Reversed Holocene temperature-moisture relationship in the Horn of Africa.

Anthropogenic climate change is predicted to severely impact the global hydrological cycle1, particularly in tropical regions where agriculture-based economies depend on monsoon rainfall2. In the Horn of Africa, more frequent drought conditions in recent decades3,4 contrast with climate models projecting precipitation to increase with rising temperature5. Here we use organic geochemical climate-proxy data from the sediment record of Lake Chala (Kenya and Tanzania) to probe the stability of the link between hydroclimate and temperature over approximately the past 75,000 years, hence encompassing a sufficiently wide range of temperatures to test the 'dry gets drier, wet gets wetter' paradigm6 of anthropogenic climate change in the time domain. We show that the positive relationship between effective moisture and temperature in easternmost Africa during the cooler last glacial period shifted to negative around the onset of the Holocene 11,700 years ago, when the atmospheric carbon dioxide concentration exceeded 250 parts per million and mean annual temperature approached modern-day values. Thus, at that time, the budget between monsoonal precipitation and continental evaporation7 crossed a tipping point such that the positive influence of temperature on evaporation became greater than its positive influence on precipitation. Our results imply that under continued anthropogenic warming, the Horn of Africa will probably experience further drying, and they highlight the need for improved simulation of both dynamic and thermodynamic processes in the tropical hydrological cycle.

The epidemiology and global burden of autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASDs) are persistent disabling neurodevelopmental disorders clinically evident from early childhood. For the first time, the burden of ASDs has been estimated for the Global Burden of Disease Study 2010 (GBD 2010). The aims of this study were to develop global and regional prevalence models and estimate the global burden of disease of ASDs. METHOD: A systematic review was conducted for epidemiological data (prevalence, incidence, remission and mortality risk) of autistic disorder and other ASDs. Data were pooled using a Bayesian meta-regression approach while adjusting for between-study variance to derive prevalence models. Burden was calculated in terms of years lived with disability (YLDs) and disability-adjusted life-years (DALYs), which are reported here by world region for 1990 and 2010. RESULTS: In 2010 there were an estimated 52 million cases of ASDs, equating to a prevalence of 7.6 per 1000 or one in 132 persons. After accounting for methodological variations, there was no clear evidence of a change in prevalence for autistic disorder or other ASDs between 1990 and 2010. Worldwide, there was little regional variation in the prevalence of ASDs. Globally, autistic disorders accounted for more than 58 DALYs per 100 000 population and other ASDs accounted for 53 DALYs per 100 000. CONCLUSIONS: ASDs account for substantial health loss across the lifespan. Understanding the burden of ASDs is essential for effective policy making. An accurate epidemiological description of ASDs is needed to inform public health policy and to plan for education, housing and financial support services.

The global burden of anxiety disorders in 2010.

BACKGROUND: Despite their high prevalence, the global burden of anxiety disorders has never been calculated comprehensively. The new Global Burden of Disease (GBD) study has estimated burden due to morbidity and mortality caused by any anxiety disorder. METHOD: Prevalence was estimated using Bayesian meta-regression informed by data identified in a systematic review. Years of life lived with disability (YLDs) were calculated by multiplying prevalent cases by an average disability weight based on severity proportions (mild, moderate and severe). Disability-adjusted life years (DALYs) were then calculated and age standardized using global standard population figures. Estimates were also made for additional suicide mortality attributable to anxiety disorders. Findings are presented for YLDs, DALYs and attributable burden due to suicide for 21 world regions in 1990 and 2010. RESULTS: Anxiety disorders were the sixth leading cause of disability, in terms of YLDs, in both high-income (HI) and low- and middle-income (LMI) countries. Globally, anxiety disorders accounted for 390 DALYs per 100,000 persons [95% uncertainty interval (UI) 191-371 DALYs per 100,000] in 2010, with no discernible change observed over time. Females accounted for about 65% of the DALYs caused by anxiety disorders, with the highest burden in both males and females experienced by those aged between 15 and 34 years. Although there was regional variation in prevalence, the overlap between uncertainty estimates means that substantive differences in burden between populations could not be identified. CONCLUSIONS: Anxiety disorders are chronic, disabling conditions that are distributed across the globe. Future estimates of burden could be further improved by obtaining more representative data on severity state proportions.

Global prevalence of anxiety disorders: a systematic review and meta-regression.

