A High-End Estimate of Sea Level Rise for Practitioners.

Sea level rise (SLR) is a long-lasting consequence of climate change because global anthropogenic warming takes centuries to millennia to equilibrate for the deep ocean and ice sheets. SLR projections based on climate models support policy analysis, risk assessment and adaptation planning today, despite their large uncertainties. The central range of the SLR distribution is estimated by process-based models. However, risk-averse practitioners often require information about plausible future conditions that lie in the tails of the SLR distribution, which are poorly defined by existing models. Here, a community effort combining scientists and practitioners builds on a framework of discussing physical evidence to quantify high-end global SLR for practitioners. The approach is complementary to the IPCC AR6 report and provides further physically plausible high-end scenarios. High-end estimates for the different SLR components are developed for two climate scenarios at two timescales. For global warming of +2°C in 2100 (RCP2.6/SSP1-2.6) relative to pre-industrial values our high-end global SLR estimates are up to 0.9 m in 2100 and 2.5 m in 2300. Similarly, for a (RCP8.5/SSP5-8.5), we estimate up to 1.6 m in 2100 and up to 10.4 m in 2300. The large and growing differences between the scenarios beyond 2100 emphasize the long-term benefits of mitigation. However, even a modest 2°C warming may cause multi-meter SLR on centennial time scales with profound consequences for coastal areas. Earlier high-end assessments focused on instability mechanisms in Antarctica, while here we emphasize the importance of the timing of ice shelf collapse around Antarctica. This is highly uncertain due to low understanding of the driving processes. Hence both process understanding and emission scenario control high-end SLR.

The human imperative of stabilizing global climate change at 1.5°C.

Increased concentrations of atmospheric greenhouse gases have led to a global mean surface temperature 1.0°C higher than during the pre-industrial period. We expand on the recent IPCC Special Report on global warming of 1.5°C and review the additional risks associated with higher levels of warming, each having major implications for multiple geographies, climates, and ecosystems. Limiting warming to 1.5°C rather than 2.0°C would be required to maintain substantial proportions of ecosystems and would have clear benefits for human health and economies. These conclusions are relevant for people everywhere, particularly in low- and middle-income countries, where the escalation of climate-related risks may prevent the achievement of the United Nations Sustainable Development Goals.

Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels.

Ataxia is the predominant clinical manifestation of cerebellar dysfunction. Mutations in the human CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 (P/Q-type) calcium channels, underlie several neurological disorders, including Episodic Ataxia type 2 and Familial Hemiplegic Migraine type 1 (FHM1). Several mouse mutants exist that harbor mutations in the orthologous Cacna1a gene. The spontaneous Cacna1a mutants Rolling Nagoya (tg(rol)), Tottering (tg) and Leaner (tg(ln)) mice exhibit behavioral motor phenotypes, including ataxia. Transgenic knock-in (KI) mouse strains with the human FHM1 R192Q and S218L missense mutations have been generated. R192Q KI mice are non-ataxic, whereas S218L KI mice display a complex behavioral phenotype that includes cerebellar ataxia. Given the dependence of γ-aminobutyric acid type A (GABAA) receptor subunit functioning on localized calcium currents, and the functional link between GABAergic inhibition and ataxia, we hypothesized that cerebellar GABAA receptor expression is differentially affected in Cacna1a mutants and contributes to the ataxic phenotype. Herein we quantified functional GABAA receptors and pharmacologically dissociated cerebellar GABAA receptors in several Cacna1a mutants. We did not identify differences in the expression of GABAA receptor subunits or in the number of functional GABAA receptors in the non-ataxic R192Q KI strain. In contrast, tg(rol) mice had a ∼15% decrease in the number of functional GABAA receptors, whereas S218L KI mice showed a ∼29% increase. Our data suggest that differential changes in cerebellar GABAA receptor expression profile may contribute to the neurological phenotype of cerebellar ataxia and that targeting GABAA receptors might represent a feasible complementary strategy to treat cerebellar ataxia.

Novel mechanism of increased Ca2+ release following oxidative stress in neuronal cells involves type 2 inositol-1,4,5-trisphosphate receptors.

