Helium in the eroding atmosphere of an exoplanet.

Helium is the second-most abundant element in the Universe after hydrogen and is one of the main constituents of gas-giant planets in our Solar System. Early theoretical models predicted helium to be among the most readily detectable species in the atmospheres of exoplanets, especially in extended and escaping atmospheres 1 . Searches for helium, however, have hitherto been unsuccessful 2 . Here we report observations of helium on an exoplanet, at a confidence level of 4.5 standard deviations. We measured the near-infrared transmission spectrum of the warm gas giant 3 WASP-107b and identified the narrow absorption feature of excited metastable helium at 10,833 angstroms. The amplitude of the feature, in transit depth, is 0.049 ± 0.011 per cent in a bandpass of 98 angstroms, which is more than five times greater than what could be caused by nominal stellar chromospheric activity. This large absorption signal suggests that WASP-107b has an extended atmosphere that is eroding at a total rate of 1010 to 3 × 1011 grams per second (0.1-4 per cent of its total mass per billion years), and may have a comet-like tail of gas shaped by radiation pressure.

Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system.

Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70-1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22-2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.

Effects of early and late diabetic neuropathy on sciatic nerve block duration and neurotoxicity in Zucker diabetic fatty rats.

BACKGROUND: The neuropathy of type II diabetes mellitus (DM) is increasing in prevalence worldwide. We aimed to test the hypothesis that in a rodent model of type II DM, neuropathy would lead to increased neurotoxicity and block duration after lidocaine-induced sciatic nerve block when compared with control animals. METHODS: Experiments were carried out in Zucker diabetic fatty rats aged 10 weeks (early diabetic) or 18 weeks (late diabetic, with or without insulin 3 units per day), and age-matched healthy controls. Left sciatic nerve block was performed using 0.2 ml lidocaine 2%. Nerve conduction velocity (NCV) and F-wave latency were used to quantify nerve function before, and 1 week after nerve block, after which sciatic nerves were used for neurohistopathology. RESULTS: Early diabetic animals did not show increased signs of nerve dysfunction after nerve block. In late diabetic animals without insulin vs control animals, NCV was 34.8 (5.0) vs 41.1 (4.1) ms s(-1) (P<0.01), and F-wave latency was 7.7 (0.5) vs 7.0 (0.2) ms (P<0.01), respectively. Motor nerve block duration was prolonged in late diabetic animals, but neurotoxicity was not. Late diabetic animals receiving insulin showed intermediate results. CONCLUSIONS: In a rodent type II DM model, nerves have increased sensitivity for short-acting local anaesthetics without adjuvants in vivo, as evidenced by prolonged block duration. This sensitivity appears to increase with the progression of neuropathy. Our results do not support the hypothesis that neuropathy due to type II DM increases the risk of nerve injury after nerve block.

Additional femoral catheter in combination with popliteal catheter for analgesia after major ankle surgery.

BACKGROUND: The contribution of the saphenous nerve in pain after major ankle surgery is unknown. The aim of this study was to evaluate its contribution in this context. METHODS: Fifty patients were included in this prospective, randomized, controlled study. In all patients [Group P (popliteal) and Group F (popliteal+femoral)], a popliteal catheter was placed before operation and ropivacaine 0.5% (30 ml) administered via this catheter; major ankle surgery was then performed under spinal anaesthesia. In Group PF patients, an additional femoral catheter was sited before operation and ropivacaine 0.5% (10 ml) administered. Six hours after spinal anaesthesia (defined as T(0)), a continuous infusion of ropivacaine 0.3% (14 ml h(-1)) was started through the popliteal catheter until T(24). Then, the concentration was reduced to 0.2% until T(48). Patients in Group PF received continuous ropivacaine 0.2% (5 ml h(-1)) through the femoral catheter from T(0) to T(48). I.V. morphine patient-controlled analgesia was used as a rescue analgesia. Pain at rest, pain with movement, adverse effects, and i.v. morphine consumption were assessed. Pain at rest and on movement was evaluated 6 months after operation. RESULTS: Pain at rest was comparable in the two groups. In Group PF, patients had significantly reduced pain during movement in the postoperative period (P=0.01) and 6 months after operation (P=0.03). Morphine consumption was significantly reduced in Group PF at T(0)-T(24) and T(24)-T(48) (P=0.01). Adverse effects were comparable in both groups. CONCLUSIONS: The addition of continuous femoral catheter infusion of ropivacaine to a continuous popliteal catheter infusion improved postoperative analgesia during movement after major ankle surgery. This effect was still present 6 months after surgery.

