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Abstract: Burning solid fuels to fulfill daily household energy needs results in chronic exposure to household air pollution (HAP), which is among the world's greatest health risks. This paper presents the results of a cross‐sectional study of cookstove usage, fuel consumption, and indoor PM2.5 concentrations in rural and urban Honduran homes cooking with the Envirofit HM‐5000 metal plancha stove (n = 32) as compared to control households using baseline cooking technologies (n = 33). Temperature‐based stove usage measurements showed high HM‐5000 acceptance, with significant displacement of the traditional cookstoves at both the urban (99%, P < .05) and rural study sites (75%, P < .05). However, longer‐term usage data collected in peri‐urban households showed that participants cooked on the HM‐5000 more frequently during the 3‐day monitoring period than during the following 3 weeks. Average indoor PM2.5 was 66% lower in HM‐5000 households as compared to control households (P < .05). Lower indoor PM2.5 concentrations observed in participant homes as compared to control households, supported by high usage and traditional stove displacement, suggest the potential for the HM‐5000 to yield health improvements in adopting Honduran households. [ABSTRACT FROM AUTHOR]

Endothelium-dependent hyperpolarizing factor ( EDHF) is a powerful vasodilator influence in small resistance arteries and thus an important modulator of blood pressure and flow. As the name suggests, EDHF was thought to describe a diffusible factor stimulating smooth muscle hyperpolarization (and thus vasodilatation). However, this idea has evolved with the recognition that a factor can operate alongside the spread of hyperpolarizing current from the endothelium to the vascular smooth muscle ( VSM). As such, the pathway is now termed endothelium-dependent hyperpolarization ( EDH). EDH is activated by an increase in endothelial [Ca2+]i, which stimulates two Ca2+-sensitive K channels, SKCa and IKCa. This was discovered because apamin and charybdotoxin applied in combination blocked EDHF responses, but iberiotoxin - a blocker of BKCa - was not able to substitute for charybdotoxin. SKCa and IKCa channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, which are rich in IKCa channels and close to interendothelial gap junctions where SKCa channels, are prevalent. KCa activation hyperpolarizes endothelial cells, and K+ efflux through them can act as a diffusible ' EDHF' by stimulating VSM Na+,K+- ATPase and inwardly rectifying K channels (KIR). In parallel, hyperpolarizing current spreads from the endothelium to the smooth muscle through myoendothelial gap junctions located on endothelial projections. The resulting radial EDH is complemented by the spread of 'conducted' hyperpolarization along the endothelium of arteries and arterioles to affect conducted vasodilatation ( CVD). Retrograde CVD effectively integrates blood flow within the microcirculation, but how the underlying hyperpolarization is sustained is unclear. [ABSTRACT FROM AUTHOR]

