Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith–Wiedemann Syndrome: Clinical Spectrum and Functional Characterization

Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.     

The Uncompetitive N-methyl-D-Aspartate Antagonist Memantine Reduces Binge-Like Eating,Food-Seeking Behavior,and Compulsive Eating: Role of the Nucleus Accumbens Shell

Binge-eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. The role of the glutamatergic N-methyl-D-aspartate (NMDA) receptor system in hedonic feeding is poorly understood. The aim of this study was to characterize the effects of the uncompetitive NMDA receptor antagonist memantine on palatable food-induced behavioral adaptations using a rat model, which mimics the characteristic symptomatology observed in binge-eating disorder. For this purpose, we allowed male Wistar rats to respond to obtain a highly palatable, sugary diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day, under a fixed-ratio 1 (FR1) schedule of reinforcement. Upon stabilization of food responding, we tested the effects of memantine on the Chow and Palatable food groups'' intake. Then, we tested the effects of memantine on food-seeking behavior, under a second-order schedule of reinforcement. Furthermore, we investigated the effects of memantine on the intake of food when it was offered in an aversive, bright compartment of a light/dark conflict test. Finally, we evaluated the effects of memantine on FR1 responding for food, when microinfused into the nucleus accumbens (NAcc) shell or core. Memantine dose-dependently decreased binge-like eating and fully blocked food-seeking behavior and compulsive eating, selectively in the Palatable food group. The drug treatment did not affect performance of the control Chow food group. Finally, intra-NAcc shell, but not core, microinfusion of memantine decreased binge-like eating. Together, these findings substantiate a role of memantine as a potential pharmacological treatment for binge-eating disorder.     

Conservative surgery for early cancer of the distal rectum

From 1967 through 1988, 36 patients underwent local excision of a distal rectal cancer as an initial operative procedure with curative intent. A diagnostic, preoperative protocol was performed to assess the histologic grade of the tumor, the depth of penetration in the rectal wall, and the presence of positive lymph nodes or distant metastases. All patients had a transanal local excision performed under general anesthesia. If preoperative criteria were not confirmed by histopathologic specimen examination, a major operation was advised. To increase the chance of local control, external adjuvant radiotherapy was used in T2 cancers. Postoperative mortality was 0 percent. The postoperative complication rate was 9.3 percent. The observed local recurrence rate was 3 percent, and the rectal cancer-specific death rate was 6 percent. We compared these results with those obtained in 70 concomitant patients operated on by us employing a traditional resection for Dukes' A rectal cancer. There are no statistically significant differences between groups. In light of our findings, a policy of curative local excision is justified in accurately selected cases of distal rectal cancer.     

Web-Based STAR E-Learning Course Increases Empathy and Understanding in Dementia Caregivers: Results from a Randomized Controlled Trial in the Netherlands and the United Kingdom

BackgroundThe doubling of the number of people with dementia in the coming decades coupled with the rapid decline in the working population in our graying society is expected to result in a large decrease in the number of professionals available to provide care to people with dementia. As a result, care will be supplied increasingly by untrained informal caregivers and volunteers. To promote effective care and avoid overburdening of untrained and trained caregivers, they must become properly skilled. To this end, the European Skills Training and Reskilling (STAR) project, which comprised experts from the domains of education, technology, and dementia care from 6 countries (the Netherlands, Sweden, Italy, Malta, Romania, and the United Kingdom), worked together to create and evaluate a multilingual e-learning tool. The STAR training portal provides dementia care training both for informal and formal caregivers.ObjectiveThe objective of the current study was to evaluate the user friendliness, usefulness, and impact of STAR with informal caregivers, volunteers, and professional caregivers.MethodsFor 2 to 4 months, the experimental group had access to the STAR training portal, a Web-based portal consisting of 8 modules, 2 of which had a basic level and 6 additional modules at intermediate and advanced levels. The experimental group also had access to online peer and expert communities for support and information exchange. The control group received free access to STAR after the research had ended. The STAR training portal was evaluated in a randomized controlled trial among informal caregivers and volunteers in addition to professional caregivers (N=142) in the Netherlands and the United Kingdom. Assessments were performed with self-assessed, online, standardized questionnaires at baseline and after 2 to 4 months. Primary outcome measures were user friendliness, usefulness, and impact of STAR on knowledge, attitudes, and approaches of caregivers regarding dementia. Secondary outcome measures were empathy, quality of life, burden, and caregivers’ sense of competence.ResultsSTAR was rated positively by all user groups on both usefulness and user friendliness. Significant effects were found on a person-centered care approach and on the total score on positive attitudes to dementia; both the experimental and the control group increased in score. Regarding empathy, significant improvements were found in the STAR training group on distress, empathic concern, and taking the perspective of the person with dementia. In the experimental group, however, there was a significant reduction in self-reported sense of competence.ConclusionsThe STAR training portal is a useful and user-friendly e-learning method, which has demonstrated its ability to provide significant positive effects on caregiver attitudes and empathy.     

