Evaluation of felodipine as a potential perpetrator of pharmacokinetic drug-drug interactions.

OBJECTIVE: To evaluate felodipine as a potential perpetrator of pharmacokinetic drug-drug interactions (PK-DDIs) involving cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). METHODS: Felodipine extended-release 10 mg was administered daily to six healthy subjects for 7 days (days 1-7). Subjects were administered a modified Inje cocktail comprising the selective probe substrates caffeine 100 mg (CYP1A2), losartan 25 mg (CYP2C9), omeprazole 20 mg (CYP2C19), dextromethorphan 30 mg (CYP2D6), midazolam 2 mg (CYP3A) and digoxin 250 µg (P-gp) on day 0 (prior to felodipine exposure) and day 7 (after felodipine exposure). Plasma samples were collected over 24 h and drug concentrations measured by UPLC-MS/MS. RESULTS: The geometric means of the area under the plasma concentration-time curve ratios (probe AUC after felodipine exposure/probe AUC prior to felodipine exposure) and 95% confidence intervals for each probe were: caffeine 0.91 (0.64-1.30), losartan 1.05 (0.95-1.15), omeprazole 1.17 (0.78-1.76), dextromethorphan 1.46 (1.00-2.12), midazolam 1.23 (0.99-1.52) and digoxin 1.01 (0.89-1.15). CONCLUSION: Felodipine may be a weak in vivo inhibitor of CYP3A and CYP2D6 but is unlikely to act as a significant perpetrator of PK-DDIs.

Foreskin restorers: insights into motivations, successes, challenges, and experiences with medical and mental health professionals - An abridged summary of key findings.

Demographically diverse surveys in the United States suggest that 5-10% of non-voluntarily circumcised American males wish that they had not been circumcised. Similar data are unavailable in other countries. An unknown proportion of circumcised males experience acute circumcision-related distress; some attempt to regain a sense of bodily integrity through non-surgical foreskin restoration. Their concerns are often ignored by health professionals. We conducted an in-depth investigation into foreskin restorers' lived experiences. An online survey containing 49 qualitative and 10 demographic questions was developed to identify restorers' motivations, successes, challenges, and experiences with health professionals. Targeted sampling was employed to reach this distinctive population. Invitations were disseminated to customers of commercial restoration devices, online restoration forums, device manufacturer websites, and via genital autonomy organizations. Over 2100 surveys were submitted by respondents from 60 countries. We report results from 1790 fully completed surveys. Adverse physical, sexual, emotional/psychological and self-esteem impacts attributed to circumcision had motivated participants to seek foreskin restoration. Most sought no professional help due to hopelessness, fear, or mistrust. Those who sought help encountered trivialization, dismissal, or ridicule. Most participants recommended restoration. Many professionals are unprepared to assist this population. Circumcision sufferers/foreskin restorers have largely been ill-served by medical and mental health professionals.

A Psychotherapy Private Practice Social Work Practicum: Expanding Our Boundaries of Field Education Placement.

Many social workers go into private practice, providing crucial mental health services; however, there is a dearth in the scholarship outlining the social work student training for these career options. It may be argued that social work students receive little or no clinical training on how to run a private practice providing psychotherapy services. To mend this pedagogical shortcoming, a private practice field education placement is a legitimate teaching opportunity to prepare social work students to meet the mental health needs of individuals, families, and the public. Authors drew on borderlands theory described by Gloria Anzaldua as a contested space that focuses on "both and" thinking, which resonated with a sense of navigating a border filled with cultural tension between private practice and social work. Five social workers explore their unique experiences of a private practice field education placement using borderlands theory as a lens. Qualitative analysis of autoethnography narratives resulted in six themes: (1) benefits to private practice site, (2) preparation for social work, (3) private practice is social work, (4) balanced picture, (5) practicum landscape, and (6) learning opportunities. The article concludes with recommendations for social work education and research.

The small RNA profile during Drosophila melanogaster development.

Small RNAs ranging in size between 20 and 30 nucleotides are involved in different types of regulation of gene expression including mRNA degradation, translational repression, and chromatin modification. Here we describe the small RNA profile of Drosophila melanogaster as a function of development. We have cloned and sequenced over 4000 small RNAs, 560 of which have the characteristics of RNase III cleavage products. A nonredundant set of 62 miRNAs was identified. We also isolated 178 repeat-associated small interfering RNAs (rasiRNAs), which are cognate to transposable elements, satellite and microsatellite DNA, and Suppressor of Stellate repeats, suggesting that small RNAs participate in defining chromatin structure. rasiRNAs are most abundant in testes and early embryos, where regulation of transposon activity is critical and dramatic changes in heterochromatin structure occur.

