Redox and proteolytic regulation of cardiomyocyte β1-adrenergic receptors – a novel paradigm for the regulation of catecholamine responsiveness in the heart

Conventional models view β1-adrenergic receptors (β1ARs) as full-length proteins that activate signaling pathways that influence contractile function and ventricular remodeling - and are susceptible to agonist-dependent desensitization. This perspective summarizes recent studies from my laboratory showing that post-translational processing of the β1-adrenergic receptor N-terminus results in the accumulation of both full-length and N-terminally truncated forms of the β1AR that differ in their signaling properties. We also implicate oxidative stress and β1AR cleavage by elastase as two novel mechanisms that would (in the setting of cardiac injury or inflammation) lead to altered or decreased β1AR responsiveness

The efficacy of a daily self-weighing weight loss intervention using smart scales and email

ObjectiveTo examine the impact of a weight loss intervention that focused on daily self-weighing for self-monitoring as compared to a delayed control group among 91 overweight adults.Design and MethodsThe 6-month intervention included a cellular-connected “smart” scale for daily weighing, web-based weight loss graph, and weekly emails with tailored feedback and lessons. An objective measure of self-weighing frequency was obtained. Weight was measured in clinic at 3 and 6 months. Caloric intake and expenditure, and perceptions of daily self-weighing were also measured.ResultsUsing intent-to-treat analyses, the intervention group lost significantly more weight compared to the control group [Mean (95%CI); 3 months: −4.41%(−5.5, −3.3) vs. −0.37%(−1.5, .76); 6 months: −6.55%(−7.7, −5.4) vs. −0.35%(−1.5, .79); group×time interaction: p<.001] and a greater percentage achieved 5% (42.6% vs. 6.8%; p<.0001) and 10% (27.7% vs. 0%; p<.0001) weight loss. On average, the intervention group self-weighed more days/week (6.1±1.1 vs. 1.1±1.5; p<.0001) and consumed fewer calories/day compared to the control group [Mean (95% CI); 6 months: 1509 (1291,1728) vs. 1856 (1637,2074); group×time interaction: p=.006]. Among intervention participants, daily self-weighing was perceived positively.ConclusionsThese results indicate that an intervention focusing on daily self-weighing can produce clinically significant weight loss

Daily Self-Weighing and Adverse Psychological Outcomes: A Randomized Controlled Trial

Despite evidence that daily weighing is an effective strategy for weight control, concerns remain regarding the potential for negative psychological consequences

Hb H disease resulting from the association of an α0-thalassemia allele [-(α)20.5] with an unstable α-globin variant [Hb Icaria]: First report on the occurrence in Brazil

Hb H Disease is caused by the loss or inactivation of three of the four functional α-globin genes. Patients present chronic hemolytic anemia and splenomegaly. In some cases, occasional blood transfusions are required. Deletions are the main cause of this type of thalassemia ( α-thalassemia). We describe here an unusual case of Hb H disease caused by the combination of a common α0 deletion [-( α) 20.5 ] with a rare point mutation (c.427T > A), thus resulting in an elongated and unstable α-globin variant, Hb Icaria, (X142K), with 31 additional amino-acid residues. Very high levels of Hb H and Hb Bart's were detected in the patient's red blood cells (14.7 and 19.0%, respectively). This is the first description of this infrequent association in the Brazilian population

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Medical Pluralism Predicts Non-ART Use among Parents in Need of ART: A Community Survey in KwaZulu-Natal, South Africa

Despite documented common use of traditional healers and efforts to scale up antiretroviral treatment (ART) in sub-Saharan Africa, evidence on whether medical pluralism predicts ART use is inconclusive and restricted to clinic settings. This study quantitatively assesses whether medical pluralism predicts ART use among parents in need of ART in South Africa. 2,477 parents or primary caregivers of children were interviewed in HIV-endemic communities of KwaZulu-Natal. Analysis used multiple logistic regression on a subsample of 435 respondents in need of ART, who reported either medical pluralism (24.6 %) or exclusive public healthcare use (75.4 %). Of 435 parents needing ART, 60.7 % reported ART use. Medical pluralism emerged as a persistent negative predictor of ART utilization among those needing it (AOR [95 % CI] = .556 [.344 - .899], p = .017). Use of traditional healthcare services by those who need ART may act as a barrier to treatment access. Effective intersectoral collaboration at community level is urgently needed

The effect of pH, aluminum, and chelator manipulations on the growth of acidic and circumneutral species of Asterionella

The growth rates of two diatoms, acidophilic Asterionella ralfsii and circumneutral A. formosa , were differentially affected by varying pH, Al, and EDTA in chemically defined media. Free Al ion concentration increased as pH and EDTA concentration decreased. Free trace metal ion concentration decreased as EDTA levels increased but increased by orders of magnitude upon addition of Al. pH had an overriding species specific effect on growth rate; at low pH A. ralfsii had higher growth rates than A. formosa and vice versa at high pH. For both species higher EDTA levels depressed growth rates. Moderate additions of Al generally resulted in growth stimulation. The growth rate stimulations, especially at 200 and 400 μg L −1 Al additions, correlate to increases in free trace metal ion concentrations. The EDTA-AI interaction effects on growth rate were both pH and concentration dependent: at pH 7 both species were stimulated by addition of Al at all EDTA levels (except A. ralfsii at 5.0 mM EDTA and A. formosa at 0.5 mNM EDTA); at pH 6 Al addition either stimulated or had no effect on the growth rates of both species (except at low EDTA and high Al levels); at pH 5 A. formosa did not grow and additions of 200 μg L −1 Al stimulated growth of A. ralfsii . It is likely that the effect of pH, Al, and EDTA on speciation of essential or toxic trace metals affects growth rates of these diatoms in a species specific manner.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43905/1/11270_2004_Article_BF00282626.pd

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe