"Stem cell" origin of the hematopoietic defect in dyskeratosis congenita

We have used the long-term bone marrow culture (LTBMC) system to analyze hematopoiesis in three patients with dyskeratosis congenita (DC), two of whom had aplastic anemia, and the third had a normal blood count (apart from mild macrocytosis) and normal BM cellularity. Hematopoiesis was severely defective in all three patients, as measured by a low incidence of colony-forming cells and a low level of hematopoiesis in LTBMC. The function of the marrow stroma was normal in its ability to support the growth of hematopoietic progenitors from normal marrows seeded onto them in all three cases, but the generation of hematopoietic progenitors from patients marrow cells inoculated onto normal stromas was reduced, thus suggesting the defect to be of stem cell origin. The parents and unaffected brother of one of the families have also been studied in LTBMC and all showed normal hematopoietic and stromal cell function. From this study we speculate that there are some similarities between DC and the defect in the W/Wv mouse.     

Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease

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Epidemiology of Confirmed COVID-19 Deaths in Adults,England, March–December 2020

Of the 58,186 coronavirus deaths among adults in England during March–December 2020, 77% occurred in hospitals, 93% were in patients >60 years, and 91% occurred within 28 days of positive specimen. Cumulative mortality rates were highest among persons of Black, Asian, other, or mixed ethnicities and in socioeconomically deprived areas.     

From recipe to research: introducing undergraduate students to the nature of science using a hybrid practical course centred on drug discovery for neglected diseases

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What is the most cost-effective strategy to screen for left ventricular systolic dysfunction: natriuretic peptides, the electrocardiogram, hand-held echocardiography, traditional echocardiography, or their combination?

AIMS: To assess the screening characteristics and cost-effectiveness of screening for left ventricular systolic dysfunction (LVSD) in community subjects. METHODS AND RESULTS: A total of 1392 members of the general public and 928 higher risk subjects were randomly selected from seven community practices. Attending subjects underwent an ECG, N-terminal pro-brain natriuretic peptide (NTproBNP) serum levels, and traditional echocardiography (TE). A total of 533 consecutive subjects underwent hand-held echocardiography (HE). The screening characteristics and cost-effectiveness (cost per case of LVSD diagnosed) of eight strategies to predict LVSD (LVSD <45% on TE) were compared. A total of 1205 subjects attended. Ninety six per cent of subjects with LVSD in the general population had identifiable risk factors. All screening strategies gave excellent negative predictive value. Screening high-risk subjects was most cost-effective, screening low-risk subjects least cost-effective. TE screening was the least cost-effective strategy. NTproBNP screening gave similar cost savings to ECG screening; HE screening greater cost-savings, and HE screening following NTproBNP or ECG pre-screening the greatest cost-savings, costing approximately 650 Euros per case of LVSD diagnosed in high-risk subjects (63% cost-savings vs.TE). CONCLUSION: Thus several different modalities allow cost-effective community-based screening for LVSD, especially in high-risk subjects. Such programmes would be cost-effective and miss few cases of LVSD in the community.     

Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure.

AIMS: Although cardiac sympathetic activation is associated with adverse outcome in patients with chronic heart failure (CHF), the influence of renal sympathetic activity on outcome is unknown. We assessed the hypothesis that renal noradrenaline (NA) spillover is a predictor of the combined endpoint of all-cause mortality and heart transplantation in CHF. METHODS AND RESULTS: Sixty-one patients with CHF, New York Heart Association (NYHA) I-IV (66% NYHA III-IV), and left ventricular ejection fraction (LVEF) 26+/-9% (mean+/-SD) were studied with cardiac and renal catheterizations at baseline and followed for 5.5+/-3.7 years (median 5.5 years, range 12 days to 11.6 years). Nineteen deaths and 13 cases of heart transplantation were registered. Only renal NA spillover above median, 1.19 (interquartile range 0.77-1.43) nmol/min, was independently associated with an increased relative risk (RR) of the combined endpoint (RR 3.1, 95% CI 1.2-7.6, P=0.01) in a model also including total body NA spillover, LVEF, glomerular filtration rate (GFR), renal blood flow, cardiac index, aetiology, and age. CONCLUSION: Renal noradrenergic activation has a strong negative predictive value on outcome independent of overall sympathetic activity, GFR, and LVEF. These findings suggest that treatment regimens that further reduce renal noradrenergic stimulation could be advantageous by improving survival in patients with CHF.     

Effect of portal hypertension onIn Vivo bile acid-mediated small intestinal mucosal injury in the rat

This study's purpose was to determine whether portal hypertension adversely affects small intestinal mucosal injury. Portal hypertension was produced in male Sprague-Dawley rats by two-stage ligation of the portal vein. Sham-operated rats were used as controls. Two weeks later, intestinal injury was produced byin vivo perfusion with 5 mM chenodeoxycholic acid for 30 min. Intestinal injury was assessed by quantitative morphometry and by measuring intestinal water and mannitol absorption. Portal hypertension resulted in more injury in the distal perfused intestine as manifested by increased villus tip denudation [portal hypertensive 52.5±9.6sem) vs controls 28.1±5.7m, P=0.05). Additionally there was a significant decrease in the unperfused duodenal villus height in portal hypertensive rats (portal hypertensive 755±22 vs controls 848±28m, P<0.02). Portal hypertension had no significant effect on the increase in mannitol absorption or water secretion caused by chenodeoxycholic acid perfusion. This study suggests that portal hypertension alters small intestinal mucosa and increases susceptibility to injury.This work was supported in part by a grant from the Research Service of the Veterans Administration.     

