Stromal vascular fraction in the treatment of myositis.

Muscle regeneration is a physiological process that converts satellite cells into mature myotubes under the influence of an inflammatory environment progressively replaced by an anti-inflammatory environment, with precise crosstalk between immune and muscular cells. If the succession of these phases is disturbed, the immune system can sometimes become auto-reactive, leading to chronic muscular inflammatory diseases, such as myositis. The triggers of these autoimmune myopathies remain mostly unknown, but the main mechanisms of pathogenesis are partially understood. They involve chronic inflammation, which could be associated with an auto-reactive immune response, and gradually with a decrease in the regenerative capacities of the muscle, leading to its degeneration, fibrosis and vascular architecture deterioration. Immunosuppressive treatments can block the first part of the process, but sometimes muscle remains weakened, or even still deteriorates, due to the exhaustion of its capacities. For patients refractory to immunosuppressive therapies, mesenchymal stem cells have shown interesting effects but their use is limited by their availability. Stromal vascular fraction, which can easily be extracted from adipose tissue, has shown good tolerance and possible therapeutic benefits in several degenerative and autoimmune diseases. However, despite the increasing use of stromal vascular fraction, the therapeutically active components within this heterogeneous cellular product are ill-defined and the mechanisms by which this therapy might be active remain insufficiently understood. We review herein the current knowledge on the mechanisms of action of stromal vascular fraction and hypothesise on how it could potentially respond to some of the unmet treatment needs of refractory myositis.

Recurring acute urticaria and abdominal pain: Consider a diagnosis of alpha-galactose anaphylaxis.

BACKGROUND: Food urticaria is common and generally benign, and it may be of viral or idiopathic aetiology. A food origin of the allergy is frequently sought but rarely found. Mammalian meat anaphylaxis, or alpha-galactose (α-gal) anaphylaxis, is a rare and recently discovered entity. PATIENTS AND METHODS: Herein, we report a case of alpha-galactose (α-gal) anaphylaxis in a 60-year-old woman presenting four episodes of acute urticaria with signs of anaphylaxis occurring a few hours after meals containing mammalian meat (beef meat, pork meat and offal). The diagnosis was confirmed by a positive gelatine prick-test and the presence of α-gal IgE. DISCUSSION: In the event of acute urticaria associated with systemic symptoms, in particular gastrointestinal signs, allergy to α-galactose should be considered.

Assessment of endothelial damage and cardiac injury in a mouse model mimicking thrombotic thrombocytopenic purpura.

Essentials Endothelial injury is thought to be a key event in thrombotic thrombocytopenic purpura (TTP). Endothelial and cardiac damages were assessed in a model of TTP using ADAMTS-13 knockout mice. Damages of cardiac perfusion and function were associated with nitric oxide pathway alteration. Endothelial dysfunction constitutes a critical event in TTP development and cardiac injury. SUMMARY: Background Cardiac alterations represent a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). Endothelial injury remains poorly defined, but seems to be a key initiating event leading to the formation of platelet-rich thrombi in TTP patients. Objectives To assess the changes in endothelial function and the induced cardiac damage in a mouse model of TTP. Patients/methods We used an animal model in which TTP-like symptoms are triggered by injection of 2000 units kg-1 of recombinant von Willebrand factor in ADAMTS-13 knockout mice. Results These mice developed TTP-like symptoms, i.e. severe thrombocytopenia, schistocytosis, and anemia. On day 2, magnetic resonance imaging demonstrated a decrease in left ventricular perfusion associated with alteration of left ventricular ejection fraction, fractional shortening, and cardiac output, suggesting early systolic dysfunction. This was associated with decrease in endothelium-mediated relaxation responses to acetylcholine in mesenteric and coronary arteries, demonstrating severe early endothelial dysfunction. In parallel, we showed decreased cardiac expression of endothelial nitric oxide (NO) synthase and increased expression of antioxidant enzymes, suggesting alteration of the NO pathway. At this time, cardiac immunohistochemistry revealed an increase in the expression of VCAM-1 and E-selectin. Conclusion This study provides evidence that the heart is a sensitive target organ in TTP, and shows, for the first time, strong mesenteric and coronary endothelial dysfunction in an induced-TTP model. The mechanisms incriminated are the occurrence of a pro-oxidant state, and proadhesive and proinflammatory phenotypes. This previously largely unrecognized vascular dysfunction may represent an important contributor to the systemic organ failure occurring in TTP.