Postconditioning with a volatile anaesthetic in alveolar epithelial cells in vitro.

Acute lung injury is a common complication in critically ill patients. The present study examined possible immunomodulating effects of the volatile anaesthetic sevoflurane on lipopolysaccharide (LPS)-stimulated alveolar epithelial cells (AEC) in vitro. Sevoflurane was applied after the onset of injury, simulating a "postconditioning" scenario. Rat AEC were stimulated with LPS for 2 h, followed by a 4-h co-exposure to a CO(2)/air mixture with sevoflurane 2.2 volume %; control cells were exposed to the CO(2)/air mixture only. Cytokine-induced neutrophil chemoattractant-1, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, as well as the potential protective mediators inducible nitric oxide synthase (iNOS)2 and heat shock protein (HSP)-32, were analysed. Additionally, functional assays (chemotaxis, adherence and cytotoxicity assay) were performed. A significant reduction of inflammatory mediators in LPS-stimulated, sevoflurane-exposed AEC was found, leading to reduced chemotaxis, neutrophil adherence and neutrophil-induced AEC killing. While iNOS2 was increased in the sevoflurane group, blocking experiments with iNOS2 inhibitor did not affect sevoflurane-induced decrease of inflammatory mediators and AEC killing. Interestingly, sevoflurane treatment also resulted in an enhanced expression of HSP-32. The data presented in the current study provide strong evidence that anaesthetic postconditioning with sevoflurane mediates cytoprotection in the respiratory compartment in an in vitro model of acute lung injury.

Sedation and regional anaesthesia in the adult patient.

This review discusses sedation for regional anaesthesia in the adult population. The first section deals with general aspects of sedation and shows that the majority of patients receiving sedation for regional anaesthesia are satisfied and would choose it again. Methods of assessing the level of sedation are discussed with emphasis on clinical measures. The pharmacology of the drugs involved in sedation is discussed, with propofol and remifentanil appearing to be the combination of choice for sedation in regional anaesthesia. The techniques for administering sedation are discussed and replacement of the traditional repeated boluses or continuous infusion with pharmacokinetic and patient-controlled systems is supported. Patient satisfaction studies suggest that patient-controlled systems are preferred.

Regulation of pH in rat papillary tubule cells in primary culture.

To investigate the mechanisms responsible for urinary acidification in the terminal nephron, primary cultures of cells isolated from the renal papilla were grown as monolayers in a defined medium. Morphologically, cultured cells were epithelial in type, and similar to collecting duct principal cells. Cell pH measured fluorometrically in monolayers grown on glass slides showed recovery from acid loads in Na+-free media. Recovery was inhibited by cyanide, oligomycin A, and N-ethylmaleimide. Cyanide and oligomycin inhibited recovery less in the presence than in the absence of glucose. When cells were first acid loaded in a Na+-free medium and then exposed to external Na+, pH recovery also took place. This recovery exhibited first-order dependence on Na+ concentration and was inhibited by 5-(N-ethyl-N-isopropyl)amiloride. These studies demonstrate that in culture, collecting duct principal cells possess at least two mechanisms for acid extrusion: a proton ATP-ase and an Na+-H+ exchanger. The former may be responsible for some component of the urinary acidification observed in the papillary collecting duct in vivo; the role of the latter in acid-base transport remains uncertain.

Hypoxia attenuates effector-target cell interaction in the airway and pulmonary vascular compartment.

Leucocyte infiltration is known to play an important role in hypoxia-induced tissue damage. However, little information is available about hypoxia and interaction of effector (neutrophils) with target cells (alveolar epithelial cells, AEC; rat pulmonary artery endothelial cells, RPAEC). The goal of this study was to elucidate hypoxia-induced changes of effector-target cell interaction. AEC and RPAEC were exposed to 5% oxygen for 2-6 h. Intercellular adhesion molecule-1 (ICAM-1) expression was determined and cell adherence as well as cytotoxicity assays were performed. Nitric oxide and heat shock protein 70 (HSP70) production was assessed in target cells. Under hypoxic conditions enhanced ICAM-1 production was found in both cell types. This resulted in an increase of adherent neutrophils to AEC and RPAEC. The death rate of hypoxia-exposed target cells decreased significantly in comparison to control cells. Nitric oxide (NO) concentration was enhanced, as was production of HSP70 in AEC. Blocking NO production in target cells resulted in increased cytotoxicity in AEC and RPAEC. This study shows for the first time that target cells are more resistant to effector cells under hypoxia, suggesting hypoxia-induced cell protection. An underlying mechanism for this phenomenon might be the protective effect of increased levels of NO in target cells.

