Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

The effectiveness of peer health coaching in improving glycemic control among low-income patients with diabetes: protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Although self-management support improves diabetes outcomes, it is not consistently provided in health care settings strained for time and resources. One proposed solution to personnel and funding shortages is to utilize peer coaches, patients trained to provide diabetes education and support to other patients. Coaches share similar experiences about living with diabetes and are able to reach patients within and beyond the health care setting. Given the limited body of evidence that demonstrates peer coaching significantly improves chronic disease care, this present study examines the impact of peer coaching delivered in a primary care setting on diabetes outcomes.</p> <p>Methods/Design</p> <p>The aim of this multicenter, randomized control trial is to evaluate the effectiveness of utilizing peer coaches to improve clinical outcomes and self-management skills in low-income patients with poorly controlled diabetes. A total of 400 patients from six primary health centers based in San Francisco that serve primarily low-income populations will be randomized to receive peer coaching (n = 200) or usual care (n = 200) over 6 months. Patients in the peer coach group receive coaching from patients with diabetes who are trained and mentored as peer coaches. The primary outcome is change in HbA1c. Secondary outcomes include change in: systolic blood pressure, body mass index (BMI), LDL cholesterol, diabetes self-care activities, medication adherence, diabetes-related quality of life, diabetes self-efficacy, and depression. Clinical values (HbA1c, LDL cholesterol and blood pressure) and self-reported diabetes self-efficacy and self-care activities are measured at baseline and after 6 months for patients and coaches. Peer coaches are also assessed at 12 months.</p> <p>Discussion</p> <p>Patients with diabetes, who are trained as peer health coaches, are uniquely poised to provide diabetes self management support and education to patients. This study is designed to investigate the impact of peer health coaching in patients with poorly controlled diabetes. Additionally, we will assess disease outcomes in patients with well controlled diabetes who are trained and work as peer health coaches.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01040806">NCT01040806</a></p

Investigating preferences for mosquito-control technologies in Mozambique with latent class analysis

<p>Abstract</p> <p>Background</p> <p>It is common practice to seek the opinions of future end-users during the development of innovations. Thus, the aim of this study is to investigate latent classes of users in Mozambique based on their preferences for mosquito-control technology attributes and covariates of these classes, as well as to explore which current technologies meet these preferences.</p> <p>Methods</p> <p>Surveys were administered in five rural villages in Mozambique. The data were analysed with latent class analysis.</p> <p>Results</p> <p>This study showed that users' preferences for malaria technologies varied, and people could be categorized into four latent classes based on shared preferences. The largest class, constituting almost half of the respondents, would not avoid a mosquito-control technology because of its cost, heat, odour, potential to make other health issues worse, ease of keeping clean, or inadequate mosquito control. The other three groups are characterized by the attributes which would make them avoid a technology; these groups are labelled as the bites class, by-products class, and multiple-concerns class. Statistically significant covariates included literacy, self-efficacy, willingness to try new technologies, and perceived seriousness of malaria for the household.</p> <p>Conclusions</p> <p>To become widely diffused, best practices suggest that end-users should be included in product development to ensure that preferred attributes or traits are considered. This study demonstrates that end-user preferences can be very different and that one malaria control technology will not satisfy everyone.</p

Development of outcome measures for autoimmune dermatoses

Validated outcome measures are essential in monitoring disease severity. Specifically in dermatology, which relies heavily on the clinical evaluation of the patient and not on laboratory values and radiographic tests, outcome measures help standardize patient care. Validated cutaneous scoring systems, much like standardized laboratory values, facilitate disease management and follow therapeutic response. Several cutaneous autoimmune dermatoses, specifically cutaneous lupus erythematosus (CLE), dermatomyositis (DM), and pemphigus vulgaris (PV), lack such outcome measures. As a result, evaluation of disease severity and patients’ response to therapy over time is less reliable. Ultimately, patient care is compromised. These diseases, which are often chronic and relapsing and remitting, are also often refractory to treatment. Without outcome measures, new therapies cannot be systematically assessed in these diseases. Clinical trials that are completed without standardized outcome measures produce less reliable results. Therefore, the development of validated outcome measures in these autoimmune dermatoses is critical. However, the process of developing these tools is as important, if not more so, than their availability. This review examines the steps that should be considered when developing outcome measures, while further examining their importance in clinical practice and trials. Finally, this review more closely looks at CLE, DM, and PV and addresses the recent and ongoing progress that has been made in the development of their outcome measures