BACKGROUND: The literature describing the global prevalence of anxiety disorders is highly variable. A systematic review and meta-regression were undertaken to estimate the prevalence of anxiety disorders and to identify factors that may influence these estimates. The findings will inform the new Global Burden of Disease study. Method A systematic review identified prevalence studies of anxiety disorders published between 1980 and 2009. Electronic databases, reference lists, review articles and monographs were searched and experts then contacted to identify missing studies. Substantive and methodological factors associated with inter-study variability were identified through meta-regression analyses and the global prevalence of anxiety disorders was calculated adjusting for study methodology. RESULTS: The prevalence of anxiety disorders was obtained from 87 studies across 44 countries. Estimates of current prevalence ranged between 0.9% and 28.3% and past-year prevalence between 2.4% and 29.8%. Substantive factors including gender, age, culture, conflict and economic status, and urbanicity accounted for the greatest proportion of variability. Methodological factors in the final multivariate model (prevalence period, number of disorders and diagnostic instrument) explained an additional 13% of variance between studies. The global current prevalence of anxiety disorders adjusted for methodological differences was 7.3% (4.8-10.9%) and ranged from 5.3% (3.5-8.1%) in African cultures to 10.4% (7.0-15.5%) in Euro/Anglo cultures. CONCLUSIONS: Anxiety disorders are common and the substantive and methodological factors identified here explain much of the variability in prevalence estimates. Specific attention should be paid to cultural differences in responses to survey instruments for anxiety disorders.

Global variation in the prevalence and incidence of major depressive disorder: a systematic review of the epidemiological literature.

BACKGROUND: Summarizing the epidemiology of major depressive disorder (MDD) at a global level is complicated by significant heterogeneity in the data. The aim of this study is to present a global summary of the prevalence and incidence of MDD, accounting for sources of bias, and dealing with heterogeneity. Findings are informing MDD burden quantification in the Global Burden of Disease (GBD) 2010 Study. METHOD: A systematic review of prevalence and incidence of MDD was undertaken. Electronic databases Medline, PsycINFO and EMBASE were searched. Community-representative studies adhering to suitable diagnostic nomenclature were included. A meta-regression was conducted to explore sources of heterogeneity in prevalence and guide the stratification of data in a meta-analysis. RESULTS: The literature search identified 116 prevalence and four incidence studies. Prevalence period, sex, year of study, depression subtype, survey instrument, age and region were significant determinants of prevalence, explaining 57.7% of the variability between studies. The global point prevalence of MDD, adjusting for methodological differences, was 4.7% (4.4-5.0%). The pooled annual incidence was 3.0% (2.4-3.8%), clearly at odds with the pooled prevalence estimates and the previously reported average duration of 30 weeks for an episode of MDD. CONCLUSIONS: Our findings provide a comprehensive and up-to-date profile of the prevalence of MDD globally. Region and study methodology influenced the prevalence of MDD. This needs to be considered in the GBD 2010 study and in investigations into the ecological determinants of MDD. Good-quality estimates from low-/middle-income countries were sparse. More accurate data on incidence are also required.

The global coverage of prevalence data for mental disorders in children and adolescents.

AIMS: Children and adolescents make up almost a quarter of the world's population with 85% living in low- and middle-income countries (LMICs). Globally, mental (and substance use) disorders are the leading cause of disability in young people; however, the representativeness or 'coverage' of the prevalence data is unknown. Coverage refers to the proportion of the target population (ages 5-17 years) represented by the available data. METHODS: Prevalence data for conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), eating disorders (EDs), depression, and anxiety disorders were sourced from systematic reviews conducted for the Global Burden of Disease Study 2010 (GBD 2010) and 2013 (GBD 2013). For each study, the location proportion was multiplied by the age proportion to give study coverage. Location proportion was calculated by dividing the total study location population by the total study location population. Age proportion was calculated by dividing the population of the country aged within the age range of the study sample by the population of the country aged within the age range of the study sample. If a study only sampled one sex, study coverage was halved. Coverage across studies was then summed for each country to give coverage by country. This method was repeated at the region and global level, and separately for GBD 2013 and GBD 2010. RESULTS: Mean global coverage of prevalence data for mental disorders in ages 5-17 years was 6.7% (CD: 5.0%, ADHD: 5.5%, ASDs: 16.1%, EDs: 4.4%, depression: 6.2%, anxiety: 3.2%). Of 187 countries, 124 had no data for any disorder. Many LMICs were poorly represented in the available prevalence data, for example, no region in sub-Saharan Africa had more than 2% coverage for any disorder. While coverage increased between GBD 2010 and GBD 2013, this differed greatly between disorders and few new countries provided data. CONCLUSIONS: The global coverage of prevalence data for mental disorders in children and adolescents is limited. Practical methodology must be developed and epidemiological surveys funded to provide representative prevalence estimates so as to inform appropriate resource allocation and support policies that address mental health needs of children and adolescents.