Immune-mediated necrotizing myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is a newly identified subgroup of idiopathic inflammatory myopathies. It is defined as a rare and severe disease, with symmetrical and proximal muscle weakness and a characteristic histology. An autoimmune aspect of IMNM is suggested by its association with autoantibodies directed against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the majority of patients. Statin use is strongly associated with anti-HMGCR-positive IMNM. The pathophysiological mechanisms of this disease are still poorly understood, and as a result, no therapeutic strategy has been validated to date. OBJECTIVE: The aim of this article is to provide an overview of the current knowledge about epidemiology, clinical features, and pathophysiology of IMNM, as well as treatment strategies. RESULTS AND CONCLUSION: IMNM is a subject of widespread interest, with quick and meaningful advances being made. In recent years, huge progress has been made in terms of diagnosis and patient management. However, the understanding of pathophysiological mechanisms and treatment strategies still requires further investigation.

Rituximab, a new treatment for difficult-to-treat chronic erythema multiforme major? Five cases.

BACKGROUND: Erythema multiforme major (EMM) is an inflammatory disease affecting skin and mucosae, often triggered by infection with Herpes simplex virus. Some patients have a chronic disease associated with antidesmoplakin autoantibodies, but the pathophysiology remains to be elucidated. First-line treatment is antiviral therapy. With treatment failure or in patients without herpes-triggered disease, thalidomide is effective but has neurological side-effects. Alternatives (dapsone, immunosuppressant agents) are not codified. For many patients, systemic steroids use is chronic. The immunosuppressant drug rituximab (RTX) may be effective. OBJECTIVES: We report five cases of severe chronic EMM treated with rituximab (RTX). METHODS: Five patients with severe chronic EMM for 9-20 years received RTX after failure or side-effects of several treatments, especially antiviral therapy and thalidomide. All had chronic use of steroids. Four patients had antidesmoplakin autoantibodies. RESULTS: Four patients experienced complete or quasi-complete remission of EMM with withdrawal of steroids and one patient partial remission, for 3-11 months. Disease relapsed in all patients, and three received a second cycle of RTX with shorter duration of efficacy. Two patients received a third cycle, one without efficacy. CONCLUSION: The use of RTX for many autoimmune diseases, especially pemphigus, is increasing. Chronic EMM, especially EMM associated to antidesmoplakin autoantibodies, is an inflammatory disease in which the role of B cells is not well understood. However, we report a favourable benefit of RTX treatment for months in five patients with severe disease. RTX could be a therapeutic option in severe, difficult-to-treat EMM.

The importance of EN ISO 15189 accreditation of allergen-specific IgE determination for reliable in vitro allergy diagnosis.

BACKGROUND: Allergen-specific serum immunoglobulin E detection and quantification have become an important step in allergy diagnosis and follow-up. In line with the current trend of laboratory test accreditation to international standards, we set out to design and assess an accreditation procedure for allergen-specific serum IgE. METHODS: Method validation according to the accreditation procedure under the EN ISO 15189 standard was carried out for allergen-specific immunoglobulin E determination using the fluoroimmunoenzymatic method ImmunoCAP(®) (ThermoFisher). Data were produced by 25 hospital laboratories in France. A total of 29 allergen specificities including mixes, extracts, and molecular allergens were assayed. Allergen-specific serum immunoglobulin E concentrations ranged from 0.1 to 100 kUA /l. RESULTS: Repeatability, reproducibility, and accuracy results fulfilled method validation criteria for automated laboratory tests and proved similar irrespective of the allergen specificity, allergen-specific serum immunoglobulin E concentration, or individual laboratory. CONCLUSION: Allergen-specific serum immunoglobulin E determination with the fluoroimmunoenzymatic method ImmunoCAP(®) is a highly repeatable, reproducible, and accurate method which may be considered as a single analyte assay in view of the EN ISO 15189 accreditation procedure.

