Meckel–Gruber Syndrome: a population-based study on prevalence,prenatal diagnosis,clinical features,and survival in Europe

Meckel–Gruber Syndrome is a rare autosomal recessive lethal ciliopathy characterized by the triad of cystic renal dysplasia, occipital encephalocele and postaxial polydactyly. We present the largest population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. The study population consisted of 191 cases of MKS identified between January 1990 and December 2011 in 34 European registries. The mean prevalence was 2.6 per 100 000 births in a subset of registries with good ascertainment. The prevalence was stable over time, but regional differences were observed. There were 145 (75.9%) terminations of pregnancy after prenatal diagnosis, 13 (6.8%) fetal deaths, 33 (17.3%) live births. In addition to cystic kidneys (97.7%), encephalocele (83.8%) and polydactyly (87.3%), frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with post mortem examination) and orofacial clefts (31.8%). Various other anomalies were present in 64 (37%) patients. As nowadays most patients are detected very early in pregnancy when liver or kidney changes may not yet be developed or may be difficult to assess, none of the anomalies should be considered obligatory for the diagnosis. Most cases (90.2%) are diagnosed prenatally at 14.3±2.6 (range 11–36) gestational weeks and pregnancies are mainly terminated, reducing the number of LB to one-fifth of the total prevalence rate. Early diagnosis is important for timely counseling of affected couples regarding the option of pregnancy termination and prenatal genetic testing in future pregnancies.     

Hereditary overexpression of adenosine deaminase in erythrocytes: studies in erythroid cell lines and transgenic mice

Overexpression of adenosine deaminase (ADA) in red blood cells is characterized by a marked, tissue-specific increase in levels of structurally normal ADA mRNA and enzymatic activity in the erythrocytes of affected individuals, leading to adenosine triphosphate (ATP) depletion and hemolytic anemia. This autosomal dominant trait is linked to the ADA gene. To investigate the molecular mechanism responsible for this disorder, we examined relative reporter gene activity using constructs containing 10.6 kb of 5' flanking sequence and 12.3 kb of the first intron of the ADA gene from the normal and mutant alleles. No differences in chloramphenicol acetyltransferase (CAT) activity were found in transient transfection experiments using erythroleukemia cell lines. Transgenic mice containing the ADA constructs expressed CAT in the appropriate tissue-specific fashion, with 10(2)- to 10(4)-fold higher activity in the thymus. However, CAT activities in erythrocytes and bone marrow of mice containing high transgene copy numbers did not differ between the normal and mutant alleles. These results indicate that the mutation responsible for ADA overexpression is unlikely to reside in the 5' and promoter regions or in the regulatory regions of the first intron. It is possible that the erythroid-specific overexpression of ADA results from a mutation at some distance from the gene or requires an interaction of a proximal mutation with more distal DNA elements.     

Monoclonal antibody therapy in rheumatoid arthritis

Monoclonal antibodies bind to their targets with high specificity and therefore have excellent potential as therapeutic agents. Biotechnological advances have allowed the production of large quantities of engineered monoclonal antibodies for therapeutic use. Recent research in rheumatoid arthritis has identified important mediators of synovitis. Monoclonal antibodies targeting these have been tested in clinical trials over the last decade. Anti-cytokine therapies, in particular anti-tumour necrosis factor alpha monoclonal antibodies, suppressed inflammation and produced rapid symptomatic improvement. Anti-lymphocyte monoclonal antibodies produced long- lasting disease suppression in animal models of rheumatoid arthritis. The use of depleting anti-lymphocyte monoclonal antibodies in rheumatoid arthritis had been disappointing as they did not penetrate the synovial joint in sufficient quantity to suppress disease without producing severe and protracted peripheral blood lymphopenia. Consequently, their use in rheumatoid arthritis had been abandoned. In contrast, clinical trials of non-depleting anti-CD4 monoclonal antibodies in rheumatoid arthritis showed that they could suppress synovitis. However, it remains unclear whether they could lead to prolonged disease improvement.      