Dysregulation of Ca(2+) signaling following oxidative stress is an important pathophysiological mechanism of many chronic neurodegenerative disorders, including Alzheimer's disease, age-related macular degeneration, glaucomatous and diabetic retinopathies. However, the underlying mechanisms of disturbed intracellular Ca(2+) signaling remain largely unknown. We here describe a novel mechanism for increased intracellular Ca(2+) release following oxidative stress in a neuronal cell line. Using an experimental approach that included quantitative polymerase chain reaction, quantitative immunoblotting, microfluorimetry and the optical imaging of intracellular Ca(2+) release, we show that sub-lethal tert-butyl hydroperoxide-mediated oxidative stress result in a selective up-regulation of type-2 inositol-1,4,5,-trisphophate receptors. This oxidative stress mediated change was detected both at the transcriptional and translational level and functionally resulted in increased Ca(2+) release into the nucleoplasm from the membranes of the nuclear envelope at a given receptor-specific stimulus. Our data describe a novel source of Ca(2+) dysregulation induced by oxidative stress with potential relevance for differential subcellular Ca(2+) signaling specifically within the nucleus and the development of novel neuroprotective strategies in neurodegenerative disorders.

Intrapartum amnioinfusion for meconium-stained liquor in developing countries.

BACKGROUND: Intrapartum amnioinfusion (AI) has been reported to decrease perinatal mortality and morbidity in women with meconium-stained liquor. Such work has not previously been performed at King Edward VIII Hospital (KEH), in a developing country, where the incidence of meconium-stained liquor is said to be extremely high. OBJECTIVE: To establish whether AI during the intrapartum period for meconium-stained liquor decreases Caesarean section rates for fetal distress and decreases perinatal morbidity. METHOD: Informed consent was obtained from patients in labour who were 3-8 cm dilated, with meconium-staining of the liquor, grades I to III inclusive, and who had a normal cardiotocograph on presentation at term. Sixty patients were included in the trial; 30 had AI. The control group was managed by standard methods. The study group had an amnioinfusion of 0.9% normal saline at 15 ml/min under continuous cardiotocographic monitoring, until a volume of 11 was completed. This was repeated if delivery did not occur within 4 h. RESULTS: The mean pH of umbilical arterial blood was significantly higher in the AI group (7.30 versus 7.23; P = 0.0029). In addition fewer patients in this group developed hypoxic ischaemic encephalopathy (0 versus 2 controls) or meconium aspiration syndrome (1 versus 4 controls). This was not statistically significant. Caesarean section for fetal distress was performed on fewer patients in the AI group (3 versus 7 controls), although this was not statistically significant. CONCLUSION: These results demonstrate that amnioinfusion is an effective technique for improving the perinatal outcome of pregnancies complicated by meconium-stained liquor in labour. The decrease in Caesarean sections for fetal distress, though not statistically significant in this study, has clinical relevance. Furthermore, this study suggests that amnioinfusion is cost effective in a busy, high-risk labour ward unit and consequently should become standard practice in the management of meconium-stained liquor in labour.

Correlation of acid detergent lignin and Klason lignin with digestibility of forage dry matter and neutral detergent fiber.

The acid detergent lignin and Klason lignin methods were compared for their correlation with forage digestibility. Thirty-six forages, including C3 legumes and C3 and C4 grasses, were analyzed for sulfuric acid detergent lignin, Klason lignin, and in vitro digestibilities of dry matter (DM) and neutral detergent fiber (NDF). Twenty of these forages were also fed to lambs at restricted intake for measurement of DM and NDF digestibilities. Lignin concentrations determined by the two lignin methods were positively correlated, and the Klason lignin value was always greater than the acid detergent lignin concentration. The largest differences were observed for grass forages. Digestibilities of forage DM and NDF were negatively correlated with both lignin methods for the in vitro system and the lamb digestibility trials. The degree of correlation for the two lignin methods with digestibility was generally similar across all forages and within forage classes. Slopes of linear regressions of digestibility on lignin concentration did not differ between legumes and grasses. Although the sulfuric acid detergent lignin and Klason lignin procedures gave very different estimates of forage lignin concentration, they were similarly correlated with digestibility and should yield predictions of forage digestibility that have similar accuracy.

Maternal mortality in Kwazulu/Natal: need for an information database system and confidential enquiry into maternal deaths in developing countries.

In a 2-year retrospective analysis of 147 maternal deaths in South African urban and rural hospitals, the maternal mortality rate (MMR) was estimated to be 144 per 100,000 live births. MMR was significantly higher (P = 0.025) in urban hospitals (160 per 100,000) and the main causes of death were hypertensive disease in pregnancy (33%), of which eclampsia contributed to 70% of deaths and haemorrhage (18%). Only 49.7% of women who died, attended an antenatal clinic. The MMR in South Africa is lower than sub-Saharan countries but unacceptably high for a country with a mix of private and public medicine. Disparities have been noted in maternal mortality rates within the country due to different study rates within the country due to different study designs and poor documentation, Structural changes in the health care system would only be possible if a common information database system were established and confidential enquiries held into maternal deaths.

Randomised study assessing the effect of phenytoin and magnesium sulphate on maternal cerebral circulation in eclampsia using transcranial Doppler ultrasound.

