Kohlschütter–Tönz Syndrome: Mutations in ROGDI and Evidence of Genetic Heterogeneity

Kohlschütter–Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease.     

Practice patterns in high-risk bariatric venous thromboembolism prophylaxis

Background

In the morbidly obese population that undergoes bariatric surgery, venous thromboembolism (VTE) is the leading cause of morbidity and mortality. Certain factors place a patient at higher risk for VTE. No consensus exists on VTE screening or prophylaxis for the high-risk patient. This report describes the results of a survey on VTE screening and prophylaxis patterns in high-risk bariatric surgery.

Methods

Members of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) were queried on factors that identified bariatric patients as high risk for VTE and on routine screening and prophylaxis practices. This included mechanical and chemical prophylaxis, duration of therapy, and use of inferior vena cava (IVC) filters.

Results

Of the 385 surgeons who responded to the survey, 81 % were bariatric surgeons, and the majority managed more than 50 cases annually. One or more of the following risk factors qualified patients as high risk: history of VTE, hypercoagulable status, body mass index (BMI) exceeding 55 kg/m², partial pressure of arterial oxygen (PaO₂) lower than 60 mmHg, and severe immobility. Preoperative screening of patients for VTE was practiced routinely by 56 % of the surgeons, and 92.4 % used preoperative chemoprophylaxis. The most common agent used preoperatively was heparin (48 %), and Lovenox was most commonly used postoperatively (49 %). Whereas 48 % of the patients discontinued chemoprophylaxis at discharge, 43 % continued chemoprophylaxis as outpatients, and 47 % routinely screened for VTE postoperatively. Use of IVC filters was routine for 28 % of the patients, who most commonly removed them after 1–3 months.

Conclusions

This study describes current practice patterns of VTE screening and prophylaxis in high-risk bariatric surgery. Nearly all surgeons agree on risk factors that qualify patients as high risk, but only half routinely screen patients preoperatively. Preoperative VTE chemoprophylaxis is used by nearly all surgeons, but the duration of therapy varies. Use of IVC filters is not routine, and postoperative screening was performed by less than half of the respondents. An understanding of current practice patterns yields insight into the rates of VTE and shows variability in the need for evidence-based prophylaxis and standardized screening.     

Efficient radiosynthesis and preclinical evaluation of [18F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

Herein we report an efficient radiolabeling of a ¹⁸F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R). [¹⁸F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated ¹⁸F-fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [¹⁸F]FOMPyD showed moderate brain permeability in wild-type rats (SUV_max = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC_40–90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [¹⁸F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self-blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [¹⁸F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated ¹⁸F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.     

BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups

Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.     

The radioactive autopsy: safe working practices

Autopsy cases involving individuals retaining radioactive substances are fortunately rare, but when they occur they can impose significant radiation safety and legal requirements. This review aims to improve the understanding of these issues so that appropriate precautions are implemented when necessary. This review describes the properties of ionizing radiations, natural and man-made sources of ionizing radiation and its use in healthcare. It identifies the most likely circumstances leading to radioactive substances being present during autopsy and sources of information, including radiation protection advice. It discusses precautions that may need to be implemented prior to, during and following autopsy. Despite the issue of appropriate information to patients and next of kin, it is inevitable that some cases will be identified only at autopsy and it is important that robust local procedures are maintained. Information must be communicated to assist safe management of the body and liaison between relevant professional groups may be needed to standardize methods of communication. Provided that appropriate precautions are implemented, determined through consultation with a qualified expert in radiation protection and by completion of risk assessment, the radioactive autopsy can be undertaken safely and in compliance with relevant legislative requirements.     

RecA.oligonucleotide filaments bind in the minor groove of double-stranded DNA.

Escherichia coli RecA protein, in the presence of ATP or its analog adenosine 5'-[gamma-thio]triphosphate, polymerizes on single-stranded DNA to form nucleoprotein filaments that can then bind to homologous sequences on duplex DNA. The three-stranded joint molecule formed as a result of this binding event is a key intermediate in general recombination. We have used affinity cleavage to examine this three-stranded joint by incorporating a single thymidine-EDTA.Fe (T*) into the oligonucleotide part of the filament. Our analysis of the cleavage patterns from the joint molecule reveals that the nucleoprotein filament binds in the minor groove of an extended Watson-Crick duplex.