The HepCar registry: report on a one-year registration program of hepatocellular carcinoma (HCC) in Belgium. What is daily practice in HCC?

INTRODUCTION: Due to a rise in HCV induced liver cirrhosis, hepatocellular carcinoma becomes more prevalent in Western European countries. The HepCar registry is an initiative in which patients with hepatocellular carcinoma, their treatment and follow up are registered. MATERIALS AND METHODS: Belgian physicians were asked to report all new cases of hepatocellular carcinoma which were seen between January 2003 and December 2003. Reporting was done on a voluntary basis. Data reported were: demographic figures, the nature of the underlying liver disease, presentation characteristics of the tumour, laboratory findings and choice of therapy. Every six months, a reminder was sent to determine survival. RESULTS: 131 patients (94 male/37 female) were reported. Mean age was 63 years +/- 13. Underlying liver disease was HCV (n = 54, 41%), HBV (n = 22, 17%), alcoholic liver disease (n = 39, 30%) and miscellaneous (n =16, 12%). Diagnosis of hepatocellular carcinoma was made by surveillance in 47 (36%) patients. After logistic regression, survival was 5 times better for patients inside the Milan criteria (one lesion less than 5 cm in diameter or less than 3 nodules each less than 3 cm in the absence of vascular invasion and metastasis). DISCUSSION: Tumours inside the Milan criteria have a better survival. The majority of the patients have an underlying cirrhosis as background for the development of a HCC.

[Ten years of clinical experience with clozapine about 170 patients]. / Dix ans d'expérience clinique de la clozapine portant sur 170 patients.

The authors describe a clinical trial of 170 patients who received clozapine over a ten year period between September 1989 and September 1999. It is a retrospective study, describing individual responses. Each patient was his own control before and with treatment. The study also compared individuals within the group of patients whose treatment was stopped and those whose treatment was continuing at the time of the study. Data was collected by analysing all patients' records and by direct enquiry of prescribers. Diagnosis was according to DSM IV criteria. Assessment included: socio-epidemiological data (sex, age, marital status and family situation, education, military and professional status, level of benefits and social support); data related to the illness (age of onset, age at first contact with a psychiatrist, diagnosis, level of hospital contact); data concerning prescriptions of drugs (indications, average dose, duration of treatment, side effects, reason for stopping and other drugs taken at the same time); 170 patients were prescribed clozapine: 96 of them were continuing to take clozapine at the time of the study while 74 patients had stopped. The characteristics of the two groups are described. They show the severity of the illnesses concerned: early onset of illness and early psychiatric care, the absence in many patients of a partner or family, their low level of employment, high dependence on social assistance. Concerning diagnostic criteria, the range of diagnoses included mostly paranoid schizophrenia, then unclassified schizophrenia then schizoaffective disorders. The indication of clozapine prescription was in the majority of the cases (87%) an inefficiency of classical neuroleptic therapy. The average dose was 401 mg per day: 388 mg for the group continuing treatment; 417 for the group which had stopped their treatment. For the patients who continued taking clozapine, the average time of treatment was just over 4 years, with a maximum of 110 months. The tolerance of clozapine was good, with 35% not suffering any side effects. Neutropenia was the commonest side effect (4.1% - a higher incidence than previously reported with one case only of agranulocytosis (0.59%). The other adverse effects were in accordance with known data: sedation affected 22.4% of patients; hypersalivation 13.5%; postural hypotension 7.6%; malocclusion 7.6%; weight gain (>5 kg) 7.1%. Treatment was stopped for side effects in 17.1% of patients; for ineffectiveness in 14.7% and 3% of patients died during treatment (their death attributed to clozapine) from seizures, intestinal obstruction or agranulocytosis. Clozapine significantly reduced the need for other associated psychotropic drugs. 25.3% of all patients were on monotherapy when on clozapine compared with 6.5% before (31.2% compared with 3.1% for those patients continuing treatment). The need for supplementary medication to reduce side effects was much less. However 22% of patients taking clozapine at the time of the study are still on an anticholinergic drug. On the basis of the analysis of 5 successive terms of treatment lasting 12 months, we have shown that for each patient: clozapine significantly reduces the length of hospitalisation compared with standard neuroleptics; it allows for out patient management and continuing integration in the community; the critical length of treatment for the group of patients studied with regard to the need for hospitalisation is 18 months. For patients whose treatment with clozapine was stopped, we noted that with the continued input from the team of carers even after clozapine was stopped, patients who had been seriously ill for long period of time continued to improve.