OBJECTIVE: To assess maternal middle cerebral artery flow velocity patterns as measured by transcranial Doppler ultrasound (TCD) in eclampsia and to investigate the effect of the anticonvulsants magnesium sulphate (MgSO4) and phenytoin on cerebral circulation. DESIGN: Prospective randomised study. SETTING: High care obstetric unit, King Edward VIII Hospital, Durban, South Africa. PARTICIPANTS: Twenty-four eclamptic patients: 13 received MgSO4 and 11 phenytoin. INTERVENTION: Middle cerebral artery flow velocity waveforms were measured using 2 MHz pulsed Doppler ultrasound via the transtemporal approach in eclamptic patients, before and 15 minutes after the loading dose of anticonvulsant. RESULTS: Magnesium sulphate significantly reduced the pulsatility index (P = 0.002) and mean flow velocity (P = 0.02) in the middle cerebral artery, whereas phenytoin failed to produce any statistically significant effect. However, differences between groups were not statistically significant. Systolic and diastolic blood pressures were reduced in both the MgSO4 and phenytoin groups. CONCLUSION: These findings provide firm evidence that MgSO4 relieves cerebral vasospasm, compared with phenytoin, and may therefore be the better drug for the prevention of eclamptic convulsion.

Thrombelastography after aspirin ingestion in pregnant and non-pregnant subjects.

The thrombelastograph (TEG) and bleeding time were performed before and 6 h after a single oral dose of aspirin 600 mg in a group of eight healthy volunteers and 12 pregnant patients. Measured TEG variables (r, k, r+k times and maximum amplitude) were unaltered after aspirin although there was a significant prolongation of the bleeding time in both groups. Although the TEG appeared not to detect aspirin-induced changes in platelet function, the TEG measures all phases of coagulation and the unaltered TEG after aspirin suggested a functioning coagulation system.

Castanospermine blocks the hyperglycemic response to carbohydrates in vivo: a result of intestinal disaccharidase inhibition.

Castanospermine is a potent inhibitor of rat intestinal glycohydrolases in vitro and prevents the hyperglycemic response to an oral sucrose challenge in vivo. Among the glycohydrolases tested, castanospermine was most effective against sucrase with an IC50 of 1.1 x 10(-7) M. In vivo, a significant effect was seen at doses less than 1 mg/kg in both normal and streptozotocin-treated rats. Castanospermine has a prolonged duration of activity in vivo with significant activity when administered 4 hours before sucrose.

Inhibition of intestinal disaccharidases and suppression of blood glucose by a new alpha-glucohydrolase inhibitor--MDL 25,637.

MDL 25,637 is a novel compound designed as a transition-state inhibitor of alpha-glucohydrolases. This compound inhibits rat intestinal sucrase, maltase, isomaltase, glucoamylase and trehalase activities at micromolar concentrations. It is a much weaker inhibitor of alpha-amylase and lactase. Inhibition of sucrase was competitive with sucrose. In mice, MDL 25,637 inhibited the rise in serum glucose after a sucrose or starch load but not after a glucose load. MDL 25,637 also reduced the glycemic response to sucrose in rats. The drug was most effective when administered 0 to 30 min before the sucrose load and was as effective in streptozotocin-treated rats as in normals. The inhibition by MDL 25,637 of intestinal glucohydrolases is an effective means of reducing the hyperglycemic response to an oral sucrose or starch load and, as such, warrants further investigation as a potential drug for the treatment of diabetes mellitus.

Effect of a new hypoglycemic agent (MDL-310) on glucose metabolism.

N-[3-(dimethylamino)-2-propoxy-2-propenylidene]- N-methylmethanaminium as the iodide or camsylate salt (MDL-310) is a newly reported chemical which has been shown to produce hypoglycemia in vivo. The studies reported here describe in vivo and in vitro effects of MDL-310 on carbohydrate metabolism. In nonfasted mice, MDL-310 decreased liver glycogen and then produced hypoglycemia, concomitant with a near total depletion of liver glycogen stores. In fasted rats, nonhypoglycemic doses of MDL-310 increased glucose production and utilization as determined by tracer studies with [6-3H]glucose. Hypoglycemic doses decreased glucose production and increased blood lactate, which suggests an inhibition of gluconeogenesis. In isolated rat hepatocytes MDL-310, at concentrations of greater than or equal to 5 X 10(-6) M, inhibited gluconeogenesis from lactate (10 mM) plus pyruvate (2 mM). We conclude that the primary action of MDL-310 is to increase glucose utilization and that decreased production due to the inhibition of gluconeogenesis is involved in the hypoglycemic action. A single metabolic action of MDL-310 to increase glycolytic metabolism of glucose is proposed which could explain both the increase in glucose utilization and decrease in glucose production.