The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.      

Lipoma of the temporal region: a rare case series

Lipomas are common benign tumours that can occur in most parts of the body. Lipomas arising from the deep temporal fat pad, found between the two layers of the deep temporal fascia, are rare, however; there has been only one documented case report to our knowledge. We describe a second case arising from the temporal fat pad in a patient treated at our unit, having previously reported the first one, and discuss the relevant anatomy and management.     

Evaluating and Strengthening the Evidence for Nutritional Bone Research: Ready to Break New Ground?

A healthy diet is essential to attain genetically determined peak bone mass and maintain optimal skeletal health across the adult lifespan. Despite the importance of nutrition for bone health, many of the nutritional requirements of the skeleton across the lifespan remain underexplored, poorly understood, or controversial. With increasingly aging populations, combined with rapidly changing diets and lifestyles globally, one anticipates large increases in the prevalence of osteoporosis and incidence of osteoporotic fractures. Robust, transparent, and reproducible nutrition research is a cornerstone for developing reliable public health recommendations to prevent osteoporosis and osteoporotic fractures. However, nutrition research is often criticized or ignored by healthcare professionals due to the overemphasis of weak science, conflicting, confusing or implausible findings, industry interests, common misconceptions, and strong opinions. Conversely, spurious research findings are often overemphasized or misconstrued by the media or prominent figures especially via social media, potentially leading to confusion and a lack of trust by the general public. Recently, reforms of the broader discipline of nutrition science have been suggested and promoted, leading to new tools and recommendations to attempt to address these issues. In this perspective, we provide a brief overview of what has been achieved in the field on nutrition and bone health, focusing on osteoporosis and osteoporotic fractures. We discuss what we view as some of the challenges, including inherent difficulties in assessing diet and its change, disentangling complex interactions between dietary components and between diet and other factors, selection of bone-related outcomes for nutrition studies, obtaining evidence with more unbiased designs, and perhaps most importantly, ensuring the trust of the public and healthcare professionals. This perspective also provides specific recommendations and highlights new developments and future opportunities for scientists studying nutrition and bone health. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Cytomegalovirus associated oral ulcerations in HIV-infected patients

Oral ulcerations associated with disseminated cytomegalovirus (CMV) infection were observed in four patients with AIDS manifestations showing low CD4 counts. Virus cultures of urine and saliva samples were positive for CMV in all cases. The lesions were characterized by a punched-out appearance, non-indurated borders, low bleeding tendency and lack of inflammatory wall. Light microscopy revealed granulation tissue containing "owl's eye" like cells in all specimens. Presence of CMV was confirmed by immunohistochemistry and in situ hybridization. The ulcerations were infiltrated with T-lymphocytes of the helper, suppressor and cytotoxic subset, most were positive for HLA DR. Despite the local invasion with immunocytes and high serum titers of serum antibodies the patients experienced progressive CMV disease.     

Mitral commissurotomy, a technique outdated? Long-term follow-up over a period of 35 years

Background. The objective of this study was to evaluate long-term survival, valve-related complications as well as prognostic factors for early and late outcome after open and closed mitral commissurotomy covering a follow-up period of 35 years.

Methods. From 1955 to 1977, 183 patients with mitral stenosis underwent mitral commissurotomy at our institution. Closed valvotomy was performed on 143 patients (group A) and open valvotomy on 40 patients (group B).

Results. Survival rates after 10, 20, and 30 years were 89%, 67.8%, and 49.1% in group A and 91.7%, 66.7%, and 45.9% in group B (p = not significant). The risk of late death increased significantly with an advanced preoperative New York Heart Association functional class, atrial fibrillation, higher age at operation, pre- or postoperative mitral regurgitation, and leaflet calcification. Forty-four patients in group A and 5 patients in group B required reoperation (p < 0.05). Independent predictors for reoperation in a multivariate analysis were a remaining postoperative mitral stenosis or regurgitation. A total of 68 patients showed valve-related complications. The linearized rate of valve-related morbidity and mortality was 2.1% per patient-years in group A versus 1.1% per patient-years in B (p < 0.01).

Conclusions. Long-term survival for open and closed commissurotomy are excellent, showing no difference between the groups. However, both the incidence of reoperation as well as valve-related morbidity and mortality were significantly lower after open commissurotomy. In well-selected patients with pure mitral stenosis and no leaflet calcification, open commissurotomy still remains a valid surgical option.     

