Nonequilibrium microbial dynamics unveil a new macroecological pattern beyond Taylor's law.

We introduce a comprehensive analytical benchmark, relying on Fokker-Planck formalism, to study microbial dynamics in the presence of both biotic and abiotic forces. In equilibrium, we observe a balance between the two kinds of forces, leading to no correlations between species abundances. This implies that real microbiomes, where correlations have been observed, operate out of equilibrium.

Structural dynamics of plant-pollinator mutualistic networks.

The discourse surrounding the structural organization of mutualistic interactions mostly revolves around modularity and nestedness. The former is known to enhance the stability of communities, while the latter is related to their feasibility, albeit compromising the stability. However, it has recently been shown that the joint emergence of these structures poses challenges that can eventually lead to limitations in the dynamic properties of mutualistic communities.

Sparse species interactions reproduce abundance correlation patterns in microbial communities.

During the last decades, macroecology has identified broad-scale patterns of abundances and diversity of microbial communities and put forward some potential explanations for them. However, these advances are not paralleled by a full understanding of the dynamical processes behind them. In particular, abundance fluctuations of different species are found to be correlated, both across time and across communities in metagenomic samples.

[The by law required assessment by a child psychiatrist before cosmetic interventions; retrospective file research].

Surgical and non-surgical cosmetic interventions are on the rise, also in minors. Therefore, the society, healthcare system and government are searching for an ethical-medical-legal framework. Numerous studies have shown the importance of patient selection.

Factors influencing adherence to therapeutic recommendations made after diagnostic reassessment of medically unexplained symptoms in children and adolescents.

Background: Medically unexplained symptoms (MUS) are common among children and adolescents and may be highly impairing. Even after long diagnostic and/or therapeutic trajectories, many of these children and their parents feel dissatisfied with the advice and therapies they were given.

Objectives: After a 2-week hospitalisation for somatic and psychiatric reassessment, children and their families were given recommendations for further treatment.

Using Polarons for sub-nK Quantum Nondemolition Thermometry in a Bose-Einstein Condensate.

We introduce a novel minimally disturbing method for sub-nK thermometry in a Bose-Einstein condensate (BEC). Our technique is based on the Bose polaron model; namely, an impurity embedded in the BEC acts as the thermometer. We propose to detect temperature fluctuations from measurements of the position and momentum of the impurity.

Preclinical toxicity and pharmacokinetics of a new orally bioavailable flubendazole formulation and the impact for clinical trials and risk/benefit to patients.

Background: Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed.

Dose- and Time-dependency of the Toxicity and Pharmacokinetic Profiles of Bedaquiline and Its N-desmethyl Metabolite in Dogs.

Bedaquiline (BDQ) is an antibiotic to treat pulmonary multidrug-resistant tuberculosis (MDR-TB). Studies up to 39 weeks were conducted orally in dogs to assess the toxicity and pharmacokinetics of BDQ and its N-desmethyl metabolite (D-BDQ). Phospholipidosis (PLD) seen in the monocytic phagocytic system was considered an adaptive change.

An Intervention Supporting the Mental Health of Children with a Refugee Background.

This contribution proposes an intervention methodology that provides improved access to and effectiveness of mental health care facilities in Brussels, Belgium, for children and their families with a refugee and migration background. Migration is a complex process that involves several potential risk factors, and referral to mental health facilities is often ineffective. Consequently, optimal developmental opportunities for refugee children are hampered.

Can clinical characteristics be criteria to perform chromosomal microarray analysis in children and adolescents with autism spectrum disorders?

Background: Chromosomal microarray analysis (CMA) has become increasingly important in the assessment of patients with autism spectrum disorders (ASD), but is sometimes restricted to patients with specific additional characteristics or comorbidities. We aim to evaluate whether certain clinical characteristics could be criteria to perform CMA and also to investigate the diagnostic value of CMA compared to other genetic analyses in our patient population.

Methods: The files of 311 children diagnosed with ASD were retrospectively analyzed.

Forearm bone mineralization in recently diagnosed female adolescents with a premenarchal onset of anorexia nervosa.

Objective: Data available on bone mineralization by peripheral quantitative computed tomography (pQCT) in adolescents with an early onset anorexia nervosa (AN) is limited. We investigated whether a disturbed bone mineralization can be observed at the distal radius in recently diagnosed female adolescents with AN and a premenarchal onset of this disease.

Method: Twenty-four premenarchal patients with AN and 22 healthy females which were age and height matched, were selected from our reference database; both groups underwent a pQCT bone assessment at the distal radius of the nondominant arm.

Association of ADHD and Celiac Disease: What Is the Evidence? A Systematic Review of the Literature.

