Adrenocorticotropic hormone-responsive guanylate cyclase in the particulate fraction of rat adrenal glands

Low concentrations of ACTH, 7 x 10(-12) M, caused a marked stimulation of the 100,000 x g particulate guanylate cyclase without any detectable change in the adenylate cyclase activity. The lowest concentration of the hormone that elicited adenylate cyclase stimulation was 7 x 10(-10) M, a concentration 100--fold higher than that required to stimulate the guanylate cyclase. Although calcium was found to be obligatory in the hormonally--dependent guanylate cyclase activity, calcium alone could not duplicate the ACTH effect. Sodium nitroprusside and ascorbic acid inhibited the particulate guanylate cyclase activity. While ACTH was unable to stimulate the soluble guanylate cyclase, sodium nitroprusside markedly stimulated this enzyme. From these data, we conclude that the adrenal guanylate cyclase exists in two forms, particulate and soluble. The particulate form is specifically responsive to ACTH, and calcium is one of the essential coupling factors of this hormonally--responsive guanylate cyclase.     

STRL33, A Novel Chemokine Receptor–like Protein, Functions as a Fusion Cofactor for Both Macrophage-tropic and T Cell Line–tropic HIV-1

The chemokine receptors CXCR4, CCR2B, CCR3, and CCR5 have recently been shown to serve along with CD4 as coreceptors for HIV-1. The tropisms of HIV-1 strains for subgroups of CD4⁺ cells can be explained, at least partly, by the selective use of G protein–coupled receptors (GPCRs). We have identified a novel human gene, STRL33, located on chromosome 3 that encodes a GPCR with sequence similarity to chemokine receptors and to chemokine receptor–like orphan receptors. STRL33 is expressed in lymphoid tissues and activated T cells, and is induced in activated peripheral blood lymphocytes. When transfected into nonhuman NIH 3T3 cells expressing human CD4, the STRL33 cDNA rendered these cells competent to fuse with cells expressing HIV-1 envelope glycoproteins (Envs). Of greatest interest, STRL33, in contrast with CXCR4 or CCR5, was able to function as a cofactor for fusion mediated by Envs from both T cell line–tropic and macrophage-tropic HIV-1 strains. STRL33-transfected Jurkat cell lines also supported enhanced productive infection with HIV-1 compared with control Jurkat cells. Despite the sequence similarities between STRL33 and chemokine receptors, STRL33-transfected cell lines did not respond to any in a panel of chemokines. Based on the pattern of tissue expression of the STRL33 mRNA, and given the ability of STRL33 to function with Envs of differing tropisms, STRL33 may play a role in the establishment and/or progression of HIV-1 infection.     

Design considerations for a study to evaluate the impact of smoking cessation treatment on stimulant use outcomes in stimulant-dependent individuals

Cigarette smoking is prevalent in cocaine/methamphetamine-dependent patients and associated with significant morbidity and mortality, yet, the provision of smoking cessation treatment in conjunction with substance use disorder (SUD) treatment is not standard practice. This is due, in part, to clinician concern that combining smoking cessation treatment with SUD treatment could lead to poorer SUD outcomes. The NIDA Clinical Trials Network is conducting a 10-week, two-group, randomized trial to evaluate the impact of providing smoking cessation treatment (SCT) with SUD treatment as usual (TAU), compared to TAU alone, in smokers who are in outpatient treatment for cocaine or methamphetamine dependence. Approximately 528 participants, recruited from 12 community treatment programs, will be randomized into the trial. The present paper describes key design decisions made during protocol development. The trial is designed to evaluate the relationship between cigarette smoking and stimulant use, which prior research suggests is linked, and should contribute to our understanding of how best to address the co-occurring problems of nicotine dependence and cocaine/methamphetamine-dependence. Unique aspects of the trial include the primary question of interest, which concerns the impact of providing SCT on SUD outcomes rather than on smoking outcomes, and the intensity of the SCT chosen, which includes bupropion, nicotine replacement, and two psychosocial interventions.     

False‐positive stress testing: Does endothelial vascular dysfunction contribute to ST‐segment depression in women? A pilot study

Background

The utility of exercise‐induced ST‐segment depression for diagnosing ischemic heart disease (IHD) in women is unclear.

Hypothesis

Based on evidence that IHD pathophysiology in women involves coronary vascular dysfunction, we hypothesized that coronary vascular dysfunction contributes to exercise electrocardiography (Ex‐ECG) ST‐depression in the absence of obstructive coronary artery disease, so‐called false positive results. We tested our hypothesis in a pilot study evaluating the relationship between peripheral vascular endothelial function and Ex‐ECG.