BIPASS: BioInformatics Pipeline Alternative Splicing Services.

BioInformatics Pipeline Alternative Splicing Services (BIPASS) offer support to scientists interested in gathering information related to alternative splicing (AS) events. The service BIPAS-SpliceDB provides access to AS information that has been extracted a priori from various public databases and stored in a data warehouse. In contrast, the BIPAS-Align&Splice service allows scientists to submit their own sequences and genome to compute AS analysis results. BIPAS services offer various user-friendly ways to navigate through the results. AS results are organized at different conceptual levels (clusters and sequences), and are displayed in graphs or summarized in tables that can be downloaded in XML or text format. The two BIPAS services SpliceDB and Align&Splice are available online at http://bip.umiacs.umd.edu:8080/.

Neonatal injections of methoxychlor decrease adult rat female reproductive behavior.

Methoxychlor (MXC), a commonly used pesticide, has been labeled as an endocrine disruptor. To evaluate the impact of neonatal exposure to MXC on female reproduction, female Sprague-Dawley rats were given subcutaneous injections on postnatal days 1, 3, and 5. The injections contained 1.0mg MXC, 2.0mg MXC, 10 µg 17ß-estradiol benzoate (positive control), or sesame oil (vehicle). The injections of MXC had no effect on anogenital distance or day of vaginal opening. Treatment with either 2.0mg MXC or estradiol significantly increased the total number of days with vaginal keratinization. Treatment with MXC had no effect on ability to exhibit a mating response as an adult female, although the high dose MXC (2.0) and the positive control (estradiol) animals demonstrated a decrease in degree of receptivity, a decrease in proceptive behavior and an increase in rejection behavior. These data suggest that higher doses of MXC given directly to pups during the neonatal period can act as an estrogen and alter aspects of the nervous system, impacting adult reproductive characteristics.

Alternative splicing of mouse transcription factors affects their DNA-binding domain architecture and is tissue specific.

BACKGROUND: Analyzing proteins in the context of all available genome and transcript sequence data has the potential to reveal functional properties not accessible through protein sequence analysis alone. To analyze the impact of alternative splicing on transcription factor (TF) protein structure, we constructed a comprehensive database of splice variants in the mouse transcriptome, called MouSDB3 containing 461 TF loci. RESULTS: Our analysis revealed that 62% of these loci in MouSDB3 have variant exons, compared to 29% of all loci. These variant TF loci contain a total of 324 alternative exons, of which 23% are in-frame. When excluded, 80% of in-frame alternative exons alter the domain architecture of the protein as computed by SMART (simple modular architecture research tool). Sixty-eight % of these exons directly affect the coding regions of domains important for TF function. Seventy-five % of the domains affected are DNA-binding domains. Tissue distribution analyses of variant mouse TFs reveal that they have more alternatively spliced forms in 14 of the 18 tissues analyzed when compared to all the loci in MouSDB3. Further, TF isoforms are homogenous within a given single tissue and are heterogeneous across different tissues, indicating their tissue specificity. CONCLUSIONS: Our study provides quantitative evidence that alternative splicing preferentially adds or deletes domains important to the DNA-binding function of the TFs. Analyses described here reveal the presence of tissue-specific alternative splicing throughout the mouse transcriptome. Our findings provide significant biological insights into control of transcription and regulation of tissue-specific gene expression by alternative splicing via creation of tissue-specific TF isoforms.

Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene.

The BB (BioBreeding) rat is one of the best models of spontaneous autoimmune diabetes and is used to study non-MHC loci contributing to Type 1 diabetes. Type 1 diabetes in the diabetes-prone BB (BBDP) rat is polygenic, dependent upon mutations at several loci. Iddm1, on chromosome 4, is responsible for a lymphopenia (lyp) phenotype and is essential to diabetes. In this study, we report the positional cloning of the Iddm1/lyp locus. We show that lymphopenia is due to a frameshift deletion in a novel member (Ian5) of the Immune-Associated Nucleotide (IAN)-related gene family, resulting in truncation of a significant portion of the protein. This mutation was absent in 37 other inbred rat strains that are nonlymphopenic and nondiabetic. The IAN gene family, lying within a tight cluster on rat chromosome 4, mouse chromosome 6, and human chromosome 7, is poorly characterized. Some members of the family have been shown to be expressed in mature T cells and switched on during thymic T-cell development, suggesting that Ian5 may be a key factor in T-cell development. The lymphopenia mutation may thus be useful not only to elucidate Type 1 diabetes, but also in the function of the Ian gene family as a whole.