Diversity in mitochondrial function explains differences in vascular oxygen sensing

Renal arteries (RAs) dilate in response to hypoxia, whereas the pulmonary arteries (PAs) constrict. In the PA, O2 tension is detected by an unidentified redox sensor, which controls K+ channel function and thus smooth muscle cell (SMC) membrane potential and cytosolic calcium. Mitochondria are important regulators of cellular redox status and are candidate vascular O2 sensors. Mitochondria-derived activated oxygen species (AOS), like H2O2, can diffuse to the cytoplasm and cause vasodilatation by activating sarcolemmal K+ channels. We hypothesize that mitochondrial diversity between vascular beds explains the opposing responses to hypoxia in PAs versus RAs. The effects of hypoxia and proximal electron transport chain (pETC) inhibitors (rotenone and antimycin A) were compared in rat isolated arteries, vascular SMCs, and perfused organs. Hypoxia and pETC inhibitors decrease production of AOS and outward K+ current and constrict PAs while increasing AOS production and outward K+ current and dilating RAs. At baseline, lung mitochondria have lower respiratory rates and higher rates of AOS and H2O2 production. Similarly, production of AOS and H2O2 is greater in PA versus RA rings. SMC mitochondrial membrane potential is more depolarized in PAs versus RAs. These differences relate in part to the lower expression of proximal ETC components and greater expression of mitochondrial manganese superoxide dismutase in PAs versus RAs. Differential regulation of a tonically produced, mitochondria-derived, vasodilating factor, possibly H2O2, can explain the opposing effects of hypoxia on the PAs versus RAs. We conclude that the PA and RA have different mitochondria.     

Fecal glucocorticoid metabolites as a measure of adrenal activity in dairy cattle

The feasibility of monitoring acute adrenal activity in New Zealand dairy cattle by measuring fecal glucocorticoid metabolites was investigated. Fecal glucocorticoid measurement has potential as an indicator of adrenal activity and animal stress because sampling is relatively noninvasive, does not interfere with the stress response itself, and permits on-farm monitoring. Fecal samples were collected from dairy cattle following ACTH challenge and exposure to stressors (novel environment, transport). Two immunoassays (11,17-dioxoandrostane enzymeimmunoassay and ICN corticosterone radioimmunoassay) were compared. Both assays detected increased immunoreactive fecal glucocorticoid metabolites following acute adrenal activity and the temporal relationship between plasma corticosteroids and fecal metabolite excretion was determined. The time to peak excretion was closely related to the transit time of digesta passing between the bile duct and the rectum and was affected by seasonal changes in feed intake and pasture digestibility. We conclude that measurement of glucocorticoid metabolites reliably indicates acute adrenal activity in dairy cattle and in combination with other physiological and behavioral measures has potential for monitoring health and welfare in dairy cattle. (c) 2002 Elsevier Science (USA).     

Lifestyle determinants of serum insulin-like growth-factor-I (IGF-I), C-peptide and hormone binding protein levels in British women

Objective: This study aims to identify the lifestyle determinants of insulin-like growth factor-I (IGF-I) and its main binding proteins (IGFBPs), C-peptide, and sex hormone-binding globulin (SHBG) to help elucidate the mechanism through which lifestyle factors may affect cancer risk. Methods: This study is based on a sample of 292 British women, aged 20–70 years, whose lifestyle characteristics were assessed using a self-administered questionnaire and whose serum hormone concentrations were measured using immunoassays. Results: Age was a strong determinant of both IGF-I and IGFBP levels; women aged 65–70 years had significantly lower IGF-I and IGFBP-3 concentrations and significantly higher IGFBP-1 and IGFBP-2 concentrations than women aged 20–24 years. Body mass index (BMI) was not strongly associated with IGF-I, although women with a BMI of 26–27.9 kg/m² had a higher IGF-I concentration compared with both lean (BMI <20 kg/m²) and obese (BMI 30+ kg/m²) women. However, obese women had a significantly higher C-peptide and IGFBP-3 concentration and a significantly lower IGFBP-1, IGFBP-2, and SHBG concentration compared with lean women. Increasing vigorous exercise was associated with a significantly lower C-peptide concentration and increasing leisure-time activity was associated with a significantly higher IGFBP-1 concentration. Other lifestyle factors such as job activity, smoking, and reproductive factors were not associated with any hormone. Conclusions: Our data show that age is a major determinant of both IGF-I and its main binding proteins in women. BMI has strong effects on IGFBPs, C-peptide, and SHBG, but its effects on IGF-I remain unclear. The possible effect of physical activity on IGFBP-1 requires further investigation.     