Gender-related patterns and determinants of recent help-seeking for past-year affective, anxiety and substance use disorders: findings from a national epidemiological survey.

AIMS: To examine: (1) gender-specific determinants of help-seeking for mental health, including health professional consultation and the use of non-clinical support services and self-management strategies (SS/SM) and; (2) gender differences among individuals with unmet perceived need for care. METHOD: Analyses focused on 689 males and 1075 females aged 16-85 years who met ICD-10 criteria for a past-year affective, anxiety or substance use disorder in an Australian community-representative survey. Two classifications of help-seeking for mental health in the previous year were created: (1) no health professional consultation or SS/SM, or health professional consultation, or SS/SM only, and; (2) no general practitioner (GP) or mental health professional consultation, or GP only consultation, or mental health professional consultation. Between- and within-gender help-seeking patterns were explored using multinomial logistic regression models. Characteristics of males and females with unmet perceived need for care were compared using chi-square tests. RESULTS: Males with mental or substance use disorders had relatively lower odds than females of any health professional consultation (adjusted odds ratio [AOR] = 0.46), use of SS/SM only (AOR = 0.59), and GP only consultation (AOR = 0.29). Notably, males with severe disorders had substantially lower odds than females of any health professional consultation (AOR = 0.29) and GP only consultation (AOR = 0.14). Most correlates of help-seeking were need-related. Many applied to both genders (e.g., severity, disability, psychiatric comorbidity), although some were male-specific (e.g., past-year reaction to a traumatic event) or female-specific (e.g., past-year affective disorder). Certain enabling and predisposing factors increased the probability of health professional consultation for both genders (age 30+ years) or for males (unmarried, single parenthood, reliance on government pension). Males with unmet perceived need for care were more likely to have experienced a substance use disorder and to want medicine or tablets or social intervention, whereas their females peers were more likely to have experienced an anxiety disorder and to want counselling or talking therapy. For both genders, attitudinal/knowledge barriers to receiving the types of help wanted (e.g., not knowing where to get help) were more commonly reported than structural barriers (e.g., cost). CONCLUSIONS: Findings suggest a need to address barriers to help-seeking in males with severe disorders, and promote GP consultation. Exploring gender-specific attitudinal/knowledge barriers to receiving help, and the types of help wanted, may assist in designing interventions to increase consultation. Mental health promotion/education efforts could incorporate information about the content and benefits of evidence-based treatments and encourage males to participate in other potentially beneficial actions (e.g., physical activity).

Excess mortality from mental, neurological and substance use disorders in the Global Burden of Disease Study 2010.

AIMS: Mortality-associated burden of disease estimates from the Global Burden of Disease 2010 (GBD 2010) may erroneously lead to the interpretation that premature death in people with mental, neurological and substance use disorders (MNSDs) is inconsequential when evidence shows that people with MNSDs experience a significant reduction in life expectancy. We explore differences between cause-specific and excess mortality of MNSDs estimated by GBD 2010. METHODS: GBD 2010 cause-specific death estimates were produced using the International Classification of Diseases death-coding system. Excess mortality (all-cause) was estimated using natural history models. Additional mortality attributed to MNSDs as underlying causes but not captured through GBD 2010 methodology is quantified in the comparative risk assessments. RESULTS: In GBD 2010, MNSDs were estimated to be directly responsible for 840 000 deaths compared with more than 13 million excess deaths using natural history models. CONCLUSIONS: Numbers of excess deaths and attributable deaths clearly demonstrate the high degree of mortality associated with these disorders. There is substantial evidence pointing to potential causal pathways for this premature mortality with evidence-based interventions available to address this mortality. The life expectancy gap between persons with MNSDs and the general population is high and should be a focus for health systems reform.

Discovery and synthesis of methyl 2,5-dimethyl-4-[2- (phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176) and analogues: the first examples of a new class of calcium channel activator.

Methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate, FPL 64176 (1), is the first example of a new class of calcium channel activator (CCA) that does not act on any of the well-defined calcium channel modulator receptor sites, as typified by verapamil, diltiazem, and the dihydropyridines. The potent activity of 1, having the 2-(phenylmethyl)benzoyl substituent, was predicted using QSAR on an initial set of less potent benzoylpyrroles. When compared to the CCA Bay K 8644, 1 has similar potency on calcium uptake into GH3 cells (both have EC50 approximately 0.015 microM) but is appreciably more potent functionally at increasing contractility in a guinea pig atria preparation (1 has EC50 = 0.049 microM vs Bay K 8644 EC50 = 1.95 microM). 1 is an achiral, pharmacologically clean agonist with no demonstrable partial agonist properties and possesses appreciably higher efficacy than Bay K 8644. It should therefore become a useful biochemical and pharmacological tool for the study of calcium channels in many cell types.

Potent human immunodeficiency virus type 1 protease inhibitors that utilize noncoded D-amino acids as P2/P3 ligands.

Noncoded D-amino acids have been designed to replace the quinaldic amide-asparaginyl moiety (P2/P3 ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a CH2CONH2 (asparagine side chain mimic), while the amino acid side chain became the backbone and P3 ligand of these novel inhibitors. Compounds derived from S-aryl-D-cysteine proved to be potent HIV protease inhibitors which also exhibited potent whole cell antiviral activity. Oxidation of the cysteines to the sulfoxide or sulfone oxidation states resulted in significant improvements in potency. For example, the compound derived from N-(methyl-sulfonyl)-2-S-naphthylcysteine sulfone, 17c, was a 3.5 nM inhibitor of HIV protease which inhibited the spread of virus in MT4 cells with an IC50 = 4.3 nM. Compounds 17c,g,i were found to be orally bioavailable in a rat model.

Effect of naloxone, domperidone and idazoxan on the delay in gastric emptying induced by ileal lipid.

Studies were carried out on 22 healthy male volunteers to investigate whether intravenous administration of either the opiate antagonist, naloxone, or the dopamine antagonist, domperidone, or the alpha 2-adrenoreceptor antagonist, idazoxan, could reverse the delay in gastric emptying induced by ileal infusion of lipid emulsion. Ileal infusion of 50% lipid emulsion significantly delayed the rate of gastric emptying compared with ileal infusion of isotonic saline (P less than 0.01). Intravenous infusion of naloxone (20 micrograms kg-1 hour-1) or prior administration of either intravenous domperidone (20 mg) or idazoxan (0.2 mg kg-1) did not inhibit the delay in gastric emptying induced by ileal infusion of lipid emulsion. These observations indicate that feedback regulation of gastric emptying by ileal lipid does not appear to be mediated by either dopaminergic or enkephalinergic neurons, nor by alpha 2-adrenoreceptors.

The effect of two alpha 2-adrenoreceptor agonists and an antagonist on gastric emptying and mouth to caecum transit time in humans.

Experiments were performed to investigate the effect of two alpha 2-adrenoreceptor agonists, clonidine and lidamidine, and a specific alpha 2-adrenoreceptor antagonist, idazoxan, on gastric emptying and mouth to caecum transit time (MCTT) of a radiolabelled meal in 27 healthy male subjects. Lidamidine (20 mg p.o.) and clonidine (0.3 mg p.o.), given alone had no significant effect on gastric emptying or MCTT suggesting that the anti-diarrhoeal action of clonidine and lidamidine are unlikely to be explained by a slowing of small intestinal transit. Idazoxan (20 mg p.o.) reversed the effect of clonidine in 10 subjects, who showed a delay in MCTT after taking clonidine, but did not alter MCTT under basal conditions. These results suggest that although the sympathetic nervous system can influence upper gastrointestinal motility by an action on alpha 2-adrenoreceptors, this action does not exert a tonic influence on upper gastrointestinal motility under basal conditions.

Approaches to vector control: new and trusted. 1. Humoral immune responses in blackfly and mosquito vectors of filariae.

The vectors of filariasis, mosquitoes and blackflies, are capable of mounting a defence response to the infection. This selective review describes the molecules that are involved in these immune systems. Several antibacterial peptides are known to be induced and secreted into the haemolymph by the fat body and the circulating haemocytes. In addition, haemagglutinating lectins with carbohydrate specificities to the surface of the developing filarial larvae appear. Activation of a range of proteases occurs rapidly as does activation of the prophenoloxidase pathway. The possible roles of these and other molecules is discussed, together with mention of a working hypothesis as to how these molecules may be regulated.

Diastolic heart failure in older people--myth or lost tribe?

