Shear-dependent attenuation of cellular ROS levels can suppress proinflammatory cytokine injury to human brain microvascular endothelial barrier properties

The regulatory interplay between laminar shear stress and proinflammatory cytokines during homeostatic maintenance of the brain microvascular endothelium is largely undefined. We hypothesized that laminar shear could counteract the injurious actions of proinflammatory cytokines on human brain microvascular endothelial cell (HBMvEC) barrier properties, in-part through suppression of cellular redox signaling. For these investigations, HBMvECs were exposed to either shear stress (8 dynes/cm², 24 hours) or cytokines (tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6), 0 to 100 ng/mL, 6 or 18 hours). Human brain microvascular endothelial cell ‘preshearing''±cytokine exposure was also performed. Either cytokine dose–dependently decreased expression and increased phosphorylation (pTyr/pThr) of interendothelial occludin, claudin-5, and vascular endothelial-cadherin; observations directly correlating to endothelial barrier reduction, and in precise contrast to effects seen with shear. We further observed that, relative to unsheared cells, HBMvECs presheared for 24 hours exhibited significantly reduced reactive oxygen species production and barrier permeabilization in response to either TNF-α or IL-6 treatment. Shear also downregulated NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) activation in HBMvECs, as manifested in the reduced expression and coassociation of gp91phox and p47phox. These findings lead us to conclude that physiologic shear can protect the brain microvascular endothelium from injurious cytokine effects on interendothelial junctions and barrier function by regulating the cellular redox state in-part through NADPH oxidase inhibition.     

A comparison of total, respirable, and real-time airborne particulate sampling in horse barns

Measurements of total, respirable, and real-time airborne particulate were obtained in 12 horse barns in summer and winter. Respirable and total particulate concentrations were measured gravimetrically; real-time particulate was measured with an aerosol photometer. Total particulate (TP) ranged from nondetectable (ND) to 2.1 mg/m3 and from ND to 1.2 mg/m3 for winter and summer sampling, respectively. Respirable particulate (RP) ranged from ND to 0.2 mg/m3 and from ND to 0.7 mg/m3 for winter and summer measurements, respectively. The mean respirable fraction of particulate for summer and winter measurements was 0.63 and 0.34, respectively Real-time particulate (RTP) concentration was significantly correlated with TP for winter measurements and for pooled data but was not significantly correlated with RP for winter, summer, or pooled measurements. Peak, 10-sec average levels of RTP were estimated to range up to 22 mg/m3 in the samples collected. The data suggest that (a) airborne particulate concentrations and particle size distributions vary considerably among horse barns, and (b) real-time sampling, with an aerosol photometer, may be a more reliable measure of airborne TP than airborne RP in these environments.     

Incentive program decreases no-shows in nontreatment substance abuse research

This study examined the use of a low-cost incentive program to decrease the rate of unanticipated no-shows in a nontreatment study of the genetics of substance dependence. Low-cost retail items (such as calling cards or gift certificates) were offered contingent on attendance at the first scheduled research appointment. Although the intervention did not result in an increase in the rate of attendance at appointments, it reduced the likelihood of unanticipated no-shows by almost 50%. This reduction was accompanied by a significant increase in advance cancellations. Despite limitations due to the study's A-B design, this research demonstrates that it may be possible to use modest incentives to increase the efficiency of research enrollment and increase service provision for substance abusers.     

Wide excision without radiation for desmoplastic melanoma

BACKGROUND: Adjuvant radiation has been proposed for the treatment of patients with desmoplastic melanoma, who reportedly have local recurrence rates as high as 40-60%. The authors investigated local recurrence rates at a tertiary referral center to determine the success of wide excision alone for patients with desmoplastic melanoma. METHODS: A review of a prospectively maintained melanoma clinical data base identified 65 patients between March 1997 and March 2004 with pure cutaneous desmoplastic melanoma. Complete surgical, histopathologic, and staging information was collected along with data on outcome, including local, regional, and distant recurrence and survival. RESULTS: Similar to previous reports, patients with desmoplastic melanoma had a male-to-female ratio of 2 to 1, a mean age of 65.0 years (range, 31-92 yrs), and the majority of their tumors (55%) were located on the head and neck. The mean Breslow depth at diagnosis was 4.21 mm, with 38% of tumors thicker than 4.0 mm. All patients in this series underwent wide excision without radiation therapy. Surgical margins < or = 2 cm were obtained for all trunk and extremity lesions and for 63% of head and neck lesions that measured > 1 mm in depth (63%). Margins of 1-2 cm were obtained for the remaining patients. Among 49 patients who had a minimum of 2 years of follow-up (mean, 3.7 yrs), the local recurrence rate was 4% (2 of 49 patients). Seventy-eight percent of the patients studied remained alive with no evidence of disease. CONCLUSIONS: Local recurrence rates in the current series were considerably lower than the historically reported rates. This finding suggests that, for patients with desmoplastic melanoma, wide local excision with careful attention to appropriate margins produces excellent local control rates without the need for adjuvant radiation.     

Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents

Caspofungin is a parenteral antifungal that inhibits beta-1,3-D-glucan synthesis. Although licensed for adult use, the appropriate caspofungin dosing regimen in pediatric patients is not yet known. We therefore investigated the pharmacokinetics and safety of caspofungin in pediatric patients. Thirty-nine children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) with neutropenia were administered caspofungin using either a weight-based regimen (1 mg/kg of body weight/day) or a body surface area regimen (50 mg/m2/day or 70 mg/m2/day). Plasma samples for caspofungin profiles were collected on days 1 and 4. These results were compared to those from adults treated with either 50 or 70 mg/day for mucosal candidiasis. In children receiving 1 mg/kg/day (maximum, 50 mg/day), the area under the concentration-time curve over 24 h (AUC(0-24)) was significantly smaller (46% after multiple doses) than that observed in adults receiving 50 mg/day (P < 0.001). In children and adolescents receiving 50 mg/m2/day (maximum, 70 mg/day), the AUC(0-24) following multiple doses was similar to that for the exposure in adults receiving 50 mg/day. The AUC(0-24) and concentration trough (at 24 h) in pediatric patients receiving the 50-mg/m2 daily regimen were consistent across the range of ages. Caspofungin was generally well tolerated in this study. None of the patients developed a serious drug-related adverse event or were discontinued for toxicity. These results demonstrate that caspofungin at 1 mg/kg/day in pediatric patients is suboptimal. Caspofungin administration at 50 mg/m2/day provides a comparable exposure to that of adult patients treated with 50 mg/day.     

Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer

The Lung Screening Study (LSS) was a pilot study designed to assess the feasibility of conducting a large scale randomized controlled trial (RCT) of low radiation dose spiral computed tomography (LDCT) versus chest X-ray (CXR) for lung cancer screening. Baseline results of LSS have been previously reported. Here, we report on the findings at the year one screen and on the final results of the LSS study. A total of 1660 subjects were randomized to the LDCT arm and 1658 to the CXR arm. Compliance with screening declined from 96% at baseline to 86% at year one in the LDCT arm and declined from 93% at baseline to 80% at year one in the CXR arm. Positivity rates for the year one screen were 25.8% for LDCT and 8.7% for CXR. Cancer yield was significantly less at year one for LDCT, 0.57%, than at baseline, 1.9%; cancer yield for CXR increased from 0.45% at baseline to 0.68% at year one. Forty lung cancers in the LDCT arm and 20 in the CXR arm were diagnosed over the study period. Stage I cancers comprised 48% of cases in the LDCT arm and 40% in the CXR arm. A total of 16 stage III-IV cancers were observed in the LDCT arm versus nine in the CXR arm. The LSS has established the feasibility of a RCT comparing annual spiral CT to chest X-ray for lung cancer screening.     

A comparison of two individual amiodarone regimens to placebo in open heart surgery patients

BACKGROUND: This study compares the ability of two oral amiodarone regimens to reduce the risk of atrial fibrillation (AF) as compared with the placebo among elderly open heart surgery (OHS) patients receiving beta blockade. METHODS: This is a randomized, double-blinded, placebo-controlled trial of 220 patients undergoing OHS. Patients (average age, 73 years) received 7 g of oral amiodarone more than 10 days starting 5 days before OHS (slow load; n = 56), a 6 g oral amiodarone regimen more than 6 days starting 1 day before OHS (fast load; n = 64), or matching placebo in one of the two previously mentioned regimens (n = 100). RESULTS: Patients receiving the slow load amiodarone regimen had a significant reduction in the risk of AF (48.4%; p = 0.013), AF lasting more than 24 hours (76.5%; p = 0.003), symptomatic AF (90.0%; p = 0.002), and recurrent AF (64.5%; p = 0.025) as compared with the placebo. Patients receiving the fast load amiodarone regimen had significant reductions in the risk of AF lasting more than 24 hours (52.6%; p = 0.038) and symptomatic AF (65.0%; p = 0.024), but the incidence of any AF or any recurrence of AF only showed a trend toward significance (34.0% and 45.5%; p = 0.054 and 0.09, respectively). CONCLUSIONS: Oral amiodarone in a slow loading regimen provides significant suppression of all AF factors and can be used when a patient has started it at least 5 days before OHS. If a patient has less than 5 days before OHS, the fast loading regimen is an efficacious alternative as it provides significant benefits in preventing AF from lasting more than 24 hours and for preventing symptomatic AF. Both regimens were well tolerated and safe in elderly patients receiving beta blockade according to the hospital's standard protocol.     

