Mechanism of action and initial evaluation of a membrane active all-D-enantiomer antimicrobial peptidomimetic

Development of therapy against infections caused by antibiotic-resistant pathogens is a major unmet need in contemporary medicine. In previous work, our group chemically modified an antimicrobial peptidomimetic motif for targeted applications against cancer and obesity. Here, we show that the modified motif per se is resistant to proteolytic degradation and is a candidate antiinfective agent. We also show that the susceptibility of microorganisms to the drug is independent of bacterial growth phase. Moreover, this peptidomimetic selectively interferes with the integrity and function of the microbial surface lipid bilayer, data indicative that bacterial death results from membrane disruption followed by dissipation of membrane potential. Finally, we demonstrate two potential translational applications: use against biofilms and synergy with antibiotics in use. In summary, we introduce the mechanism of action and the initial evaluation of a prototype drug and a platform for the development of D-enantiomer antimicrobial peptidomimetics that target bacterial membranes of certain Gram-negative problem pathogens with promising translational applications.     

Self-reported use of novel psychoactive substances among attendees of electronic dance music venues

Background: Novel psychoactive substances (NPSs) continue to emerge in the United States and worldwide. Few epidemiological studies have examined the prevalence and correlates of use. Objective: We examined the extent of NPS use in a high-risk population—attendees of electronic dance music (EDM) parties at nightclubs and festivals. Methods: We surveyed 682 adults (age 18–25) entering EDM events at nightclubs and festivals in New York City (NYC) in 2015. A variation of time–space sampling was used. We examined the prevalence of self-reported use of 196 NPS and correlates of any NPS use. Results: Over a third (35.1%) of participants reported lifetime use of any NPS. Self-reported use of synthetic cannabinoids was most prevalent (16.3%), followed by psychedelic phenethylamines (14.7%; 2C series: 10.3%, 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine [NBOMe] series: 9.0%, Dox series: 3.5%), synthetic cathinones (“bath salts”, 6.9%), other psychedelics (6.6%), tryptamines (5.1%), and dissociatives (4.3%). 2C-I was the most prevalent 2C series drug (5.1%); methylone was the most prevalent synthetic cathinone (3.3%), 2-MeO-ketamine was the most prevalent dissociative (3.7%), and 1P-lysergic acid diethylamide (LSD) (2.9%) was the most prevalent non-phenethylamine psychedelic. Risk factors for NPS use included Ecstasy/MDMA/Molly, LSD, and ketamine use; identifying as bisexual (compared to heterosexual), reporting higher frequency of nightclub/festival attendance, and being surveyed outside of a festival (compared to those surveyed outside of nightclubs). Discussion: NPS use is prevalent in the nightclub and festival scenes in NYC. Since individuals in these scenes—especially frequent attendees—are at high risk for use, prevention and harm reduction services need to be geared toward this population.     

Adolescent Substance Use Assessment in a Primary Care Setting

Health initiatives suggest that adolescent substance use assessment may be beneficial as part of primary care to screen for early problematic behaviors. To examine the accuracy of such reporting, we compared the anonymous and confidential self-reports of 180 adolescents in a primary care setting. Matching samples to control for demographic variables, we found that adolescents were more likely to report marijuana use and substance use behaviors, such as selling drugs, when reporting anonymously vs. reporting confidentially. These results challenge the accuracy of confidential self-reports within this setting, and suggest further research is needed.     

Immunohistochemical study of the digestive tract of Oligosarcus hepsetus

AIM: To describe the histology of the digestive tract and to investigate the occurrence of endocrine cells in Oligosarcus hepsetus (O. hepsetus ). METHODS: The digestive tract (DT) of O. hepsetus was divided into esophagus, two stomach regions (glandular and non-glandular) and two intestinal regions (anterior and posterior). These specimens were processed by routine histological techniques and stained with hematoxylin-eosin, Gomori’s trichrome, periodic acid Schiff (PAS) and Alcian blue (AB). An immunohistochemical method using avidin-biotin-peroxidase was employed.RESULTS: The esophagus is lined with a non-keratinized stratified squamous epithelium that is reactive to PAS and AB. The stomach has a mucosa lined with a simple columnar epithelium with mucus-secreting cells that are reactive only to PAS. The intestine has a simple columnar epithelium with a brush border and goblet cells that are reactive to PAS and AB. Somatostatin, serotonin and cholecystokinin immunoreactive cells were identified throughout the DT.CONCLUSION: This study revealed adaptations for the species’ diet and showed that the distribution and relative frequency of immunoreactive cells are similar to those of other fish.     

Antibody levels correlate with detection of Trypanosoma cruzi DNA by sensitive polymerase chain reaction assays in seropositive blood donors and possible resolution of infection over time

BACKGROUND: The clinical significance of anti‐Trypanosoma cruzi low‐level reactive samples is incompletely understood. Polymerase chain reaction (PCR)‐positive rates and antibody levels among seropositive blood donors in three countries are described. STUDY DESIGN AND METHODS: Follow‐up samples were collected from T. cruzi–seropositive donors from 2008 through 2010 in the United States (n = 195) and Honduras (n = 58). Also 143 samples from Brazil in 1996 to 2002, originally positive by three serologic assays, were available and paired with contemporary follow‐up samples from these donors. All samples were retested with Ortho enzyme‐linked immunosorbent assay (ELISA). PCR assays were performed on coded sample panels by two laboratories (Blood Systems Research Institute [BSRI] and American Red Cross Holland Laboratory [ARC]) that amplified kinetoplast minicircle DNA sequences of T. cruzi. RESULTS: PCR testing at BSRI yielded slightly higher overall sensitivity and specificity (33 and 98%) compared with those at the ARC (28 and 94%). Among seropositive donors, PCR‐positive rates varied by country (p < 0.0001) for the BSRI laboratory: Brazil (57%), Honduras (32%), and the United States (14%). ELISA signal‐to‐cutoff ratios (S/CO) were significantly higher for PCR‐positive compared to PCR‐negative donors (p < 0.05 for all comparisons). Additionally, PCR‐negative Brazilian donors exhibited greater frequencies of antibody decline over time versus PCR‐positive donors (p = 0.003). CONCLUSION: For all three countries, persistent DNA positivity correlated with higher ELISA S/CO values, suggesting that high‐level seroreactivity reflects chronic parasitemia. Significant S/CO declines in 10% of the PCR‐negative Brazilian donors may indicate seroreversion after parasite clearance in the absence of treatment.     

A Highly Bioavailable Omega-3 Free Fatty Acid Formulation Improves the Cardiovascular Risk Profile in High-Risk,Statin-Treated Patients With Residual Hypertriglyceridemia (the ESPRIT Trial)

Background

A novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia.

Objective

This study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non–HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease.

Methods

In this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events.

Results

In the 627 subjects in the intention to treat sample, non–HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (–3.9% and –6.9%, respectively) compared with OO (–0.9%) (both, P < 0.05), as were TG levels (–14.6% and –20.6%, respectively, vs –5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d.

Conclusions

OM3-FFA was well tolerated and lowered non–HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d. ClinicalTrials.gov identifier: NCT01408303.