Gender-specific brachial artery blood pressure-independent relationship between pulse wave velocity and left ventricular mass index in a group of African ancestry

AIM: As it is uncertain whether arterial stiffness is related to left ventricular mass and left ventricle mean wall thickness independent of blood pressure measured at the brachial artery, we aimed to ascertain this effect in never-treated participants with a high prevalence of risk factors for large artery dysfunction. METHODS: The conventional and ambulatory blood pressure-independent relations between indices of large artery function and either left ventricular mass or mean wall thickness were determined in 309 never-treated randomly recruited South Africans of African ancestry with prevalent risk factors for large artery changes [24% were hypertensive, 63% were overweight/obese, and 17% had diabetes mellitus or abnormal blood glucose control (glycosylated hemoglobin A1c > 6.1%)]. Large artery function was assessed from applanation tonometry performed at the carotid, radial and femoral arteries and central augmentation index and aortic pulse wave velocity (carotid femoral pulse wave velocity) derived from these measures. Left ventricular mass indexed for height (left ventricular mass index) and mean wall thickness were determined using echocardiography. RESULTS: Pulse wave velocity was associated with left ventricular mass index (r = 0.67, P < 0.0001) and mean wall thickness (r = 0.61, P < 0.0001) in women, but not in men (r = 0.04-0.08) (P < 0.0001 for the interaction between pulse wave velocity and gender). On multivariate analysis with appropriate adjustments including either conventional systolic blood pressure, pulse pressure or mean arterial pressure, pulse wave velocity was independently associated with left ventricular mass index (partial r = 0.25, P < 0.005 after adjustments for systolic blood pressure) and with mean wall thickness (partial r = 0.17, P < 0.05 after adjustments for systolic blood pressure) in women, but not in men. With the inclusion of 24-h ambulatory rather than conventional systolic blood pressure, pulse pressure or mean arterial pressure in the regression equation, pulse wave velocity was similarly independently associated with left ventricular mass index (partial r = 0.39, P < 0.001 after adjustments for 24-h systolic blood pressure) and mean wall thickness (partial r = 0.33, P < 0.003 after adjustments for 24-h systolic blood pressure) in women, but not in men. Central augmentation index was not independently associated with left ventricular mass index or mean wall thickness. In women, the contribution of pulse wave velocity to left ventricular mass index or mean wall thickness independent of systolic blood pressure (standardized beta-coefficient for left ventricular mass index=0.37 +/- 0.13, P < 0.005) was equivalent to the contribution of systolic blood pressure (standardized beta-coefficient for left ventricular mass index = 0.38 +/- 0.13, P < 0.005). Moreover, after adjusting for clinic or ambulatory systolic blood pressure and other confounders, in women every one standard deviation increase in pulse wave velocity (2.1 m/s) translated into a 4.3 or 6.2 g/m increase in left ventricular mass index, respectively. CONCLUSION: Arterial stiffness is associated with left ventricular mass index and left ventricle wall thickness independent of conventional or ambulatory blood pressure and additional confounders in a never-treated population sample of women, but not men, of African ancestry with prevalent risk factors for large artery dysfunction.     

Longitudinal changes in the well-being of Japanese caregivers: variations across kin relationships

This study examined how the psychological well-being of Japanese caregivers changed over time; it also examined the variation across kin relationships with care recipients. Three interviews over the course of 30 months were conducted with a representative sample of community-dwelling caregivers of frail elderly persons living in a Tokyo suburb. Latent growth modeling demonstrated that mean levels of both depression and emotional exhaustion worsened over time. Change in emotional exhaustion over time showed significant individual variability, whereas change in depression showed little individual variability. Although wife caregivers tended to experience the worst trajectory of emotional exhaustion, daughters-in-law also showed a similar negative trend. The difference in individuals' well-being trajectories by kinship may be explained partly by differences in care recipients' disabilities.     

Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential therapeutic value against cancers because of its selective cytotoxicity to many transformed, but not normal, cells. The "decoy receptors" TRAIL-R3 (TR3) and TRAIL-R4 (TR4) were believed to negatively regulate TRAIL-induced cytotoxicity by competing for ligand binding with TRAIL-R1 (TR1) and TRAIL-R2 (TR2). Here, we show that inhibition of TRAIL-induced apoptosis by TR4 critically depends on its association with TR2 via the NH(2)-terminal preligand assembly domain overlapping the first partial cysteine-rich domain of both receptors. By contrast, ligand binding by TR4 is dispensable for its apoptosis inhibitory function, thereby excluding the possibility that TR4 was a "decoy" to inhibit apoptosis by binding up TRAIL. In primary CD8(+) T cells, which express only TR2 and TR4 and are resistant to TRAIL-induced apoptosis, stimulation with phorbol myristate acetate abrogated the ligand-independent interaction between TR2 and TR4 and enhanced their sensitivity to TRAIL-induced apoptosis. Hence, whereas most TNF receptors normally form only homotrimeric complexes, the preligand assembly domains in TR2 and TR4 permit mixed complex formation as a means to regulate apoptosis induction. We propose that TR4 is a "regulatory" rather than "decoy" receptor that inhibits apoptosis signaling by TRAIL through this previously uncharacterized ligand-independent mechanism.