Melanocortin receptors mediate leptin effects on feeding and body weight but not adipose apoptosis

The melanocortin (MC) system is a known downstream mediator of leptin signaling in the brain; thus, activation of MC receptors by melanotan II (MTII), a MC3/4 receptor agonist, was hypothesized to increase adipose apoptosis, a phenomenon seen after leptin treatments. To test this hypothesis, male Sprague-Dawley rats received pretreatments of intracerebroventricular injections of artificial cerebrospinal fluid (aCSF, 5 microl) or SHU9119 (1.0 nmol/5 microl), an MC3/4 receptor antagonist. One hour later, aCSF (5 microl), leptin (10 microg/5 microl), or MTII (0.1 nmol/5 microl) was injected intracerebroventricularly in the aCSF-pretreated groups, and either leptin (10 microg/5 microl) or MTII (0.1 nmol/5 microl) was injected intracerebroventricularly in SHU9119-pretreated groups. Each pair of treatments was given once daily for four successive days. Body weight (BW), food intake (FI), and body temperature (BT) were measured daily at 4- and 24-h intervals. SHU9119 completely prevented the decrease in FI and BW caused by either MTII or leptin. Muscle mass remained unchanged regardless of treatment, but both leptin and MTII significantly reduced mass of inguinal (iWAT), retroperitoneal (rWAT), and epididymal (eWAT) white adipose tissues (P<.05). SHU9119 prevented the decrease in mass of intrascapular brown fat, iWAT, and rWAT (P<.05). Leptin, but not MTII, increased DNA fragmentation in eWAT (P<.05), but SHU9119 pretreatment had no effect on leptin-induced apoptosis. Thus, although the MC receptors in the brain are involved in mediating actions of leptin on FI, fat mass, and BW, leptin-induced adipose apoptosis is regulated independently of MC receptors.     

High SARS-CoV-2 Seroprevalence among Healthcare Workers in Bamako,Mali

In Mali, a country in West Africa, cumulative confirmed COVID-19 cases and deaths among healthcare workers (HCWs) remain enigmatically low, despite a series of waves, circulation of SARS-CoV-2 variants, the country’s weak healthcare system, and a general lack of adherence to public health mitigation measures. The goal of the study was to determine whether exposure is important by assessing the seroprevalence of anti-SARS-CoV-2 IgG antibodies in HCWs. The study was conducted between November 2020 and June 2021. HCWs in the major hospitals where COVID-19 cases were being cared for in the capital city, Bamako, Mali, were recruited. During the study period, vaccinations were not yet available. The ELISA of the IgG against the spike protein was optimized and quantitatively measured. A total of 240 HCWs were enrolled in the study, of which seropositivity was observed in 147 cases (61.8%). A continuous increase in the seropositivity was observed, over time, during the study period, from 50% at the beginning to 70% at the end of the study. HCWs who provided direct care to COVID-19 patients and were potentially highly exposed did not have the highest seropositivity rate. Vulnerable HCWs with comorbidities such as obesity, diabetes, and asthma had even higher seropositivity rates at 77.8%, 75.0%, and 66.7%, respectively. Overall, HCWs had high SARS-CoV-2 seroprevalence, likely reflecting a “herd” immunity level, which could be protective at some degrees. These data suggest that the low number of cases and deaths among HCWs in Mali is not due to a lack of occupational exposure to the virus but rather related to other factors that need to be investigated.     

Nutritional Therapies and Their Influence on the Intestinal Microbiome in Pediatric Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic, autoimmune disorder of the gastrointestinal tract with numerous genetic and environmental risk factors. Patients with Crohn’s disease (CD) or ulcerative colitis (UC) often demonstrate marked disruptions of their gut microbiome. The intestinal microbiota is strongly influenced by diet. The association between the increasing incidence of IBD worldwide and increased consumption of a westernized diet suggests host nutrition may influence the progression or treatment of IBD via the microbiome. Several nutritional therapies have been studied for the treatment of CD and UC. While their mechanisms of action are only partially understood, existing studies do suggest that diet-driven changes in microbial composition and function underlie the diverse mechanisms of nutritional therapy. Despite existing therapies for IBD focusing heavily on immune suppression, nutrition is an important treatment option due to its superior safety profile, potentially low cost, and benefits for growth and development. These benefits are increasingly important to patients. In this review, we will describe the clinical efficacy of the different nutritional therapies that have been described for the treatment of CD and UC. We will also describe the effects of each nutritional therapy on the gut microbiome and summarize the strength of the literature with recommendations for the practicing clinician.