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.     

Laparoscopic versus open colonic resection for complicated diverticular disease in the emergency setting: a safe choice? A retrospective comparative cohort study

Background

We conducted a retrospective cohort study to compare the outcomes of laparoscopic colon resection (LCR) with open colon resection (OCR) for complicated diverticular disease (CDD) during emergent hospital admission.

Methods

Charts from all patients undergoing colon resection for CDD during emergent hospital admission at a single academic institution were reviewed. The primary outcomes were overall 30-day postoperative morbidity and mortality.

Results

From 2000 to 2010, 125 cases were retrieved (49 LCR and 86 OCR). Conversion rate was 5.1%. Overall morbidity significantly decreased with laparoscopic surgery compared with OCR. No mortality occurred with LCR. Prolonged ileus was less frequent (12.8% vs 32.6%; P = .02), time to oral intake shorter (3 vs 6 days; P < .01), and LOS shorter (5 vs 8 days; P = .05) for LCR.

Conclusions

In our series, in the patients selected, LCR for CDD during emergent hospital admission appears to be a safe procedure associated with decreased morbidity, time to oral intake, and LOS compared with OCR.     

Effects of long-term negative energy balance with exercise on plasma lipid and lipoprotein levels in identical twins

Plasma lipid and lipoprotein concentrations were measured before and after a 58,000kcal (244MJ) negative energy balance protocol induced entirely by supervised endurance exercise over a 93-day period in seven pairs of young sedentary and healthy male monozygotic twins. The negative energy balance induced significant changes in all measures of body weight and composition except fat free mass. The mean weight loss was 5.0+/-0.6kg, and it was entirely accounted for by the loss of body fat. In response to the program, improvement in the plasma lipid profile was seen including decreases in plasma total (P=0.028) and low density lipoprotein (LDL) (P=0.004) cholesterol; total cholesterol/high density lipoprotein (HDL) cholesterol ratio (P=0.002); and HDL apolipoprotein A-I concentration (P=0.062). Statistically significant within-pair resemblance was found for the changes in total and very low density lipoprotein (VLDL) cholesterol; total, VLDL and LDL triglycerides, and total, VLDL and LDL apolipoprotein B. The findings suggest that favorable changes in the lipid profile can be obtained through chronic negative energy balance achieved by clamping daily energy intake and adding daily moderate intensity exercise even in persons with relatively normal lipid levels at baseline. Furthermore, within-pair resemblance among twin brothers strongly suggests that genetic differences partially account for the variation in the response of lipids and lipoproteins to the negative energy balance protocol.     

Evaluation of erythropoiesis in long-term hamster bone marrow suspension cultures: absence of a requirement for adherent monolayer cells

In long-term hamster bone marrow cultures, proliferation and differentiation of hemopoietic stem cells occurs for several months without need for hydrocortisone or adherent stromal elements, which are requirements for bone marrow growth in all other species studied. Only the most primitive erythroid progenitors (BFU-E) are produced in the cultures. Following treatment of the cells with erythropoietin, these progenitor cells undergo differentiation into mature hemoglobinized red blood cells. Concomitant addition of erythropoietin (Epo) and prostaglandin-E1 (PGE1) results in the production of large numbers of maturing red blood cells. In cultures stimulated with Epo and PGE1, as many as 70% of the cells are benzidine-positive, while Epo alone stimulated as many as 45% of the cells to become erythroid. Epo and PGE1 do not have any apparent deleterious effect on the continuous hemopoiesis occurring in these cultures. Under identical conditions, syngeneic adherent cell cultures do not produce any erythroid elements. The development of mature red blood cells from primitive erythroid precursors occurs in the presence of Epo alone and without any apparent need for adherent stromal elements. These cultures provide a useful in vitro model for dissecting the positive and negative signals that regulate erythropoiesis.     

Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody

Antigenic modulation is one of many factors determining the effectiveness of monoclonal antibody (MoAb)-mediated therapy. To select the isotype of a CD19 MoAb most suitable for radioimmunotherapy of patients with B-cell malignancies, we studied the influence of MoAb isotype on modulation, after binding of the MoAb to different cell-line cells. The CD19-IgG1 MoAb was found to induce modulation of CD19 antigens on Daudi cell line cells more rapidly than did its IgG2a switch variant. We provide evidence that this difference in modulation rate is caused by the expression of Fc gamma receptor II (Fc gamma RII) on these cells. Experiments aimed at elucidating the mechanism of Fc gamma RII involvement in modulation induction by CD19-IgG1 showed that Fc gamma RII did not comodulate with CD19 MoAbs. However, cocrosslinking of CD19 and Fc gamma RII with CD19-IgG1 MoAb resulted in enhanced calcium mobilization in Daudi cells. This increased signal induction accompanies the enhanced capping and subsequent modulation of CD19 antigens. Because Fc gamma RII is expressed in varying densities on malignant B cells in all differentiation stages, our results have implications for the MoAb isotype most suitable for use in MoAb-based therapy of patients with B-cell malignancies.     

