Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Douleur morale,douleur physique : mécanismes neurobiologiques et traitement

Emotional pain endured by depressed patients often resembles to physical pain. Overlaps between pain and suffering are based on several observations and suggest common pathophysiological mechanisms: Neuroimaging studies have highlighted neural networks common to emotional pain and physical pain in healthy subjects; major depressive disorders often occur in patients with chronic pain, and conversely, painful events often occur in depressed patients; antidepressants, including tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors (SNRIs), are efficient in the treatment of chronic pain, and conversely, certain analgesics are useful in relieving grief. Better understanding of the pathophysiology of emotional pain and its relationship with physical pain could lead to other therapeutic approaches, some of which, such as ketamine, are promising.     

Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.     

Perioperative outcomes after totally robotic gastric bypass: a prospective nonrandomized controlled study

Background

Perioperative short-term outcomes could be improved after totally robotic Roux-en-Y gastric bypass (TR-RYGBP) compared with conventional laparoscopic gastric bypass.

Methods

This is a nonrandomized controlled prospective study (N = 200) to evaluate perioperative short-term outcomes. The primary endpoint was to investigate risk factors for 30-day surgical complications.

Results

Mean total operative time was shorter in patients who underwent TR-RYGBP (130 vs 147 minutes; P < .0001). However, postoperative surgical complications rate (13% vs 1%; P = .001), and mean overall hospital stay (9.3 vs 6.7 days; P < .0001) were higher after TR-RYGBP. By multivariate analysis, robotic surgery (hazard ratio [HR] = 15.1; 95% confidence interval [CI], 2.8 to 280; P = .01), and conversion to laparotomy (HR = 18.8; 95% CI, 1.7 to 250.8; P = .014) were independent risk factors for 30-day surgical complications.

Conclusions

Although robotic gastric bypass reduces mean operative time, TR-RYGBP is associated with an increased postoperative surgical complications rate and longer hospitalization.