Methods

Twenty‐nine asymptomatic women without cardiac risk factors underwent maximal Bruce protocol exercise treadmill testing and peripheral endothelial function assessment using peripheral arterial tonometry (Itamar EndoPAT 2000) to measure reactive hyperemia index (RHI). The relationship between RHI and Ex‐ECG ST‐segment depression was evaluated using logistic regression and differences in subgroups using 2‐tailed t tests.

Results

Mean age was 54 ± 7 years, body mass index 25 ± 4 kg/m², and RHI 2.51 ± 0.66. Three women (10%) had RHI <1.68, consistent with abnormal peripheral endothelial function, whereas 18 women (62%) met criteria for positive Ex‐ECG based on ST‐segment depression in contiguous leads. Women with and without ST‐segment depression had similar baseline and exercise vital signs, metabolic equivalents achieved, and RHI (all P > 0.05). RHI did not predict ST‐segment depression.

Conclusions

Our pilot study demonstrates high prevalence of exercise‐induced ST‐segment depression in asymptomatic, middle‐aged, overweight women. Peripheral vascular endothelial dysfunction did not predict Ex‐ECG ST‐segment depression. Further work is needed to investigate the utility of vascular endothelial testing and Ex‐ECG for IHD diagnostic and management purposes in women.     

Liver transplantation and atrial fibrillation: A meta-analysis

AIM To assess prevalence of pre-existing atrial fibrillation(AF) and/or incidence of AF following liver transplantation, and the trends of patient's outcomes overtime; to evaluate impact of pre-existing AF and post-operative AF on patient outcomes following liver transplantation. METHODS A literature search was conducted utilizing MEDLINE, EMBASE and Cochrane Database from inception throughMarch 2018. We included studies that reported:(1) prevalence of pre-existing AF or incidence of AF following liver transplantation; or(2) outcomes of liver transplant recipients with AF. Effect estimates from the individual study were extracted and combined utilizing randomeffect, generic inverse variance method of DerSimonian and Laird. The protocol for this meta-analysis is registered with PROSPERO(International Prospective Register of Systematic Reviews, No. CRD42018093644). RESULTS Twelve observational studies with a total of 38586 liver transplant patients were enrolled. Overall, the pooled estimated prevalence of pre-existing AF in patients undergoing liver transplantation was 5.4%(95%CI: 4.9%-5.9%) and pooled estimated incidence of AF following liver transplantation was 8.5%(95%CI: 5.2%-13.6%). Meta-regression analyses were performed and showed no significant correlations between year of study and either prevalence of pre-existing AF(P = 0.08) or post-operative AF after liver transplantation(P = 0.54). The pooled OR of mortality among liver transplant recipients with pre-existing AF was 2.34(2 studies; 95%CI: 1.10-5.00). In addition, pre-existing AF is associated with postoperative cardiovascular complications among liver transplant recipients(3 studies; OR: 5.15, 95%CI: 2.67-9.92, I2 = 64%). With limited studies, two studies suggested significant association between new-onset AF and poor clinical outcomes including mortality, cerebrovascular events, post-transplant acute kidney injury, and increased risk of graft failure among liver transplant recipients(P 0.05).CONCLUSION The overall estimated prevalence of pre-existing AF and incidence of AF following liver transplantation are 5.4% and 8.5%, respectively. Incidence of AF following liver transplant does not seem to decrease overtime. Preexisting AF and new-onset AF are potentially associated with poor clinical outcomes post liver transplantation.     

Left ventricular angiography on exercise. A new method of assessing left ventricular function in ischaemic heart disease.

Left ventricular function was studied in 17 patients with ischaemic heart disease and compared with 4 patients with normal left ventricular function. The patients in the homogeneous group of ischaemic heart disease were further subdivided into those 'without angina' (n=5) and those 'with angina' (n=12), depending upon the presence of angina during supine leg exercise at the time of definitive study. At rest there was no significant difference in the heart rate, cardiac output, stroke volume, and left ventricular end-diastolic pressure (LVEDP) in the three groups. During exercise the cardiac output and stroke volume were significantly depressed and LVEDP was significantly raised in the ischaemic heart disease group as a whole but within this group failed to show any significant difference in patients with and without angina. The left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) measurements showed clear separation of these three groups only on exercise. On exercise, there was decrease in LVEDV and LVESV (P less than 0.05; P less than 0.02) in the group with normal left ventricular function, no change in the group with ischaemic heart disease without angina, and striking increase in LVEDV and LVESV in the group with ischaemic heart disease and angina (P less than 0.01 and P less than 0.02, respectively). This angiographic method of assessing left ventricular function shows clear separation of the three groups and also highlights the significance of angina. Ejection fraction (EF), a commonly measured parameter of left ventricular function, failed to reflect consistent changes on exercise as compared to values at rest which emphasizes the limitations of the measurement of ejection fraction at rest.     

