Role of detrusor PDGFRα+ cells in mouse model of cyclophosphamide-induced detrusor overactivity

Cyclophosphamide (CYP)-induced cystitis is a rodent model that shares many features common to the cystitis occurring in patients, including detrusor overactivity (DO). Platelet-derived growth factor receptor alpha positive (PDGFRα(+)) cells have been proposed to regulate muscle excitability in murine bladders during filling. PDGFRα(+) cells express small conductance Ca(2+)-activated K(+) channels (predominantly SK3) that provide stabilization of membrane potential during filling. We hypothesized that down-regulation of the regulatory functions of PDGFRα(+) cells and/or loss of PDGFRα(+) cells generates the DO in CYP-treated mice. After CYP treatment, transcripts of Pdgfrα and Kcnn3 and PDGFRα and SK3 protein were reduced in detrusor muscle extracts. The distribution of PDGFRα(+) cells was also reduced. Inflammatory markers were increased in CYP-treated detrusor muscles. An SK channel agonist, CyPPA, increased outward current and hyperpolarization in PDGFRα(+) cells. This response was significantly depressed in PDGFRα(+) cells from CYP-treated bladders. Contractile experiments and ex vivo cystometry showed increased spontaneous contractions and transient contractions, respectively in CYP-treated bladders with a reduction of apamin sensitivity, that could be attributable to the reduction in the SK conductance expressed by PDGFRα(+) cells. In summary, PDGFRα(+) cells were reduced and the SK3 conductance was downregulated in CYP-treated bladders. These changes are consistent with the development of DO after CYP treatment

The effect of dynaCleft[R] on presurgical orthopedics in bilateral cleft lip and palate patients

Aims: The aim of this study was to determine the effects DynaCleft® has on patients with bilateral cleft lip and palate. Subjects and Methods: Comparative data were collected from a total of 46 infants diagnosed with bilateral cleft lip and palate between 1981 and 2017. Twenty-three infants were treated with DynaCleft® and an obturator and 23 infants received an obturator only. Maxillary impressions were taken at each infant's initial clinic visit and again on the day of his/her surgical cleft lip repair. Differences in maxillary retraction, sagittal repositioning, and cleft widths were compared between the two groups. Statistical Analysis Used: Paired t-tests were used to determine if there was significant change before and after DynaCleft® therapy, and two-sample t-tests were used to compare the data between the two study groups. Results: Clinically, DynaCleft® averaged more maxillary retraction and cleft size reduction on both the right and left sides compared to the control group. Within the DynaCleft® group, a statistically significant difference was found for premaxillary retraction on both the right and left sides. However, all the other comparisons between the two groups were not found to be statistically significant. Conclusions: DynaCleft® as a presurgical orthopedic therapy may help to limit uncontrolled physiological changes and reposition the premaxillary segment, while reducing cleft widths prior to definitive lip surgery

Identification of a major locus interacting with MC1R and modifying black coat color in an F2 Nellore-Angus population

BACKGROUND: In cattle, base color is assumed to depend on the enzymatic activity specified by the MC1R locus, i.e. the extension locus, with alleles coding for black (E( D )), red (e), and wild-type (E( + )). In most mammals, these alleles are presumed to follow the dominance model of E( D ) > E( + ) > e, although exceptions are found. In Bos indicus x Bos taurus F(2) cattle, some E( D )E( + ) heterozygotes are discordant with the dominance series for MC1R and display various degrees of red pigmentation on an otherwise predicted black background. The objective of this study was to identify loci that modify black coat color in these individuals. RESULTS: Reddening was classified with a subjective scoring system. Interval analyses identified chromosome-wide suggestive (P < 0.05) and significant (P < 0.01) QTL on bovine chromosomes (BTA) 4 and 5, although these were not confirmed using single-marker association or Bayesian methods. Evidence of a major locus (F = 114.61) that affects reddening was detected between 60 and 73 Mb on BTA 6 (Btau4.0 build), and at 72 Mb by single-marker association and Bayesian methods. The posterior mean of the genetic variance for this region accounted for 43.75% of the genetic variation in reddening. This region coincided with a cluster of tyrosine kinase receptor genes (PDGFRA, KIT and KDR). Fitting SNP haplotypes for a 1 Mb interval that contained all three genes and centered on KIT accounted for the majority of the variation attributed to this major locus, which suggests that one of these genes or associated regulatory elements, is responsible for the majority of variation in degree of reddening. CONCLUSIONS: Recombinants in a 5 Mb region surrounding the cluster of tyrosine kinase receptor genes implicated PDGFRA as the strongest positional candidate gene. A higher density marker panel and functional analyses will be required to validate the role of PDGFRA or other regulatory variants and their interaction with MC1R for the modification of black coat color in Bos indicus influenced cattle

