In vitro and in vivo activities of C-terminally truncated PTH peptides reveal a disconnect between cAMP signaling and functional activity

There is considerable evidence implicating the cAMP-signaling pathway in the anabolic action of PTH; and to date, all PTH and PTHrp peptides that stimulate cyclic AMP are active in animal models of osteogenesis. We have tested two C-terminally truncated peptides, PTH(1–29) and a modified PTH(1–21) (MPTH(1–21)), in in vitro and in vivo assays of PTH action. Each of the C-terminally truncated peptides was of low nanomolar potency in assays of receptor binding and cAMP stimulation. However, when we tested these peptides for functional response in Saos-2 cells stably transfected with a cyclic AMP response element (CRE) reporter, the C-terminally truncated peptides were two to four times less potent than would be expected from their binding and cAMP-stimulating properties. Furthermore, PTH(1–29), although active, was approximately 20-fold less potent than PTH(1–34) in a rat model of osteogenesis while MPTH(1–21) was inactive. The relative lack of activity of these peptides in vivo suggests that while activation of the cAMP pathway may be important for the anabolic effect of PTH fragments, it is not, of itself, predictive of their in vivo activity.     

Dementia Deficits Scale. Rating self-awareness of deficits

Impaired deficit awareness is important to detect because of its clinical implications; for example, patients with impaired awareness are more likely to engage in potentially dangerous activities, such as operating the stove. This study evaluated the reliability and validity of the Dementia Deficits Scale (DDS), a new multidimensional instrument for the assessment of self-awareness of cognitive, emotional, and functional deficits associated with dementia. Three parallel forms of the DDS were independently completed by the patient, clinician, and informant. The DDS yields two measures of deficit awareness: the discrepancy between clinician and patient assessments of the patient's deficits, and the discrepancy between informant and patient assessments. The DDS demonstrated adequate reliability and good divergent and convergent validity. Clinician and informant reports each added unique information, highlighting the importance of including both perspectives in the awareness assessment process. The DDS is recommended as a reliable and valid tool for the clinical and empirical assessment of deficit awareness in patients with dementia.     

Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity

Background  

Controlled clinical trials of health care interventions are either explanatory or pragmatic. Explanatory trials test whether an intervention is efficacious; that is, whether it can have a beneficial effect in an ideal situation. Pragmatic trials measure effectiveness; they measure the degree of beneficial effect in real clinical practice. In pragmatic trials, a balance between external validity (generalizability of the results) and internal validity (reliability or accuracy of the results) needs to be achieved. The explanatory trial seeks to maximize the internal validity by assuring rigorous control of all variables other than the intervention. The pragmatic trial seeks to maximize external validity to ensure that the results can be generalized. However the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability. We are conducting two pragmatic randomized controlled trials on interventions in the management of hypertension in primary care. We describe the design of the trials and the steps taken to deal with the competing demands of external and internal validity.     

Gene-Specific Differential DNA Methylation and Chronic Arsenic Exposure in an Epigenome-Wide Association Study of Adults in Bangladesh

Background: Inorganic arsenic is one of the most common naturally occurring contaminants found in the environment. Arsenic is associated with a number of health outcomes, with epigenetic modification suggested as a potential mechanism of toxicity.Objective: Among a sample of 400 adult participants, we evaluated the association between arsenic exposure, as measured by blood and urinary total arsenic concentrations, and epigenome-wide white blood cell DNA methylation.Methods: We used linear regression models to examine the associations between arsenic exposure and methylation at each CpG site, adjusted for sex, age, and batch. Differentially methylated loci were subsequently examined in relation to corresponding gene expression for functional evidence of gene regulation.Results: In adjusted analyses, we observed four differentially methylated CpG sites with urinary total arsenic concentration and three differentially methylated CpG sites with blood arsenic concentration, based on the Bonferroni-corrected significance threshold of p < 1 × 10^–7. Methylation of PLA2G2C (probe cg04605617) was the most significantly associated locus in relation to both urinary (p = 3.40 × 10^–11) and blood arsenic concentrations (p = 1.48 × 10^–11). Three additional novel methylation loci—SQSTM1 (cg01225779), SLC4A4 (cg06121226), and IGH (cg13651690)—were also significantly associated with arsenic exposure. Further, there was evidence of methylation-related gene regulation based on gene expression for a subset of differentially methylated loci.Conclusions: We observed significant associations between arsenic exposure and gene-specific differential white blood cell DNA methylation, suggesting that epigenetic modifications may be an important pathway underlying arsenic toxicity. The specific differentially methylated loci identified may inform potential pathways for future interventions.Citation: Argos M, Chen L, Jasmine F, Tong L, Pierce BL, Roy S, Paul-Brutus R, Gamble MV, Harper KN, Parvez F, Rahman M, Rakibuz-Zaman M, Slavkovich V, Baron JA, Graziano JH, Kibriya MG, Ahsan H. 2015. Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh. Environ Health Perspect 123:64–71; http://dx.doi.org/10.1289/ehp.1307884     

