Recommendations for the diagnosis and management of vaccine-induced immune thrombotic thrombocytopenia.

There have recently been safety concerns regarding an increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) following administration of SARS-CoV-2 adenoviral vector vaccines. The Southern African Society of Thrombosis and Haemostasis reviewed the emerging literature on this idiosyncratic complication. A draft document was produced and revised by consensus agreement by a panel of professionals from various specialties. The recommendations were adjudicated by independent international experts to avoid local bias. We present concise, practical guidelines for the clinical management of VITT.

South African dyslipidaemia guideline consensus statement: 2018 update A joint statement from the South African Heart Association (SA Heart) and the Lipid and Atherosclerosis Society of Southern Africa (LASSA).

South Africa (SA) is home to a heterogeneous population with a wide range of cardiovascular risk factors. Cholesterol reduction in combination with aggressive management of modifiable risk factors, including nutrition, physical activity, blood pressure and smoking, can help to reduce and prevent morbidity and mortality in individuals who are at increased risk of cardiovascular events. This updated consensus guide to management of dyslipidaemia in SA is based on the updated European Society of Cardiology and European Atherosclerosis Society dyslipidaemia guidelines published in 2016. For individuals who are not considered to be at high or very high cardiovascular risk, the decision whether to treat and which interventional strategy to use is based on a cardiovascular risk score calculated using total cholesterol, high-density lipoprotein cholesterol (HDL-C), gender, age and smoking status. The cardiovascular risk score refers to the 10-year risk of any cardiovascular event and includes 4 categories of risk (low, moderate, high and very high). People with established cardiovascular disease, diabetes mellitus, chronic kidney disease and genetic or severe dyslipidaemias are considered to already be at high or very high risk and do not require risk scoring. Therapeutic lifestyle change is the mainstay of management for all patients. The need for and intensity of drug therapy is determined according to baseline low-density lipoprotein (LDL-C) levels and the target LDL-C concentration appropriate to the individual. LDL-C treatment targets are based on pre-treatment risk and are as follows: <3 mmol/L in low- and moderate risk cases; <2.5 mmol/L and a reduction of at least 50% if the baseline concentration is 2.5 - 5.2 mmol/L in high-risk cases; and <1.8 mmol/L and a reduction of at least 50% if the baseline concentration is 1.8 - 3.5 mmol/L in very high-risk cases. A statin is usually recommended first-line; the specific agent is based on the required degree of cholesterol reduction, comorbidities and co-prescribed medication. Special attention should be paid to children with a family history of genetic or severe dyslipidaemia, who should be screened for dyslipidaemia from 8 years of age. In SA, HIV infection is not considered to be a significant cardiovascular risk factor and treatment recommendations for HIV-positive individuals are the same as for the general population, with careful choice of pharmacotherapy to avoid potential adverse drug-drug interactions. The benefit of statins in individuals older than 70 years is uncertain and clinical judgement should be used to guide treatment decisions and to avoid side-effects and overmedication in this group.

Pathogenic mechanisms in rheumatic carditis: focus on valvular endothelium.

To clarify immune-mediated mechanisms in rheumatic heart disease caused by group A streptococcal infection, valve tissues from rheumatic patients with valvular heart disease who required valve replacement were studied for reactivity with monoclonal anti-CD4 or anti-CD8 monoclonal antibodies or anti-vascular cell adhesion molecule-1 (VCAM-1). At the valve surface, CD4(+) and CD8(+) T lymphocytes were adherent to valve endothelium and penetrated through the subendothelial layer. T cell extravasation into the valve through the surface valvular endothelium appeared to be an important event in the development of rheumatic heart disease. VCAM-1 was expressed on the valvular endothelium in rheumatic valves. Evidence suggested that the pathogenesis of rheumatic heart disease involved the activation of surface valvular endothelium with the expression of VCAM-1 and the extravasation of CD4(+) and CD8(+) lymphocytes through the activated endothelium into the valve. Lymphocytic infiltration through the valve surface endothelium has not been appreciated as a potential initiating step in disease pathogenesis.

