Changes in very low density lipoproteins with cholesterol loading in man

We have studied the effects of cholesterol loading in man, seeking changes in VLDL that may define a population of particles that resemble the atherogenic β-VLDL in experimental animals. Comparisons were made in 6 men during two diets, containing either 200 mg or 1700 mg cholesterol daily. Although the total plasma cholesterol did not rise significantly over 4 wk of cholesterol loading (mean ± SD 178 ± 41 to 194 ± 48 mg/dl), distinct changes in lipoprotein composition occurred; (1) HDL cholesterol rose significantly (34 ± 4 to 41 ± 5) and plasma apoprotein Al rose from 118 ± 10 to 129 ± 9 mg/dl, (2) Within VLDL, the proportion of apoproteins E:C rose from 0.18 to 0.32 (p < 0.005), though the apoprotein E concentration did not change, (3) Within VLDL, the ratio of cholesteryl esters:triglyceride rose, (4) Within VLDL (Sf 20–400) a population of particles that bound to heparin on heparin-sepharose columns increased threefold; since these particles were richer in apoprotein E and in cholesteryl ester than were VLDL not bound to heparin, we conclude that cholesterol loading leads to an increase in smaller VLDL particles, possibly partly catabolized VLDL or independently secreted IDL, that resemble findings in cholesterol fed animals, and (5) Transport kinetics of apoprotein B in VLDL studied in four subjects did not show a rise in production but this does not rule out increased secretion of a cholesteryl ester, apoprotein E enriched subpopulation of VLDL.     

Detection of 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae in the United Kingdom,December 2021 to June 2022

Between December 2021 and June 2022, 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae (ST8123; n = 8) were detected in the United Kingdom, compared with nine cases during the previous 6 years. Most of these cases were associated with travel from the Asia-Pacific region; all were heterosexual people, with most in their 20s. Although all cases were successfully treated, not all partners of cases could be traced, and there is a risk of further transmission of ceftriaxone-resistant gonococcal infection within the UK.     

Unexpected structural and functional consequences of the R33Q homozygous mutation in cardiac calsequestrin: a complex arrhythmogenic cascade in a knock in mouse model

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by life threatening arrhythmias elicited by physical and emotional stress in young individuals. The recessive form of CPVT is associated with mutation in the cardiac calsequestrin gene (CASQ2). We engineered and characterized a homozygous CASQ2(R33Q/R33Q) mouse model that closely mimics the clinical phenotype of CPVT patients. CASQ2(R33Q/R33Q) mice develop bidirectional VT on exposure to environmental stress whereas CASQ2(R33Q/R33Q) myocytes show reduction of the sarcoplasmic reticulum (SR) calcium content, adrenergically mediated delayed (DADs) and early (EADs) afterdepolarizations leading to triggered activity. Furthermore triadin, junctin, and CASQ2-R33Q proteins are significantly decreased in knock-in mice despite normal levels of mRNA, whereas the ryanodine receptor (RyR2), calreticulin, phospholamban, and SERCA2a-ATPase are not changed. Trypsin digestion studies show increased susceptibility to proteolysis of mutant CASQ2. Despite normal histology, CASQ2(R33Q/R33Q) hearts display ultrastructural changes such as disarray of junctional electron-dense material, referable to CASQ2 polymers, dilatation of junctional SR, yet normal total SR volume. Based on the foregoings, we propose that the phenotype of the CASQ2(R33Q/R33Q) CPVT mouse model is portrayed by an unexpected set of abnormalities including (1) reduced CASQ2 content, possibly attributable to increased degradation of CASQ2-R33Q, (2) reduction of SR calcium content, (3) dilatation of junctional SR, and (4) impaired clustering of mutant CASQ2.