Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics.

GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as a powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.

Utility of propensity score-based Bayesian borrowing of external adult data in pediatric trials: A pragmatic evaluation through a case study in acute lymphoblastic leukemia (ALL).

A fully powered randomized controlled cancer trial can be challenging to conduct in children because of difficulties in enrollment of pediatric patients due to low disease incidence. One way to improve the feasibility of trials in pediatric patients, when clinically appropriate, is through borrowing information from comparable external adult trials in the same disease. Bayesian analysis of a pediatric trial provides a way of seamlessly augmenting pediatric trial efficacy data with data from external adult trials. However, not all external adult trial subjects may be equally clinically relevant with respect to the baseline disease severity, prognostic factors, co-morbidities, and prior therapy observed in the pediatric trial of interest. The propensity score matching method provides a way of matching the external adult subjects to the pediatric trial subjects on a set of clinically determined baseline covariates, such as baseline disease severity, prognostic factors and prior therapy. The matching then allows Bayesian information borrowing from only the most clinically relevant external adult subjects. Through a case study in pediatric acute lymphoblastic leukemia (ALL), we examine the utility of propensity score matched mixture and power priors in bringing appropriate external adult efficacy information into pediatric trial efficacy assessment, and present considerations for scaling fixed borrowing from external adult data.

A Conserved Requirement for Fbxo7 During Male Germ Cell Cytoplasmic Remodeling.

Fbxo7 is the substrate-recognition subunit of an SCF-type ubiquitin E3 ligase complex. It has physiologically important functions in regulating mitophagy, proteasome activity and the cell cycle in multiple cell types, like neurons, lymphocytes and erythrocytes. Here, we show that in addition to the previously known Parkinsonian and hematopoietic phenotypes, male mice with reduced Fbxo7 expression are sterile. In these males, despite successful meiosis, nuclear elongation and eviction of histones from chromatin, the developing spermatids are phagocytosed by Sertoli cells during late spermiogenesis, as the spermatids undergo cytoplasmic remodeling. Surprisingly, despite the loss of all germ cells, there was no evidence of the symplast formation and cell sloughing that is typically associated with spermatid death in other mouse sterility models, suggesting that novel cell death and/or cell disposal mechanisms may be engaged in Fbxo7 mutant males. Mutation of the Drosophila Fbxo7 ortholog, nutcracker (ntc) also leads to sterility with germ cell death during cytoplasmic remodeling, indicating that the requirement for Fbxo7 at this stage is conserved. The ntc phenotype was attributed to decreased levels of the proteasome regulator, DmPI31 and reduced proteasome activity. Consistent with the fly model, we observe a reduction in PI31 levels in mutant mice; however, there is no alteration in proteasome activity in whole mouse testes. Our results are consistent with findings that Fbxo7 regulates PI31 protein levels, and indicates that a defect at the late stages of spermiogenesis, possibly due to faulty spatial dynamics of proteasomes during cytoplasmic remodeling, may underlie the fertility phenotype in mice.

Noise-induced hearing loss alters hippocampal glucocorticoid receptor expression in rats.

Although the effects of intense noise exposure on the peripheral and central auditory pathway have been well characterized, its effects on non-classical auditory structures in the brain, such as the hippocampus, are less well understood. Previously, we demonstrated that noise-induced hearing loss causes a significant long-term reduction in hippocampal neurogenesis and cell proliferation. Given the known suppressive effects of stress hormones on neurogenesis, the goal of the present study was to determine if activation of the stress response is an underlying mechanism for the long-term reduction in hippocampal neurogenesis observed following noise trauma. To accomplish this, we monitored basal and reactive blood plasma levels of the stress hormone corticosterone in rats for ten weeks following acoustic trauma, and quantified changes in hippocampal glucocorticoid and mineralocorticoid receptors. Our results indicate that long-term auditory deprivation does not cause a persistent increase in basal or reactive stress hormone levels in the weeks following noise exposure. Instead, we observed a greater decline in reactive corticosterone release in noise-exposed rats between the first and tenth week of sampling compared to control rats. We also observed a significant increase in hippocampal glucocorticoid receptor expression which may cause greater hippocampal sensitivity to circulating glucocorticoid levels and result in glucocorticoid-induced suppression of neurogenesis, as well as increased feedback inhibition on the HPA axis. No change in mineralocorticoid receptor expression was observed between control and noise exposed rats. These results highlight the adverse effect of intense noise exposure and auditory deprivation on the hippocampus.

Axial strength test for round flat faced versus capsule shaped bilayer tablets.

There has been increasing interest in fixed dose combination (FDC) therapy. Multi-layer tablets are a popular choice among various technologies to deliver FDCs. In most cases, round flat faced tooling is used in testing tablets as they have the simplest geometry. However, shaped tooling is more common for commercial products and may have an effect on bilayer tablet strength. Capsule shaped bilayer tablets, similar to a commercial image, and holders conforming to the tablet topology, were compared with similar round flat faced bilayer tablets and their corresponding holders. Bilayer tablets were subjected to an axial test device, until fracture and the quantitative breaking force value was recorded. As the second layer compression force increases, regardless of holder design, an increase in breaking force occurs as expected. This consistent trend provides insight regarding the breaking force of capsule shaped bilayer tablets. The results of this study show that at lower second layer compression forces, tablet geometry does not significantly impact the results. However, at higher compression forces, a significant difference in breaking force between tablet geometries exists. Therefore, using a test geometry close to the final commercial tablet image is recommended to have the most accurate prediction for tablet breakage.

