Characteristics and Treatments of Patients with Peripheral Arterial Disease Referred to UK Vascular Clinics: Results of a Prospective Registry

BackgroundPeripheral arterial disease (PAD) is often associated with risk factors including cigarette smoking, hypertension and hypercholesterolaemia, and patients have a high risk of future vascular events. Good medical management results in improved outcomes and quality of life, but previous studies have documented sub-optimal treatment of risk factors. We assessed the management of cardiovascular risk factors in patients with PAD referred to specialist vascular clinics.MethodsThis was a prospective, protocol driven registry carried out in UK vascular clinics. Patients who were first-time referrals for evaluation of PAD were eligible if they had claudication plus ankle-brachial pressure index (ABPI) ≤0.9. Statistical associations between key demographic and treatment variables were explored using a chi-squared test.ResultsWe enrolled 473 patients from 23 sites. Mean age was 68 years (SD 10) and 66% were male. Mean estimated claudication distance was 100m, and ABPI was 0.74. Mean systolic blood pressure (SBP) was 155mmHg, and 42% had a SBP >160mmHg. Forty percent were current smokers and half had tried to give up in the prior 6 months, but there was no evidence of a systematic method of smoking cessation. Mean total cholesterol was 5.4 (SD1.2) mmol/l and 30% had levels >6mmol/l. Antiplatelet therapy had been given to 70% and statins to 44%. Prior CHD was present in 29% and these patients had significantly higher use of antiplatelet therapy, statins and ACE-inhibitors.ConclusionsIn spite of attempts to raise awareness about PAD as an important marker of cardiovascular risk, patients are still poorly treated prior to referral to a vascular clinic. In particular, the use of evidence-based treatments is sub-optimal, while hypertension and cigarette smoking are poorly managed. More work needs to be done to educate health professionals about the detection and optimal medical management of PAD

1.2 MW klystron for Asymmetric Storage Ring B Factory

A cw klystron operating at 476 MHz has been developed jointly by SLAC and Varian Associates. The unique set of characteristics of this tube were strongly guided by requirements of the fast feedback necessary to prevent oscillations of the storage ring beams caused by the detuned accelerating cavity. This requires a combination of bandwidth and short group delay within the klystron. The RF feedback stabilization scheme also requires amplitude modulation making it necessary to operate the klystron about 10% below saturation. Performance specifications and initial operating results are presented

Low dose aspirin and cognitive function in middle aged to elderly adults: randomised controlled trial

Objective To determine the effects of low dose aspirin on cognitive function in middle aged to elderly men and women at moderately increased cardiovascular risk

Peripheral arterial disease (PAD) – A challenging manifestation of atherosclerosis

The diagnosis of peripheral arterial disease (PAD) is not always evident as symptoms and signs may show great variation. As all grades of PAD are linked to both an increased risk for cardiovascular complications and adverse limb events, awareness of the condition and knowledge about diagnostic measures, prevention and treatment is crucial. This article presents in a condensed form information on PAD and its management

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 association between naturally acquired IgG subclass specific antibodies to the PfRH5 invasion complex and protection from Plasmodium falciparum malaria

Understanding the targets and mechanisms of human immunity to malaria is important for advancing the development of highly efficacious vaccines and serological tools for malaria surveillance. The PfRH5 and PfRipr proteins form a complex on the surface of P. falciparum merozoites that is essential for invasion of erythrocytes and are vaccine candidates. We determined IgG subclass responses to these proteins among malaria-exposed individuals in Papua New Guinea and their association with protection from malaria in a longitudinal cohort of children. Cytophilic subclasses, IgG1 and IgG3, were predominant with limited IgG2 and IgG4, and IgG subclass-specific responses were higher in older children and those with active infection. High IgG3 to PfRH5 and PfRipr were significantly and strongly associated with reduced risk of malaria after adjusting for potential confounding factors, whereas associations for IgG1 responses were generally weaker and not statistically significant. Results further indicated that malaria exposure leads to the co-acquisition of IgG1 and IgG3 to PfRH5 and PfRipr, as well as to other PfRH invasion ligands, PfRH2 and PfRH4. These findings suggest that IgG3 responses to PfRH5 and PfRipr may play a significant role in mediating naturally-acquired immunity and support their potential as vaccine candidates and their use as antibody biomarkers of immunity