Rheumatic Aschoff nodules revisited. II: Cytokine expression corroborates recently proposed sequential stages.

AIMS: A recent immunohistochemical analysis of the Aschoff lesions in rheumatic fever, combining immunohistochemical analysis with comparative morphology, permitted the division of the Aschoff nodules into three stages: (1) Aschoff nodule without admixed lymphocytes, (2) Aschoff nodules with a few T lymphocytes, and (3) Aschoff nodules containing many admixed lymphocytes of both B- and T-cell phenotype. It was postulated that the order of progression was from stage 1 with macrophages only, to accumulation of first T lymphocytes (stage 2) and then B lymphocytes (stage 3). This study was undertaken to determine the role and distribution of interleukin 1 (IL-1), interleukin 2 (IL-2) and tumour necrosis factor alpha (TNF alpha) in the various stages of the rheumatic Aschoff nodule to investigate our hypothesis on the progression of these nodules. METHODS AND RESULTS: Sixteen fresh valve specimens from patients with acute rheumatic fever undergoing valve surgery were obtained. Tissue sections from 14 specimens identified as containing Aschoff nodules were subjected to immunohistochemistry for (1) T and B lymphocytes, to stage the lesions according to our previously proposed criteria; (2) IL-1, IL-2 and TNF alpha; and (3) CD4 and CD8 to phenotype the T lymphocytes. The stage 1 and 2 lesions expressed IL-1 and TNF alpha in the macrophages. The stage 3 lesions showed more variable expression of all three cytokines including IL-2 within T lymphocytes. CONCLUSION: TNF alpha and IL-1 secretion in macrophages is required for T and B lymphocytes activation and aggregation; suggesting that macrophages arrive at the scene of rheumatic injury prior to the lymphocytes. IL-2 is usually expressed later in the inflammatory process and was found only in the lymphoid aggregates. This study therefore produces corroborative evidence for our previously proposed developmental stages of the Aschoff nodule.

A comparative study of atenolol, nifedipine and their combination in the treatment of hypertension.

The antihypertensive effects, as assessed by clinical and ambulatory blood pressure measurement, of nifedipine slow-release (SR), atenolol and the two in combination were evaluated in 28 known hypertensives in a placebo-controlled, double-blind, randomised cross-over trial. Clinical blood pressure was significantly lower on combination therapy (P less than 0.025) than on either agent alone, although all therapeutic agents reduced blood pressure significantly when compared with placebo (P less than 0.01). All ambulatory blood pressure measurements obtained on any therapeutic agent were significantly lower than those obtained on placebo (P less than 0.01). The mean daytime (08h00-17h00) ambulatory blood pressure measurement as well as the percentage of this monitoring period during which patients were hypertensive were significantly lower (P less than 0.01) on combination therapy than on nifedipine SR. A similar pattern was observed for 24-hour ambulatory blood pressure measurements. Headache was the most significant adverse effect. This was most common with nifedipine SR, less common with combination therapy and least common with atenolol. Combination therapy with nifedipine SR and atenolol is therefore a viable therapeutic alternative in the treatment of patients with benign essential hypertension.

The aeromedical implications of atrial fibrillation.

A retrospective study was undertaken to determine the incidence of spontaneous atrial fibrillation (AF) in a group of asymptomatic pilots. The electrocardiograms of 13,037 aircrew members accumulated between 1964 and 1986 were reviewed and those coded for AF were extracted. In each case an attempt was made to investigate factors relating to the onset, course, and prognosis of the AF. Eight subjects (mean age 50.1 years) were found to have AF. Of this group, two had a single isolated episode of AF for which a specific precipitating factor was implicated, three had recurrent paroxysmal AF of which one progressed to chronic persistent AF, and three had chronic persistent AF from the outset. The mean follow-up period for the eight subjects was 13.6 years. The two pilots who had isolated attacks of AF have thus far had no subsequent episodes of AF. Five of the remaining six have been completely well, while one required treatment for an embolus to his left leg. Concerning the aeromedical implications, we believe that pilots demonstrating single isolated episodes of AF in the presence of a normal heart, and in whom recovery is complete, should be allowed to return to full aviation duties on a waiver clause. Patients with chronic AF, lone AF, or paroxysmal AF should be excluded from all flying duties.