[Assisted suicide in Germany: medical diagnoses and personal reasons of 117 decedents]. / Organisierte Suizidbeihilfe in Deutschland: Medizinische Diagnosen und persönliche Motive von 117 Suizidenten.

BACKGROUND: In Germany both scientific and public debates on physician assisted suicide often focus on patients with unbearable suffering in terminal condition. Proponents of physician assisted suicide bring forward the argument that there are end-of-life situations where only assisted suicide can bring relief from intolerable pain, dyspnea or other symptoms. But does focusing on unbearable symptoms in terminal condition reflect the reality of assisted suicide? Our data from 117 assisted suicides in Germany indicates that the reasons for assisted suicide are more complex than the current debate in Germany suggests. METHODS: We analyzed diagnoses and reasons that prompted patients to suicide with the help of the German right-to-die organization "Sterbehilfe Deutschland" (StHD) between 2010 and 2013. 118 case reports of assisted suicide published by StHD were evaluated retrospectively. RESULTS: Between 2010 and 2013 StHD provided assistance in 118 suicides. 71 % of the deceased were women. 67 % were aged 70 years or older. 25,6 % suffered from metastasized cancer, 20,5 % had a severe neurological disease. 23 % suffered from age-associated diseases or disability. 14,5 % of the decedents had a predominant psychiatric diagnose, 7,7 % were physically and mentally healthy. The main reasons for suicide were loss of life perspective in the face of a severe disease (29 %), fear of care dependency (23,9 %), weariness of life without any severe disease (20,5 %). Only 12,8 % named non-treatable symptoms as a reason. CONCLUSION: Loss of life perspective in the face of a severe disease, fear of long-term care and weariness of life without any severe disease rather than unbearable suffering of non-treatable symptoms seem to be the most common reasons for members of StHD to commit suicide. These empirical findings should be mentioned in future debates on assisted suicide in Germany.

Observations on sodium retention related to insulin treatment of experimental diabetes.

Streptozotocin (STZ)-diabetic rats regularly retained sodium (Na+), and tended to retain potassium (K+) as well, in response to insulin. Diabetic patients have also been reported to exhibit antinatriuresis and antikaliuresis early in the course of insulin therapy. Insulin-related Na+ retention can occur without a marked reduction in blood glucose level and does not appear to be attributable to preexisting Na+ depletion, mineralocorticoid effect, or suppression of glucosuria. The decrease in urinary Na+ excretion (UNaV) in the rats incident to insulin administration was appreciably greater than the decrease in chloride (Cl-) or water excretion. The significance of this observation is uncertain. It may be, in part, a consequence of the nephrotoxicity of STZ. Insulin-related Na+ retention may be closely related pathogenetically to the Na+ retention of refeeding and may reflect a direct renal action of insulin or, less likely, an alteration of renal tubular metabolism in response to insulin-mediated changes in sytemic metabolism.

Potentiation of the hepatic action of insulin by chlorpropamide.

In perfused livers of fed rats, chlorpropamide inhibits glucagon-stimulated glucose production by augmenting the action of insulin. This effect is associated with a decrease in cyclic AMP accumulation in liver and perfusate. Alterations in glucose production appear to correlate more closely with changes in the amount of cyclic AMP in the perfusate than with changes in intrahepatic concentration of nucleotide. Potenitation by chlorpropamide of the hepatic action of insulin does not require administration of the drug prior to perfusion. Further, it is demonstrable at concentrations of insulin and glucagon (10(-11M) that approximate the normal plasma levels of these hormones.

Hepatic effects of chlorpropamide: inhibition of glucagon-stimulated gluconeogenesis in perfused livers of fasted rats.

In perfused livers of rats fasted for 24 h, glucagon (5 x 10(-10) M) significantly elevated tissue and perfusate levels of cyclic AMP and caused a twofold increase in glucose formation from lactate. Chlorpropamide (0.8 x 10(-3) M) consistently blocked these effects. Measurements of metabolic intermediates suggest that chlorpropamide may inhibit gluconeogenesis by antagonizing the action of glucagon on the phosphoenolpyruvate cycle. In the experiments described, chlorpropamide did not lower hepatic ATP concentration or energy charge, and exerted its effects at perfusate concentrations comparable to serum concentrations reported in patients on maintenance doses of the drug.

