Circulating platelet‐derived extracellular vesicles correlate with night‐time blood pressure and vascular organ damage and may represent an integrative biomarker of vascular health

Elevated office blood pressure (BP) has previously been associated with increased levels of circulating extracellular vesicles (EVs). The present study aimed to assess the relationship between levels of platelet derived EVs, ambulatory BP parameters, and pulse wave velocity as a marker of macrovascular organ damage. A total of 96 participants were included in the study. Platelet‐derived extracellular vesicles (pEVs) were evaluated by flow cytometry (CD41+/Annexin v+). BP evaluation included unobserved automated office BP and ambulatory BP monitoring. Carotid‐femoral pulse wave velocity (PWV) was measured as a marker of macrovascular damage. pEVs correlated with nocturnal systolic BP (r = 0.31; p = .003) and nocturnal dipping (r = ‐0.29; p = .01) in univariable analysis. Multivariable regression models confirmed robustness of the association of EVs and nocturnal blood pressure (p = .02). In contrast, systolic office, 24h‐ and daytime‐BP did not show significant associations with pEVs. No correlations were found with diastolic BP. Circulating pEVs correlated with pulse wave velocity (r = 0.25; p = .02). When comparing different hypertensive phenotypes, higher levels of EVs and PWV were evident in patients with sustained hypertension compared to patients with white coat HTN and healthy persons. Circulating platelet derived EVs were associated with nocturnal BP, dipping, and PWV. Given that average nocturnal BP is the strongest predictor of CV events, platelet derived EVs may serve as an integrative marker of vascular health, a proposition that requires testing in prospective clinical trials.     

Hot air electric hand driers compared with paper towels for potential spread of airborne bacteria

Hot air hand driers are increasingly used in both public areas and hospitals, but there is little literature on their bacteriology. Four units were examined by comparing the bacterial aerosols released from hands during use by sets of twelve subjects with those released by paper towels. Tests on two units also included hand imprints on agar plates for detection of residual bacteria. No significant difference between aerosols liberated by towels and driers were observed for two units, while the other two generated significantly fewer aerosols than towels. Impression plates revealed similar numbers of bacteria on the hands after drying by either method. Hot air hand driers appear safe from a bacteriological viewpoint.     

Secondary biogenic amine deficiencies: genetic etiology,therapeutic interventions,and clinical effects

neurogenetics - Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that...     

The Role of Streptococcal Cell-Envelope Proteases in Bacterial Evasion of the Innate Immune System

Bacteria possess the ability to evolve varied and ingenious strategies to outwit the host immune system, instigating an evolutionary arms race. Proteases are amongst the many weapons employed by bacteria, which specifically cleave and neutralize key signalling molecules required for a coordinated immune response. In this article, we focus on a family of S8 subtilisin-like serine proteases expressed as cell-envelope proteases (CEPs) by group A and group B streptococci. Two of these proteases known as Streptococcus pyogenes CEP (SpyCEP) and C5a peptidase cleave the chemokine CXCL8 and the complement fragment C5a, respectively. Both CXCL8 and C5a are potent neutrophil-recruiting chemokines, and by neutralizing their activity, streptococci evade a key defence mechanism of innate immunity. We review the mechanisms by which CXCL8 and C5a recruit neutrophils and the characterization of SpyCEP and C5a peptidase, including both in vitro and in vivo studies. Recently described structural insights into the function of this CEP family are also discussed. We conclude by examining the progress of prototypic vaccines incorporating SpyCEP and C5a peptidase in their preparation. Since streptococci-producing SpyCEP and C5a peptidase are responsible for a considerable global disease burden, targeting these proteases by vaccination strategies or by small-molecule antagonists should provide protection from and promote the resolution of streptococcal infections.     

Encapsulation of Drug Molecules into Calix[n]arene Nanobaskets. Role of Aminocalix[n]arenes in Biopharmaceutical Field

Calix[n]arenes (CAs) are supramolecular compounds able to form guest-host inclusion complexes with metal ions, small organic molecules, and small moieties of larger molecules. Although the CA literature is extensive, relatively few publications deal with water-soluble CAs, especially those containing nitrogen-based functionality. These CAs possess antibacterial and antifungal activity. Because of their molecular structure, they are surface active and also able to form water-soluble drug complexes, giving additional potential as enabling pharmaceutical excipients. This article provides an overview of the published data regarding synthesis, physicochemical properties, and pharmaceutical application of water-soluble CAs with emphasis on those that contain nitrogen-based substituents in their structure, particularly aminoCAs. In particular, it describes state-of-the-art in complexation of water-soluble CAs with pharmaceutically relevant ions and organic molecules up to amino acids, DNA, and proteins.     

Posthypnotic Conflict and Psychopathology - Controlling for the Effects of Posthypnotic Suggestions: A Brief Communication

Hypnotically implanted paramnesias (false memories) designed to arouse Oedipal and non-Oedipal sexual conflicts were implanted in 2 groups of male undergraduate Ss. Ss in a third condition were hypnotized but no paramnesia wasm implanted. In a fourth condition, the Oedipal paramnesia was presented to Ss who had been instructed by coexperimenters to simulate hypnosis. All Ss had achieved a score of 7 or higher on the Harvard Group Scale of Hypnotic Susceptibility, Form A (Shor & E. C. Orne, 1962). Following implantation of the paramnesia, Ss were given conflict activating instructions consisting of posthypnotic suggestions to express strong sexual feelings in response to cue words contained in the paramnesias. Ss in all conditions produced significantly more symptoms of discomfort to cue words than to neutral words. No significant between-group differences were found. These results question the contention that discomfort following the implantation of an Oedipal paramnesia constitutes empirical support for psychoanalytic theory.     

Palliative Treatment of the Constitutionally Inadequate Patient

Traumatic shock is hemorrhagic until proved otherwise; there is no completely reliable way to assess the severity of blood loss. Adequate ventilation has first priority in management of multiple-injury patients. Often these patients receive too many narcotics, spinal taps, and vasopressors and too little in the way of physical examination, diagnostic paracentesis and blood transfusions. Tourniquets and tracheostomies are last resorts; there are better ways. The best place for the multiple-injury patient is the operating room.     

Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials

In the multinational IRIS study comparing imatinib with interferon plus cytarabine (IFN/Ara-C) in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyRs) and improved progression-free survival (PFS). However, because of a high early crossover rate to imatinib, survival benefit was not assessable. Here, we report the result of a study comparing long-term outcome of patients included in 2 prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/Ara-C in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation, and overall survival were significantly higher with imatinib compared with IFN/Ara-C (P < .001, P = .004, and P < .001, respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Of interest, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C.     

Knowledge and Attitudes About Pre-Exposure Prophylaxis Among Young Adults Experiencing Homelessness in Seven U.S. Cities

Purpose

Evidence suggests that young adults experiencing homelessness (YEH) are at elevated risk of HIV compared to housed youth. Given the limited research on pre-exposure prophylaxis (PrEP) awareness among YEH, this study examined their PrEP knowledge and attitudes.

Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.