Bezafibrate and simvastatin (MK-733) in the treatment of primary hypercholesterolaemia.

Simvastatin, a new 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor, was compared to bezafibrate, a fibric acid derivative, in an open cross-over placebo-controlled study. Bezafibrate was administered as a 200 mg dose 3 times daily, while simvastatin dosage ranged from 10 mg to 40 mg once daily at night. Bezafibrate produced a non-significant 13.1% (P = 0.113) decrease in total cholesterol (TC), a 20.7% (P less than 0.05) decrease in low-density lipoprotein cholesterol (LDL-C), an increase of 26.5% (P less than 0.01) in high-density lipoprotein cholesterol (HDL-C) and an improvement in the HDL:LDL ratio of 77.3% (P less than 0.01). Simvastatin 10 mg and 20 mg daily reduced TC by 18.6% and 22.6%, respectively, and LDL-C by 23.9% and 28.6% respectively (P less than 0.01), while no significant increase was noted in HDL-C. Simvastatin 40 mg daily reduced TC and LDL-C by 27.1% and 37.6%, respectively (P less than 0.01), increased HDL-C by 32.0% (P less than 0.05) and improved on the HDL:LDL ratio by 130.8% (P less than 0.01). This showed improvements over bezafibrate of 13.5% for TC, 18.9% for LDL-C, 6.0% for HDL-C and 55.8% for HDL:LDL ratio. It was concluded that simvastatin was well tolerated and had significant hypocholesterolaemic effects when taken once daily.

Safety, tolerability and efficacy of acipimox in type II hyperlipidaemia.

Twenty-one patients with type II hyperlipidaemia were treated with the nicotinic acid analogue, acipimox (Olbetam; Farmitalia), for 6 months. Total cholesterol decreased by 10% and the high-density lipoprotein: low-density lipoprotein cholesterol ratio increased by 13%. Triglycerides were unaltered. Two patients stopped the drug after developing gastro-intestinal side-effects. Acipimox therapy warrants ongoing use and further investigation.

Metabolic and hormonal responses to salbutamol in asthma. Evidence of beta-adrenergic overactivity?

The possibility that beta-adrenergic hyposensitivity may be involved in the pathogenesis of bronchial asthma remains a controversial issue. The hormonal, metabolic and cardiovascular responses to selective beta 2-adrenergic stimulation with salbutamol were compared in 11 asthmatic and 11 non-asthmatic subjects. There was no consistent difference between the two groups in the plasma free fatty acid, glucose and potassium responses, or in the cardiovascular variables studied, but the asthmatic patients demonstrated a marked dose-dependent hyperinsulinaemic response to salbutamol. Although this phenomenon cannot be accounted for with certainty, it may be a manifestation of pancreatic beta-adrenergic overactivity which would not be in keeping with the concept of generalised hyposensitivity of beta-adrenergic mechanisms in asthma. The present results provide a clear demonstration of the difficulties involved in attempts to relate extrapulmonary autonomic phenomena to the pathogenesis of bronchial asthma.

Nocturnal events related to "morning dipping" in bronchial asthma.

The mechanism of early morning bronchospasm in asthma was investigated by analyzing circadian variations in the plasma levels of cortisol, ACTH, epinephrine, and norepinephrine, as well as in the serum neutrophil chemotactic activity and heart rate in asthmatic patients with (n = 6) and without (n = 7) "morning dipping" and normal subjects. Findings suggested that an exaggerated nocturnal nadir in plasma cortisol levels may precipitate "morning dipping" in some patients with asthma.