Devastating salt‐wasting crisis in a four‐month‐old male child with congenital adrenal hyperplasia,highlighting the essence of neonatal screening

Congenital adrenal hyperplasia (CAH) is a rare condition usually referred to as a group of genetic disorders resulting due to a deficiency of steroid enzymes required by adrenal glands to produce cortisol and mineralocorticoid hormones. It has an autosomal recessive mode of inheritance and is further categorized into two types—Classic and Non‐Classic. Non‐Classic CAH is a more common milder form that presents late after puberty. Classic CAH, although more severe, is rare and detected at birth and is associated with the life‐threatening adrenal crisis in both sexes and virilization of the external genitalia in females (46, XX) patients, whereas in males, no overt abnormality of the external genitalia is present. We present a case of a four‐month‐old male child with the classic form of CAH who was brought with complaints of loose stools, projectile non bilious vomiting, decreased urine output, and failure to feed for 3 days. The child had a clinical presentation of salt wasting with hypoglycemia and hyperpigmentation of his genitalia. The USG findings revealed increased anteroposterior diameter of renal pelvis indicative of a growth in the suprarenal area. 17‐hydroxyprogesterone (17‐OHP) was found to be elevated confirming the diagnosis. He was treated with hydrocortisone with gradual improvement in his glucose and electrolytes. The patient was discharged home on replacement therapy consisting of oral prednisolone and fludrocortisone acetate and followed up as outpatient with significant improvement in the clinical findings. The fact that the child was not screened for CAH at birth led to the critical consequences of the disease in this case. To prevent life‐threatening adrenal crisis and help perform appropriate sex assignments for affected female patients, newborn screening (NBS) programs for the classical form of CAH should be made mandatory even in low‐ and middle‐income countries.     

Fas-mediated apoptosis of neutrophils in sera of patients with infection

In the presence of infection, neutropenia is considered to be a marker of poor prognosis; conversely, neutrophilia may not be a determinant of a better prognosis. Since apoptotic neutrophils are compromised functionally, we evaluated the effect of infection on neutrophil apoptosis. The rate of apoptosis was greater for neutrophils isolated from patients with infection than for healthy controls. Escherichia coli did not directly modulate the rate of neutrophil apoptosis. However, sera from infected patients promoted (P < 0.001) neutrophil apoptosis. Interestingly, the sera of patients with different types of infection (gram negative, gram positive, or culture negative) exerted a more or less identical response on neutrophil apoptosis. Sera of infected patients showed a fivefold greater content of FasL compared to controls. Moreover, anti-FasL antibody partly attenuated the infected-serum-induced neutrophil apoptosis. In in vitro studies, E. coli enhanced monocyte FasL expression. Moreover, conditioned media prepared from activated macrophages from control mice showed enhanced apoptosis of human as well as mouse neutrophils. On the contrary, conditioned media prepared from activated macrophages isolated from FasL-deficient mice induced only a mild degree of neutrophil apoptosis. These results suggest that neutrophils in patients with infection undergo apoptosis at an accelerated rate. Infection not only promoted monocyte expression of FasL but also increased FasL content of the serum. Because the functional status of apoptotic cells is compromised, a significant number of neutrophils may not be participating in the body's defense. Since neutrophils play the most important role in innate immunity, their compromised status in the presence of infection may transfer the host defense burden from an innate response to acquired immunity. The present study provides some insight into the lack of correlation between neutrophilia and the outcome of infection.     

Modification of gamma ray induced changes in the mouse hepatocytes by Centella asiatica extract: in vivo studies

Ionizing radiation, besides causing direct damage also generates reactive oxygen species that are capable of inducing damage to various organs. Pretreatment with Centella asiatica 1 h prior to irradiation at a dose rate of 100 mg/kg body weight was found to be effective against radiation induced damage in the liver. The number of normal hepatocytes was higher in the Centella asiatica pretreated group in comparison with the irradiated only group. The number of binucleated cells and abnormal hepatocytes was less in comparison with the animals irradiated without Centella asiatica pretreatment.