The renin-angiotensin-aldosterone system in diabetic patients with hyperkalemia.

Seven long-standing diabetic patients with spontaneous and intermittent hyperkalemia were studied in an effort to assess the normality of their renin-aldosterone axis. The administration of oral glucose, in the absence of insulin, caused a paradoxical rise in serum potassium with no significant change in plasma aldosterone concentration from controls. All displayed subnormal aldosterone-secreting capacity to known stimuli of aldosterone secretion such as low salt diet, angiotensin II infusion, and ACTH infusion. The paradoxical rise in serum potassium with hyperglycemia was corrected in all by concomitant administration of insulin or pretreatment with a mineralocorticoid. Our observations question the role of aldosterone deficiency in the phenomenon of glucose-induced hyperkalemia.

The molar ratio of insulin to C-peptide. An aid to the diagnosis of hypoglycemia due to surreptitious (or inadvertent) insulin administration.

After beta-cell stimulation by carbohydrate or other secretagogues, insulin and C-peptide are secreted into the portal vein in a 1:1 molar ratio. A large fraction of endogenous insulin is cleared by the liver, whereas C-peptide, which is cleared primarily by the kidney and has a lower metabolic clearance rate than insulin, traverses the liver with essentially no extraction by hepatocytes. Hence, the molar ratio of insulin to C-peptide in peripheral venous blood (ICPR) should be less than 1.0 during fasting and feeding, unless exogenous insulin is introduced into the systemic circulation. Consequently, an ICPR in excess of 1.0 in a hypoglycemic patient argues persuasively for surreptitious or inadvertent insulin administration and against insulinoma (or sulfonylurea ingestion) as the cause of the hypoglycemia. This conclusion is supported by personal experience and by the literature.

The calcium oxalate crystal growth inhibitor protein produced by mouse kidney cortical cells in culture is osteopontin.

Urine contains proteins that inhibit the growth of calcium oxalate (CaOx) crystals and may prevent the formation of kidney stones. We have identified a potent crystal growth inhibitor in the conditioned media from primary cultures of mouse kidney cortical cells. Conditioned media, incubated with the kidney cells for 6-72 h, was assayed for crystal growth inhibition; inhibitory activity increased 15-fold by 24 h. Inhibitory activity was purified from serum-free media containing proteinase inhibitors using anion-exchange and gel-filtration chromatography. A single band of molecular weight 80,000 daltons was seen after SDS-polyacrylamide gel electrophoresis. The sequence of the N-terminal 21 amino acids of this protein matched that of osteopontin (OP), a phosphoprotein initially isolated from bone matrix. Antisera raised to fusion proteins produced by plasmids containing the N-terminal or C-terminal portions of OP cDNA also cross-reacted with the protein purified from cell culture media on western blots. The effect of the purified protein on the growth of CaOx crystals was measured using a constant composition assay. A 50% inhibition of growth occurred at a protein concentration of 0.85 micrograms/ml, and the dissociation constant of the protein with respect to CaOx crystal was 3.7 x 10(-8) M. The concentration of OP in mouse urine, measured using antibodies raised to the purified protein, was approximately 8 micrograms/ml. We conclude that OP is synthesized by kidney cortical tubule cells and functions as a crystal growth inhibitory protein in urine.

Evidence that stimulation of 1,25(OH)2D3 production in primary cultures of mouse kidney cells by cyclic AMP requires new protein synthesis.

