Reversal of granulocyte adherence to nylon fibers using local anesthetic agents: possible application to filtration leukapheresis

The effects of the cationic anesthetic agents tetracaine and lidocaine on granulocyte function, morphology, and adherence to nylon fibers were studied in an attempt to improve current methods of granulocyte collection by filtration leukapheresis (FL). When dissolved in acid- citrate-dextrose (ACD) plasma, these drugs significantly increased granulocyte elution from the fibers in a dose-related fashion. Granulocytes exposed to tetracaine and lidocaine remained more than 95% viable, retained normal bactericidal capacity after the drugs were washed from the cells, and had preserved membrane integrity, as evidenced by the normal ultrastructural appearance of tetracaine- exposed cells and an absence of leakage of lysozyme or lactic dehydrogenase. Granulocytes eluted with the anesthetic agents were rounded in shape with a reduction in the number of filopodial cytoplasmic projections and a relative absence of cytoplasmic vacuolization when compared to granulocytes eluted with ACD plasma alone. Dose-related inhibition of phagocytosis and adherence, which was largely reversible after washing the granulocytes, was noted. Greater than 95% of the lidocaine could be removed from the eluate with a single centrifugation and resuspension, indicating that granulocytes prepared by FL with anesthetic-enhanced elution could be potentially transfusable.     

A review of novel technologies and techniques associated with identification of bloodstream infection etiologies and rapid antimicrobial genotypic and quantitative phenotypic determination

Introduction: The antimicrobial aspect of management of patients with blood stream infections (BSI) and sepsis is time critical. In an era of increasing antimicrobial resistance, rapid detection and identification of bacteria with antimicrobial susceptibility is crucial to direct therapy early in the course of illness. Molecular techniques offer a potential solution to this.

Areas covered: In the present review the authors have discussed a number of novel solutions utilizing a variety of molecular techniques for pathogen detection, identification and antimicrobial susceptibility. The review is not designed to be an exhaustive literature review covering all diagnostic solutions ever developed, instead the authors have focused on what they have had experience using, evaluating or currently view as new and exciting with potential to revolutionize BSI diagnosis.

The authors searched PubMed (Medline) and Google Scholar with terms: BSI, Bacteraemia, Candidaemia, Diagnostics, AST, Rapid, AMR, Novel and Blood Culture. The authors attended recent clinical microbiology technology congresses.

Expert commentary: There are multiple exciting novel technologies at differing stages of development with potential to revolutionize diagnosis of BSI. More work is needed as well as a standardized assessment of different platforms in order to better understand the clinical and financial impacts these will have in clinical microbiology laboratories.     

Antiviral Therapies for Herpesviruses: Current Agents and New Directions

Purpose

The objective of this review was to summarize the recent literature describing the current burden of disease due to herpesviruses in the antiviral and transplant era; describe mechanisms of action of antiviral agents and the development of resistance; summarize the literature of recent antiviral agents brought to market as well as agents under development; and to present literature on future strategies for herpesvirus therapeutics.

Changes in the concentration of 17 alpha,20 alpha-dihydroxypregn-4-en-3-one during pregnancy, labor, and delivery and the effect of dexamethasone treatment during the third trimester of pregnancy