This article tries to answer the question whether or not there is evidence for a relationship between celiac disease (CD) and ADHD. A review of the current literature on this topic is provided. PUBMED/MEDLINE, Web of Science, and Google scholar were searched to include all published trials on ADHD and CD (no date limitation, both noncontrolled and controlled trials).

The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.

Purpose: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor.

Experimental Design: We performed a phase I dose-escalation study according to the standard 3+3 design.

Psychosis in an adolescent girl: a common manifestation in Niemann-Pick Type C disease.

Niemann-Pick disease type C (NP-C) is a rare autosomal-recessively inherited lysosomal storage disorder. It is caused by mutations in the NPC1 (95%) or NPC2 gene. It is a progressive and highly heterogeneous disease, characterized by the presentation of visceral, neurological, and psychiatric symptoms.

Differential responses to JNJ-37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague-Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics.

JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively.

Evaluation of miR-122 and other biomarkers in distinct acute liver injury in rats.

The detection of drug-induced hepatotoxicity remains an important safety issue in drug development. A liver-specific microRNA species, microRNA-122 (miR-122), has recently shown potential for predicting liver injury in addition to the standard hepatic injury biomarkers. The objective of this study was to measure miR-122 together with several other liver markers in distinct settings of acute liver toxicity in rats to determine the value of miR-122 as a biomarker for liver injury in this species.

Tissue Kim-1 and urinary clusterin as early indicators of cisplatin-induced acute kidney injury in rats.

The kidney is one of the main targets of drug toxicity, and early detection of renal damage is critical in preclinical drug development. A model of cisplatin-induced nephrotoxicity in male Sprague Dawley rats treated for 1, 3, 5, 7, or 14 days at 1 mg/kg/day was used to monitor the spatial and temporal expression of various indicators of kidney toxicity during the progression of acute kidney injury (AKI). As early as 1 day after cisplatin treatment, positive kidney injury molecule-1 (Kim-1) immunostaining, observed in the outer medulla of the kidney, and changes in urinary clusterin indicated the onset of proximal tubular injury in the absence of functional effects.

Phospholipidosis in rats treated with amiodarone: serum biochemistry and whole genome micro-array analysis supporting the lipid traffic jam hypothesis and the subsequent rise of the biomarker BMP.

To provide mechanistic insight in the induction of phospholipidosis and the appearance of the proposed biomarker di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP), rats were treated with 150 mg/kg amiodarone for 12 consecutive days and analyzed at three different time points (day 4, 9, and 12). Biochemical analysis of the serum revealed a significant increase in cholesterol and phospholipids at the three time points. Bio-analysis on the serum and urine detected a time-dependent increase in BMP, as high as 10-fold compared to vehicle-treated animals on day 12.

Optimisation of the cell cultivation methods in the embryonic stem cell test results in an increased differentiation potential of the cells into strong beating myocard cells.

In order to support drug research in the selection process for non-embryotoxic pharmaceutical compounds, a screening method for embryotoxicity is needed. The murine embryonic stem cell test (EST) is a validated in vitro test based on two permanent mouse cell lines and delivering results in 10-days. Implementation of this test within our laboratory, revealed variability in the differentiation potential of the embryonic stem cells and, as a consequence, a lot of assays needed to be rejected due the fact the acceptance criteria were not reached.

A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development.

Regulatory guidelines indicate acute toxicity studies in animals are considered necessary for pharmaceuticals intended for human use. This is the only study type where lethality is mentioned as an endpoint. The studies are carried out, usually in rodents, to support marketing of new drugs and to identify the minimum lethal dose.

Flow cytometric analysis of micronucleated reticulocytes: Time- and dose-dependent response of known mutagens in mice, using multiple blood sampling.

According to the current Organization of Economic Cooperation and Development (OECD) and International Committee on Harmonization (ICH) guidelines for the mammalian erythrocyte micronucleus (MN) test, analysis of peripheral blood reticulocytes (RETs) for the presence of micronuclei can be performed using flow cytometry. The MicroFlow PLUS method (Litron Laboratories, Rochester, NY) for MN analysis by flow cytometry is based on the binding of FITC-labeled antibodies to the CD71 transferrin receptor of immature RETs, on parallel RNA degradation, and on propidium iodide staining of DNA present as micronuclei. The objective of this study was to assess the sensitivity of this flow cytometry method to detect time- and dose-dependent induction of micronuclei in mouse peripheral blood RETs after treatment with nine chemical agents.

In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine).

Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.

Carcinogenicity studies of astemizole in mice and rats.

The histamine H1 antagonist astemizole (Hismanal) was tested for carcinogenicity in Swiss mice and Wistar rats. Astemizole was administered with the food to mice for 18 and to rats for 24 consecutive months. The doses given--approximately 5, 20, and 80 mg/kg body weight.