Antiphospholipid antibodies in critically ill COVID-19 patients with thromboembolism: cause of disease or epiphenomenon?

Coronavirus 2019 disease (COVID-19) is associated with coagulation dysfunction that predisposes patients to an increased risk for both arterial (ATE) and venous thromboembolism (VTE) and consequent poor prognosis; in particular, the incidence of ATE and VTE in critically ill COVID-19 patients can reach 5% and 31%, respectively. The mechanism of thrombosis in COVID-19 patients is complex and still not completely clear. Recent literature suggests a link between the presence of antiphospholipid antibodies (aPLs) and thromboembolism in COVID-19 patients. However, it remains uncertain whether aPLs are an epiphenomenon or are involved in the pathogenesis of the disease.

     

The quantitative distribution of cytosolic androgen receptors in microdissected areas of the male rat brain: effects of estrogen treatment

Estrogen and androgen synergize in the regulation of various neuroendocrine functions. To determine a potential cellular basis of this synergism, we measured androgen receptor (AR) in the cytosol of 16 hypothalamic and limbic nuclei and subregions in castrated male rats and castrated rats treated with estradiol. Androgen receptor was measured by a previously validated in vitro binding assay using the synthetic androgen methyltrienolone [( 3H]R1881). Male Sprague-Dawley rats (250-350 g) were castrated 2 weeks before the implantation of a 2.5-cm Silastic capsule filled with crystalline 17 beta-estradiol. Control rats were sham implanted. Estrogen treatment lasted for 1 week, after which time the animals were killed, their brains were frozen and sectioned, and individual nuclei and subregions were removed by a tissue punch technique. Tissue from six rats were combined for each determination. The highest levels of AR were found in the ventromedial nucleus (16.5 +/- 1.4 fmol/mg protein), medial preoptic area (12.1 +/- 1.4 fmol/mg protein), bed nucleus of the stria terminalis (11.6 +/- 1.4 fmol/mg protein), lateral septum (11.4 +/- 1.4 fmol/mg protein), arcuate nucleus-median eminence (10.9 +/- 2.1 fmol/mg protein), and medial amygdala (10.3 +/- 0.9 fmol/mg protein). Estrogen treatment resulted in significant increases in AR in medial preoptic area (14.8 +/- 0.6 fmol/mg protein; P less than 0.05) and medial amygdala (14.6 +/- 1.2 fmol/mg protein; P less than 0.02). Subsequent studies using block-dissected hypothalamus-preoptic area, anterior pituitary, and prostate revealed significant estrogen-mediated elevations in AR in anterior pituitary cytosol [42.2 +/- 3.0 vs. 26.4 +/- 1.6 fmol/mg protein (control); P less than 0.01], but not in hypothalamus-preoptic area or prostate cytosols. Estrogen treatment had no effect on AR affinity. The binding of [3H]R1881 was specific for AR and was not affected by the addition of radioinert progesterone to the incubation tube. Estimates of AR concentration were similar regardless of whether [3H]R1881 or [3H]dihydrotestosterone was used as the ligand. In this study, we describe the distribution of AR throughout the hypothalamus and limbic areas using biochemical techniques. In addition, we have identified some cellular events that may mediate the synergistic actions of estrogen and androgen on the neuroendocrine system.     

Diet and exercise in type 2 diabetes mellitus.

The question is no longer whether diet and exercise can benefit the individual with type 2 diabetes. Rather, the type and duration of exercise the magnitude of the effects on glycemic control, insulin sensitivity, and on risk factors for cardiovascular disease must be considered in determining the feasibility and acceptability of an intervention program. It is now clear that regular physical exercise is important in both the prevention and treatment of type 2 diabetes. The benefits of exercise are many and include increased energy expenditure, which, combined with dietary restriction, leads to decreased body fat, increased insulin sensitivity, improved long-term glycemic control, improved lipid profiles, lower blood pressure, and increased cardiovascular fitness. Persons with type 2 diabetes often find it difficult to exercise and are at increased risk for injury or exacerbation of underlying diseases or diabetic complications. Therefore, before starting an exercise program, all patients with type 2 diabetes should have a complete history and physical examination, with particular attention to evaluation of cardiovascular disease, medications that may affect glycemic control during or after exercise, and diabetic complications including retinopathy, nephropathy, and neuropathy. Exercise programs should be designed to start slowly, build up gradually, and emphasize moderately intense exercise performed at least three times a week and preferably five to seven times a week for best results.     

