Cocaine reduces thymic endocrine function: another mechanism for accelerated HIV disease progression

Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4(+) cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4(+) cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4(+) and CD8(+) cell counts and the CD4(+)/CD8(+) ratio, and the covariate effects of substance use cross-sectionally in 80 HIV(+) active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (β = -0.908,95% CI: -1.704, -0.112; p = 0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR = 0.634, 95% CI: 0.406, 0.989 p = 0.045) and were 75 times more likely to show a decrease in thymulin activity (OR = 74.7, 95% CI: 1.59, 3519.74; p = 0.028) over time. CD4(+) cell count was positively associated with thymulin activity (β = 0.127, 95% CI: 0.048,0.205; p = 0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4 cell count ≥200 cells/μl (RR = 2.324, 95% CI: 1.196, 4.513, p = 0.013), and those with an increase in CD4 cell counts were more likely to show an increase in thymulin activity (OR = 1.02, 95% CI: 1.00, 1.034; p = 0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides opportunities to find alternative strategies to counteract immunosuppression.     

Dual chamber pacing in hypertrophic cardiomyopathy: long-term effects on diastolic function

To assess the effects of chronic dual chamber pacing (DDD) on LV diastolic function in obstructive hypertrophic cardiomyopathy (HCM), 21 patients with obstructive HCM paced for refractory symptoms were studied at baseline and at 3 and 12 months. HCM patients were matched to 21 patients with obstructive HCM on conventional treatment. Left atrial fractional shortening was calculated by M-mode echocardiography; this index reflects LV end-diastolic pressure. LV outflow tract gradient decreased 65 +/- 21% with DDD pacing and the NYHA class improved (P = 0.033). Left atrial fractional shortening worsened with DDD pacing (P < 0.001). Patients with abnormal baseline left atrial fractional shortening (< 16%) were older, had a higher NYHA class, and had more severe mitral regurgitation. In this subgroup, left atrialfractional shortening did not worsen with DDD pacing and the NYHA class improved more than in patients with normal left atrialfractional shortening (P = 0.033). In conclusion, chronic DDD pacing reduces obstruction but impairs diastolic function in HCM. In patients with normal diastolic function, the untoward effects of pacing on diastolic function are more evident than in patients with abnormal diastolic function at baseline. This suggests that DDD pacing might be beneficial in a subgroup of patients with obstructive HCM and abnormal diastolic function.     

The dynamic and complex role of mast cells in allergic disease

Mast cells (MCs) are found widely distributed in tissues and contribute to regulation of inflammatory responses and ongoing modulation of the tissues. Although MCs are important in a variety of processes, including innate immunity, their role in allergic disease has received increasing attention in the past decade. MCs are located throughout the human body and, upon allergen exposure, they are stimulated via the immunoglobulin E (IgE) receptor (Fc(epsilon)RI) to release several pro-inflammatory mediators such as tumor necrosis factor (TNF), reactive oxygen species such as nitric oxide (NO), proteases, and lipid-derived mediators. However, we now recognize that MCs can be activated by a variety of mechanisms and that mediator release is a consequence of several intra- and extracellular signals. Some of these mechanisms, such as Fc receptor aggregation and proteinase-activated receptor (PAR)-mediated activation facilitate and augment local inflammatory responses. Other mechanisms, such as interferon gamma (IFN-gamma) induction of NO, may inhibit MC function and downregulate inflammatory responses. Increased understanding of these complex pathways has encouraged the development of therapies for allergic inflammation that target specific MC functions and mediators. Some novel strategies include oligonucleotides that induce or inhibit the production of specific mediators. Such approaches may yield useful therapies for allergic individuals in the near future.     

Computed tomography and magnetic resonance imaging in the assessment of acute pancreatitis

BACKGROUND & AIMS: This study aimed to compare the accuracy of magnetic resonance imaging (MRI) with computed tomography (CT) in assessing acute pancreatitis (AP) and to explore the correlation between MRI findings and clinical outcome. METHODS: Patients with AP were investigated by contrast-enhanced CT and MRI on admission and 7 and 30 days thereafter. MRI was performed with intravenous secretin and contrast medium. Balthazar's grading system was used to measure CT and MRI severity indices (CTSI and MRSI, respectively). RESULTS: Thirty-nine patients (median age, 47 years; range, 15-86) were studied. AP was of biliary etiology in 19 patients (49%). On admission, AP was assessed clinically as severe in 7 patients (18%). A strong correlation was demonstrated between CTSI and MRSI on admission and 7 days later. MRSI on admission correlated with the following: the Ranson score, C-reactive protein levels 48 hours after admission, duration of hospitalization, and clinical outcome regarding morbidity, including local and systemic complications. Considering the Ranson score as the gold standard, MRI detected severe AP with 83% (58-96, 95% CI) sensitivity, 91% (68-98) specificity vs. 78% (52-93) and 86% (63-96) for CT. Magnetic resonance cholangiopancreatography after i.v. secretin injection showed pancreatic duct leakage in 3 patients (8%). CONCLUSIONS: MRI is a reliable method of staging AP severity, has predictive value for the prognosis of the disease, and has fewer contraindications than CT. It can also detect pancreatic duct disruption, which may occur early in the course of AP.     

Characterization of soluble glycoprotein D-mediated herpes simplex virus type 1 infection

Herpes simplex virus type 1 (HSV-1) entry into permissive cells involves attachment to cell-surface glycosaminoglycans (GAGs) and fusion of the virus envelope with the cell membrane triggered by the binding of glycoprotein D (gD) to cognate receptors. In this study, we characterized the observation that soluble forms of the gD ectodomain (sgD) can mediate entry of gD-deficient HSV-1. We examined the efficiency and receptor specificity of this activity and used sequential incubation protocols to determine the order and stability of the initial interactions required for entry. Surprisingly, virus binding to GAGs did not increase the efficiency of sgD-mediated entry and gD-deficient virus was capable of attaching to GAG-deficient cells in the absence of sgD. These observations suggested a novel binding interaction that may play a role in normal HSV infection.     