The present study utilises dental histological methods to analyse enamel micro-defects as indicators of early life stress in indigenous Muchik individuals interred at two sites: La Capilla Santa María Magdalena de Eten (CSMME) ( n = 15) and La Capilla del Niño Serranito (CNS) ( n = 15), both located in the Lambayeque Valley region of northern Peru. Individuals interred at CNS date to the Early Colonial Period (AD 1533-1610), and individuals interred at CSMME date to the Middle/Late Colonial Period (AD 1625-1760), thus permitting comparison of childhood stress events between the Early and Middle/Late Colonial Periods. Results reveal a high prevalence of Wilson bands at both sites, although a lower prevalence at the CSMME was observed in comparison with the CNS. This indicates that, over time, Muchik individuals in this town may have been able to acclimate to life under Spanish oppression. Stress chronologies suggest that early life stress possibly resulted from inadequate and less than desirable food and/or water available for supplemental feeding during early infancy, especially around the ages of 4 and 5 months. Furthermore, results show that individuals with enamel defects in the form of Wilson bands at both the CNS and CSMME had an earlier mean age-at-death (9.6 and 4.05 years, respectively) in comparison with those without observed Wilson bands (19.75 and 8.8 years, respectively). These results underscore the importance of not only regional and temporal studies of the biological consequences of Spanish contact in the Americas but also of investigating the relationship between early life stress and adult health and longevity in archaeological populations. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and Purpose: Smooth muscle transient receptor potential melastatin 4 (TRPM4) channels play a fundamental role in the development of the myogenic arterial constriction that is necessary for blood flow autoregulation. As TRPM4 channels are present throughout the vasculature, we investigated their potential role in non-myogenic resistance arteries using the TRPM4 inhibitor 9-phenanthrol.Experimental Approach: Pressure and wire myography were used to assess the reactivity of rat arteries, the latter in combination with measurements of smooth muscle membrane potential. Immunohistochemistry (IHC) and endothelial cell (EC) calcium changes were assessed in pressurized vessels and patch clamp measurements made in isolated ECs.Key Results: The TRPM4 inhibitor 9-phenanthrol reversibly hyperpolarized mesenteric arteries to circa EK and blocked α1 -adrenoceptor-mediated vasoconstriction. Hyperpolarization was abolished and vasoconstriction re-established by damaging the endothelium. In mesenteric and cerebral artery smooth muscle, 9-phenanthrol hyperpolarization was effectively blocked by the KCa 3.1 inhibitor TRAM-34. 9-Phenanthrol did not increase mesenteric EC [Ca(2+)]i , and Na(+) substitution with N-methyl-D-glucamine only increased the muscle resting potential by 10 mV. Immunolabelling for TRPM4 was restricted to the endothelium and perivascular tissue.Conclusions and Implications: These data reveal a previously unrecognized action of the TRPM4 inhibitor 9-phenanthrol - the ability to act as an activator of EC KCa 3.1 channels. They do not indicate a functionally important role for TRPM4 channels in the reactivity of non-myogenic mesenteric arteries. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Smooth muscle transient receptor potential melastatin 4 (TRPM4) channels play a fundamental role in the development of the myogenic arterial constriction that is necessary for blood flow autoregulation. As TRPM4 channels are present throughout the vasculature, we investigated their potential role in non-myogenic resistance arteries using the TRPM4 inhibitor 9-phenanthrol. EXPERIMENTAL APPROACH: Pressure and wire myography were used to assess the reactivity of rat arteries, the latter in combination with measurements of smooth muscle membrane potential. Immunohistochemistry (IHC) and endothelial cell (EC) calcium changes were assessed in pressurized vessels and patch clamp measurements made in isolated ECs. KEY RESULTS: The TRPM4 inhibitor 9-phenanthrol reversibly hyperpolarized mesenteric arteries to circa EK and blocked a1-adrenoceptor-mediated vasoconstriction. Hyperpolarization was abolished and vasoconstriction re-established by damaging the endothelium. In mesenteric and cerebral artery smooth muscle, 9-phenanthrol hyperpolarization was effectively blocked by the KCa3.1 inhibitor TRAM-34. 9-Phenanthrol did not increase mesenteric EC [Ca2+]i, and Na+ substitution with N-methyl-D-glucamine only increased the muscle resting potential by 10 mV. Immunolabelling for TRPM4 was restricted to the endothelium and perivascular tissue. CONCLUSIONS AND IMPLICATIONS: These data reveal a previously unrecognized action of the TRPM4 inhibitor 9-phenanthrol - the ability to act as an activator of EC KCa3.1 channels. They do not indicate a functionally important role for TRPM4 channels in the reactivity of non-myogenic mesenteric arteries. [ABSTRACT FROM AUTHOR]