A 12-lipoxygenase product of arachidonate metabolism is involved in angiotensin action on renin release

Angiotensin II (AII) action is coupled to the hydrolysis of phospholipids resulting in the formation of arachidonic acid, the precursor of both prostaglandins, and hydroxyeicosatetraenoic acids (HETEs). Since 12-HETE is not only a major arachidonate lipoxygenase (LO) product in the kidney, but is also a potent inhibitor of renin release, we studied the role of AII on renin inhibition and 12-HETE formation using rat renal cortical slices and isolated juxtaglomerular-like cells. In both preparations, 12-HETE was produced in a basal state. AII significantly inhibited renin release (control 100 +/- 3%, AII (10(8) M) 79 + 4%, P less than 0.01) and stimulated 12-HETE formation in slices (control 106 +/- 6%, AII 10(-8) M 177 +/- 18%, P less than 0.01) and in an enriched juxtaglomular cell preparation (control 96 +/- 3%, AII 10(-8) M 130 +/- 6%, P less than 0.001). A specific cyclooxygenase blocker, meclofenomate, or 5-LO blocker, U60,257, did not alter basal or AII-induced renin inhibition or 12-HETE formation by slices. The LO blockers BW755c, at 10(-5) M, or baicalein, 10(-6) M, did not significantly alter basal renin or 12-HETE levels, but BW755c at 10(-4) M, significantly stimulated basal renin (131 +/- 4%) and decreased basal 12-HETE levels (72 +/- 5%). However, both BW755c and baicalein blunted AII-induced renin inhibition (AII, 10(-8) M 70 +/- 3%, AII + BW755c, 10(-5) M 85 +/- 4%, P less than 0.02, AII + baicalein, 10(-6) M, 90 +/- 4%, P less than 0.005) and AII mediated 12-HETE formation (AII, 10(-8) M 150 +/- 5%, AII + BW755c, 10(-5) M 117 +/- 8%, P less than 0.02, AII + baicalein, 10(-6) M 110 +/- 3%, P less than 0.005). These results suggest that AII inhibition of renin is not mediated by the cyclooxygenase or 5-LO pathway, but rather by the 12-LO pathway. These findings reveal a new action for 12-LO products which may play a pivotal role in stimulus secretion coupling of renin secretion.     

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease

Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.     

