Screening for complement deficiency in bacterial meningitis

Seventy-seven children with bacterial meningitis were screened for complement deficiency. Both the classical and the alternate pathways were normal in 75 patients. Transiently reduced total haemolytic activity of the classical pathway was documented in a boy with meningococcal meningitis. Total haemolytic activity of both the classical and the alternate pathways were reduced in another patient with pneumococcal meningitis: individual complement components determination indicated predominant activation of the alternate pathway.     

Identification of differentially expressed genes in aflatoxin B1- treated cultured primary rat hepatocytes and Fischer 344 rats

Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is a contaminant of the human food supply, particularly in parts of Africa and Asia. AFB1-induced changes in gene expression may play a part in the development of the toxic, immunosuppressive and carcinogenic properties of this fungal metabolite. An understanding of the-role of AFB1 in modulating gene regulation should provide insight regarding mechanisms of AFB1-induced carcinogenesis. We used three PCR- based subtractive techniques to identify AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential display PCR (DD-PCR), representational difference analysis (RDA) and suppression subtractive hybridization (SSH). Each of the three techniques identified AFB1- responsive genes, although no individual cDNA was isolated by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH were found to represent eight genes that are differentially expressed as a result of AFB1 exposure. Genes whose mRNA levels were increased in cultured primary rat hepatocytes after AFB1 treatment were corticosteroid binding globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin, C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When liver RNA from AFB1-treated male F344 rats was evaluated for transferrin, CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen. Analysis of the potential function of these genes in maintaining cellular homeostasis suggests that their differential expression could contribute to the toxicity associated with AFB1 exposure.      

SARS-CoV-2 Accessory Protein ORF8 Decreases Antibody-Dependent Cellular Cytotoxicity

Viruses use many different strategies to evade host immune responses. In the case of SARS-CoV-2, its Spike mutates rapidly to escape from neutralizing antibodies. In addition to this strategy, ORF8, a small accessory protein encoded by SARS-CoV-2, helps immune evasion by reducing the susceptibility of SARS-CoV-2-infected cells to the cytotoxic CD8+ T cell response. Interestingly, among all accessory proteins, ORF8 is rapidly evolving and a deletion in this protein has been linked to milder disease. Here, we studied the effect of ORF8 on peripheral blood mononuclear cells (PBMC). Specifically, we found that ORF8 can bind monocytes as well as NK cells. Strikingly, ORF8 binds CD16a (FcγRIIIA) with nanomolar affinity and decreases the overall level of CD16 at the surface of monocytes and, to a lesser extent, NK cells. This decrease significantly reduces the capacity of PBMCs and particularly monocytes to mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, our data identifies a new immune-evasion activity used by SARS-CoV-2 to escape humoral responses.     

Clinical and angiographic assessment 6 months after double vessel percutaneous coronary angioplasty

Percutaneous transluminal coronary angioplasty is an accepted treatment for selected patients with single vessel disease but has not been rigorously evaluated in patients with double vessel disease. Among 769 patients undergoing transluminal coronary angioplasty between 1980 and 1984, 74 with double vessel stenosis of 50% or more underwent double vessel coronary angioplasty. Primary success was obtained for both lesions in 63 patients (85%), for one lesion in 11 patients (15%) and for 137 (93%) of 148 segments overall. Except for myocardial infarction in one patient, no serious complication occurred. Before coronary angioplasty, 15 patients had unstable angina, 14 had Canadian Cardiovascular Society class III and 32 class I to II effort angina and only 2 were asymptomatic. Six months after coronary angioplasty, 27 were asymptomatic, 27 had class I to II and 5 had class III effort angina and 2 had sustained an episode of unstable angina. During the follow-up study, two patients had an infarction and one had coronary artery bypass surgery. Coronary arteriography was performed at a mean of 5.5 +/- 2.1 months after coronary angioplasty in all but three patients. Restenosis was found in 30 (23%) of 132 segments with angiographic control. Restenosis was present in one vessel in 17 patients and in both vessels in 4; 40 patients (66%) had no restenosis. Of the 34 patients with definite or probable angina, 50% had restenosis and 19% of patients with restenosis were symptom free.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice.

We have studied the effects of endogenous and exogenous estrogen on atherosclerotic lesions in apolipoprotein E-deficient mice. Female mice ovariectomized (OVX) at weaning displayed increases (P < 0.01) in fatty streak lesions in the proximal aorta and aortic sinus compared with female mice with intact ovarian function. These differences between the OVX and sham controls were apparent in both chow- and "Western-type" diet-fed mice. Moreover, increases in lesion size following OVX occurred without changes in plasma cholesterol. Hormone replacement with subdermal 17-beta-estradiol pellets releasing either 6, 14, or 28 micrograms/day significantly decreased (P < 0.001) atherosclerotic lesion area in both male and OVX female mice. In contrast, neither 17-alpha-estradiol (28 micrograms/day) or tamoxifen (85 micrograms/day) affected lesion progression in OVX female mice. In the Western diet-fed group, exogenous estradiol markedly reduced plasma cholesterol and triglycerides, whereas, in animals fed the chow diet, exogenous estrogen and tamoxifen treatment only decreased plasma and very low density lipoprotein triglycerides. However, lesion area was only weakly correlated with plasma cholesterol and triglycerides, 0.35 and 0.44 tau values, respectively (P < 0.01). In summary, in the apolipoprotein E-deficient mouse 17-beta-estradiol protects against atherosclerotic lesion formation, and this can only be partially explained through effects on plasma lipoprotein levels.     

Hemodynamic studies during intermittent left bundle branch block

A patient with intermittent left bundle branch block and moderate aortic insufficiency, presumably due to rheumatic heart disease, is presented.

At retrograde left heart catheterization, left bundle branch block recurred repeatedly and was always converted to normal conduction and left ventricular hypertrophy by administration of oxygen. Electrocardiograms, intracardiac pressures and indicator-dilution curves for cardiac output were recorded with both types of conduction.

The following hemodynamic alterations consistently accompanied intermittent left bundle branch block:

1. 1. There was a significant fall in the systolic pressures in the left ventricle, central aorta and radial artery, a decreased stroke volume and an increased heart rate. These findings suggest that the force and intensity of left ventricular contraction and, consequently, systolic ejection are significantly decreased with the onset of delayed conduction.

2. 2. A prolonged phase of isometric contraction was the most important alteration in the time relationships of the hemodynamic events of ventricular contraction. This resulted in delay in onset and termination of systolic ejection, with a normal duration of the ejection phase. Isometric relaxation was also prolonged proportionately, but duration of diastole shortened as the cardiac rate increased. Prolonged isometric contraction of the left ventricle is probably responsible for the delayed closure of the aortic valve and paradoxic or fixed splitting of the second heart sound very often seen with left bundle branch block.

     

Heart rate reduction through lifestyle modification: reply

We thank Drs Michalsen and Dobos for their comments. Restingheart rate is indeed a strong predictor of mortality in patientswith coronary artery disease.¹