006314 [PubMed - indexed for MEDLINE]

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CLOSTRIDIAL EMPYEMA.

GOLDBERG NM, RIFKIND D.

PMID: 14272370 [PubMed - indexed for MEDLINE]

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THE DIAGNOSTIC VALUE OF CALORIC TESTS IN OTONEUROLOGY.

GULICK RP, PFALTZ CR.

PMID: 14243728 [PubMed - OLDMEDLINE]

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[RESULTS OF WIDE SPECTRUM ANTIBIOTIC THERAPY IN 30 CHRONIC CASES OF RICKETTSIAL AND NEORICKETTSIAL MULTIPLE SCLEROSIS.]

[Article in French]

LEGAC P, WULLFAUERT F, ARQUIE E, VILLIERS C, RABINOVICI J, MORANGE D, TERRASSONDEFOUGERES C.

PMID: 14184778 [PubMed - indexed for MEDLINE]

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CORTISONE THERAPY IN FASCICULITIS OPTICA.

OKSALA A.

PMID: 14185130 [PubMed - indexed for MEDLINE]

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[Broad-spectrum antibiotic therapy in chronic forms of multiple sclerosis of rickettsial origin.]

[Article in French]

LE GAC P.

PMID: 13928789 [PubMed - indexed for MEDLINE]

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[Determination of properdin and inoculation into the chick embryo of the blood serum in multiple sclerosis. Comparative study of results with cancer and neurologic diseases.]

[Article in Spanish]

DELMAR A, SCHCOLNICOV B, SACERDOTE DE LUSTIG E, YANEZ M, SASKO C.

PMID: 13885222 [PubMed - indexed for MEDLINE]

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[Treatment of multiple sclerosis with rimifon.]

[Article in Bulgarian]

GOSPODINOVA-MAKEDONSKA D, CHUKOVA-BOZHINOVA T.

PMID: 13615662 [PubMed - indexed for MEDLINE]

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[Trials of therapy of multiple sclerosis based on pathogenetic aspects.]

[Article in German]

TSCHABITSCHER H, SLUGA-GASSER E, SCHINKO H.

PMID: 13604315 [PubMed - indexed for MEDLINE]

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FEUERLEIN W.

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FLORIS V, MOROCUTTI C, DELLA ROCCA G.

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BERLIN L, KURTZKE JF.

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[No authors listed]

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BAUER H, THIEMANN KJ, WIEDING E.

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JORDAN D.

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ROSS J, WELTE E.

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Isoniazid in disseminated sclerosis.

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[No authors listed]

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