The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes

Estrogens protect healthy women from cardiovascular disease. However, epidemiological data suggest that women with diabetes are denied the cardioprotection associated with estrogens. Whether or not hormonal replacement therapy (HRT) confers cardiovascular benefits in postmenopausal women with diabetes is not known. The aim of this study was to examine the effects of HRT on the microvascular reactivity and endothelial function of individuals with and without diabetes. We studied the following groups of individuals: premenopausal healthy women [n = 28, age 41 +/- 8 yr (mean +/- SD)], premenopausal women with type 2 diabetes (n = 16, age 43 +/- 6 yr); postmenopausal healthy women (n = 12, age 57 +/- 4 yr), postmenopausal women with diabetes (n = 17, age 62 +/- 5 yr); postmenopausal healthy women on HRT (n = 13, age 51 +/- 5 yr), postmenopausal women with diabetes on HRT (n = 11, age 57 +/- 7 yr). We used laser Doppler flowmetry to measure forearm cutaneous vasodilatation in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium independent). The endothelium-dependent vasodilation was significantly higher in premenopausal healthy women (180 +/- 67%; increase over baseline) compared to premenopausal diabetic women (87 +/- 41%; P < 0.001). endothelium-dependent vasodilation was also higher in postmenopausal healthy women on HRT (143 +/- 52) compared with postmenopausal diabetic women on HRT (86 +/- 61), postmenopausal healthy women without HRT (104 +/- 43), and postmenopausal diabetic women without HRT (74 +/- 28; P < 0.001). A similar pattern of responses was observed in the endothelium-independent vasodilation (premenopausal healthy women, 126 +/- 56; premenopausal diabetic women, 88 +/- 26; postmenopausal healthy women on HRT, 121 +/- 37; postmenopausal diabetic women on HRT, 88 +/- 41; postmenopausal healthy women without HRT, 84 +/- 36; and postmenopausal diabetic women without HRT, 73 +/- 36; P < 0.001). Soluble intercellular adhesion molecule (sICAM) was also measured among all the women with diabetes. Premenopausal women with diabetes (248.9 +/- 56 ng/ml) and postmenopausal women with diabetes on HRT (257.7 +/- 49 ng/ml) had lower sICAM levels compared with the postmenopausal diabetic women without HRT (346.4 +/- 149 ng/ml; P < 0.05). We conclude that menopausal status and type 2 diabetes are associated with impaired microvascular reactivity. HRT substantially improves microvascular reactivity in postmenopausal healthy women. In contrast, the effect of HRT on the microvascular reactivity of postmenopausal diabetic women is less apparent. However, the use of HRT among women with diabetes is associated with lower sICAM levels, suggesting an attenuation in endothelial activation.     

North and South: bridging the information gap

Information exchange is critical for development of health systems. The information needs of less-developed countries are especially challenging, but many factors inhibit free flow of knowledge. There is much talk about how technical fixes--such as the internet--might fill this information gap. Yet few attempts have been made to ask clinical investigators who work in resource-poor regions for their views on these difficulties and the possible solutions. The messages reported here, from a survey of Lancet editorial advisors, suggest that information, research, and publication capacities are intimately linked. Investigators, publishers, editors, and editorial organisations all have important parts to play in solving this global information poverty.     

Metabolic studies in human obesity during overnutrition and undernutrition: thermogenic and hormonal responses to norepinephrine

Overfeeding increases the thermogenic response of norepinephrine (NE) in normal but not in certain genetically obese rodents. It has been suggested that human obesity may be associated with a similar thermogenic defect. To determine whether there are differences in the thermogenic sensitivity to NE in human obesity, energy expenditure in response to graded infusions of NE (0.05, 0.10, 0.15, 0.20 micrograms/min/kg fat-free mass) was measured in six lean and six obese subjects (9.5 +/- 1.8 v 36.3 +/- 3.8% body fat P less than 0.005). Resting metabolic rate (RMR), thermogenic response to NE, and thermogenic response to exercise were measured during weight maintenance and during the third week of feeding 1000 extra Kcal/d in the lean and obese subjects. These components of energy expenditure were also measured in the obese subjects during the third week of a 589 Kcal/d diet. Resting metabolic rate increased during overfeeding in lean (6.6%, P less than 0.05) but not in the obese subjects (2.7%, P = NS) and fell during underfeeding in the obese (-9.1%, P less than 0.02). There was a logarithmic increment above baseline in VO2 v plasma NE concentration during the NE infusions (r = 0.75, P less than 0.005) in lean subjects which was unaltered by overfeeding. The obese exhibited equivalent VO2 responses to NE to that measured in the lean. Supine plasma NE concentrations were lower but metabolic clearance rates (MCR) of NE were similar in the obese compared to lean subjects during both weight maintenance and overfeeding. Overfeeding minimally increased plasma concentration but not MCR of NE in both groups. The thermogenic response to exercise was similar in the lean and obese subjects and was unaltered by overfeeding or underfeeding. The increments in plasma glycerol and free fatty acid in response to the NE infusions were proportional to the total fat mass of each individual and were greater in the obese subjects. Overfeeding partially suppressed the lipolytic response to NE in both groups and underfeeding increased the lipolytic response in the obese. There are no differences in thermogenic responses to NE in human obesity to account for excessive fat deposition. Overfeeding does not increase the thermogenetic responses to NE in humans as has been reported in small mammals.