Hypoxia- or PDGF-BB-dependent paxillin tyrosine phosphorylation in pulmonary hypertension is reversed by HIF-1α depletion or imatinib treatment.

Chronic exposure to hypoxia induces a pronounced remodelling of the pulmonary vasculature leading to pulmonary hypertension (PH). The remodelling process also entails increased proliferation and decreased apoptosis of pulmonary arterial smooth muscle cells (PASMC), processes regulated by the cytoskeletal protein paxillin. In this study, we aimed to examine the molecular mechanisms leading to deregulation of paxillin in PH. We detected a time-dependent increase in paxillin tyrosine 31 (Y31) and 118 (Y118) phosphorylation following hypoxic exposure (1 % O2) or platelet-derived growth factor (PDGF)-BB stimulation of primary human PASMC. In addition, both, hypoxia- and PDGF-BB increased the nuclear localisation of phospho-paxillin Y31 as indicated by immunofluorescence staining in human PASMC. Elevated paxillin tyrosine phosphorylation in human PASMC was attenuated by hypoxia-inducible factor (HIF)-1α depletion or by treatment with the PDGF-BB receptor antagonist, imatinib. Moreover, we observed elevated paxillin Y31 and Y118 phosphorylation in the pulmonary vasculature of chronic hypoxic mice (21 days, 10 % O2) which was reversible by imatinib-treatment. PDGF-BB-dependent PASMC proliferation was regulated via the paxillin-Erk1/2-cyclin D1 pathway. In conclusion, we suggest paxillin up-regulation and phosphorylation as an important mechanism of vascular remodelling underlying pulmonary hypertension.

Inflammation, immunological reaction and role of infection in pulmonary hypertension.

Inflammation underlies a wide variety of physiological and pathological processes. Acute inflammation is the initial response of the body to harmful stimuli. Chronic inflammation, by contrast, is a prolonged, dysregulated and maladaptive response that involves active inflammation, tissue destruction and attempts at tissue repair. Over the past few years, such persistent inflammation has been shown to be associated with pulmonary hypertension (PH). Substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to PH. This review summarizes the experimental and clinical evidence for inflammation in various types of PH. In addition, it assesses the current state of knowledge regarding the inducers/triggers of chronic inflammation and infection, as well as the inflammatory mediators and cells that are involved in PH. Infiltration of inflammatory cells, such as dendritic cells, macrophages, mast cells, T-lymphocytes and B-lymphocytes, in the vascular lesions and an elevation of serum/tissue concentrations of proinflammatory cytokines and chemokines and their contribution to pulmonary vascular remodelling are reported in detail. We review the data supporting the use of inflammatory markers as prognostic and predictive factors in PH. Finally, we consider how new insights into inflammation in PH may identify innovative therapeutic strategies.

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension.

An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH. This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH. Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells. Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.

Arsenic contamination of soils and agricultural plants through irrigation water in Nepal.

This study monitored the influence of arsenic-contaminated irrigation water on alkaline soils and arsenic uptake in agricultural plants at field level. The arsenic concentrations in irrigation water ranges from <0.005 to 1.014 mg L(-1) where the arsenic concentrations in the soils were measured from 6.1 to 16.7 mg As kg(-1). The arsenic content in different parts of plants are found in the order of roots>shoots>leaves>edible parts. The mean arsenic content of edible plant material (dry weight) were found in the order of onion leaves (0.55 mg As kg(-1))>onion bulb (0.45 mg As kg(-1))>cauliflower (0.33 mg As kg(-1))>rice (0.18 mg As kg(-1))>brinjal (0.09 mg As kg(-1))>potato (<0.01 mg As kg(-1)).

Seasonality in urinary and household salt iodine content among pregnant and lactating women of the plains of Nepal.

OBJECTIVE: To determine the extent and causes of iodine deficiency among women during pregnancy and lactation in the southeastern plains of Nepal. DESIGN, SETTING AND SUBJECTS: Urinary iodine (UI) was assessed as an indicator of iodine status in spot urine samples of women participating in a field trial in three rural communities in the plains of southeastern Nepal. Samples were collected during pregnancy (n=1021) and during lactation at 3-4 months postpartum (n=1028) at a central clinic; 613 women were assessed at both times. Salt iodine (SI) content was assessed semiquantitatively at 6-7 months postpartum in households (n=1572). RESULTS: During pregnancy and lactation, median UI concentrations were 0.756 and 0.483 micromol/l, respectively, indicating mild iodine deficiency. UI and SI concentrations covaried markedly by season and were highest during hot, dry, premonsoon months and lowest during and following the humid monsoon season. Within women who contributed urine samples during both pregnancy and the postpartum period, iodine status determined by UI was not correlated. The percentage of households with adequately iodized salt (30 ppm) ranged from 85 to 44% from the hot, dry to the humid seasons, respectively. CONCLUSIONS: In the rural southern plains of Nepal, iodine deficiency remains a mild-to-moderate public health problem among pregnant and lactating women despite the availability of iodized salt. Marked seasonality in SI content may account for the lack of intraindividual correlation between maternal iodine status during pregnancy and postpartum periods and contribute to periodicity in the risk of iodine deficiency.

