Determination of transmitter function by neuronal activity

The role of neuronal activity in the determination of transmitter function was studied in cultures of dissociated sympathetic neurons from newborn rat superior cervical ganglia. Cholinergic and adrenergic differentiation were assayed by incubating the cultures with radioactive choline and tyrosine and determining the rate of synthesis and accumulation of labelled acetylcholine and catecholamines. As in previous studies, pure neuronal cultures grown in control medium displayed much lower ratios of acetylcholine synthesis to catecholamine synthesis than did sister cultures grown in medium previously conditioned by incubation on appropriate nonneuronal cells (conditioned medium). However, here we report that neurons treated with the depolarizing agents elevated K+ or veratridine, or stimulated directly with electrical current, either before or during application of conditioned medium, displayed up to 300-fold lower acetylcholine/catecholamine ratios than they would have without depolarization, and thus remained primarily adrenergic. Elevated K+ and veratridine produced this effect on cholinergic differentiation without significantly altering neuronal survival. Because depolarization causes Ca2+ entry in a number of cell types, the effects of several Ca2+ agonists and antagonists were investigated. In the presence of the Ca2+ antagonists D600 or Mg2+, K+ did not prevent the induction of cholinergic properties by conditioned medium. Thus depolarization, either steady or accompanying activity, is one of the factors determining whether cultured sympathetic neurons become adrenergic or cholinergic, and this effect may be mediated by Ca2+

Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood-onset beta-mannosidosis.

BACKGROUND: Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available. METHODS: We report 2-year outcomes following the first umbilical cord blood transplant in a 4-year-old boy with early childhood-onset disease. RESULTS: We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma β-mannosidase activity and dramatic decrease in urine-free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers. CONCLUSION: Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge

Microarray detection of human parainfluenzavirus 4 infection associated with respiratory failure in an immunocompetent adult.

A pan-viral DNA microarray, the Virochip (University of California, San Francisco), was used to detect human parainfluenzavirus 4 (HPIV-4) infection in an immunocompetent adult presenting with a life-threatening acute respiratory illness. The virus was identified in an endotracheal aspirate specimen, and the microarray results were confirmed by specific polymerase chain reaction and serological analysis for HPIV-4. Conventional clinical laboratory testing using an extensive panel of microbiological tests failed to yield a diagnosis. This case suggests that the potential severity of disease caused by HPIV-4 in adults may be greater than previously appreciated and illustrates the clinical utility of a microarray for broad-based viral pathogen screening

Nycteribiid bat flies (Arthropoda, Insecta, Diptera, Nycteribiidae) of Kenya

Bat flies (Diptera: Nycteribiidae and Streblidae) are hematophagous ectoparasites of bats characterized by viviparous pupiparity and generally high host specificity. Nycteribiid bat flies are wingless, morphologically constrained, and are most diverse in the Eastern Hemisphere. Africa hosts approximately 22% of global bat biodiversity and nearly one-third of all African bat species occur in Kenya, one of Africa’s most bat-rich countries. However, records of nycteribiid bat fly diversity in Kenya remain sparse and unconsolidated. This paper combines all past species records of nycteribiid bat flies with records from a survey of 4,255 Kenyan bats across 157 localities between 2006 and 2015. A total of seven nycteribiid genera and 17 species are recorded, with seven species from the recent ‘Bats of Kenya’ surveys representing previously undocumented country records. Host associations and geographic distributions based on all available records are also described. This comprehensive species catalog addresses and further emphasizes the need for similar investigations of nycteribiid biodiversity across Africa

Assessment of murine collagen-induced arthritis by longitudinal non-invasive duplexed molecular optical imaging

In the present study we evaluated the use of four commercially available fluorescent probes to monitor disease activity in murine CIA and its suppression during glucocorticoid therapy.  Arthritis was induced in male DBA/1 mice by immunization with type II collagen in Complete Freund's Adjuvant, followed by a boost of collagen in PBS. Four fluorescent probes from PerkinElmer in combination [ProSense 750 fluorescent activatable sensor technology (FAST) with Neutrophil Elastase 680 FAST and MMPSense 750 FAST with CatK 680 FAST] were used to monitor disease development from day 5 through to day 40 post-immunization. Fluorescence generated in vivo by the probes was correlated with clinical and histological score and paw measurements.  The fluorescence intensity emitted by each probe was shown to correlate with the conventional measurements of disease. The highest degree of correlation was observed with ProSense 750 FAST in combination with Neutrophil Elastase 680 FAST; these probes were then used to successfully assess CIA suppression during dexamethasone treatment.  We have demonstrated that longitudinal non-invasive duplexed optical fluorescence imaging provides a simple assessment of arthritic disease activity within the joints of mice following the induction of CIA and may represent a powerful tool to monitor the efficacy of drug treatments in preclinical studies

Initial Observations of Lunar Impact Melts and Ejecta Flows with the Mini-RF Radar

