A randomized pilot trial of a full subsidy vs. a partial subsidy for obesity treatment

Intensive obesity treatment is mandated by federal health care reform but is costly. A partial subsidy for obesity treatment could lower the cost of treatment, without reducing its efficacy. This study sought to test whether a partial subsidy for obesity treatment would be feasible, as compared to a fully subsidized intervention. The study was a pilot randomized trial. Participants (n = 50) were primary care patients with obesity and at least one comorbid condition (diabetes, hypertension, dyslipidemia, or obstructive sleep apnea). Each participant received eight weight loss counseling visits as well as portion-controlled foods for weight loss. Participants were randomized to full subsidy or partial subsidy (2 vs. 1 meal per day provided). The primary outcome was weight change after 4 months. Secondary outcomes included changes in blood pressure, waist circumference, and health-related quality of life. Participants in the full and partial subsidy groups lost 5.9 and 5.3 kg, equivalent to 5.3% and 5.1% of initial weight, respectively (P = 0.71). Changes in secondary outcomes were similar in the two groups. A partial subsidy was feasible and induced a clinically similar amount of weight loss, compared to a full subsidy. Large-scale testing of economic incentives for weight control is merited given the federal mandate to offer weight loss counseling to obese patients.     

Three-dimensional structure of the Trypanosome flagellum suggests that the paraflagellar rod functions as a biomechanical spring

Flagellum motility is critical for normal human development and for transmission of pathogenic protozoa that cause tremendous human suffering worldwide. Biophysical principles underlying motility of eukaryotic flagella are conserved from protists to vertebrates. However, individual cells exhibit diverse waveforms that depend on cell-specific elaborations on basic flagellum architecture. Trypanosoma brucei is a uniflagellated protozoan parasite that causes African sleeping sickness. The T. brucei flagellum is comprised of a 9+2 axoneme and an extra-axonemal paraflagellar rod (PFR), but the three-dimensional (3D) arrangement of the underlying structural units is poorly defined. Here, we use dual-axis electron tomography to determine the 3D architecture of the T. brucei flagellum. We define the T. brucei axonemal repeating unit. We observe direct connections between the PFR and axonemal dyneins, suggesting a mechanism by which mechanochemical signals may be transmitted from the PFR to axonemal dyneins. We find that the PFR itself is comprised of overlapping laths organized into distinct zones that are connected through twisting elements at the zonal interfaces. The overall structure has an underlying 57 nm repeating unit. Biomechanical properties inferred from PFR structure lead us to propose that the PFR functions as a biomechanical spring that may store and transmit energy derived from axonemal beating. These findings provide insight into the structural foundations that underlie the distinctive flagellar waveform that is a hallmark of T. brucei cell motility.     

Lung heparan sulfates modulate K(fc) during increased vascular pressure: evidence for glycocalyx-mediated mechanotransduction

Lung endothelial cells respond to changes in vascular pressure through mechanotransduction pathways that alter barrier function via non-Starling mechanism(s). Components of the endothelial glycocalyx have been shown to participate in mechanotransduction in vitro and in systemic vessels, but the glycocalyx's role in mechanosensing and pulmonary barrier function has not been characterized. Mechanotransduction pathways may represent novel targets for therapeutic intervention during states of elevated pulmonary pressure such as acute heart failure, fluid overload, and mechanical ventilation. Our objective was to assess the effects of increasing vascular pressure on whole lung filtration coefficient (K(fc)) and characterize the role of endothelial heparan sulfates in mediating mechanotransduction and associated increases in K(fc). Isolated perfused rat lung preparation was used to measure K(fc) in response to changes in vascular pressure in combination with superimposed changes in airway pressure. The roles of heparan sulfates, nitric oxide, and reactive oxygen species were investigated. Increases in capillary pressure altered K(fc) in a nonlinear relationship, suggesting non-Starling mechanism(s). nitro-l-arginine methyl ester and heparanase III attenuated the effects of increased capillary pressure on K(fc), demonstrating active mechanotransduction leading to barrier dysfunction. The nitric oxide (NO) donor S-nitrosoglutathione exacerbated pressure-mediated increase in K(fc). Ventilation strategies altered lung NO concentration and the K(fc) response to increases in vascular pressure. This is the first study to demonstrate a role for the glycocalyx in whole lung mechanotransduction and has important implications in understanding the regulation of vascular permeability in the context of vascular pressure, fluid status, and ventilation strategies.     

