High Dose Pharmaceutical Grade Biotin (MD1003) Accelerates Differentiation of Murine and Grafted Human Oligodendrocyte Progenitor Cells In Vivo.

Accumulating evidences suggest a strong correlation between metabolic changes and neurodegeneration in CNS demyelinating diseases such as multiple sclerosis (MS). Biotin, an essential cofactor for five carboxylases, is expressed by oligodendrocytes and involved in fatty acid synthesis and energy production. The metabolic effect of biotin or high-dose-biotin (MD1003) has been reported on rodent oligodendrocytes in vitro, and in neurodegenerative or demyelinating animal models. However, clinical studies, showed mild or no beneficial effect of MD1003 in amyotrophic lateral sclerosis (ALS) or MS. Here, we took advantage of a mouse model of myelin deficiency to study the effects of MD1003 on the behavior of murine and grafted human oligodendrocytes in vivo. We show that MD1003 increases the number and the differentiation potential of endogenous murine oligodendroglia over time. Moreover, the levels of MD1003 are increased in the plasma and brain of pups born to treated mothers, indicating that MD1003 can pass through the mother's milk. The histological analysis of the grafted animals shows that MD1003 increased proliferation and accelerates differentiation of human oligodendroglia, but without enhancing their myelination potential. These findings provide important insights into the role of MD1003 on murine and human oligodendrocyte maturation/myelination that may explain the mitigated outcome of ALS/MS clinical trials.

Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo.

Remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic or intrinsic regulators in oligodendroglial biology. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient mouse model to compare induced pluripotent stem cell-derived oligodendroglia from MS and healthy donors following engraftment in the developing CNS. We show that the MS-progeny behaves and differentiates into oligodendrocytes to the same extent as controls. They generate equal amounts of myelin, with bona fide nodes of Ranvier, and promote equal restoration of their host slow conduction. MS-progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glia. Thus, MS oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia/glia-glia connections, reinforcing the view that the MS oligodendrocyte differentiation block is not from major intrinsic oligodendroglial deficits.

5-HTT independent effects of fluoxetine on neuroplasticity.

Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB.

Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression.

Depression is a major health problem with a high prevalence and a heavy socioeconomic burden in western societies. It is associated with atrophy and impaired functioning of cortico-limbic regions involved in mood and emotion regulation. It has been suggested that alterations in neurotrophins underlie impaired neuroplasticity, which may be causally related to the development and course of depression. Accordingly, mounting evidence suggests that antidepressant treatment may exert its beneficial effects by enhancing trophic signaling on neuronal and synaptic plasticity. However, current antidepressants still show a delayed onset of action, as well as lack of efficacy. Hence, a deeper understanding of the molecular and cellular mechanisms involved in the pathophysiology of depression, as well as in the action of antidepressants, might provide further insight to drive the development of novel fast-acting and more effective therapies. Here, we summarize the current literature on the involvement of neurotrophic factors in the pathophysiology and treatment of depression. Further, we advocate that future development of antidepressants should be based on the neurotrophin theory.

Fistula response to methotrexate in Crohn's disease: a case series.

BACKGROUND: Controlled trials have demonstrated the efficacy of methotrexate in the induction and maintenance of remission in luminal Crohn's disease; however, its effect on fistulizing disease is unknown. AIM: To describe the response to methotrexate therapy in a series of patients with fistulizing Crohn's disease. METHODS: A retrospective chart review was conducted of all patients with Crohn's disease receiving methotrexate in one practice. The response of patients with fistulizing and luminal disease was assessed using clinical and laboratory criteria. Fistula response was categorized as either complete or partial closure. RESULTS: Thirty-seven courses of methotrexate therapy were given to 33 patients with luminal and/or fistulizing Crohn's disease. In 16 patients with fistulas, four (25%) had complete closure, five (31%) had partial closure and all had failed or were intolerant to 6-mercaptopurine therapy. Overall, response to methotrexate was seen in 23 of 37 (62%) treatment courses in patients with luminal and/or fistulizing Crohn's disease. Two of the 33 patients (6%) had a significant adverse event. CONCLUSIONS: In this case series, 56% of patients with Crohn's fistulas on methotrexate showed a complete or partial response to therapy. Further studies are needed to confirm the role of methotrexate alone, and in combination with other therapies, for the treatment of fistulizing Crohn's disease.

Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum complicates inflammatory bowel disease in 2-3% of patients and often fails to respond to antibiotics, steroids, surgical debridement or even colectomy. METHODS: We performed a retrospective chart analysis of 11 consecutive steroid-refractory pyoderma patients (5 ulcerative colitis, 6 Crohn's disease) referred to our practice and then treated with intravenous cyclosporine. Pyoderma gangrenosum was present on the extremities in 10 patients, the face in 2, and stomas in 21. At initiation of intravenous cyclosporine, bowel activity was moderate in 3 patients, mild in 4, and inactive in 4. All patients received intravenous cyclosporine at a dose of 4 mg/kg/d for 7-22 days. They were discharged on oral cyclosporine at a dose of 4-7 mg/kg/d. RESULTS: All 11 patients had closure of their pyoderma with a mean time to response of 4.5 days and a mean time to closure of 1.4 months. All seven patients with bowel activity went into remission. Nine patients were able to discontinue steroids, and nine were maintained on 6-mercaptopurine or azathioprine. One patient who could not tolerate 6-mercaptopurine had a recurrence of pyoderma. No patient experienced significant toxicity. CONCLUSION: Intravenous cyclosporine is the treatment of choice for pyoderma gangrenosum refractory to steroids and 6-mercaptopurine should be used as maintenance therapy.

Crohn's disease and ulcerative colitis: when is a diagnostic procedure necessary?