Heat tolerance predicts the importance of species interaction effects as the climate changes

Few studies have quantified the relative importance of direct effects of climate change on communities versus indirect effects that are mediated thorough species interactions, and the limited evidence is conflicting. Trait-based approaches have been popular in studies of climate change, but can they be used to estimate direct versus indirect effects? At the species level, thermal tolerance is a trait that is often used to predict winners and losers under scenarios of climate change. But thermal tolerance might also inform when species interactions are likely to be important because only subsets of species will be able to exploit the available warmer climatic niche space, and competition may intensify in the remaining, compressed cooler climatic niche space. Here, we explore the relative roles of the direct effects of temperature change and indirect effects of species interactions on forest ant communities that were heated as part of a large-scale climate manipulation at high-A nd low-latitude sites in eastern North America. Overall, we found mixed support for the importance of negative species interactions (competition), but found that the magnitude of these interaction effects was predictable based on the heat tolerance of the focal species. Forager abundance and nest site occupancy of heat-intolerant species were more often influenced by negative interactions with other species than by direct effects of temperature. Our findings suggest that measures of species-specific heat tolerance may roughly predict when species interactions will influence responses to global climate change

Climatic warming destabilizes forest ant communities

How will ecological communities change in response to climate warming? Direct effects of temperature and indirect cascading effects of species interactions are already altering the structure of local communities, but the dynamics of community change are still poorly understood. We explore the cumulative effects of warming on the dynamics and turnover of forest ant communities that were warmed as part of a 5-year climate manipulation experiment at two sites in eastern North America. At the community level, warming consistently increased occupancy of nests and decreased extinction and nest abandonment. This consistency was largely driven by strong responses of a subset of thermophilic species at each site. As colonies of thermophilic species persisted in nests for longer periods of time under warmer temperatures, turnover was diminished, and species interactions were likely altered. We found that dynamical (Lyapunov) community stability decreased with warming both within and between sites. These results refute null expectations of simple temperature-driven increases in the activity and movement of thermophilic ectotherms. The reduction in stability under warming contrasts with the findings of previous studies that suggest resilience of species interactions to experimental and natural warming. In the face of warmer, no-analog climates, communities of the future May become increasingly fragile and unstable

Intranasal oxytocin in children and adolescents with autism spectrum disorder

BACKGROUND Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was −3.7 in the oxytocin group and −3.5 in the placebo group (least-squares mean difference, −0.2; 95% confidence interval, −1.5 to 1.0; P=0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures

What is the Optimal Method Assessing for Persistent Villous Atrophy in Adult Coeliac Disease

Background and Aims: Methods of assessing gluten-free diet (GFD) adherence in adults with coeliac disease (CD) include serological testing, dietitian evaluation, questionnaires and repeat duodenal biopsies. Persisting villous atrophy (VA) is associated with CD complications, however gastroscopy with biopsies is expensive and invasive. This study aimed to assess the abilities of a duodenal bulb (D1) biopsy and the Celiac Dietary Adherence Test (CDAT) to detect persisting VA in adults with CD. Methods: A prospective observational study of adult CD patients referred for follow-up duodenal biopsies was performed. Quadrantic biopsies were taken from the second part of the duodenum (D2), in addition to a D1 biopsy. Patients underwent follow-up serological testing, and completed the CDAT and Biagi Score. These non-invasive adherence markers were compared against duodenal histology. Results: 368 patients (mean age 51.0 years, 70.1% female) had D1 and D2 biopsies taken at follow-up gastroscopy. Compared to D2 biopsies alone, additional D1 biopsies increased detection of VA by 10.4% (p<0.0001). 201 patients (mean age 50.3 years, 67.7% female) completed adherence questionnaires and serology. When detecting VA, sensitivities and specificities of these markers were 39.7% and 94.2% for IgA- tTG, 38.1% and 96.4% for IgA-EMA, 55.6% and 52.2% for CDAT and 20.6% and 96.4% for the Biagi score. Conclusions: Bulbar biopsies increase detection of persisting VA by 10.4%. Serology, CDAT and Biagi performed poorly when predicting VA. The gold standard for predicting persisting VA remains repeat biopsy