Treatment of acute hepatitis C with interferon alpha-2b: early initiation of treatment is the most effective predictive factor of sustained viral response.

AIM: To evaluate the efficacy of early interferon alpha-2b in non-post-transfusion acute hepatitis C virus: a prospective study with historical comparison. PATIENTS: Group A: 28 patients prospectively treated for acute hepatitis C virus with daily regimen of interferon 5 million units for 2 months. Group B: historical series of 16 patients with untreated acute hepatitis C virus. RESULTS: There was no significant difference between the two groups with regard to gender, age, icterus, alanine aminotransferase, or genotypes. In group B, hepatitis spontaneously resolved in three of 16 (19%) patients (follow-up 1-7 years). In group A, 21 of 25 patients became sustained viral responders (75%; P = 0.0003 vs. group B). Factors include not predictive of sustained viral response: age, gender, sources of infection, presence of icterus, alanine aminotransferase peak, bilirubin peak, incubation period, presence of hepatitis C virus antibodies at presentation, or genotypes. The time from presentation to the start of therapy was, however, significantly shorter in sustained viral responders (43 +/- 31 days) than in relapsers or non-responders (88 +/- 52 days) (P = 0.016). CONCLUSIONS: Early treatment of acute hepatitis C virus with interferon prevents chronicity. A short waiting time from presentation to treatment appears as the most relevant predictive factor for sustained response.

Chronic lymphocytic leukemia with portal hypertension and without liver involvement: a case report underlining the roles of increased spleno-portal blood flow and "protective" sinusoidal vasoconstriction.

We report the case of a 72-year-old woman with well-controlled chronic lymphocytic leukemia (CLL) and splenomegaly who developed portal hypertension with bleeding oesophageal varices in the absence of liver fibrosis or regenerative nodular hyperplasia at surgical wedge liver biopsy. The hepatic venous pressure gradient (HVPG) was elevated and splenectomy resulted in both its normalisation and the regression of oesophageal varices. This case shows the potential for an increased spleno-poral flow to generate severe portal hypertension likely through a "protective" sinusoidal vasoconstriction.

Oesophageal self expanding metal stents. Preliminary report about covered and non-covered types.

OBJECTIVE: The aim of this study was to evaluate the effectiveness and complications rate of covered and non-covered self expanding metal stents in the palliative treatment of oesophageal dysphagia. DESIGN: In this retrospective non-randomized study, we evaluated 11 non-covered and 17 covered stents of different types. RESULTS: Grade of dysphagia and improvement after treatment were similar in both groups, all the seven fistulas were sealed by covered stents. Covered stents seem to be safer regarding the rate of life-threatening complications and reinterventions. In contrast to published studies, bleeding was our major complication with death related in half of these patients. Aorto-Oesophageal fistula was proved by autopsy in two of them. CONCLUSIONS: Covered stents lead to less drawbacks than non-covered ones and seem to be recommended in the palliation of oesophageal dysphagia even in the absence of fistula.