Modulating effects of nonselective and selective phosphodiesterase inhibitors on lymphocyte subsets and humoral immune response in mice

Phosphodiesterase (PDE) inhibitors can regulate the activity of immune cells by increasing intracellular levels of cyclic nucleotides. The aim of this study was to determine the effects of milrinone, a selective PDE3 inhibitor, sildenafil, a selective PDE5 inhibitor, and aminophylline, a nonselective PDE inhibitor, on lymphocyte subsets and humoral immune response in mice when administered in vivo. Aminophylline (20 mg/kg, i.m.), milrinone (1 mg/kg, i.m.) or sildenafil (1 mg/kg, p.o.) were administered to mice either once or five times at 24 h intervals. Some mice were immunized with a sheep red blood cell (SRBC) suspension administered i.p. either 2 h after the single dose or 2 h after the second of the five doses. In non-immunized mice treated five times with PDE inhibitors, the subsets of T lymphocytes in the thymus and T and B lymphocytes in the spleen and mesenteric lymph nodes were determined 12, 24 or 72 h after the last dose. The humoral immune response was determined on days 4, 7 and 14 after SRBC injection in SRBC-immunized mice treated with PDE inhibitors. A modulating effect of the drugs on lymphocyte subpopulations was observed. The greatest impact was observed in splenocyte subpopulations, and resulted in decreased percentages of B cells (CD19(+)) and increased percentages of T cells (CD3(+), CD4(+), CD8(+)). No effect or slight influence of the drugs on anti-SRBC hemagglutinins was observed, but the number of plaque-forming splenocytes was increased. The drugs under investigation did not show a significant immunosuppressive effect.     

Association Between Smoking and SARS-CoV-2 Infection: Cross-sectional Study of the EPICOVID19 Internet-Based Survey

BackgroundSeveral studies have reported a low prevalence of current smoking among hospitalized COVID-19 cases; however, no definitive conclusions can be drawn.ObjectiveWe investigated the association of tobacco smoke exposure with nasopharyngeal swab (NPS) test results for SARS-CoV-2 infection and disease severity accounting for possible confounders.MethodsThe nationwide, self-administered, cross-sectional web-based Italian National Epidemiological Survey on COVID-19 (EPICOVID19) was administered to an Italian population of 198,822 adult volunteers who filled in an online questionnaire between April 13 and June 2, 2020. For this study, we analyzed 6857 individuals with known NPS test results. The associations of smoking status and the dose-response relationship with a positive NPS test result and infection severity were calculated as odds ratios (ORs) with 95% CIs by means of logistic and multinomial regression models adjusting for sociodemographic, clinical, and behavioral characteristics.ResultsOut of the 6857 individuals (mean age 47.9 years, SD 14.1; 4516/6857, 65.9% female), 63.2% (4334/6857) had never smoked, 21.3% (1463/6857) were former smokers, and 15.5% (1060/6857) were current smokers. Compared to nonsmokers, current smokers were younger, were more educated, were less affected by chronic diseases, reported COVID-19–like symptoms less frequently, were less frequently hospitalized, and less frequently tested positive for COVID-19. In multivariate analysis, current smokers had almost half the odds of a positive NPS test result (OR 0.54, 95% CI 0.45-0.65) compared to nonsmokers. We also found a dose-dependent relationship with tobacco smoke: mild smokers (adjusted OR [aOR] 0.76, 95% CI 0.55-1.05), moderate smokers (aOR 0.56, 95% CI 0.42-0.73), and heavy smokers (aOR 0.38, 95% CI 0.27-0.53). This inverse association also persisted when considering the severity of the infection. Current smokers had a statistically significantly lower probability of having asymptomatic (aOR 0.50, 95% CI 0.27-0.92), mild (aOR 0.65, 95% CI 0.53-0.81), and severe infections (aOR 0.27, 95% CI 0.17-0.42) compared to those who never smoked.ConclusionsCurrent smoking was negatively associated with SARS-CoV-2 infection with a dose-dependent relationship. Ad hoc experimental studies are needed to elucidate the mechanisms underlying this association.Trial RegistrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04471701","term_id":"NCT04471701"}}NCT04471701; https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT04471701","term_id":"NCT04471701"}}NCT04471701     

In Controlled Ovarian Hyperstimulation, Steroid Production, Oocyte Retrieval, and Pregnancy Rate Correlate with Gene Expression of Vascular Endothelial Growth Factor

Purpose: Whether the gene expression of vascular endothelial growth factor (VEGF) in human granulosa cells is a predictor of fertilization was evaluated in patients participating in an in vitro fertilization program. Methods: Fifty patients with normal ovaries who were participating in an in vitro fertilization program at the University of Milan, San Raffaele Scientific Institute, were included in the study. We correlated E ₂ and P serum levels on the day of oocyte collection, the number of follicles, oocytes collected, and fertilized, and pregnancies with mRNA for VEGF of luteinizing granulosa cells obtained at the time of oocyte retrieval. Results: Comparing E ₂ and P serum levels, the number of follicles, oocytes collected and fertilized, and pregnancies with gene expression for VEGF, we found a positive correlation. E ₂ and P serum levels were higher in patients with increased VEGF (P < 0.01). Furthermore, there were more follicles, oocytes collected and fertilized, and pregnancies in patients with maximum expression of VEGF, and the difference was statistically significant (P < 0.05). Conclusions: Our results suggest that VEGF may be important for vascular development during follicular growth and luteal differentiation, oocyte maturation, and fertilization.