In the diagnosis and differential diagnosis of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis, a simple but careful history and physical examination remain the keys. Routine screening laboratory tests are much less sensitive and almost totally non-specific, although microbiologic studies are often essential in order to rule out specific intestinal infections. The characteristics of the patient's history of abdominal pain and bowel pattern, and the physical findings of abdominal mass and perianal lesions, are most helpful in distinguishing Crohn's disease from ulcerative colitis. Similarly, clinical features, physical signs, and endoscopic appearances can tell us most of what we need to know about the severity of the disease. More advanced laboratory, radiologic, and histologic testing can clarify the nature and extent of the disease and identify complications, but we still treat patients, not blood tests or X-rays. With respect to treatment of inflammatory bowel disease, the mainstays are aminosalicylates, corticosteroids, immunomodulators, and antibiotics. Acute induction of remission is rarely difficult, but the greatest challenge in management is maintenance of long-term steroid-free remission throughout the entire course of these life-long diseases.

The medical management of acute and chronic ulcerative colitis.

The current medical therapy of severe, acute ulcerative colitis is reviewed. The role and of 5-ASA, corticosteroids, immunosuppressive agents and surgery are outlined. A systematic approach using a combination of these agents to induce a remission is presented. A model for long term maintenance therapy following a response in the acute setting to avoid steroid dependence and surgery is proposed. The role of surgery in ulcerative colitis should be limited to patients who either fail medical therapy or in whom dysplasia or cancer have been detected. A realistic assessment of the potential pitfalls of surgical intervention, such as ileal pouch-anal anastomosis, is discussed.

The modern medical management of acute, severe ulcerative colitis.

The management of patients with acute, severe ulcerative colitis requires careful in-hospital assessment of the patient and the coordinated treatment of a team of experienced gastroenterologists and surgeons. Complete understanding of the potential complications and their management, especially toxic megacolon, is essential. We review the current medical arsenal and advocate a standardized approach to management that includes continuous, high dose intravenous hydrocortisone, more aggressive use of topical steroids as well as feeding the patients and continuing (but not initiating) oral 5-aminosalicylic acid (5-ASA) agents. For those patients whose disease proves refractory to intravenous steroids, intravenous cyclosporin (with an acute response rate of 82%) is an essential component in the medical management of these patients. Antibiotics should be used only when specifically indicated. Total parenteral nutrition has not been shown to be helpful in the acute setting. Air contrast barium enema and colonoscopy have been used to predict response but may be dangerous diagnostic modalities in these acutely ill patients and are no better than good clinical judgement. We review and advocate long-term management of acute response using 6-mercaptopurine or azathioprine. The surgical experience and the postoperative complications of the ileal pouch anal anastomosis, which include acute pouchitis in 50-60%, chronic pouchitis in 5-10% and recent reports of dysplasia among patients with chronic pouchitis, must be considered before colectomy is advised. Over 80% of patients with acute severe colitis can be spared colectomy using our current arsenal of medical therapies.

How effective is current medical therapy for severe ulcerative and Crohn's colitis? An analytic review of selected trials.

To determine the efficacy of current medical therapies in the treatment of severe ulcerative and Crohn's colitis, we conducted a MEDLINE computer-assisted literature search using the terms "severe ulcerative colitis," "severe Crohn's colitis," "drugs," and "therapy." Studies were compared and then selected based, in decreasing order of importance, on the use of standard criteria to assess disease severity, uniform entrance criteria with prospective drug protocols using defined end points; prospective placebo-controlled trials; and retrospective studies. We then conducted an analytic review of those studies selected. For severe ulcerative colitis, we identified seven studies comprising 319 treatment episodes in 306 patients. Clinical remission was achieved on average in 62% of subjects (range, 43-80%); 38% (25-57%) came to prompt colectomy. Remission was maintained in 38-71% of patients achieving success in the acute phase. For severe Crohn's colitis, we identified five studies comprising 68 patients. Clinical remission was achieved on average in 65% of patients (range, 55-94%). Remission was maintained in 54-69% of those achieving success in the acute phase. Current medical therapies have improved the outlook for severe ulcerative colitis; however, physicians cannot predict response to therapy based upon individual's clinical features or previous presentations. Current medical therapy for severe Crohn's colitis appears to spare many patients early colectomy, but the current dearth of clinical trials postpones any further advances in the medical management of these patients.

Rarity of fistulas in Crohn's disease of the jejunum.

: To compare the fistulizing tendency of Crohn's disease of the jejunum versus the ileum, we reviewed the records of 1,920 patients with Crohn's disease admitted to the Mount Sinai Hospital between 1960 and 1994. Fifty-eight of the cases (3%) had jejunal involvement. Of these 58 patients, six (10%) had fistulas originating from the jejunum. Four of the cases of jejunal fistulas came from a subgroup of 41 patients who had both jejunum and distal ileum involvement (10%); by contrast, there were 12 cases of ileal fistulas in the same subgroup (29%, p = 0.05). As another measure of the relative rarity of jejunal versus ileal fistulization, there were 252 cases of ileal fistulas in our overall series among 723 patients with distal ileal Crohn's disease (34%), compared with the 10% (six of 60) incidence of jejunal fistulization (p = 0.001). Only 50% (316) of our cases of jejunal fistulization were spontaneous, compared with 86% of a random sample (43 of 50) from our 252 cases of fistulas with ileitis. The development of jejunal fistulas did not appear to depend upon the presence of stricturing; they were nearly as common among nonstricturing cases (two of 27, 7%) as among stricturing cases (four of 31, 13%; p = NS). The inherent proclivity of Crohn's disease to fistulize thus appears to increase with a progressively distal location in the gastrointestinal tract.