Comparison of visual estimates of children's portion sizes under both shared-plate and individual-plate conditions.

OBJECTIVE: This paper compares the accuracy of visual estimations of children's food intake in settings where several children eat together off 1 plate vs individual-plate eating scenarios. DESIGN: Eight trained observers were tested in their ability to estimate food portions consumed by children enacting common eating scenarios. Foods were categorized by food group and according to their presentation by individual-plate and shared-plate. Observed food weight estimates were compared to actual weights. SUBJECTS/SETTING: The 8 observers visually estimated 69 food portions of children eating alone and 26 portions where children were eating from a shared plate. This study was carried out in Sarlahi District, a rural, central lowland region of Nepal. STATISTICAL ANALYSES: Pearson's correlation coefficients were calculated to examine associations between estimated and actual weights. A fixed effects model was constructed to compare observers. RESULTS: Analyses revealed that observer estimates of food weights under field conditions were well correlated with actual weights for individual-plate (r = 0.89) and for shared-plate (r = 0.84) scenarios. Observers estimated food weights when children ate together on a shared plate less accurately than they did in settings where children ate alone. With the exception of 1 observer, observers did not differ significantly in their ability to estimate food weights. Accuracy of estimations was influenced by food weight with greater error associated with food quantities of less than 70 g. CONCLUSIONS: Visual estimation is a relatively accurate, valid method of assessing child food intake under rural field conditions, and the only method to obtain accurate information on dietary intake in regions where shared-plate eating is frequent.

Infant feeding practices reflect antecedent risk of xerophthalmia in Nepali children.

OBJECTIVE: To determine the relationship between infant feeding history and risk of xerophthalmia due to vitamin A deficiency (VAD) in early childhood. DESIGN: A case-control study of previously xerophthalmic and non-xerophthalmic children. SETTING: Rural lowland region of Nepal. SUBJECTS: One hundred and fifty-six children (aged 1-6 y old), half of whom previously had xerophthalmia due to vitamin A-deficiency, the other half matched by locale, age and the presence and age of a younger sibling (n = 102). METHODS: Xerophthalmia was determined by trained ophthalmic assistants on the basic of current Bitot's spots, corneal xerosis or report of night blindness. Infant feeding history was collected through a diet history method obtained from the mother of the focus child. Exploratory factor analysis was conducted to determine the presence of underlying patterns in infant feeding practices. Conditional logistic regression was used to estimate odds ratios. RESULTS: Mothers of control children tended to have a higher level of education (P < 0.10) and to have fewer children who had died (P < 0.10) than mothers of case children. Feeding of meat (OR = 0.09, CI = 0.01-0.70) or fish (OR = 0.41, CI = 0.17-0.99) with liver, eggs (OR = 0.11, CI = 0.01-0.88) and mango (OR = 0.28, CI = 0.13-0.60) were protective in association with xerophthalmia in early childhood. Factor analysis uncovered several distinct patterns in infant feeding, which varied by age of the infant. Only the 'animal flesh' feeding pattern (factor), practiced in the second year of life, proved significantly protective from xerophthalmia (OR = 0.43, CI = 0.20-0.94). Feeding patterns of younger children closely paralleled those of their older siblings with and without VAD. CONCLUSIONS: The study supports the hypothesis that infant dietary practices can influence subsequent risk for VAD. Our findings emphasize the importance of introducing vitamin A-rich foods during weaning to reduce the risk of VAD-associated xerophthalmia in the later preschool years.

PIP: The association between infant feeding patterns and vitamin A deficiency (VAD)-associated xerophthalmia was investigated in a case-control study of 156 children, 1-6 years old, from a rural lowland region of Nepal. The 78 children with previous xerophthalmia determined on the basis of current Bitot's spots, corneal xerosis, or night blindness were matched with 78 controls on the basis of locale, age, and the presence and age of a younger sibling. The diet history method was used to elicit infant feeding practices from mothers. Frequency of consumption of 21 key foods was calculated over the 2-year period of the diet history. The analysis supported the hypothesis that infant dietary practices can influence the subsequent risk for VAD. The feeding of meat (odds ratio (OR), 0.09; 95% confidence interval (CI), 0.01-0.70) or fish (OR, 0.41; 95% CI, 0.17-0.99) with eggs (OR, 0.11; 95% CI, 0.01-0.88) and mango (OR, 0.28; 95% CI, 0.13-0.60) was protective in association with xerophthalmia in early childhood. In factor analysis, only the "animal flesh" feeding pattern, practiced in the second year of life, was significantly protective against xerophthalmia (OR, 0.43; 95% CI, 0.20-0.94). These findings confirm the importance of introducing vitamin A-rich foods during weaning to reduce the risk of VAD-associated xerophthalmia in the later preschool years.