In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068.

BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.

Music and video as distractors for boys with ADHD in the classroom: comparison with controls, individual differences, and medication effects.

This study examined the effects of music and video on the classroom behavior and performance of boys with and without attention deficit hyperactivity disorder (ADHD) and examined the effects of 0.3 mg/kg methylphenidate (MPH). In one study, 41 boys with ADHD and 26 controls worked in the presence of no distractor, music, or video. Video produced significant distraction, particularly for the boys with ADHD, and MPH improved the performance of boys with ADHD across distractor conditions.There were individual differences in response to the music such that some boys were adversely affected and others benefited relative to no-distractor.In a second study, music and MPH were assessed in an additional 86 boys with ADHD to examine further the music results. In the presence or absence of music, MPH improved performance relative to placebo. Similar individual differences were found as in Experiment 1.

Viable mouse gene ablations that robustly alter brain Aß levels are rare.

BACKGROUND: Accumulation of amyloid-ß (Aß) peptide in the brain is thought to play a key pathological role in Alzheimer's disease. Many pharmacological targets have therefore been proposed based upon the biochemistry of Aß, but not all are equally tractable for drug discovery. RESULTS: To search for novel targets that affect brain Aß without causing toxicity, we screened mouse brain samples from 1930 novel gene knock-out (KO) strains, representing 1926 genes, using Aß ELISA assays. Although robust Aß lowering was readily apparent in brains from a BACE1 KO strain, none of the novel strains exhibited robust decreases in brain Aß, including a GPR3 KO strain, which had previously been proposed as an Aß target. However, significantly increased Aß was observed in brain samples from two KO strains, corresponding to genes encoding the glycosylphosphatidylinositol mannosyl transferase PIGZ and quinolinate phosphoribosyltransferase (QPRT). CONCLUSIONS: Thus, gene ablations that are permissive for mouse survival and that also have a robust effect on Aß levels in the brain are rare.

The efficacy and tolerability of methylphenidate and behavior modification in children with attention-deficit/hyperactivity disorder and severe mood dysregulation.

OBJECTIVES: This study examines the tolerability and efficacy of methylphenidate (MPH) and behavior modification therapy (BMOD) in children with attention-deficity/hyperactivity disorder (ADHD) and severe mood dysregulation (SMD). METHODS: Children (ages 5-12) from a summer program for ADHD were screened for SMD and additional manic-like symptoms using structured assessments and direct clinical interview with the Young Mania Rating Scale (YMRS). The SMD group was comprised of 33 subjects with SMD and elevated YMRS scores (mean = 23.7). They underwent weekly mood assessments plus the daily ADHD measures that are part of the program. The comparison group (n = 68) was comprised of the rest of the program participants. Using a crossover design, all subjects in both groups were treated with three varying intensities of BMOD (no, low, high) each lasting 3 weeks, with MPH dose (placebo, 0.15 mg/kg t.i.d., 0.3mg/kg t.i.d., and 0.6 mg/kg t.i.d.) varying daily within each behavioral treatment. RESULTS: Groups had comparable ADHD symptoms at baseline, with the SMD group manifesting more oppositional defiant disorder/conduct disorder (ODD/CD) symptoms (p < 0.001). Both groups showed robust improvement in externalizing symptoms (p < 0.001). There was no evidence of differential treatment efficacy or tolerability. Treatment produced a 34% reduction in YMRS ratings in SMD subjects (p - 0.001). However, they still exhibited elevated YMRS ratings, more ODD/CD symptoms (p < 0.001), and were more likely to remain significantly impaired at home than non-SMD subjects (p < 0.05). CONCLUSIONS: MPH and BMOD are tolerable and effective treatments for children with ADHD and SMD, but additional treatments may be needed to optimize their functioning.

The effect of water solubility of solutes on their flux through human skin in vitro: an extended Flynn database fitted to the Roberts-Sloan equation.

The edited Flynn database (n=62) for determining the effect of the physicochemical properties of solutes on their skin absorption has been extended (n=114) to give a database for which solubilities of the solutes in water, S(AQ), and their maximum fluxes from water through human skin in vitro, J(MAQ), are known or can be calculated. Besides the six major contributors to the original and edited Flynn database, nine more contributors have been included in the extended database to give 15 contributors. As in the edited Flynn database, data for solutes that were significantly ionized or for experiments using different thicknesses of skin were not excluded from the extended database so that the diversity of the original database was maintained. The extended database was fit to five equations where the independent variables were solubility in octanol (S(OCT)), in water (S(AQ)) or molecular weight (MW) and combinations of those three variables; and the dependent variable was J(MAQ). The best fit was obtained from the Roberts-Sloan (RS) equation: logJ(MAQ) = x + ylogS(OCT) + (1 - y)logS(AQ) - z MW, x = -2.574, y = 0.586, z = 0.00440, r(2) = 0.887, S.D. = 0.399, F = 139. This result is comparable to the best fit published using permeability coefficients, P, as the dependent variable, but gives greater insight into the factors affecting permeation. J(MAQ) is more important clinically because it described how much is permeating per unit area and time, while P is in the units of speed (cmh(-1)). Because of the dependence of J(MAQ) on S(AQ), the selection of new drugs with improved topical delivery should include considerations of their S(AQ) in their design.