The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future

A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G).

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies

Utility of routine versus selective upper gastrointestinal series to detect anastomotic leaks after laparoscopic gastric bypass

BACKGROUND: In up to 4% of laparoscopic Roux-en-Y gastric bypass (LRYGB) procedures, anastomotic leaks occur. Early detection of gastrointestinal leakage is important for successful treatment. Consequently, many centers advocate routine postoperative upper gastrointestinal (UGI) series. The aim of this study was to determine the utility of this practice after LRYGB. METHODS: Eight hundred four consecutive patients undergoing LRYGB from June 2000 to April 2010 were analyzed prospectively. The first 382 patients received routine UGI series between the third and fifth postoperative days (group A). Thereafter, the test was only performed when clinical findings (tachycardia, fever, and drainage content) were suspicious for a leak of the gastrointestinal anastomosis (group B; n = 422). RESULTS: Overall, nine of 804 (1.1%) patients suffered from leaks at the gastroenterostomy. In group A, four of 382 (1%) patients had a leak, but only two were detected by the routine UGI series. This corresponds to a sensitivity of 50%. In group B, the sensitivity was higher with 80%. Specificities were comparable with 97% and 91%, respectively. Routine UGI series cost only 1.6% of the overall costs of a non-complicated gastric bypass procedure. With this leak rate and sensitivity, US $86,800 would have to be spent on 200 routine UGI series to find one leak which is not justified. CONCLUSIONS: This study shows that routine UGI series have a low sensitivity for the detection of anastomotic leaks after LRYGB. In most cases, the diagnosis is initiated by clinical findings. Therefore, routine upper gastrointestinal series are of limited value for the diagnosis of a leak