The Mini-RF radar on the Lunar Reconnaissance Orbiter's spacecraft has revealed a great variety of crater ejecta flow and impact melt deposits, some of which were not observed in prior radar imaging. The craters Tycho and Glushko have long melt flows that exhibit variations in radar backscatter and circular polarization ratio along the flow. Comparison with optical imaging reveals that these changes are caused by features commonly seen in terrestrial lava flows, such as rafted plates, pressure ridges, and ponding. Small (less than 20 km) sized craters also show a large variety of features, including melt flows and ponds. Two craters have flow features that may be ejecta flows caused by entrained debris flowing across the surface rather than by melted rock. The circular polarization ratios (CPRs) of the impact melt flows are typically very high; even ponded areas have CPR values between 0.7-1.0. This high CPR suggests that deposits that appear smooth in optical imagery may be rough at centimeter- and decimeter- scales. In some places, ponds and flows are visible with no easily discernable source crater. These melt deposits may have come from oblique impacts that are capable of ejecting melted material farther downrange. They may also be associated with older, nearby craters that no longer have a radar-bright proximal ejecta blanket. The observed morphology of the lunar crater flows has implications for similar features observed on Venus. In particular, changes in backscatter along many of the ejecta flows are probably caused by features typical of lava flows

Correlation Between Trough Plasma Dabigatran Concentrations and Estimates of Glomerular Filtration Rate Based on Creatinine and Cystatin C

AIMS: Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft–Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys). METHODS: A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations. RESULTS: The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38–94 years) taking dabigatran etexilate was 60 µg/L (range 9–279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R(2), 95 % CI) 32 % (9–55), 37 % (12–60), 41 % (16–64) and 47 % (20–69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R(2) values for each equation was not statistically significant (p = 0.74). DISCUSSION: Estimates of renal function using the four equations accounted for 32–47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40268-014-0045-9) contains supplementary material, which is available to authorized users

Repetitions in Reserve Is a Reliable Tool for Prescribing Resistance Training Load

This study investigated the reliability of repetitions in reserve (RIR) as a method for prescribing resistance training load for the deadlift and bench press exercises. Fifteen novice trained men (age: 17.3 ± 0.9 years, height: 176.0 ± 8.8 cm, body mass: 71.3 ± 10.7 kg) were assessed for 1 repetition maximum (1RM) for deadlift (118.1 ± 27.3 kg) and bench press (58.2 ± 18.6 kg). Subsequently, they completed 3 identical sessions (one familiarization session and 2 testing sessions) comprising sets of 3, 5, and 8 repetitions. For each repetition scheme, the load was progressively increased in successive sets until subjects felt they reached 1-RIR at the end of the set. Test-retest reliability of load prescription between the 2 testing sessions was determined using intraclass correlation coefficient (ICC) and coefficient of variation (CV). A 2-way analysis of variance with repeated measures was used for each exercise to assess differences in the load corresponding to 1-RIR within each repetition scheme. All test-retest comparisons demonstrated a high level of reliability (deadlift: ICC = 0.95–0.99, CV = 2.7–5.7% and bench press: ICC = 0.97–0.99, CV = 3.8–6.2%). Although there were no differences between time points, there was a difference for load corresponding to 1-RIR across the 3 repetition schemes (deadlift: 88.2, 84.3, and 79.2% 1RM; bench press: 93.0, 87.3, and 79.6% 1RM for the 3-, 5-, and 8-repetition sets, respectively). These results suggest that RIR is a reliable tool for load prescription in a young novice population. Furthermore, the between-repetition scheme differences highlight that practitioners can effectively manipulate load and volume (repetitions in a set) throughout a training program to target specific resistance training adaptations

Don’t turn your back on the symptoms of psychosis : a proof-of-principle, quasi-experimental public health trial to reduce the duration of untreated psychosis in Birmingham, UK

Background: Reducing the duration of untreated psychosis (DUP) is an aspiration of international guidelines for first episode psychosis; however, public health initiatives have met with mixed results. Systematic reviews suggest that greater focus on the sources of delay within care pathways, (which will vary between healthcare settings) is needed to achieve sustainable reductions in DUP (BJP 198: 256-263; 2011). Methods/Design: A quasi-experimental trial, comparing a targeted intervention area with a ‘detection as usual’ area in the same city. A proof-of–principle trial, no a priori assumptions are made regarding effect size; key outcome will be an estimate of the potential effect size for a definitive trial. DUP and number of new cases will be collected over an 18-month period in target and control areas and compared; historical data on DUP collected in both areas over the previous three years, will serve as a benchmark. The intervention will focus on reducing two significant DUP component delays within the overall care pathway: delays within the mental health service and help-seeking delay. Discussion: This pragmatic trial will be the first to target known delays within the care pathway for those with a first episode of psychosis. If successful, this will provide a generalizable methodology that can be implemented in a variety of healthcare contexts with differing sources of delay. Trial registration: http://www.controlled-trials.com/ISRCTN45058713 Keywords: Public mental health campaign, First-episode psychosis, Early detection, Duration of untreated psychosis, Youth mental healt