Circulating interferon-γ correlates with 1,25(OH)D and the 1,25(OH)D-to-25(OH)D ratio

The mechanism responsible for the decrease in vitamin D status (i.e., plasma or serum 25-hydroxyvitamin D (25(OH)D) concentration) during inflammatory stress is unknown in humans. Interferon (IFN)-γ is an inflammatory cytokine that regulates vitamin D metabolism in isolated immune cells, but data suggesting this regulation exists in vivo is lacking. The purpose of this study, therefore, was to associate circulating IFN-γ perturbations with 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)D) alterations during inflammatory stress in young adults recovering from anterior cruciate ligament (ACL) reconstruction. Plasma 25(OH)D, 1,25(OH)D and IFN-γ concentrations were measured in fasting blood draw samples obtained from twelve-male patients pre-surgery and 90-m, 3-d and 7-d post-surgery. 25(OH)D decreased significantly (p<0.05) after surgery, and strikingly, tended to inversely correlate (r=-0.32, p=0.058) with IFN-γ changes from pre- to post- (i.e., 90-m, 3-d, and 7-d) surgery. Additionally, 1,25(OH)D (r=0.37, p<0.05) and the 1,25(OH)D-to-25(OH)D ratio (r=0.52, p<0.05) changes from pre- to post- (i.e., 90-m, 3-d, and 7-d) surgery correlated with those of IFN-γ. These are the first reported in vivo findings suggesting that the 25(OH)D decrease and conversion to 1,25(OH)D increase with increasing IFN-γ in the circulation. We conclude that IFN-γ contributes to the decrease in vitamin D and the conversion of vitamin D to its active hormonal form in the circulation during inflammatory insult in humans.     

Frequency of Infant Stroking Reported by Mothers Moderates the Effect of Prenatal Depression on Infant Behavioural and Physiological Outcomes

Animal studies find that prenatal stress is associated with increased physiological and emotional reactivity later in life, mediated via fetal programming of the HPA axis through decreased glucocorticoid receptor (GR) gene expression. Post-natal behaviours, notably licking and grooming in rats, cause decreased behavioural indices of fear and reduced HPA axis reactivity mediated via increased GR gene expression. Post-natal maternal behaviours may therefore be expected to modify prenatal effects, but this has not previously been examined in humans. We examined whether, according to self-report, maternal stroking over the first weeks of life modified associations between prenatal depression and physiological and behavioral outcomes in infancy, hence mimicking effects of rodent licking and grooming. From a general population sample of 1233 first time mothers recruited at 20 weeks gestation we drew a stratified random sample of 316 for assessment at 32 weeks based on reported inter-partner psychological abuse, a risk to child development. Of these 271 provided data at 5, 9 and 29 weeks post delivery. Mothers reported how often they stroked their babies at 5 and 9 weeks. At 29 weeks vagal withdrawal to a stressor, a measure of physiological adaptability, and maternal reported negative emotionality were assessed. There was a significant interaction between prenatal depression and maternal stroking in the prediction of vagal reactivity to a stressor (p = .01), and maternal reports of infant anger proneness (p = .007) and fear (p = .043). Increasing maternal depression was associated with decreasing physiological adaptability, and with increasing negative emotionality, only in the presence of low maternal stroking. These initial findings in humans indicate that maternal stroking in infancy, as reported by mothers, has effects strongly resembling the effects of observed maternal behaviours in animals, pointing to future studies of the epigenetic, physiological and behavioral effects of maternal stroking.     

Pneumococcal antibody concentrations of subjects in communities fully or partially vaccinated with a seven-valent pneumococcal conjugate vaccine

Background

A recent trial with PCV-7 in a rural Gambian community showed reduced vaccine-type pneumococcal carriage in fully vaccinated compared with control communities. We measured pneumococcal polysaccharide antibody concentrations in this trial to understand further the mechanisms underlying the observed changes.

