Aga Khan Foundation

BACKGROUND AND AIMS: Alcohol-induced gut leakiness is a key factor in alcoholic liver disease (ALD); it allows endotoxin to enter the circulation and initiate liver damage. Zonula occludens 1 (ZO-1) protein is a major component of tight junctions that regulates intestinal permeability. microRNAs (miRNAs) are recently discovered regulatory molecules that inhibit expression of their target genes. THE AIMS OF OUR STUDY WERE: (i) to investigate the effect of alcohol on miRNA-212 (miR-212) and on expression of its predicted target gene, ZO-1, (ii) to study the potential role of miR-212 in the pathophysiology of ALD in man. METHODS: Using a TaqMan miRNA assay system, we measured miR-212 expression levels in colon biopsy samples from patients with ALD and in Caco-2 cells (a human intestinal epithelial cell line) treated with or without EtOH. We measured ZO-1 protein levels using western blots. ZO-1 mRNA was assayed using real-time PCR. Intestinal barrier integrity was measured using fluorescein sulfonic acid clearance and immunofluorescent staining for ZO-1. RESULTS: Ethanol increased miR-212 expression, decreased ZO-1 protein levels, disrupted tight junctions, and increased the permeability of monolayers of Caco-2 cells. An miR-212 over-expression is correlated with hyperpermeability of the monolayer barrier. miR-212 levels were higher in colon biopsy samples in patients with ALD than in healthy controls; ZO-1 protein levels were lower. CONCLUSION: These data suggest a novel mechanism for alcohol-induced gut leakiness, one in which EtOH induces miR-212 over-expression which causes gut leakiness by down-regulating ZO-1 translation. This mechanism is a potential therapeutic target for leaky gut in patients with or at risk for ALD.

ABSTRACT This paper documents that firms face upward‐sloping supply curves when they repurchase shares in a Dutch auction, and it analyzes the market reaction to these offers. The announcement price increase is highly correlated with the ultimate repurchase premium. Prices decline at expiration only for pro‐rated offers. The cumulative return is positive and highly correlated with the repurchase premium, excepting pro‐rated offers. Much of this price increase is consistent with movement along an upward‐sloping supply curve. Trading volume around the Dutch auction parallels fixed‐price repurchases. Supply elasticity is larger for firms with large trading volume, firms included in the S&P 500 Index, and takeover targets.

OBJECTIVE: There is evidence to suggest that anemia after severe traumatic brain injury (sTBI) is detrimental. However, there is a paucity of evidence supporting the use of transfusion of packed red blood cells in patients with sTBI. To understand the acute effect of packed red blood cell transfusion on cerebral oxygenation and metabolism in patients with sTBI. DESIGN: Prospective clinical study. SETTING: Addenbrooke's Neurosciences Critical Care Unit, a 21-bed tertiary academic unit. PATIENTS: Thirty patients with sTBI. INTERVENTIONS: Patients were randomized by computer random number generator to one of three transfusion thresholds: 8, 9, or 10 g/dL. When the patients' hemoglobin concentration fell below their assigned threshold, two units of packed red blood cells were transfused over 2 hours. A 1-hour period of stabilization was observed before final data collection. MEASUREMENTS AND MAIN RESULTS: The primary outcome was change in brain tissue oxygen (Pbto2). Secondary outcomes included dependence of baseline hemoglobin concentration and baseline Pbto2 on the relationship of transfusion and Pbto2, and the effect of transfusion on lactate pyruvate ratio (LPR) and brain pH as markers of cerebral metabolic state. Fifty-seven percent of patients experienced an increase in Pbto2 during the course of the study, whereas in 43% of patients, Pbto2 either did not change or decreased. Multivariable generalized estimating equation analysis revealed change in hemoglobin concentration to significantly and positively associated with change in Pbto2 [0.10 kPa/(g/dL) 95% confidence interval 0.03-0.17, p = 0.003]. Improvement in Pbto2 was not associated with baseline hemoglobin concentration or low Pbto2 (<1 kPa). Fifty-six percent of patients experienced an increase in LPR. No significant relationship between change in LPR or transfusion on pHbt and change in hemoglobin could be demonstrated. CONCLUSIONS: Transfusion of packed red blood cells acutely results in improved brain tissue oxygen without appreciable effect on cerebral metabolism. TRIAL REGISTRATION: ISRCTN89085577.