Ratio of hepatic arterial flow to recipient body weight predicts biliary complications after deceased donor liver transplantation

ObjectivesAdequate hepatic arterial (HA) flow to the bile duct is essential in liver transplantation. This study was conducted to determine if the ratio of directly measured HA flow to weight is related to the occurrence of biliary complications after deceased donor liver transplantation.MethodsA retrospective review of 2684 liver transplants carried out over a 25-year period was performed using data sourced from a prospectively maintained database. Rates of biliary complications (biliary leaks, anastomotic and non-anastomotic strictures) were compared between two groups of patients with HA flow by body weight of, respectively, <5 ml/min/kg (n = 884) and ≥5 ml/min/kg (n = 1800).ResultsPatients with a lower ratio of HA flow to weight had higher body weight (92 kg versus 76 kg; P < 0.001) and lower HA flow (350 ml/min versus 550 ml/min; P < 0.001). A lower ratio of HA flow to weight was associated with higher rates of biliary complications at 2 months, 6 months and 12 months (19.8%, 28.2% and 31.9% versus 14.8%, 22.4% and 25.8%, respectively; P < 0.001).ConclusionsA ratio of HA flow to weight of < 5 ml/min/kg is associated with higher rates of biliary complications. This ratio may be a useful parameter for application in the prevention and early detection of biliary complications.     

Surgical treatment for Zenker’s diverticulum: comparison between diverticulectomy and diverticulopexy

Background

The ideal surgical technique for symptomatic Zenker’s diverticulum has not been identified yet. Endoscopic treatment, although frequently performed, has not replaced the open cricopharyngeal myotomy, which is still deemed the standard therapy by many dedicated physicians. The management of the diverticular sac after myotomy is still a matter of debate. The aim of this study is to compare the results of diverticulectomy and diverticulopexy after cricopharyngeal myotomy, in homogeneous groups of patients.

Methods

Thirty-seven patients were treated for Zenker’s diverticulum at the same university medical school, but in two different units, with open cricopharyngeal myotomy, associated with diverticulectomy in 17 patients and with diverticulopexy in the remaining. No clinical criteria influenced the different choice of treatment of the diverticular pouch, but only the surgeon’s preference. Clinical data, diverticulum size, postoperative course, and complications were analyzed. Patients were followed up for median duration of 37 months (range 12–113 months) through contrast swallow study and clinical evaluation, aided by a specifically conceived questionnaire. Records were analyzed by Mann–Whitney–Wilcoxon test and Fisher’s exact test.

Results

Homogeneous comparative values for sex, age, diverticulum size, and symptoms were found in the two groups. Statistical analysis indicated that diverticulopexy, as compared with diverticulectomy, allowed reduced postoperative complications and slightly improved long-term swallowing.

Conclusions

Diverticulopexy is feasible also in large Zenker’s diverticula and can achieve equivalent or even better results than diverticulectomy with a smoother postoperative course.