Background and Purpose: In small arteries, small conductance Ca²⁺-activated K⁺ channels (SK(Ca)) and intermediate conductance Ca²⁺-activated K⁺ channels (IK(Ca)) restricted to the vascular endothelium generate hyperpolarization that underpins the NO- and PGI₂-independent, endothelium-derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IK(Ca) channels can be negatively regulated by PKA, we investigated whether β-adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation.Experimental Approach: Rat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell [Ca²⁺]i , mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording.Key Results: Intraluminal perfusion of β-adrenoceptor agonists inhibited endothelium-dependent dilatation to ACh (1 nM-10 μM) without modifying the associated changes in endothelial cell [Ca²⁺]i . The inhibitory effect of β-adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the β-adrenoceptor antagonists propranolol (non-selective), atenolol (β₁) or the PKA inhibitor KT-5720, but remained unaffected by ICI 118 551 (β₂) or glibenclamide (ATP-sensitive K⁺ channels channel blocker). Endothelium-dependent hyperpolarization to ACh was also inhibited by β-adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IK(Ca) {with 1 μM 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34)}, but not SK(Ca) (50 nM apamin) channels prevented β-adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.Conclusions and Implications: In resistance arteries, endothelial cell β₁-adrenoceptors link to inhibit endothelium-dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IK(Ca) channels and may be one consequence of raised circulating catecholamines. [ABSTRACT FROM AUTHOR]

Background and Purpose: β-Adrenoceptor stimulation causes pronounced vasodilatation associated with smooth muscle hyperpolarization. Although the hyperpolarization is known to reflect K(ATP) channel activation, it is not known to what extent it contributes to vasodilatation.Experimental Approach: Smooth muscle membrane potential and tension were measured simultaneously in small mesenteric arteries in a wire myograph. The spread of vasodilatation over distance was assessed in pressurized arteries following localized intraluminal perfusion of either isoprenaline, adrenaline or noradrenaline.Key Results: Isoprenaline stimulated rapid smooth muscle relaxation associated at higher concentrations with robust hyperpolarization. Noradrenaline or adrenaline evoked a similar hyperpolarization to isoprenaline if the α(1)-adrenoceptor antagonist prazosin was present. With each agonist, glibenclamide blocked hyperpolarization without reducing relaxation. Focal, intraluminal application of isoprenaline, noradrenaline or adrenaline during block of α(1)-adrenoceptors evoked a dilatation that spread along the entire length of the isolated artery. This response was endothelium-dependent and inhibited by glibenclamide.Conclusions and Implications: Hyperpolarization is not essential for β-adrenoceptor-mediated vasodilatation. However, following focal β-adrenoceptor stimulation, this hyperpolarization underlies the ability of vasodilatation to spread along the artery wall. The consequent spread of vasodilatation is dependent upon the endothelium and likely to be of physiological relevance in the coordination of tissue blood flow. [ABSTRACT FROM AUTHOR]

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post-approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing 'Cardiovascular Toxicity of Medicines'. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: • Fully characterize the incidence, prevalence and impact of drug-induced cardiovascular issues at all stages of the drug development process. • Ascertain the predictive value of existing non-clinical models and assays towards the clinical outcome. • Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. • Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. • Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers. [ABSTRACT FROM AUTHOR]

Background and purpose:NO/prostanoid independent, EDHF-mediated hyperpolarization and dilation in rat middle cerebral arteries is mediated solely by endothelial cell IKCa. However, when the NO-pathway is also active, both SKCa and IKCa contribute to EDHF responses. As the SKCa component can be inhibited by stimulation of thromboxane A2 (TxA2) TP receptors and NO has the potential ability to inhibit thromboxane synthesis, we investigated whether TxA2 might explain loss of functional input from SKCa during NOS inhibition in cerebral arteries.Experimental approach:Rat middle cerebral arteries were mounted in a wire myograph. Endothelium-dependent responses to the PAR2 agonist, SLIGRL were assessed as simultaneous changes in smooth muscle membrane potential and tension.Key results:Responses were obtained in the presence of L-NAME as appropriate. Inhibition of TP receptors with either ICI 192,605 or SQ 29,548, did not affect EDHF mediated hyperpolarization and relaxation, but in their presence neither TRAM-34 nor apamin (to block IKCa and SKCa respectively) individually affected the EDHF response. However, in combination they virtually abolished it. Similar effects were obtained in the presence of the thromboxane synthase inhibitor, furegrelate, which additionally revealed an iberiotoxin-sensitive residual EDHF hyperpolarization and relaxation in the combined presence of TRAM-34 and apamin.Conclusions and implications:In the rat middle cerebral artery, inhibition of NOS leads to a loss of the SKCa component of EDHF responses. Either antagonism of TP receptors or block of thromboxane synthase restores an input through SKCa. These data indicate that NO normally enables SKCa activity in rat middle cerebral arteries.British Journal of Pharmacology (2007) 151, 441–449; doi:10.1038/sj.bjp.0707240; published online 10 April 2007 [ABSTRACT FROM AUTHOR]