Chenopodium quinoa Willd., a high quality grain crop, is resistant to abiotic stresses (drought, cold, and salt) and offers an optimal source of protein. Quinoa represents a symbol of crop genetic diversity across the Andean region. In recent years, this crop has undergone a major expansion outside its countries of origin. The activities carried out within the framework of the International Year of Quinoa provided a great contribution to raise awareness on the multiple benefits of quinoa as well as to its wider cultivation at the global level. FAO is actively involved in promoting and evaluating the cultivation of quinoa in 26 countries outside the Andean region with the aim to strengthen food and nutrition security. The main goal of this research is to evaluate the adaptability of selected quinoa genotypes under different environments outside the Andean region. This paper presents the preliminary results from nine countries. Field evaluations were conducted during 2013/2014 and 2014/2015 in Asia (Kyrgyzstan and Tajikistan), and the Near East and North African countries (Algeria, Egypt, Iraq, Iran, Lebanon, Mauritania, and Yemen). In each country, the trials were carried out in different locations that globally represent the diversity of 19 agrarian systems under different agro-ecological conditions. Twenty-one genotypes of quinoa were tested using the same experimental protocol in all locations consisting in a randomized complete block design (RCBD) with three replicates. Some genotypes showed higher yields and the Q18 and Q12 landraces displayed greater adaptation than others to new environmental conditions. The Q21 and Q26 landraces were evaluated with stable and satisfactory levels of yield (>1 t.ha(-1)) in each of the different trial sites. This production stability is of considerable importance especially under climate change uncertainty. While these results suggest that this Andean crop is able to grow in many different environments, social, and cultural considerations remain crucial regarding its possible introduction as a staple food in new cropping systems around the world.

Antibodies targeting T-cell inhibitory pathways, such as CTLA-4 and PD-1/PD-L1, are emerging as an important class of cancer therapeutics, and a next generation of immunomodulatory therapies targeting alternative inhibitory (e.g. TIM-3, LAG-3, B7-H4, B7-H3, VISTA, A2aR), as well as co-stimulatory (e.g. CD27, OX40, GITR, CD137), pathways are poised to join them. Most of these immunomodulatory antibodies are of IgG isotypes that have low, or no, binding to the Fc gamma receptors (FcRs) that trigger cell-mediated cytotoxic effector functions such as antibody dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). These isotypes were selected to minimise the risk of depleting the T cells upon which such antibodies depend for their mechanism of action. However, recent preclinical data highlight a potential role for FcR engagement in the activity of such antibodies. Here we review the biology of the FcRs and IgG isotypes in both humans and mice, detail the potential roles that FcR interactions can play in the activity of monoclonal antibodies in general, and of immunomodulatory antibodies in particular, and discuss how preclinical studies on these interactions might be best interpreted and translated to a human setting.

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Abstract Acquisitions, mergers, and other business agreements face increasing regulatory scrutiny, even when they involve firms domiciled outside the territory of regulatory authorities. Recent examples include mergers between American firms that were approved by American regulators but blocked by European regulators. Regulatory reciprocity seems a likely future trend. There are obvious consequences for the successful completion of future business combinations. This paper explains the regulatory procedures of the European Commission with respect to business combinations, documents the price reactions of subject firms on dates from the initial announcement to the final regulatory decision, and studies whether European regulators tend to shield European firms from foreign competition. Our main results are: i) the market clearly reacts to European regulatory intervention even when the subject firms are non-European, ii) the probability of intervention is not related to the nationality of the bidder, however, iii) when intervention does occur, the market anticipates it will be more costly when the bidder is non-European, so protectionism cannot be rejected outright, and iv) regulatory interventions are anticipated by investors, so they affect the initial announcement returns.

OBJECTIVE: To characterize the alpha 1-adrenoceptor subtypes of the human benignly enlarged prostate using functional and binding studies. MATERIALS AND METHODS: Strips of prostatic tissue taken from nine patients with benign prostatic hypertrophy who were undergoing open prostatectomy were used in the study. RESULTS: The strips isolated from five prostates produced a large contraction in response to noradrenaline and phenylephrine but not to clonidine. The contractile response induced by noradrenaline was competitively antagonized by representative alpha 1-adrenoceptor antagonists (prazosin, WB4101, 5-methylurapidil and HV723), the dissociation constants (pKB) being < 8.5. Pre-treatment with chloroethylclonidine was without effect on the contractile response to noradrenaline. In saturation experiments with five prostates, [3H]-prazosin bound to the prostate membranes with two distinct affinities (pKD = 9.95 +/- 0.07 and 8.71 +/- 0.04, Bmax = 151 +/- 8 and 138 +/- 3 fmol/mg protein, respectively). Unlabelled prazosin and WB4101 biphasically displaced the binding of 200 pM [3H]-prazosin; the resulting high and low pKI values for each of the antagonists were consistent with the two pKD values obtained for [3H]-prazosin in the saturation experiments. 5-Methylurapidil and HV723 displaced the [3H]-prazosin binding monophasically with an affinity (pKI) close to 8.5. CONCLUSIONS: These results suggest the presence of at least two distinct alpha 1-adrenoceptor subtypes (presumably an alpha 1C subtype with a high affinity for prazosin and WB4101, and a putative alpha 1L subtype with a low affinity for the antagonists) in the human prostate, in which the latter subtype may be predominantly involved in the contractile response to noradrenaline.