Patient Perspectives of Living with Coeliac Disease and Accessing Dietetic Services in Rural Australia: A Qualitative Study

Adapting to living with coeliac disease requires individuals to learn about and follow a strict gluten-free diet. Utilising a qualitative inductive approach, this study aimed to explore the perspectives of adults diagnosed with coeliac disease who have accessed dietetic services in a rural outpatient setting. A purposive sample of adults with coeliac disease who had accessed dietetic services from two rural dietetic outpatient clinics were recruited. Semi-structured interviews were conducted by telephone. Data were thematically analysed. Six participants were recruited and interviewed. Three key themes emerged: (i) optimising individualised support and services, (ii) adapting to a gluten-free diet in a rural context, and (iii) managing a gluten-free diet within the context of interpersonal relationships. Key issues identified in the rural context were access to specialist services and the increased cost of gluten-free food in more remote areas. The findings of this study have highlighted the difficulties associated with coeliac disease management and how dietetic consultation has the potential to influence confidence in management and improve lifestyle outcomes. Further qualitative research is required to expand on the findings of this study and inform future dietetic practice that meets the expectations and individual needs of people with coeliac disease in rural settings.     

Negotiating risky bodies: childbirth and constructions of risk

Policy makers, practitioners and researchers have identified risk as a key concept in relation to maternity care and childbirth. There is however a lack of research exploring women’s discursive constructions of risk and childbirth in relation to sociological risk theories. In this article we explore pregnant women’s everyday negotiations of risk in relation to the self-chosen plan to birth either at home or via an elective Caesarean section. We use sociocultural risk theories to contextualise our findings. This article draws on data from a study conducted in 2005–2006 in which we interviewed 24 pregnant middle-class South African women who were planning a home birth or elective Caesarean section and used social constructionist discourse analysis to analyse the data. We found that women’s risk constructions were related to three different conceptions of birthing embodiment: technocratic bodies, vulnerable bodies and knowing bodies. Women who planned Caesarean sections were committed to biomedical constructions of risk and birth. Woman who planned home births shifted between endorsing and subverting biomedical models of risk. They also resisted definitions of birthing bodies as inherently abject (unclean, polluting, unruly) and constructed the process of giving birth as risky in medicalised settings. In such settings, the birthing body was constructed as vulnerable to objectification, loss of dignity and shaming. Women who planned to give birth at home constructed an alternative approach to birth which emphasised embodied ways of knowing, relational connection and empowerment over normative and medicalised risk constructions. In the process, biomedical risk definitions were destabilised.     

Teen Use of Marijuana Edibles: A Focus Group Study of an Emerging Issue

Recent research indicates that marijuana-infused food product (i.e., edible) use is becoming nearly as common as smoking marijuana where medical marijuana is available. This study explores edible use among teens. We conducted four focus groups in the San Francisco Bay Area with youth, ages 15–17. The focus groups were divided by gender and whether they used marijuana. Some teens mentioned edible use at school. Youth reported that teens consume edibles, primarily to reduce the likelihood of getting caught. Edibles are also attractive to those who do not like to smoke or have concerns about smoking. Both male and female respondents suggested that females are more likely than males to prefer edibles over smoking, one reason for which may be to avoid smelling like marijuana smoke. For some young women, edibles may be a way to avoid publicly presenting themselves as marijuana users. Findings also suggest that youth have access to edibles through multiple sources. Youth reported that they can purchase edibles at school from other students who either make the edibles themselves or are reselling edibles obtained from dispensaries. Both users and non-users were aware of potentially negative consequences related to edible use. Some youth mentioned that they have heard of youth dying from edibles, and several reported being concerned about the high produced by edibles. Female non-users appeared to be more concerned than others about edibles and compared them to drinks that could be spiked with drugs. However, sentiment among some male marijuana users was that if you cannot handle edibles you should not be using them. These findings suggest that strategies to curb access to edibles and use among youth, such as restricting sales of edibles with strong youth appeal and educating youth on the risks of edibles, will need to be developed.