Systematic investigation of imprinted gene expression and 1 enrichment in the mouse brain explored at single-cell resolution

BACKGROUND: Although a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using thirteen single-cell RNA sequencing datasets we systematically investigated imprinted gene over-representation at the organ, brain region, and cell-specific levels. RESULTS: We established that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examined brain-wide datasets to test enrichment within distinct brain regions and neuron subpopulations and demonstrated over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we identified hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression. CONCLUSIONS: These analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted gene expression converges. Our findings indicate the neuronal regulation of motivated behaviours such as feeding and sleep, alongside the regulation of pituitary function, as functional hotspots for imprinting. This adds statistical rigour to prior assumptions and provides testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-022-08986-8

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

<p>BACKGROUND: Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease.</p> <p>METHODS: We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points.</p> <p>RESULTS: Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051).</p> <p>CONCLUSIONS: Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.</p&gt

Mutation in DHP receptor alpha1 subunit (CACLN1A3) gene in a Dutch family with hypokalaemic periodic paralysis

Contains fulltext : 20690___.PDF (publisher's version ) (Open Access

Influence of pravastatin and plasma lipids on clinical events in the West of Scotland coronary prevention study (WOSCOPS)

<p>BACKGROUND: The West of Scotland Coronary Prevention Study was a primary prevention trial that demonstrated the effectiveness of pravastatin (40 mg/d) in reducing morbidity and mortality from coronary heart disease (CHD) in moderately hypercholesterolemic men. The present analysis examines the extent to which differences in LDL and other plasma lipids both at baseline and on treatment influenced CHD risk reduction.</p> <p>METHODS AND RESULTS: Relationships between baseline lipid concentrations and incidence of all cardiovascular events and between on-treatment lipid concentrations and risk reduction in patients taking pravastatin were examined by use of Cox regression models and by division of the cohort into quintiles. Variation in plasma lipids at baseline did not influence the relative risk reduction generated by pravastatin therapy. Fall in LDL level in the pravastatin-treated group did not correlate with CHD risk reduction in multivariate regression. Furthermore, maximum benefit of an approximately 45% risk reduction was observed in the middle quintile of LDL reduction (mean 24% fall); further mean decrements in LDL (up to 39%) were not associated with a greater decrease in CHD risk. Comparison of event rates between placebo- and pravastatin-treated subjects with the same LDL cholesterol level provided evidence for an apparent treatment effect that was independent of LDL.</p> <p>CONCLUSIONS: We conclude that the treatment effect of 40 mg/d of pravastatin is proportionally the same regardless of baseline lipid phenotype. There is no CHD risk reduction unless LDL levels are reduced, but a fall in the range of 24% is sufficient to produce the full benefit in patients taking this dose of pravastatin. LDL reduction alone does not appear to account entirely for the benefits of pravastatin therapy.</p&gt