Statement of the Third International Exercise-Associated Hyponatremia Consensus Development Conference, Carlsbad, California, 2015

The third International Exercise-Associated Hyponatremia (EAH) Consensus Development Conference convened in Carlsbad, California in February 2015 with a panel of 17 international experts. The delegates represented 4 countries and 9 medical and scientific sub-specialties pertaining to athletic training, exercise physiology, sports medicine, water/sodium metabolism, and body fluid homeostasis. The primary goal of the panel was to review the existing data on EAH and update the 2008 Consensus Statement.1 This document serves to replace the second International EAH Consensus Development Conference Statement and launch an educational campaign designed to address the morbidity and mortality associated with a preventable and treatable fluid imbalance. The following statement is a summary of the data synthesized by the 2015 EAH Consensus Panel and represents an evolution of the most current knowledge on EAH. This document will summarize the most current information on the prevalence, etiology, diagnosis, treatment and prevention of EAH for medical personnel, athletes, athletic trainers, and the greater public. The EAH Consensus Panel strove to clearly articulate what we agreed upon, did not agree upon, and did not know, including minority viewpoints that were supported by clinical experience and experimental data. Further updates will be necessary to both: (1) remain current with our understanding and (2) critically assess the effectiveness of our present recommendations. Suggestions for future research and educational strategies to reduce the incidence and prevalence of EAH are provided at the end of the document as well as areas of controversy that remain in this topic. [excerpt

Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure

Background: Leading malaria vaccine, RTS,S, is based on the circumsporozoite protein (CSP) of sporozoites. RTS,S confers partial protection against malaria in children, but efficacy wanes relatively quickly after primary immunization. Vaccine efficacy has some association with anti-CSP IgG; however, it is unclear how these antibodies function, and how functional antibodies are induced and maintained over time. Recent studies identified antibodycomplement interactions as a potentially important immune mechanism against sporozoites. Here, we investigated whether RTS,S vaccine-induced antibodies could function by interacting with complement. Methods: Serum samples were selected from children in a phase IIb trial of RTS,S/AS02A conducted at two study sites of high and low malaria transmission intensity in Manhiça, Mozambique. Samples following primary immunization and 5-year post-immunization follow-up time points were included. Vaccine-induced antibodies were characterized by isotype, subclass, and epitope specificity, and tested for the ability to fix and activate complement. We additionally developed statistical methods to model the decay and determinants of functional antibodies after vaccination. Results: RTS,S vaccination induced anti-CSP antibodies that were mostly IgG1, with some IgG3, IgG2, and IgM. Complement-fixing antibodies were effectively induced by vaccination, and targeted the central repeat and Cterminal regions of CSP. Higher levels of complement-fixing antibodies were associated with IgG that equally recognized both the central repeat and C-terminal regions of CSP. Older age and higher malaria exposure were significantly associated with a poorer induction of functional antibodies. There was a marked decay in functional complement-fixing antibodies within months after vaccination, as well as decays in IgG subclasses and IgM. Statistical modeling suggested the decay in complement-fixing antibodies was mostly attributed to the waning of anti-CSP IgG1, and to a lesser extent IgG3. Conclusions: We demonstrate for the first time that RTS,S can induce complement-fixing antibodies in young malaria-exposed children. The short-lived nature of functional responses mirrors the declining vaccine efficacy of RTS,S over time. The negative influence of age and malaria exposure on functional antibodies has implications for understanding vaccine efficacy in different settings. These findings provide insights into the mechanisms and longevity of vaccine-induced immunity that will help inform the future development of highly efficacious and longlasting malaria vaccines