The secretion of prolactin in intact and lutectomized pregnant ewes. Effect of the anti-progesterone steroid RU 486.

To study the role, if any, of luteal factors in the control of prolactin secretion during the last two thirds of pregnancy in the ewe, we examined: a) the effect of RU 486 administration on prolactin secretion on days 97, 112 and 131 of pregnancy in five intact ewes and in five ewes from which the corpus luteum (CL) was removed on day 78 of pregnancy; and b) the secretory patterns of prolactin on days 60, 80, 100 and 120 of pregnancy in five intact ewes and in five ewes from which the CL was removed on day 70 of pregnancy. In a pilot experiment, we showed that daily i.v. injections (from day 91 to day 105 of pregnancy) of RU 486 at a dose of 50 mg caused a marked release of prolactin, without any effect on the secretion of progesterone and progression of pregnancy. In experiment 1, a single i.v. injection of 50 mg of RU 486 resulted in a significant (P < 0.01) increase in plasma prolactin concentrations on any day of pregnancy examined in the intact and lutectomized ewes. The prolactin responses (the maximum concentrations, the time to maximum concentrations and the area under the response curves) were not different between the two groups in any stage of pregnancy examined. In the two groups, spontaneous parturition occurred at term with alive lambs. There was no difference between the two groups in gestation length and lamb birth weight. In experiment 2, we showed that plasma concentrations of prolactin fluctuated in a pulsatile manner during the last two-thirds of pregnancy. The mean prolactin concentrations, the frequency and the amplitude of prolactin pulses were not significantly different between the intact and the lutectomized ewes in any stage of pregnancy examined. In conclusion, these experiments demonstrated that the ovine CL of pregnancy is not involved in the control of prolactin secretion in the ewe. The stimulation of prolactin secretion by the RU 486 is probably due to its anti-progesterone action exerted at the level of the receptor. The placental progesterone plays a central role in the control of prolactin secretion during the last two-thirds of pregnancy.

Endoscopic therapy of Barrett's oesophagus: critical review.

Barrett's oesophagus is known as one of the most important risk factor of oesophageal adenocarcinoma. Because of the increasing incidence of these latter, many endoscopic methods such as argon plasma coagulation, photodynamic therapy or endoscopic mucosal resection are now in evaluation in order to eradicate Barrett's oesophagus or to treat dysplasia and early cancers arising from this metaplasia. The aim of this paper is to comment these techniques and discuss their usefulness.

Mesenterico-left intrahepatic portal vein shunt: original technique to treat symptomatic extrahepatic portal hypertension.

UNLABELLED: MESENTERICO-LEFT INTRAHEPATIC PORTAL VEIN SHUNT: Original technique to treat symptomatic extrahepatic portal hypertension. OBJECTIVE: Revascularization of the intrahepatic portal system as decompressive surgery for chronic extrahepatic portal hypertension. SUMMARY BACKGROUND DATA: In patients with extrahepatic portal hypertension (portal trunk thrombosis in presence of a normal liver), shunt surgery is indicated when patient is bleeding from varices at a site not accessible for the endoscopist. Although surgical portal decompression is an efficient procedure, there is a risk of depriving the liver from the splanchnic venous flow and a risk of developing porto-systemic shunt related side effects. METHOD: A shunt was created between the superior mesenteric vein and the umbilical portion of the left portal vein. This technique allows to bypass the thrombosed portion of the portal vein but avoiding dissection of the cavernoma in the liver hilum and related risk of intraoperative hemorrhage. RESULTS: The procedure was successfully performed in one adult patient considered unshuntable in view of classic surgical procedures and in whom sclerotherapy was unsuccessful. This operation achieved an effective decompression of the splanchnic venous system. CONCLUSION: Rerouting the venous splanchnic flow through the liver was possible. It had the major physiological advantage of restoring the normal hepatic vascularization. It also avoided putting the patient at risk of developing porto-systemic shunt related side effects. This option should be considered when shunt procedures are indicated in patients with extrahepatic portal hypertension.