BACKGROUND: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004). CONCLUSIONS: Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

Type 2 diabetes is increasing among youth, with minority youth at highest risk. This preliminary study tested the feasibility of a school-based program to prevent type 2 diabetes in youth at risk. Forty-one participants (age 12.6 +/- 1.1 years; 63% female, 51% African American, 44% Hispanic, and 5% Caucasian) were randomly assigned to one of two groups. Both the experimental and control groups received nutrition education and exercise training. The experimental group also received coping skills training. Data collected included body mass index (BMI), insulin resistance, dietary intake (24-Hour Food Recall), self-efficacy (Health Behavior Questionnaire), activity (Revised Godin-Shepard Activity Survey), and parents' health promoting behaviors (Health Promoting Lifestyle Profile III). At baseline BMI ranged from 27 to 53 (M = 36.2 +/- 6.0), and 95% (n = 39) demonstrated insulin resistance or pre-diabetes on an oral glucose tolerance test. After 12 months, the experimental group showed trends in improved usual food choices (p = .1) and increased dietary knowledge (p = .3). They also demonstrated lower glucose (p = .07) and insulin levels (p = .2). Experimental group parents demonstrated improved health responsibility (p = .03), healthier nutrition choices (p = .05), improved stress management skills (p = .05), increased activity (p = .2), and increased spirituality (p = .2). Data suggest a school-based program tailored to multiethnic youth may prove successful in helping these youth increase activity, improve nutrition status, and stabilize glucose and insulin metabolism, and also may be effective in changing parent health behavior.

Written patient information materials can be valuable communication tools for teaching and reinforcing the verbal message, especially in the present climate of today's health service where patients are in hospital for such short times. They are only useful if the patient is able to read and understand them, otherwise they become an expensive waste of resources. Various studies have shown that many healthcare information leaflets are written at university or postgraduate level and would cause problems with understanding for many people reading them. This study set out to examine the readability of nurse-designed written information leaflets using the Flesch Reading Ease score and the FOG and SMOG readability formulae. This descriptive study used a sample of 24 leaflets designed by trained nurses in a large teaching hospital. The results produced a mean grade of 11.3 with a range of 8.9 to 14.8. This was similar to the results of other studies and meant that patients may have difficulty comprehending the information. It would appear that little progress has been made in 40 years in this area and potential reasons are discussed. Advantages and disadvantages of readability formulae and other guidelines available for developing information leaflets are explored. Recommendations for further research are made.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9–12 months (the “shorter regimen”) and individualised regimens of ≥20 months (“longer regimens”). We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up. We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD −0.15, 95% CI −0.17– −0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0–0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07–0.16), prothionamide/ethionamide (aRD 0.07, 95% CI −0.01–0.16) or ethambutol (aRD 0.09, 95% CI 0.04–0.13). In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Workers nearing retirement face many important, and often irreversible, choices. We collected detailed demographic and financial literacy data on over 1,500 workers nearing retirement at three large companies to assess how individuals are planning for retirement. Many respondents display limited knowledge and understanding of public and company‐provided retirement benefits. Controlling for basic demographics and wealth, we find that misconceptions about eligibility ages and plan generosity influence workers' expected age of retirement. Although retirement‐related decisions will affect workers' well‐being for the remainder of their lifetimes, many do not possess enough basic financial knowledge to confidently make optimal choices . ( JEL J26, J320, J240)

Standard economic models tend to be more specific about pecuniary payoffs than nonpecuniary payoffs to education. Based on the ideas of Akerlof and Kranton, we consider a model of career choice and identity where individuals derive nonpecuniary identity payoffs. Using factor analysis on a range of attitude questions, we find two factors related to identity (career orientation and social orientation), which are important for planned educational choices and for observed gender differences. The implication is that policy makers and institutions of higher education need to focus on identity‐related issues rather than just improved financial incentives if they aim at attracting high‐ability youths to certain careers. ( JEL I21, J24)

Palladium nanoparticles supported on agarose functionalized Fe₃O₄ catalyzed C–C bond formation reactions.