1: The possibility that thromboxane (TXA2) receptor stimulation causes differential block of the SKCa and IKCa channels which underlie EDHF-mediated vascular smooth muscle hyperpolarization and relaxation was investigated in the rat isolated mesenteric artery. 2: Acetylcholine (30?nM-3?µM ACh) or cyclopiazonic acid (10?µM CPA, SERCA inhibitor) were used to stimulate EDHF-evoked smooth muscle hyperpolarization. In each case, this led to maximal hyperpolarization of around 20?mV, which was sensitive to block with 50?nM apamin and abolished by repeated stimulation of mesenteric arteries with the thromboxane mimetic, U46619 (30?nM-0.1?µM), but not the a1-adrenoceptor agonist phenylephrine (PE). 3: The ability of U46619 to abolish EDHF-evoked smooth muscle hyperpolarization was prevented by prior exposure of mesenteric arteries to the TXA2 receptor antagonist 1?µM SQ29548. 4: Similar-sized smooth muscle hyperpolarization evoked with the SKCa activator 100?µM riluzole was also abolished by prior stimulation with U46619, while direct muscle hyperpolarization in response to either levcromakalim (1?µM, KATP activator) or NS1619 (40?µM, BKCa activator) was unaffected. 5: During smooth muscle contraction and depolarization to either PE or U46619, ACh evoked concentration-dependent hyperpolarization (to -67?mV) and complete relaxation. These responses were well maintained during repeated stimulation with PE, but with U46619 there was a progressive decline, so that during a third exposure to U46619 maximum hyperpolarization only reached -52?mV and relaxation was reduced by 20%. This relaxation could now be blocked with charybdotoxin alone. The latter responses could be mimicked with 300?µM 1-EBIO (IKCa activator), an action not modified by exposure to U46619. 6: An early consequence of TXA2 receptor stimulation is a reduction in the arterial hyperpolarization and relaxation attributed to EDHF. This effect appears to reflect a loss of SKCa activity.British Journal of Pharmacology (2004) 142, 43-50. doi:10.1038/sj.bjp.0705756 [ABSTRACT FROM AUTHOR]

Activation of both small-conductance (SK[subCa]) and intermediate-conductance (IK[subCa]) Ca&sup2+;-activated K[sup+] channels in endothelial cells leads to vascular smooth muscle hyperpolarization and relaxation in rat mesenteric arteries. The contribution that each endothelial K[sup+] channel type makes to the smooth muscle hyperpolarization is unknown. In the presence of a nitric oxide (NO) synthase inhibitor, ACh evoked endothelium and concentration-dependent smooth muscle hyperpolarization, increasing the resting potential (approx. -53 mV) by around 20 mV at 3 μM. Similar hyperpolarization was evoked with cyclopiazonic acid (10 μM, an inhibitor of sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA)) while 1-EBIO (300 μM, an IK[subCa] activator) only increased the potential by a few millivolts. Hyperpolarization in response to either ACh or CPA was abolished with apamin (50 nM, an SK[subCa] blocker) but was unaltered by 1-[(2-chlorophenyl) diphenylmethyl]-lH-pyrazole (1 μM TRAM-34, an IK[subCa] blocker). During depolarization and contraction in response to phenylephrine (PE), ACh still increased the membrane potential to around -70 mV, but with apamin present the membrane potential only increased just beyond the original resting potential (circa -58 mV). TRAM-34 alone did not affect hyperpolarization to ACh but, in combination with apamin, ACh-evoked hyperpolarization was completely abolished. These data suggest that true endothelium-dependent hyperpolarization of smooth muscle cells in response to ACh is attributable to SK[subCa] channels, whereas IK[subCa], channels play an important role during the ACh-mediated depolarization These only positive followed depolarization. [ABSTRACT FROM AUTHOR]