A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine

Background: p53 is an important tumour suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. Methods: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. Results: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of β-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. Conclusion: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development

A Multi-Center, Qualitative Assessment of Pediatrician and Maternal Perspectives on Rotavirus Vaccines and the Detection of Porcine circovirus

<p>Abstract</p> <p>Background</p> <p>In 2010, researchers using novel laboratory techniques found that US-licensed rotavirus vaccines contain DNA or DNA fragments from <it>Porcine circovirus </it>(PCV), a virus common among pigs but not believed to cause illness in humans. We sought to understand pediatricians' and mothers' perspectives on this finding.</p> <p>Methods</p> <p>We conducted three iterations of focus groups for pediatricians and non-vaccine hesitant mothers in Seattle, WA, Cincinnati, OH, and Rochester, NY. Focus groups explored perceptions of rotavirus disease, rotavirus vaccination, and attitudes about the detection of PCV material in rotavirus vaccines.</p> <p>Results</p> <p>Pediatricians understood firsthand the success of rotavirus vaccines in preventing severe acute gastroenteritis among infants and young children. They measured this benefit against the theoretical risk of DNA material from PCV in rotavirus vaccines, determining overall that the PCV finding was of no clinical significance. Particularly influential was the realization that the large, randomized clinical trials that found both vaccines to be highly effective and safe were conducted with DNA material from PCV already in the vaccines.</p> <p>Most mothers supported the ideal of full disclosure regarding vaccination risks and benefits. However, with a scientific topic of this complexity, simplified information regarding PCV material in rotavirus vaccines seemed frightening and suspicious, and detailed information was frequently overwhelming. Mothers often remarked that if they did not understand a medical or technical topic regarding their child's health, they relied on their pediatrician's guidance.</p> <p>Many mothers and pediatricians were also concerned that persons who abstain from pork consumption for religious or personal reasons may have unsubstantiated fears of the PCV finding.</p> <p>Conclusions</p> <p>Pediatricians considered the detection of DNA material from PCV in rotavirus vaccines a "non-issue" and reported little hesitation in continuing to recommend the vaccines. Mothers desired transparency, but ultimately trusted their pediatrician's recommendation. Both vaccines are currently approved for their intended use, and no risk of human PCV illness has been reported. Communicating this topic to pediatricians and mothers requires sensitivity to a broad range of technical understanding and personal concerns.</p

Expression of emotional arousal in two different piglet call types

Humans as well as many animal species reveal their emotional state in their voice. Vocal features show strikingly similar correlation patterns with emotional states across mammalian species, suggesting that the vocal expression of emotion follows highly conserved signalling rules. To fully understand the principles of emotional signalling in mammals it is, however, necessary to also account for any inconsistencies in the way that they are acoustically encoded. Here we investigate whether the expression of emotions differs between call types produced by the same species. We compare the acoustic structure of two common piglet calls—the scream (a distress call) and the grunt (a contact call)—across three levels of arousal in a negative situation. We find that while the central frequency of calls increases with arousal in both call types, the amplitude and tonal quality (harmonic-to-noise ratio) show contrasting patterns: as arousal increased, the intensity also increased in screams, but not in grunts, while the harmonicity increased in screams but decreased in grunts. Our results suggest that the expression of arousal depends on the function and acoustic specificity of the call type. The fact that more vocal features varied with arousal in scream calls than in grunts is consistent with the idea that distress calls have evolved to convey information about emotional arousal

Genetic susceptibility to burnout in a Swedish twin cohort

Most previous studies of burnout have focused on work environmental stressors, while familial factors so far mainly have been overlooked. The aim of the study was to estimate the relative importance of genetic influences on burnout (measured with Pines Burnout Measure) in a sample of monozygotic (MZ) and dizygotic (DZ) Swedish twins. The study sample consisted of 20,286 individuals, born 1959–1986 from the Swedish twin registry who participated in the cross-sectional study of twin adults: genes and environment. Probandwise concordance rates (the risk for one twin to be affected given that his/her twin partner is affected by burnout) and within pair correlations were calculated for MZ and DZ same—and opposite sexed twin pairs. Heritability coefficients i.e. the proportion of the total variance attributable to genetic factors were calculated using standard biometrical model fitting procedures. The results showed that genetic factors explained 33% of the individual differences in burnout symptoms in women and men. Environmental factors explained a substantial part of the variation as well and are thus important to address in rehabilitation and prevention efforts to combat burnout