The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction

Artemin (ART) signals through the GFR alpha-3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesions including fusion of adrenal medullae with adjacent paraganglia, adrenal medullary dysplasia, and marked enlargement of sympathetic (superior cervical and sympathetic chain ganglia) and parasympathetic (enteric, pelvic) ganglia. Changes began by gestational day 12.5 and formed progressively larger masses during adulthood. Art supplementation in wild type adult mice by administering recombinant protein or an Art-bearing retroviral vector resulted in hyperplasia or neuronal metaplasia at the adrenal corticomedullary junction. Expression data revealed that Gfr alpha-3 is expressed during development in the adrenal medulla, sensory and autonomic ganglia and their projections, while Art is found in contiguous mesenchymal domains (especially skeleton) and in certain nerves. Intrathecal Art therapy did not reduce hypalgesia in rats following nerve ligation. These data (1) confirm that ART acts as a differentiation factor for autonomic (chiefly sympathoadrenal but also parasympathetic) neurons, (2) suggest a role for ART overexpression in the genesis of pheochromocytomas and paragangliomas, and (3) indicate that ART is not a suitable therapy for peripheral neuropathy.     

Reviewing maternal deaths to make pregnancy safer

Every year, some eight million women around the world suffer pregnancy-related complications; over half a million of these women die. Although most of these deaths could be averted at little or no extra cost, even where resources are limited, if we are to take action and develop and implement changes to maternity services to save the lives of mothers and newborns, we need the right kind of information. This more in-depth information might not be available through national statistics on maternal mortality rates or death certificate data; what is required is a detailed understanding of the clinical, social, cultural and other underlying factors that result in a mother's death. The World Health Organization's programme and philosophy for such maternal death or disability reviews is called Beyond the numbers. It outlines the five key methodologies for reviewing maternal deaths or disabilities that are now being introduced in a number of countries around the world.     

Rapid morphological changes in supraoptic nucleus and posterior pituitary induced by a single hypertonie saline injection

Neurosecretory neurons of the supraoptic nucleus (SON) which manufacture, transport, and secrete neuropeptide hormones are activated by administration of Hypertonie NaCl. Male rats were given single intraperitoneal injections of isotonic (0.15 M) or hypertonic (1.5 M) NaCl solution and sacrificed 5 h after injection. Electron micrographs were compared to determine morphological differences in the SON and in the neural lobe in the two conditions. In the SON, significant decreases were found in the extent of glial contact with the magnocellular neuroendocrine cell (MNC) membrane; the amount of nerve terminal contact and amount of apposition of MNC membrane with other MNC cell bodies or dendrites increased. The number of multiple synapses (one terminal contacting two or more cells) per 100 μm of somatic membrane in the 1.5 M NaCl condition was double that found in the 0.15 M NaCl condition. Size of nucleoli, overall cell body size, and amount of Golgi apparatus were significantly larger in the animals injected with 1.5 MNaCl. The neural lobes of animals receiving 1.5 MNaCl injections showed increased neural contact with the basal lamina and decreased cytoplasmic enclosure of axon terminals. The large and rapid changes induced by this stimulus suggest that it is an extremely effective activator of morphological plasticity in the hypothalmo-neurohypophysial system.     