Current Outcomes of Emergency Large Bowel Surgery

Introduction

Emergency large bowel surgery (ELBS) is known to carry an increased risk of morbidity and mortality. Previous studies have reported morbidity and mortality rates up to 14.3%. However, there has not been a recent study to document the outcomes of ELBS following several major changes in surgical training and provision of emergency surgery. The aim of this study was therefore to explore the current outcomes of ELBS.

Methods

A retrospective review was performed of a prospectively maintained database of the clinical records of all patients who had ELBS between 2006 and 2013. Data pertaining to patient demographics, ASA (American Society of Anesthesiologists) grade, diagnosis, surgical procedure performed, grade of operating surgeon and assistant, length of hospital stay, postoperative complications and in-hospital mortality were analysed.

Results

A total of 202 patients underwent ELBS during the study period. The mean patient age was 62 years and the most common cause was colonic carcinoma (n=67, 33%). There were 32 patients (15.8%) who presented with obstruction and 64 (31.7%) had bowel perforation. The overall in-hospital mortality rate was 14.8% (n=30). A consultant surgeon was involved in 187 cases (92.6%) as either first operator, assistant or available in theatre.

Conclusions

ELBS continues to carry a high risk despite several major changes in the provision of emergency surgery. Further developments are needed to improve postoperative outcomes in these patients.     

Feasibility of high-resolution, intravascular ultrasonic imaging catheters

A small-aperture, prototype ultrasonic imaging system, typical of the size necessary to be embedded in a catheter, was developed to evaluate the feasibility of intravascular ultrasonic imaging catheters (UICs). The evaluation included in vitro imaging of postmortem samples of human femoral and iliac arteries with the UIC prototype and a high-resolution magnetic resonance (MR) proton imager. Excellent correlations between results from the UIC images, MR images, and tissue specimens were demonstrated. Although the current prototype is too large to be useful in examination of smaller vessels such as coronary arteries, the signal-to-noise ratio and resolution obtained indicate that imaging with intravascular UICs is feasible and may have significant diagnostic value.     

Spinal Wada test

Various doses of pentobarbital (1.25-20 mg) and lidocaine (2.5-20 mg) were injected selectively into the artery of Adamkiewicz and anterior spinal artery of 11 monkeys. Pentobarbital produced an acute paraplegia; lidocaine caused a transient paraplegia followed by hyper-reflexia and muscular fasciculation. Duration of effect varied from 5 to 60 minutes with both drugs and was dose related. Effects were totally reversible. The use of intraarterially administered barbiturates and lidocaine may be more sensitive than angiography for predicting cord blood supply during arteriography for spinal arteriovenous malformations or embolization of critical vessels, such as the right bronchial artery.     

Lithium stimulation of murine hematopoiesis in liquid culture: an effect mediated by marrow stromal cells

Lithium has previously been observed to stimulate in vitro Dexter culture hemopoiesis with increases in granulocytes, megakaryocytes, and pluripotent stem cells (CFU-S). In the present study, a two-phase murine Dexter culture system was established to study the mechanism of lithium-mediated stem cell stimulation. Different lots of horse sera or fetal calf sera were found to have markedly different effects on Dexter culture growth; given the appropriate sera supplementation, supernatant cells from Dexter cultures established from C57BL/6J mice 3 wk previously were free of stromal-forming capacity, but had stem cells and could grow on 900-950 R irradiated stroma. Conversely, in vitro irradiation (900-950 R) of 3-wk cultures resulted in a stem-cell-free adherent monolayer that could support growth for up to 9 wk in culture. The stroma from Dexter cultures preexposed to lithium chloride (1.0 mmole/liter) for 3 wk, irradiated (900 R), and then refed with 3-wk Dexter supernatant cells has an enhanced capacity to support cell production, CFU-S, and probably granulocyte-macrophage colony-forming cell (GM-CFU-C) production, as compared to stroma not preexposed to lithium. Lithium carryover was ruled out in these experiments. These data indicate that lithium stimulates CFU-S and in vitro granulopoiesis by an indirect effect on a radioresistant adherent stromal cell.