Left ventricular diastolic dysfunction occurs due to a variable combination of abnormal myocardial relaxation and reduced ventricular compliance. The diagnosis of diastolic congestive heart failure is controversial. Some studies suggest that up to one-third of older people with symptomatic congestive heart failure (CHF) have echocardiograph evidence of diastolic dysfunction. Other authors have suggested the comorbid diseases often found in persons with suspected diastolic CHF explain the patient's symptoms and hence diastolic CHF is a misdiagnosis in many cases. Many of the characteristic echo features of diastolic dysfunction occur in normal ageing hearts. Unlike in systolic CHF, evidence for disease modifying treatment is lacking. Clinical trials currently in progress to determine the effectiveness of ACE inhibitors and angiotensin II receptor antagonists in the management of diastolic CHF may clarify the prognosis and management of this condition.

The global burden of mental and substance use disorders: changes in estimating burden between GBD1990 and GBD2010.

Background. The main aim of this paper is to compare and contrast the methodological approaches of the new Global Burden of Disease 2010 Study (GBD 2010) with the original study conducted for 1990 (GBD 1990), in terms of calculating burden for mental and substance use disorders. Methods. We reviewed the conceptual and methodological changes to GBD burden calculations in the GBD 2010 study, compared with previous studies. We then discuss the possible implications of these changes with respect to burden estimates for mental and substance use disorders. Results. It is not possible to compare burden estimates arising from the GBD 1990 study with the most recent burden estimates. There have been important advances in the categorisation and definition of mental disorders, and the input and computation of epidemiological models for disease distribution. There have also been major changes to conceptual and social value choices aimed at addressing concerns that arose following publication of earlier GBD studies. Conclusion. Advancements to the GBD conceptual framework and method of calculating burden estimates has led to more accurate and equitable consideration of the burden for mental and substance use disorders. Proposed annual updates of GBD estimates by the Institute of Health Metrics and Evaluation provide an opportunity to continue to advance the evidence base that underpins the quantification of disease burden.

Haemoperitoneum associated with ovulation in women with bleeding disorders: the case for conservative management and the role of the contraceptive pill.

Haemoperitoneum secondary to ruptured corpus luteum is a rare complication for women on anticoagulants and with certain congenital bleeding disorders. A surgical approach is often taken, leading to oophorectomy in many cases. We describe three patients presenting with haemoperitoneum in association with factor VII deficiency, factor X deficiency and sitosterolaemia. In two of the patients, recurrent episodes occurred prior to introduction of the oral contraceptive pill. Conservative management with blood product and factor concentrate support was successful in avoiding surgery in three of the five episodes of bleeding. These cases demonstrate that preservation of ovarian function is possible with a conservative approach and recurrent episodes may be prevented by suppression of ovulation.

Mechanisms of resistance to Onchocerca infection in blackflies.

In this article Peter Ham, Hans Hagen, Andrea Baxter and Jorg Grunewald focus on the susceptibility of blackflies to parasitic filarial infection (particularly Onchocera spp, most of the vectors of which belong to the genus Simulium). They outline what is known about, as well as speculating on, the various defence mechanisms of these insects. Investigations have involved the use of natural and surrogate vectors of bovine onchocerciasis as models for the human vector-parasite relationship.

Effect of bile acid on anorectal function in man.

The effects of rectal infusions (500 ml) of deoxycholic acid (1 mmol/l, 3 mmol/l) or normal saline on basal anorectal motility and responses to rectal distension were studied in 11 normal volunteers. Deoxycholic acid (1 mmol/l) did not alter anorectal motor patterns under basal conditions but reduced the rectal volumes required to induce a desire to defecate (deoxycholic acid 76 (12) ml v saline 123 (12) ml; mean (SEM) p less than 0.01), and to produce anal relaxation (deoxycholic acid 83 (14) ml v saline 152 (24) ml; p less than 0.05) and perception of the rectal balloon (deoxycholic acid 56 (10) ml v saline 104 (17) ml; p less than 0.01) that were sustained for the period of distension (1 min). Seven of 10 subjects could not tolerate an infusion of 3 mmol/l deoxycholic acid. Between two and 30 minutes after the start of the infusion they experienced an extreme urge to defecate which was associated with large amplitude pressure waves in the rectal channels (amplitude 30 (5) mmHg, duration 0.7 (0.1) min, frequency 1.7 (0.4)/min). Such contractions were never seen during saline infusion. Thus, rectal infusion of deoxycholic acid at physiological concentrations increases the sensitivity of the rectum to distension, and promotes an urgent desire to defecate in normal subjects.