Severe hypercalcaemia in metastatic prostate cancer with biallelic BRCA2 mutations and lytic bone lesions.

Molecular genetics is increasingly used to define the course and prognosis of prostate cancer. Hypercalcaemia of malignancy is a rare complication of metastatic prostate cancer associated with poor outcomes. However, no associations have yet been made in literature between pathogenic genetic mutations and hypercalcaemia in patients with prostatic malignancy.We report of a patient with bone-metastatic prostate cancer. He received sequential genetic tests for pathogenic mutations. A somatic BRCA2 truncation mutation was identified at diagnosis and suppressed on olaparib. Six months after stopping olaparib, several pathogenic mutations, including biallelic BRCA2 mutations, were identified. The patient developed large lytic bone lesions and a severe symptomatic hypercalcaemia. He was hospitalised and treated aggressively for hypercalcaemia but died shortly thereafter. To our knowledge, this is the first case of hypercalcaemia in metastatic prostate cancer to be contextualised within complex genetic mutations.

Comprehensive Phenotypic Characterization of Late Gadolinium Enhancement Predicts Sudden Cardiac Death in Coronary Artery Disease.

BACKGROUND: Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). OBJECTIVES: The authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). METHODS: Patients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. RESULTS: Of 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell's C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell's C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. CONCLUSIONS: Comprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

Maternal Hypertension Increases Risk of Preeclampsia and Low Fetal Birthweight: Genetic Evidence From a Mendelian Randomization Study.

BACKGROUND: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight. METHODS: Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. RESULTS: Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45-2.49]; P=3.23×10-6) and reduced birthweight (OR=0.83 [95% CI=0.79-0.86]; P=3.96×10-18), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44-1.94]; P=7.45×10-12; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04-1.19]; P=1.19×10-3), but not with reduced birthweight. CONCLUSIONS: Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Sulfur Doping versus Hierarchical Pore Structure: The Dominating Effect on the Fe-N-C Site Density, Activity, and Selectivity in Oxygen Reduction Reaction Electrocatalysis.

Nitrogen doping has been always regarded as one of the major factors responsible for the increased catalytic activity of Fe-N-C catalysts in the oxygen reduction reaction, and recently, sulfur has emerged as a co-doping element capable of increasing the catalytic activity even more because of electronic effects, which modify the d-band center of the Fe-N-C catalysts or because of its capability to increase the Fe-Nx site density (SD). Herein, we investigate in detail the effect of sulfur doping of carbon support on the Fe-Nx site formation and on the textural properties (micro- and mesopore surface area and volume) in the resulting Fe-N-C catalysts. The Fe-N-C catalysts were prepared from mesoporous carbon with tunable sulfur doping (0-16 wt %), which was achieved by the modulation of the relative amount of sucrose/dibenzothiophene precursors. The carbon with the highest sulfur content was also activated through steam treatment at 800 °C for different durations, which allowed us to modulate the carbon pore volume and surface area (1296-1726 m2 g-1). The resulting catalysts were tested in O2-saturated 0.5 M H2SO4 electrolyte, and the site density (SD) was determined using the NO-stripping technique. Here, we demonstrate that sulfur doping has a porogenic effect increasing the microporosity of the carbon support, and it also facilitates the nitrogen fixation on the carbon support as well as the formation of Fe-Nx sites. It was found that the Fe-N-C catalytic activity [E1/2 ranges between 0.609 and 0.731 V vs reversible hydrogen electrode (RHE)] does not directly depend on sulfur content, but rather on the microporous surface and therefore any electronic effect appears not to be determinant as confirmed by X-ray photoemission spectroscopy (XPS). The graph reporting Fe-Nx SD versus sulfur content assumes a volcano-like shape, where the maximum value is obtained for a sulfur/iron ratio close to 18, i.e., a too high or too low sulfur doping has a detrimental effect on Fe-Nx formation. However, it was highlighted that the increase of Fe-Nx SD is a necessary but not sufficient condition for increasing the catalytic activity of the material, unless the textural properties are also optimized, i.e., there must be an optimized hierarchical porosity that facilitates the mass transport to the active sites.

Long-term Impact of Bariatric Surgery on Venous Thromboembolic Risk: A Matched Cohort Study.

OBJECTIVE: The aim of this study is to evaluate the effect of bariatric surgery on long-term risk of VTEs in a large cohort of patients with obesity. BACKGROUND: Obesity is a well-established risk factor for VTEs, such as pulmonary embolism and deep vein thrombosis. The rising prevalence of obesity and its associated co-morbidities, including VTE, represent a growing public health issue. METHODS: A nested, retrospective matched cohort study was designed and conducted on prospectively collected national electronic healthcare records data from the Clinical Practice Research Datalink. Eight thousand, one hundred twelve patients were included in the study: the 4056 patients on the database who had undergone bariatric surgery, and equal numbers of age, sex, and body mass index matched controls. The primary endpoint was the occurrence of VTEs; secondary endpoints were the occurrence of deep vein thrombosis alone, pulmonary embolism alone. RESULTS: Patients were followed up for a median of 10.7 years. The bariatric surgery cohort had a significantly lower occurrence of the primary outcome [hazard ratio (HR) 0.601; 95% confidence interval (CI) 0.430-0.841, P = 0.003]; mainly driven by a reduction in deep vein thrombosis (HR 0.523; 95% CI 0.349-0.783, P = 0·002) and not in pulmonary embolism (HR 0.882; 95% CI 0.511-1.521, P = 0.651). CONCLUSIONS: The results of this nation-wide study set out to characterize the impact of bariatric surgery on long-term risk of thromboembolic events outline a significant reduction in thromboembolic events, driven by a reduction in deep vein thrombosis.

Fiberoptic endoscopic evaluation of swallowing in early-to-advanced stage Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor disturbances, cognitive decline, and behaviour changes. A well-recognized feature of advanced HD is dysphagia, which leads to malnutrition and aspiration pneumonia, the latter being the primary cause of death in HD. Previous studies have underscored the importance of dysphagia in HD patients with moderate-to-advanced stage disease, but it is unclear whether dysphagia affects patients already at an early stage of disease and whether genetic or clinical factors can predict its severity. We performed fiberoptic endoscopic evaluation of swallowing (FEES) in 61 patients with various stages of HD. Dysphagia was found in 35% of early-stage, 94% of moderate-stage, and 100% of advanced-stage HD. Silent aspiration was found in 7.7% of early-stage, 11.8% of moderate-stage, and 27.8% of advanced-stage HD. A strong correlation was observed between disease progression and dysphagia severity: worse dysphagia was associated with worsening of motor symptoms. Dysphagia severity as assessed by FEES correlated with Huntington's Disease Dysphagia Scale scores (a self-report questionnaire specific for evaluating swallowing in HD). The present findings add to our understanding of dysphagia onset and progression in HD. A better understanding of dysphagia onset and progression in HD may inform guidelines for standard clinical care in dysphagia, its recognition, and management.

Obestatin promotes proliferation and survival of adult hippocampal progenitors and reduces amyloid-ß-induced toxicity.

The ghrelin gene-derived peptide obestatin promotes survival in different cell types through a yet undefined receptor; however, its potential neuroprotective activities are still unknown. Here, obestatin effects were investigated on proliferation and survival of adult rat hippocampal progenitor cells (AHPs). Obestatin immunoreactivity was found in AHPs; moreover, obestatin binding to AHPs was displaced by the GLP-1R agonist Ex-4 and antagonist Ex-9. Furthermore, obestatin increased cell proliferation and survival in growth factor deprived medium and inhibited apoptosis; these effects were blocked by Ex-9. The underlying mechanisms involved Gαs/cAMP/PKA/CREB signaling, phosphorylation of ERK1/2 and PI3K/Akt, and the PI3K targets GSK-3ß/ß-catenin and mTOR. Obestatin also counteracted Aß1-42-induced detrimental effects through inhibition of GSK-3ß activity and Tau hyperphosphorylation, main hallmarks of neuronal death in Alzheimer's disease. These findings indicate a novel protective role for obestatin in AHPs and candidate this peptide as potential therapeutic target for increasing neurogenesis and for approaching neurodegenerative disorders.