Orale pr?kanzer?se Konditionen—eine übersicht

Zusammenfassung Präkanzeröse Konditionen (Zustände) umfassen Erkrankungen, die mit einem signifikant erhöhten Krebsrisiko verbunden sind. Dazu gehören die sideropenische Dysphagie, der orale Lichen planus (OLP), die orale submuköse Fibrose (OSF), die Syphilis, der diskoide Lupus erythematodes (DLE), das Xeroderma pigmentosum sowie die Epidermolysis bullosa. Die Zahl publizierter Fälle von oralen oder perioralen Transformationen zu Karzinomen ist für einige dieser Erkrankungen klein. Auch sind Zungenkarzinome oder Karzinome der Mundhöhle bei Spätsyphilis eher von historischem Interesse, obwohl in den 90er Jahren immer noch auf eine mögliche Assoziation einer positiven Syphilisserologie und dem Auftreten eines Zungenkarzinoms hingewiesen wurde. Der OLP ist eine nach wie vor kontrovers diskutierte präkanzeröse Kondition. Transformationsraten werden zwischen 0 und 5,6% angegeben. Neuere Untersuchungen, v. a. prospektive Studien, weisen darauf hin, dass möglicherweise die orale lichenoide Reaktion (OLR) Ausgangszustand einer Transformation ist und nicht der klassische OLP. Die Differenzierung zwischen OLP und OLR ist sowohl vom klinischen als auch vom histopathologischen Aspekt nach wie vor schwierig. Zweitwichtigste präkanzeröse Kondition ist die OSF, die durch das Kauen von Betel in Süd- und Südostasien bedingt wird. Mit 7,6% liegt für die OSF die höchste Transformationsrate aller präkanzerösen Konditionen vor.

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Ultraviolet-light induced p53 mutational spectrum in yeast is indistinguishable from p53 mutations in human skin cancer

Ultraviolet (UV) light has been associated with the development of human non-melanoma skin cancers (NMSC). Such cancers often exhibit mutations in the p53 tumour suppressor gene. In order to determine the UV-induced p53 mutation spectrum, a yeast expression vector that harbours a human wild-type p53 cDNA was UV-irradiated in vitro and transfected into a yeast strain that contained the ADE2 gene regulated by a p53-responsive promoter. Forty-five mutant clones contained 51 mutations. Seven mutations were tandem base pair substitutions, four of which being CC-->TT, hallmark mutations of UV mutagenesis. Eighty percent (41/51) of the mutations were single or non-tandem base pair substitutions, the majority of which (27/41) were C-->T transitions. Ninety-five percent of such mutations occurred at dipyrimidine sites. Through a rigorous statistical test, the UV-induced p53 mutation spectrum appears to differ significantly (P < 0.008) from the one induced by the antineoplastic drug chloroethyl-cyclohexyl-nitrosourea, and to be indistinguishable from the one observed in NMSC (P = 0.4). These results demonstrate that the assay allows the determination of carcinogen-specific p53 mutation fingerprints and represents a new tool for molecular epidemiology.      

Non-invasive assessment of the effect of cardiac sympathetic innervation on metabolism of the human heart

The role of cardiac sympathetic nerves in the regulation of myocardial metabolism is not well defined. Owing to the presence of incomplete reinnervation, heart transplant recipients provide a unique model to study the effects of efferent sympathetic innervation. Using this model, we sought to determine the influence of cardiac sympathetic signals on substrate utilisation and overall oxidative metabolism. In 21 transplant recipients, positron emission tomography was applied to determine sympathetic innervation with the noradrenaline analogue carbon11 hydroxyephedrine, oxidative metabolism with carbon11 acetate (n=14), and glucose utilisation with fluorine-18 fluorodeoxyglucose (n=7). The reinnervated area comprised 22% +/- 20% of the left ventricle. Oxidative metabolism was similar in denervated and reinnervated myocardium [0.06 +/- 0.01 vs 0.06 +/- 0.01/min for k(mono)], while glucose uptake was significantly higher in denervated myocardium (6.9 +/- 6.6 vs 6.0 +/- 6.2 micromol/min/100 g; P=0.03). Reinnervation mainly occurred in the territory of the left anterior descending artery, where retention of 11C-hydroxyephedrine (6.8 +/- 2.7%/min) was higher compared with territories of the left circumflex (4.1 +/- 1.7%/min; P<0.01) and right coronary (3.8 +/- 1.1%/min; P<0.01) arteries. Oxidative metabolism was similar in all three territories, but compared with the reinnervated territory of the left anterior descending artery (53% +/- 16% of maximum), relative FDG uptake was higher in territories of the left circumflex (76% +/- 6%, P<0.01) and right coronary (67% +/- 10%, P<0.05) arteries. Similar degrees of regional heterogeneity were not observed in normals. Thus, while overall energy production through oxidative metabolism remains unaffected, cardiac utilisation of glucose in the fasting state is increased in the absence of catecholamine uptake sites. Innervated myocardium, however, may preferentially utilise free fatty acids, suggesting a role for sympathetic tone in substrate utilisation.