Most public health statements regarding exposure to solar ultraviolet radiation (UVR) recommend avoiding it, especially at midday, and using sunscreen. Excess UVR is a primary risk factor for skin cancers, premature photoageing and the development of cataracts. In addition, some people are especially sensitive to UVR, sometimes due to concomitant illness or drug therapy.However, if applied uncritically, these guidelines may actually cause more harm than good. Humans derive most of their serum 25-hydroxycholecalciferol (25(OH)D3) from solar UVB radiation (280–315 nm). Serum 25(OH)D3 metabolite levels are often inadequate for optimal health in many populations, especially those with darker skin pigmentation, those living at high latitudes, those living largely indoors and in urban areas, and during winter in all but the sunniest climates. In the absence of adequate solar UVB exposure or artificial UVB, vitamin D can be obtained from dietary sources or supplements.There is compelling evidence that low vitamin D levels lead to increased risk of developing rickets, osteoporosis and osteomaloma, 16 cancers (including cancers of breast, ovary, prostate and non-Hodgkin's lymphoma), and other chronic diseases such as psoriasis, diabetes mellitus, hypertension, heart disease, myopathy, multiple sclerosis, schizophrenia, hyperparathyroidism and susceptibility to tuberculosis.The health benefits of UVB seem to outweigh the adverse effects. The risks can be minimized by avoiding sunburn, excess UVR exposure and by attention to dietary factors, such as antioxidants and limiting energy and fat consumption. It is anticipated that increasing attention will be paid to the benefits of UVB radiation and vitamin D and that health guidelines will be revised in the near future. [ABSTRACT FROM AUTHOR]

The movement of care into the community for the mentally ill with severe and enduring problems has important implications for primary care services. This paper reports the findings from an interview with practice nurses working in south-west London, United Kingdom, who had participated in a randomised control trial to investigate the effectiveness of training and structured assessment on clinical and social outcomes of patients receiving maintenance medication of depot antipsychotics. The aim of the interview was to explore current practice, attitudes, confidence and priorities for training in relation to these patients. Thirty-nine nurses were interviewed. The majority of practice nurses received scant referral information and worked without protocols. Even though these nurses had received the training, and as a result of the study had increased awareness of the problems of the severely mentally ill, there was a significant relationship between inadequate knowledge of schizophrenia to carry out the task of medication management and lack of confidence. Although the small size of the sample does not permit generalization, important questions are raised for further practice development and research, including the future training needs of practice nurses and partnership relationships with mental health professionals for supervision and support. [ABSTRACT FROM AUTHOR]

The effect of increasing calcium concentration on root growth and the uptake of lead from solutions of lead nitrate, by both barley seedlings and lead-tolerant and non-tolerant plants of Festuca ovina, are described. Lead uptake into the roots of all plants declined linearly with the logarithm of increasing calcium nitrate concentration up to 12·72 mM. Root extension growth in each lead solution increased as calcium concentration was raised, and this increase was greater than could be accounted for by the diminishing lead uptake; a second influence of calcium may thus be indicated. The regression of root growth, or tolerance index, on root lead content may be a useful indicator of sensitivity to the metal. [ABSTRACT FROM AUTHOR]

- Two cases of urinary retention and granulomatous prostatitis following sacral herpes zoster infection are described. This previously unrecognised association may be significant in the mechanism of retention in these cases. [ABSTRACT FROM AUTHOR]

C-type natriuretic peptide (CNP) is found in and released from vascular endothelial cells. Recently, a novel role has been suggested for this peptide, that of an endothelium-derived hyperpolarizing factor or EDHF. Implicit in this proposal is a widespread role for CNP as a key mediator of vascular dilatation. In this issue of the British Journal of Pharmacology, Leuranguer et al. compare the profile of membrane potential changes evoked with this putative EDHF or with endogenous EDHF (activated with ACh) in small carotid arteries. Marked differences between the two profiles lead them to discount a possible role for CNP as an EDHF. [ABSTRACT FROM AUTHOR]