To study whether an alteration of placental steroid metabolism occurs during human pregnancy similar to that in the ewe, we measured the concentration of 17 alpha,20 alpha-dihydroxypregn-4-en-3-one (17,20 alpha-OHP) in peripheral plasma. As the pregnant ewe nears term, the utero-ovarian venous concentrations of 17,20 alpha-OHP increase, suggesting induction of placental 17 alpha-hydroxylase. The mean plasma concentration of 17,20 alpha-OHP measured by RIA in normal menstruating women was 1.1 +/- 0.12 (+/- SE) ng/ml. Similar values were found in plasma from ovariectomized women. In the first and second trimesters of pregnancy, the plasma values of 17,20 alpha-OHP were not significantly different from those in the nonpregnant women, while in the third trimester, the mean plasma concentration was significantly increased (mean +/- SE, 2.6 +/- 0.3 ng/ml). The plasma concentration of 17,20 alpha-OHP was studied in 15 women in late pregnancy, during labor, at delivery, and postpartum. The concentration increased during labor as delivery approached and reached a maximum at the time of delivery, ranging from 4.1-11.2 ng/ml, followed by a significant decrease within 1-4 h postpartum. The mean (+/- SE) 17,20 alpha-OHP concentrations in the venous and arterial cord blood were 8.7 +/- 1.6 and 5.8 +/- 2.0 ng/ml, respectively. To study the effect of increased circulating level of corticosteroids on the serum concentration of progestins, 74 women with premature labor with or without premature rupture of membranes were treated with either placebo or 4 im injections of dexamethasone phosphate (5 mg each) at 12-h intervals. Blood samples were drawn at 0, 14, 26, and 46 h, approximately 2 h after each dexamethasone dose. Plasma progesterone, 17 alpha-hydroxyprogesterone (17-OHP), and 17,20 alpha-OHP values at zero time were 140 +/- 15.8 (+/- SE; n = 21), 7.8 +/- 1.5 ng/ml (n = 16), and 2.3 +/- 0.3 ng/ml (n = 20), respectively. In patients treated with dexamethasone, the plasma progesterone values tended to increase at 14, 20, and 46 h, but 17-OHP and 17,20 alpha-OHP values decreased significantly compared to levels in placebo-treated patients. In conclusion, the concentration of plasma 17,20 alpha-OHP increased during the third trimester of pregnancy, and the increment continued through labor and delivery. During antenatal dexamethasone administration, progesterone in the maternal circulation tended to increase, while 17-OHP and 17,20 alpha-OHP decreased significantly. In the human, in contrast to the ewe, dexamethasone treatment in the third trimester does not appear to stimulate placental 17 alpha-hydroxylase activity.     

Growth hormone-releasing factor analogue (hGRF1-29NH2): immunoreactive-GRF plasma levels after intravenous and subcutaneous administration

A homologous radioimmunoassay (RIA) system for human growth hormone-releasing factor 1-29NH2 (hGRF 1-29-NH2) was developed and applied to the measurement of immunoreactive (IR) concentrations of the peptide in anaesthetized rats to determine some of its pharmaco-kinetics after i.v. and s.c. administration. Analysis of the biphasic disappearance curve of IR-hGRF-1-29NH2 from plasma after i.v. injection (10 micrograms) gave values for the half-lives of the initial distribution phase (alpha) and for the elimination phase (beta) of 1.9 +/- 0.2 min and 10.4 +/- 0.2 min respectively. There was rapid uptake of the peptide from the site of s.c. injection but comparison of areas under the plasma IR-hGRF1-29NH2/time curves showed that the estimated total amount in the circulation after s.c. injection was only 4% of that obtained after i.v. administration. A large degree of degradation of the peptide is indicated either at the site of injection or during transfer to plasma; this susceptibility to rapid breakdown is reflected in the short half-life of the peptide in the circulation. Therefore the measurement of the above parameters is a prerequisite when assessing potency of GRF analogues in-vivo and when implementing suitable dosage regimens for clinical purposes.     

Supported discharge service versus inpatient care evaluation (SITE): a randomised controlled trial comparing effectiveness of an intensive community care service versus inpatient treatment as usual for adolescents with severe psychiatric disorders: self-harm,functional impairment,and educational and clinical outcomes

Clinical guidelines recommend intensive community care service treatment (ICCS) to reduce adolescent psychiatric inpatient care. We have previously reported that the addition of ICCS led to a substantial decrease in hospital use and improved school re-integration. The aim of this study is to undertake a randomised controlled trial (RCT) comparing an inpatient admission followed by an early discharge supported by ICCS with usual inpatient admission (treatment as usual; TAU). In this paper, we report the impact of ICCS on self-harm and other clinical and educational outcomes. 106 patients aged 12–18 admitted for psychiatric inpatient care were randomised (1:1) to either ICCS or TAU. Six months after randomisation, we compared the two treatment arms on the number and severity of self-harm episodes, the functional impairment, severity of psychiatric symptoms, clinical improvement, reading and mathematical ability, weight, height and the use of psychological therapy and medication. At six-month follow-up, there were no differences between the two groups on most measures. Patients receiving ICCS were significantly less likely to report multiple episodes (five or more) of self-harm (OR = 0.18, 95% CI: 0.05–0.64). Patients admitted to private inpatient units spent on average 118.4 (95% CI: 28.2–208.6) fewer days in hospitals if they were in the ICCS group compared to TAU. The addition of ICCS to TAU may lower the risk of multiple self-harm and may reduce the duration of inpatient stay, especially in those patients admitted for private care. Early discharge with ICCS appears to be a viable alternative to standard inpatient treatment.

     

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.