Soluble CD14 receptor expression and monocyte heterogeneity but not the C-260T CD14 genotype are associated with severe acute pancreatitis

OBJECTIVE: Soluble CD14 is derived from a membrane glycoprotein, and it enhances endothelial cytokine responses to lipopolysaccharide. We studied the role of soluble CD14 in the pathogenesis of the systemic inflammatory response associated with acute pancreatitis, to determine whether altered expression was due to a functional C-260T polymorphism in the CD14 promoter gene or altered monocyte heterogeneity. DESIGN: Prospective case-matched study. SETTING: Tertiary pancreatic treatment unit in the United Kingdom. SUBJECTS: Patients with pancreatitis and controls. INTERVENTIONS: DNA from 117 patients with pancreatitis (34 severe) and 263 controls underwent CD14 genotyping using restriction fragment length polymorphism-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Peripheral venous blood samples at 24 and 72 hrs after the onset of abdominal pain were analyzed for sCD14 levels. Isolated peripheral blood mononuclear cells were phenotyped for CD14/CD16 receptor expression using immunofluorescence flow cytometry. Disease severity was assessed using Atlanta criteria, Acute Physiology Scores, and C-reactive protein.Soluble CD14 levels were higher in severe (24-hr median, 66.6 ng/mL; 72-hr median, 72.2 ng/mL) compared with mild attacks (24-hr median, 50.7 ng/mL; 72-hr median, 49.7 ng/mL, p < .001), although the latter was similar to controls (median, 51 ng/mL). Furthermore, soluble CD14 levels correlated with Acute Physiology Scores (p < .001) and C-reactive protein (p = .01).Peripheral blood mononuclear cells CD14++ (p = .008), CD14+/16+ (p = .003), and CD16++ (p = .015) receptor densities were all increased in severe attacks at 24 hrs. Early CD14+/16+ receptor density correlated with sCD14 (p < .001), Acute Physiology Scores (p < .001), and C-reactive protein (p = 0.006). The CD14 genotype prevalence in acute pancreatitis was similar to controls and failed to correlate with any variables studied. CONCLUSIONS: Increased soluble CD14 expression is associated with the systemic inflammatory response to acute pancreatitis and an expansion of the proinflammatory CD14+/CD16+ monocyte subset. Its targeted disruption may afford some benefit in preventing the development of systemic complications.     

Lifestyle and nutritional determinants of bioavailable androgens and related hormones in British men

Objective: To investigate the lifestyle and nutritional determinants of serum bioavailable androgens and their related hormones in men. Methods: This study is based on a sample of 696 men with a wide range of nutrient intakes, whose diet and lifestyle characteristics were assessed with a questionnaire and serum sex hormones measured using immunoassays. Results: Men aged 70 years or older had 12% lower testosterone and 40% lower free-testosterone (FT) and androstanediol glucuronide (A-diol-g) concentrations than men who were 20–29 years of age. Conversely, sex hormone-binding globulin (SHBG) and luteinizing hormone (LH) concentrations were 90% and 49% higher in the oldest age group compared with the lowest, respectively. Men who had a body mass index (BMI) of 30+ kg/m² had 30% lower testosterone, 45% lower SHBG, 22% lower LH and 5% lower FT concentrations compared with men with a BMI of < 20 kg/m². Conversely, A-diol-g concentration was 15% higher in the highest BMI category compared with the lowest. A high waist circumference was further associated with a 12% lower testosterone and SHBG concentration, after adjusting for BMI. Compared with never-smokers, smoking 10+ cigarettes/day was associated with 15% higher testosterone, 22% higher SHBG and 17% higher LH concentrations; FT and A-diol-g were not associated with smoking. Compared with no exercise, vigorous exercise of 3+ hours/week was associated with 11% higher testosterone and 16% higher SHBG concentrations, whilst LH, FT, and A-diol-g were not associated with vigorous exercise. Dietary factors were not strongly associated with hormones, although saturated fat intake was negatively associated with SHBG (r = –0.10; p = 0.01) and alcohol intake was positively associated with A-diol-g (r = 0.11; p = 0.004). No dietary factors were associated with testosterone, FT, or LH. Conclusions: Age is the strongest determinant of serum bioavailable androgens. BMI and some lifestyle and dietary factors influence SHBG and testosterone concentrations, but have no strong association with FT, suggesting that homeostasis is effective. A-diol-g shows broadly similar associations to FT, with the exception of the effect of BMI and alcohol.