The clinical results of the Turnbull–Cutait delayed coloanal anastomosis: a systematic review

Turnbull and Cutait described abdominoperineal pull-through followed by delayed coloanal anastomosis (DCA) in 1961. DCA could reduce anastomotic leaks, pelvic morbidity and use of stomas. Strong evidence about its clinical benefits is still lacking. This systematic review examined the clinical outcomes of DCA for the treatment of malignant or benign colorectal conditions. A systematic search of electronic medical databases was conducted. Two independent reviewers selected studies, extracted data and assessed risk of bias. The primary outcome was pelvic morbidity (anastomotic leak, pelvic abscess or sepsis, use of stoma). Fecal continence and survival data were also analyzed. From 1,251 citations, we included seven observational studies including 1,124 patients. All included studies were considered at high risk of bias. Two studies comparing DCA with immediate anastomosis reported a significant decrease in anastomotic leak, and pelvic abscess or sepsis. Low rates of pelvic morbidity were reported in the other five studies: anastomotic leak 0–7 %, pelvic abscess 0–11.8 % and pelvic sepsis 6.8–10 %. Rates of permanent stoma after DCA were low in six studies (1–6 %), with one study reporting an incidence of 25 %. Fecal continence was reported as satisfying in all studies. No differences were observed in a comparative setting. Survival data were reported in four studies. Clinical heterogeneity and methodological issues precluded meta-analysis. Based on retrospective evidence, DCA offers a low rate of anastomotic leak, pelvic morbidity and use of stoma, with reasonable fecal continence. Results are encouraging, but prospective studies are needed for comparison with standard of care.     

Prevalence,Awareness, and Management of CKD and Cardiovascular Risk Factors in Publicly Funded Health Care

Background and objectives

It is uncertain how many patients with CKD and cardiovascular risk factors in publicly funded universal health care systems are aware of their disease and how to achieve their treatment targets.

Design, setting, participants, & measurements

The CARTaGENE study evaluated BP, lipid, and diabetes profiles as well as corresponding treatments in 20,004 random individuals between 40 and 69 years of age. Participants had free access to health care and were recruited from four regions within the province of Quebec, Canada in 2009 and 2010.

Results

CKD (Chronic Kidney Disease Epidemiology Collaboration equation; <60 ml/min per 1.73 m²) was present in 4.0% of the respondents, and hypertension, diabetes, and hypercholesterolemia were reported by 25%, 7.4%, and 28% of participants, respectively. Self-awareness was low: 8% for CKD, 73% for diabetes, and 45% for hypercholesterolemia. Overall, 31% of patients with hypertension did not meet BP goals, and many received fewer antihypertensive drugs than appropriately controlled individuals; 41% of patients with diabetes failed to meet treatment targets. Among those patients with a moderate or high Framingham risk score, 53% of patients had LDL levels above the recommended levels, and many patients were not receiving a statin. Physician checkups were not associated with greater awareness but did increase the achievement of targets.

Conclusion

In this population with access to publicly funded health care, CKD and cardiovascular risk factors are common, and self-awareness of these conditions is low. Recommended targets were frequently not achieved, and treatments were less intensive in those patients who failed to reach goals. New strategies to enhance public awareness and reach guideline targets should be developed.     

Longer sleep duration associates with lower adiposity gain in adult short sleepers

The objective of this longitudinal, observational study was to verify whether a favorable change in sleep duration over 6 years could impact objective indicators of adiposity in adults aged 18-64 years. Short-duration sleepers (≤6?h per day; n=43) at baseline were divided into two groups: (i) those who increased their sleep duration to a 'healthy' length of 7-8?h per day at year 6 (mean increase: 1.52±0.66?h per day; n=23); and (ii) those who maintained their short sleep duration habits (mean change: -0.11±0.38?h per day; n=20). Adult individuals who reported sleeping 7-8?h per day at both baseline and year 6 (n=173) were used as a control group. Change in adiposity indicators for each sleep-duration group was compared by analysis of covariance. We observed that the two short-sleep-duration groups had similar baseline characteristics. However, short-duration sleepers who maintained their short sleep duration experienced a greater increase in body mass index (BMI) (difference: 1.1±0.36?kg?m(-2), P<0.05) and fat mass (difference: 2.4±0.64?kg, P<0.05) over the 6-year follow-up period than short-duration sleepers who increased their sleep duration, even after adjustment for relevant covariates. We did not observe any significant difference in adiposity changes between the control group and short-duration sleepers who increased their sleep duration. This study suggests for the first time that shifting sleep duration from a short to a healthier length is associated with an attenuation of fat mass gain.