Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor

A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.     

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm² chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s⁻¹), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037 or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant''s power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.     

Genome-wide association mapping of blood cell traits in mice

Genetic variations in blood cell parameters can impact clinical traits. We report here the mapping of blood cell traits in a panel of 100 inbred strains of mice of the Hybrid Mouse Diversity Panel (HMDP) using genome-wide association (GWA). We replicated a locus previously identified in using linkage analysis in several genetic crosses for mean corpuscular volume (MCV) and a number of other red blood cell traits on distal chromosome 7. Our peak for SNP association to MCV occurred in a linkage disequilibrium (LD) block spanning from 109.38 to 111.75 Mb that includes Hbb-b1, the likely causal gene. Altogether, we identified five loci controlling red blood cell traits (on chromosomes 1, 7, 11, 12, and 16), and four of these correspond to loci for red blood cell traits reported in a recent human GWA study. For white blood cells, including granulocytes, monocytes, and lymphocytes, a total of six significant loci were identified on chromosomes 1, 6, 8, 11, 12, and 15. An average of ten candidate genes were found at each locus and those were prioritized by examining functional variants in the HMDP such as missense and expression variants. These results provide intermediate phenotypes and candidate loci for genetic studies of atherosclerosis and cancer as well as inflammatory and immune disorders in mice.     

Effects of alcohol mixed with energy drink and alcohol alone on subjective intoxication

Recent studies suggest that the combination of caffeine-containing drinks together with alcohol might reduce the subjective feelings of alcohol intoxication—the so-called “masking effect”. In this study, we aimed to review the effects of alcohol in combination with caffeine or energy drink with special focus on the “masking effect”. Fifty-two healthy male volunteers were analysed concerning breath alcohol concentration and subjective sensations of intoxication using a 18 item Visual Analogue Scale in a randomised, double-blinded, controlled, four treatments cross-over trial after consumption of (A) placebo, (B) alcohol (vodka 37.5 % at a dose of 46.5 g ethanol), (C) alcohol in combination with caffeine at a dose of 80 mg (equivalent to one 250 ml can of energy drink) and (D) alcohol in combination with energy drink at a dose of 250 ml (one can). Primary variables were headache, weakness, salivation and motor coordination. Out of four primary variables, weakness and motor coordination showed a statistically significant difference between alcohol and non-alcohol group, out of 14 secondary variables, five more variables (dizziness, alterations in sight, alterations in walking, agitation and alterations in speech) also showed significant differences due mainly to contrasts with the non-alcohol group. In none of these end points, could a statistically significant effect be found for the additional ingestion of energy drink or caffeine on the subjective feelings of alcohol intoxication. This within-subjects study does not confirm the presence of a “masking effect” when combining caffeine or energy drink with alcohol.     

Inhibition of Phytophthora species by secondary metabolites produced by the dark septate endophyte Phialocephala europaea

Dark septate fungal root endophytes of the Phialocephala fortinii s.l.–Acephala applanata species complex (PAC) are widely distributed throughout the temperate and subtropical regions of the Northern Hemisphere. Previous studies have shown that some PAC members are pathogenic, others suppress oomycete root pathogens and some have no obvious effect on their Norway spruce (Picea abies) host. The activity of 85 PAC isolates against Phytophthora citricola s.l. was investigated by co-culture on plates. We identified a strain of Phialocephala europaea that significantly reduced the growth of P. citricola in vitro. Characterization of its extracellular metabolites resulted in the identification of four major compounds, sclerin, sclerolide, sclerotinin A, and sclerotinin B. These compounds are known for their positive as well as negative effects on plant growth. We found that sclerin and sclerotinin inhibited the growth of P. citricola in vitro at 150 μg ml^?1 (～1 mM). This is the first report of their production by Phialocephala and of activity of these compounds against an oomycete. Therefore, our data suggest that some PAC might reduce disease resulting from P. citricola by the production of antibiotics and plant growth promoting metabolites.     

A meta‐analysis of cardio‐metabolic abnormalities in drug naïve,first‐episode and multi‐episode patients with schizophrenia versus general population controls

A meta‐analysis was conducted to explore the risk for cardio‐metabolic abnormalities in drug naïve, first‐episode and multi‐episode patients with schizophrenia and age‐ and gender‐ or cohort‐matched general population controls. Our literature search generated 203 relevant studies, of which 136 were included. The final dataset comprised 185,606 unique patients with schizophrenia, and 28 studies provided data for age‐ and gender‐matched or cohort‐matched general population controls (n=3,898,739). We found that multi‐episode patients with schizophrenia were at increased risk for abdominal obesity (OR=4.43; CI=2.52‐7.82; p<0.001), hypertension (OR=1.36; CI=1.21‐1.53; p<0.001), low high‐density lipoprotein cholesterol (OR=2.35; CI=1.78‐3.10; p<0.001), hypertriglyceridemia (OR=2.73; CI=1.95‐3.83; p<0.001), metabolic syndrome (OR=2.35; CI=1.68‐3.29; p<0.001), and diabetes (OR=1.99; CI=1.55‐2.54; p<0.001), compared to controls. Multi‐episode patients with schizophrenia were also at increased risk, compared to first‐episode (p<0.001) and drug‐naïve (p<0.001) patients, for the above abnormalities, with the exception of hypertension and diabetes. Our data provide further evidence supporting WPA recommendations on screening, follow‐up, health education and lifestyle changes in people with schizophrenia.     

The Impact of Financial Reward Contingencies on Cognitive Function Profiles in Adult ADHD

Objectives

Although it is well established that cognitive performance in children with attention-deficit/hyperactivity disorder (ADHD) is affected by reward and that key deficits associated with the disorder may thereby be attenuated or even compensated, this phenomenon in adults with ADHD has thus far not been addressed. Therefore, the aim of the present study was to examine the motivating effect of financial reward on task performance in adults with ADHD by focusing on the domains of executive functioning, attention, time perception, and delay aversion.

Methods

We examined male and female adults aged 18–40 years with ADHD (n = 38) along with a matched control group (n = 40) using six well-established experimental paradigms.

Results

Impaired performance in the ADHD group was observed for stop-signal omission errors, n-back accuracy, reaction time variability in the continuous performance task, and time reproduction accuracy, and reward normalized time reproduction accuracy. Furthermore, when rewarded, subjects with ADHD exhibited longer reaction times and fewer false positives in the continuous performance task, which suggests the use of strategies to prevent impulsivity errors.

Conclusions

Taken together, our results support the existence of both cognitive and motivational mechanisms for the disorder, which is in line with current models of ADHD. Furthermore, our data suggest cognitive strategies of “stopping and thinking” as a possible underlying mechanism for task improvement that seems to be mediated by reward, which highlights the importance of the interaction between motivation and cognition in adult ADHD.