In a case-control design the feeding in infancy of newly diagnosed 7- to 14-year-old diabetic children (n = 426) was compared with that of age- and sex-matched non-diabetic children (n = 426) randomly selected from the Finnish population registry. All 7- to 14-year-old diabetic children diagnosed from September 1986 to the end of April 1989 from all hospitals which treat diabetic children in Finland were invited to participate in the study. Breast-feeding was initiated in almost all children, but during the birth years of this study population (1972-1982), an increase was observed in the duration of breast-feeding (whether alone or in combination with supplementary feeding) and in the age of introduction of supplementary milk feeding. The risk of Type 1 diabetes was decreased in the children who were totally breast-fed for at least 2 months (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.42-0.98) or 3 months (OR 0.67, 95% CI 0.48-0.95) or exclusively breast-fed for at least 2 months (OR 0.60, 95% CI 0.41-0.89) or 3 months (OR 0.63, 95% CI 0.43-0.93). Those children who were younger than 2 months (OR 1.54, 95% CI 1.08-2.18) or 3 months (OR 1.52, 95% CI 1.11-2.08) at the time when supplementary milk feeding was begun had an increased risk of Type 1 diabetes. These associations remained significant after adjusting for the mother's education. The results suggest that early infant feeding patterns are associated with the risk of Type 1 diabetes developing at the age of 7 to 14 years.

This paper synthesizes research findings on contemporary mountain pastoralism in Kyrgyzstan and Tajikistan, based on a longer review characterizing mountain agropastoralism in Central Asia. We focus here on the principal issues that have been emphasized over the past two decades in policy, programs, and projects regarding pastoralism in Central Asia's mountains. We conclude that this emphasis has largely been driven by two unproven orthodoxies about N The extent and causes of pasture degradation; and N The need for decentralization and pasture land privatization.

The authors surveyed the universal and mental health values of 121 Muslims in the United States and their counseling preferences. The respondents were generally well educated and highly religious. They responded high in the universal values of benevolence and conformity; low in power, hedonism, and stimulation; and high in many humanistic mental health values. A comparison with typical counselor values showed both similarities and differences. A substantial minority indicated a willingness to go to a non‐Muslim counselor but most would want a counselor with an understanding of Islam. Implications for counseling practice and future research are discussed.

Abstract Aim We explore the phylogeography of Himalayan wolves using multiple genetic markers applied on a landscape‐scale dataset and relate our findings to the biogeographic history of the region. Location Himalayas of Nepal, the Tibetan Plateau of China and mountain ranges of Central Asia. Taxon Himalayan wolf (also called the Tibetan wolf), Canis lupus chanco . Methods We present a large‐scale, non‐invasive study of Himalayan wolves from across their estimated range. We analysed 280 wolf scat samples from western China, Kyrgyzstan and Tajikistan at two mtDNA loci, 17 microsatellite loci, four non‐synonymous SNPs in three nuclear genes related to the hypoxia pathway, and ZF genes on both sex chromosomes. Results Our results corroborate previous studies showing that the Himalayan wolf forms a distinct lineage adapted to high altitudes in excess of 4,000 m elevation. We found a correlation between hypoxia adaptation and the divergent Himalayan wolf mtDNA haplotype found across the Tibetan Plateau of Qinghai, the Tibetan Autonomous Region and the Nepalese Himalayas. We identified a region of admixture between Himalayan and grey wolves at the boundary of their distributions, where the Tibetan Plateau elevation gradually drops. Main Conclusion Based on multiple genetic markers, the Himalayan wolf forms a reciprocally monophyletic lineage with a unique adaptation to high altitude. We propose that the divergence of the lineage is related to past uplift of the region, and that the lineage maintains its high‐altitude niche, in part, by means of its genetic adaptation to hypoxia. We conclude that the Himalayan wolf merits taxonomic recognition and designation as an evolutionary significant unit (ESU).

Twenty-four digital artery island flaps with reversed flow were used to reconstruct 23 patients with fingertip injuries in the authors' clinic between June 1998 and August 2000. No nerve coaptation was performed in these patients. Patient age ranged between 18 and 35 years. All patients were evaluated at clinical follow-up for active range of motion, appearance, patient satisfaction, two-point discrimination, hypersensitivity and cold intolerance, previous hand injury, and flap viability in the repaired finger. Based on their experience, the authors consider that this procedure has several disadvantages: relatively high flap loss, sacrifice of one of the two major arteries of the finger, it is a time-consuming method, it is a difficult flap dissection, there is a requirement for loupe and microsurgical equipment. The authors think that this flap should not be the first choice for fingertip reconstruction especially for patients who have possibility of reinjuring their hands because of their jobs.