When primary culture of C75BL6 mouse cortical kidney cells in serum-free medium were incubated with unlabeled 25(OH)D3, they produced a metabolite which co-migrated with authentic 1,25(OH)2D3 and which could be measured by competitive receptor assay. A metabolite co-migrating with authentic 10-oxo-19-nor-25-OH-D3 was also produced. However, when cultures were incubated with 25(OH)D3 for 1 hour or longer, 10-oxo-19-nor-25-OH-D accounted for less than 15% of the total 3H-1,25(OH)2D3 displacement activity. Production of 1,25(OH)2D3 increased with increasing content of the culture, with time of incubation, and with substrate concentration. The apparent Km was 1.4 +/- 0.6 microM and Vmax 2.6 +/- 0.4 pM/mg protein/hr. These cultures possessed a very high level of phosphodiesterase activity, as indicated by their high cyclic AMP (cAMP) response to IBMX. This high phosphodiesterase activity may have been responsible for the lack of stimulation of 1,25(OH)2D3 production by physiologic or near physiologic concentrations of parathyroid hormone (PTH) in the absence of IBMX. However, when IBMX 10(-6) M was present, bPTH 10(-9) M significantly increased production of both cAMP and 1,25(OH)2D3. There was a close correlation between 1,25(OH)2D3 production and cAMP content of the cultures (basal or stimulated). An incubation time of at least 4 hours was required for cAMP to increase 1,25(OH)2D3 production and was inhibited in the presence of cycloheximide and actinomycin D. This study further documents the regulation of renal 1,25(OH)2D3 synthesis by PTH in mammalian kidney and provides evidence for cAMP as a possibly important second messenger in this effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of hormonal activation of hepatic phosphorylase by chlorpropamide: evidence for an intracellular site of drug action.

Phosphorylase a activity was measured in hepatocytes from fed rats, some of which received ip chlorpropamide injections for 5 days preceding death (20 mg/100 g BW X day for 5 days). Chlorpropamide treatment significantly depressed basal phosphorylase a activity and lessened the increments in the activity of this enzyme induced by 10(-10) -10(-8) M glucagon and arginine vasopressin. The reductions in phosphorylase a activity after treatment with chlorpropamide were more than sufficient to explain the accompanying decreases in hepatic glucose production. Since glucagon and arginine vasopressin stimulate alternate pathways of phosphorylase activation and since chlorpropamide antagonizes both hormones, it is likely that the drug acts at or distal to the intracellular site (phosphorylase kinase) at which the two activation pathways converge.

Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication.

OBJECTIVE: This review explores the theoretical background for and empirical evidence supporting gender-related differences in pharmacokinetics and pharmacodynamic properties of psychotropic medications. METHOD: The authors reviewed all English-language articles on this topic that involved original research using human subjects. RESULTS: Limited evidence suggests that young women seem to respond better to and require lower doses of antipsychotic agents and benzodiazepines than young men. The administration of exogenous hormones interacts with medications, changing plasma levels and possibly conferring greater risks for toxicity. Young women may have an enhanced response to nontricyclic antidepressants. CONCLUSIONS: Too little basic and clinical research has been conducted on sex differences in therapeutic effects and side effects of psychopharmacological treatments. Addressing these differences as well as similarities will lead to safer and more effective treatment for all patients.

PIP: A review of the English-language literature on original research with human subjects concerning sex differences in pharmacokinetics and psychotropic agents was attempted. With respect to absorption and bioavailability, women may secrete less gastric acid, and progesterone in the luteal phase slowed gastric emptying. Drugs with high affinity for adipose tissue (diazepam) would be distributed more in females with a lower ratio of lean body mass to adipose tissue. Yet, over time half-life may be prolonged with higher serum levels in patients with less lean body mass. The 1st-pass metabolism of drugs and later extensive metabolizing for systemic circulation are carried out in the liver. The menstrual cycle also affects gastric motility as dilution via fluid retention results in lower plasma levels. Estrogen may reduce monoamine oxidase activity and progesterone may increase it. Women taking oral contraceptives and diazepam during menstruation become relatively intoxicated. With respect to antipsychotic agents higher fluphenazine levels were found in women, and they required 1/2 the dose of fluspiriline as men. Women improved more after pimozide and chlorpromazine treatment than men. The incidence of severe tardive dyskinesia was higher in postmenopausal women possibly attributable to estrogen loss. Oral contraceptives reduced the clearance of benzodiazepines resulting in slower peak levels of diazepam while being off pills led to impairment of cognitive and psychomotor tasks. Temazepam and oxazepam also cleared more slowly in women. Among antidepressant agents MAO inhibitors produced better results in women than did tricyclic antidepressants. Lithium-induced hypothyroidism predominates in women as does thyroid disease, and possibly rapid-cycling bipolar illness is also linked to this condition.

Pregnancy-related affective episodes among women with recurrent depression.

The authors examined 52 women with recurrent depression to determine the differences between women with and without histories of pregnancy-related affective episodes. The women with histories of such episodes (N = 24) had been significantly younger at illness onset, were more severely depressed at baseline, and tended to show less emotional stability. The EEG-recorded sleep of the women with pregnancy-related affective episodes was distinguished by longer REM sleep time and more REM activity, differences accounted for almost entirely by the women with histories of only postpartum episodes.