Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease

The prior diagnosis of fatal astrocytoma in a 60-year-old man with Crohn's disease treated with natalizumab, a monoclonal antibody against alpha4 integrins, was reclassified as JC virus-related progressive multifocal leukoencephalopathy (PML). Analysis of frozen serum samples showed that JC virus DNA had appeared in the serum three months after the initiation of open-label natalizumab monotherapy and two months before the appearance of symptomatic PML. There was staining of the brain lesion for polyomavirus. This case report, along with two others, suggests that anti-alpha4-integrin therapy can result in JC virus-induced PML.     

Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled trial

BACKGROUND & AIMS: Crohn's disease almost inevitably recurs after ileocolonic resection, and effective prophylactic therapy has not been identified. We investigated the efficacy and safety of ornidazole, a nitroimidazole antibiotic, for the prevention of clinical recurrence of Crohn's disease after curative ileocolonic resection in a placebo-controlled double-blind clinical trial. METHODS: Eighty patients were randomized to ornidazole 1 g/day or placebo started within 1 week of resection and continued for 1 year. The primary end point was the proportion of patients with clinical recurrence at 1 year. Secondary end points were endoscopic recurrence at 3 months and 12 months after resection. RESULTS: Two patients in the ornidazole group withdrew consent and were not dosed. Ornidazole significantly reduced the clinical recurrence rate at 1 year from 15 of 40 (37.5%) patients in the placebo group to 3 of 38 (7.9%) patients in the ornidazole group (Fisher exact test, 8.03; P = .0046; odds ratio, 0.14; 95% confidence interval, 0.037-0.546). Ornidazole reduced endoscopic recurrence at 12 months from 26 of 33 (79%) in the placebo group to 15 of 28 (53.6%) in the ornidazole group (chi2 , 4.37; P = .037; odds ratio, 0.31; 95% confidence interval, 0.10-0.94). Endoscopic recurrence at 3 and 12 months predicted clinical recurrence. Significantly more patients in the ornidazole group dropped out from the study because of side effects (P = .041). CONCLUSIONS: Ornidazole 1 g/day is effective for the prevention of recurrence of Crohn's disease after ileocolonic resection.     

Male individualization using 12 rapidly mutating Y-STRs in Araein ethnic group and shared paternal lineage of Pakistani population

International Journal of Legal Medicine - A multiplex assay has been developed with newly designed primer sets comprising high mutation rate 12 RM Y-STR markers (DYS570, DYF399S1, DYS547, DYS612,...     

Cell complementation using Genebridge 4 human:rodent hybrids for physical mapping of novel mitochondrial respiratory chain deficiency genes

The mapping and identification of respiratory chain deficiency genes is particularly tedious owing to the large number of genes encoding catalytic subunits and involved in respiratory chain (RC) assembly and maintenance. We have developed a functional complementation approach by: (i) growing the patient's fibroblasts in a highly selective medium; and (ii) transferring human chromosome fragments into RC-deficient fibroblasts by microcell-mediated transfer. In the absence of carbohydrates in the culture medium, the deficient cells rapidly disappeared unless they were rescued by a chromosome fragment carrying the disease gene. Microcells prepared from human:rodent Genebridge 4 panel of whole genome radiation hybrids were fused with fibroblast strains of two patients with complex II or I+IV deficiency and allowed to map the disease-causing genes to small intervals (4 and 12 Mb) on chromosomes 12p13 and 7p21, respectively. These intervals are similar to that obtained by genetic linkage analyses in large informative families. The recovery of normal RC enzyme activity in deficient skin fibroblasts supported the relevance of the transferred chromosome fragment in the disease. This approach makes the physical mapping of the disease genes feasible in some sporadic cases of RC deficiency.     

Evaluation of the Inflammatory Response to Two Different Intensities of Exercise in Individuals with Heart Failure

The aim of this study is to compare the response of interleukin-6 (IL-6) and soluble tumor necrosis factor alpha receptor 1 (s-TNFr1) to two submaximal intensities of exercise in individuals with heart failure (HF). Thirty-two HF individuals aged 45.53 ± 9.41 years, classes II and III of the New York Heart Association (NYHA) classification underwent two sessions of exercise at low and moderate intensities with blood analysis at baseline, exercise and after exercise. The differences were evaluated by Friedman test and factorial ANOVA. Alpha = 5% was considered. No difference in IL-6 was detected for low intensity. At moderate intensity, there was a significant increase after exercise. The s-TNFr1 increased in moderate-intensity exercise and went back to baseline levels after it. A session of moderate-intensity exercise is better than low-intensity exercise at promoting positive immediate inflammatory responses in individuals with HF class II and III of the NYHA.     

Insulin- and growth factor-resistance impairs vascular regeneration in diabetes mellitus

Diabetes and pre-diabetes are major contributors to cardiovascular mortality and morbidity. Insulin resistance is a key pathophysiological determinant of the metabolic and vascular abnormalities noted in these disorders. Ineffective vascular repair is likely to be an important contributor to the development of endothelial dysfunction, and subsequently atherosclerosis, in patients with diabetes. Beyond the systemic effects of the insulin resistant phenotype, including factors such as dysglycaemia and inflammation, cellular insulin resistance is emerging as an important factor in diabetic vascular disease. Disordered signal transduction via the PI3-kinase/Akt and MAP-kinase cascades is a hallmark of cellular insulin resistance, and such changes have been linked with both endothelial dysfunction and impaired angiogenesis. In this review we highlight the importance of insulin resistance to vascular repair and regeneration, discuss important cross-talk between the intracellular signalling of insulin and key pro-angiogenic molecules, and link these concepts to common patterns of vascular disease.     

The primary site of the acrocephalic feature in Apert Syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling

Activation of osteoblastic bone anabolism in the calvarial sutures is considered to be the essential pathologic condition underlying mutant FGFR2-related craniofacial dysostosis. However, early clinical investigations indicated that abnormal cartilage development in the cranial base was rather a primary site of abnormal feature in Apert Syndrome (AS). To examine the significance of cartilaginous growth of the cranial base in AS, we generated a transgenic mouse bearing AS-type mutant Fgfr2IIIc under the control of the Col2a1 promoter-enhancer (Fgfr2IIIc(P253R) mouse). Despite the lacking expression of Fgfr2IIIc(P253R) in osteoblasts, exclusive disruption of chondrocytic differentiation and growth reproduced AS-like acrocephaly accompanied by short anterior cranial base with fusion of the cranial base synchondroses, maxillary hypoplasia and synostosis of the calvarial sutures with no significant abnormalities in the trunk and extremities. Gene expression analyses demonstrated upregulation of p21, Ihh and Mmp-13 accompanied by modest increase in expression of Sox9 and Runx2, indicating acceleration of chondrocytic maturation and hypertrophy in the cranial base of the Fgfr2IIIc(P253R) mice. Furthermore, an acquired affinity and specificity of mutant FGFR2IIIc(P253R) receptor with FGF2 and FGF10 is suggested as a mechanism of activation of FGFR2 signaling selectively in the cranial base. In this report, we strongly suggest that the acrocephalic feature of AS is not alone a result of the coronal suture synostosis, but is a result of the primary disturbance in growth of the cranial base with precocious endochondral ossification.