Methods

A single-blind, cluster-randomized (by village) trial was conducted in 21 Gambian villages. In 11 villages, all residents received PCV-7 (Vaccine group); in 10 control villages only children <30 months old or those born during the study received PCV-7. Subjects over the age of 30 months resident in vaccine villages received a single dose of PCV-7 whilst those in control villages received a single dose of a serogroup C meningococcal conjugate vaccine. Serum antibody concentrations against specific pneumococcal polysaccharides were measured in approximately 200 age-stratified subjects before, 4–6, 12 and 24 months following vaccination.

Results

Baseline pneumococcal antibody concentrations were generally high and increased with age up to 10 years. One dose of PCV-7 increased geometric mean antibody concentrations (GMC) in vaccinated versus control villages for vaccine serotypes 6B and 18C, and 4 and 18C, in the young (under 5 years) and older age groups (5+ years) respectively. There were significantly higher proportions of subjects in the vaccinated than in the control communities with an antibody concentration believed to protect against carriage (>5.0 µg/mL) for all but serotype 9V of the PCV-7 serotypes in the older group, but not in the younger age group.

Conclusion

Higher antibodies in vaccinated communities provide an explanation for the lower pneumococcal carriage rates in fully vaccinated compared to control communities.

Trial Registration

Controlled-Trials.com ISRCTN51695599 51695599.     

Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer

At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.     

NT2 derived neuronal and astrocytic network signalling

A major focus of stem cell research is the generation of neurons that may then be implanted to treat neurodegenerative diseases. However, a picture is emerging where astrocytes are partners to neurons in sustaining and modulating brain function. We therefore investigated the functional properties of NT2 derived astrocytes and neurons using electrophysiological and calcium imaging approaches. NT2 neurons (NT2Ns) expressed sodium dependent action potentials, as well as responses to depolarisation and the neurotransmitter glutamate. NT2Ns exhibited spontaneous and coordinated calcium elevations in clusters and in extended processes, indicating local and long distance signalling. Tetrodotoxin sensitive network activity could also be evoked by electrical stimulation. Similarly, NT2 astrocytes (NT2As) exhibited morphology and functional properties consistent with this glial cell type. NT2As responded to neuronal activity and to exogenously applied neurotransmitters with calcium elevations, and in contrast to neurons, also exhibited spontaneous rhythmic calcium oscillations. NT2As also generated propagating calcium waves that were gap junction and purinergic signalling dependent. Our results show that NT2 derived astrocytes exhibit appropriate functionality and that NT2N networks interact with NT2A networks in co-culture. These findings underline the utility of such cultures to investigate human brain cell type signalling under controlled conditions. Furthermore, since stem cell derived neuron function and survival is of great importance therapeutically, our findings suggest that the presence of complementary astrocytes may be valuable in supporting stem cell derived neuronal networks. Indeed, this also supports the intriguing possibility of selective therapeutic replacement of astrocytes in diseases where these cells are either lost or lose functionality.     

Diversity of Bacterial Communities Associated with the Indian Ocean Sponge Tsitsikamma favus That Contains the Bioactive Pyrroloiminoquinones, Tsitsikammamine A and B

Tsitsikamma favus is a latrunculid sponge endemic to the coast of South Africa that produces unique pyrroloiminoquinones known as tsitsikammamines. Wakayin and makaluvamine A are structurally similar to the tsitsikammamines and are the only pyrroloiminoquinones isolated from a source other than Porifera (namely a Fijian ascidian Clavelina sp. and a laboratory culture of the myxomycete Didymium bahiense, respectively). The source of the tsitsikammamines is hypothesised to be microbial, which could provide a means of overcoming the current supply problem. This study focuses on characterising the microbial diversity associated with T. favus. We have used denaturing gradient gel electrophoresis together with clonal and deep sequencing of microbial 16S rRNA gene amplicons to show that specimens of this sponge species contain a distinct and conserved microbial population, which is stable over time and is dominated by a unique Betaproteobacterium species.     

Warm body temperature facilitates energy efficient cortical action potentials

The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na(+) channel inactivation, resulting in a marked reduction in overlap of the inward Na(+), and outward K(+), currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na(+) entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37-42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code.