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.

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.

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.