Correlates of Complete Childhood Vaccination in East African Countries.

Despite the benefits of childhood vaccinations, vaccination rates in low-income countries (LICs) vary widely. Increasing coverage of vaccines to 90% in the poorest countries over the next 10 years has been estimated to prevent 426 million cases of illness and avert nearly 6.4 million childhood deaths worldwide. Consequently, we sought to provide a comprehensive examination of contemporary vaccination patterns in East Africa and to identify common and country-specific barriers to complete childhood vaccination. Using data from the Demographic and Health Surveys (DHS) for Burundi, Ethiopia, Kenya, Rwanda, Tanzania, and Uganda, we looked at the prevalence of complete vaccination for polio, measles, Bacillus Calmette-Guérin (BCG) and DTwPHibHep (DTP) as recommended by the WHO among children ages 12 to 23 months. We conducted multivariable logistic regression within each country to estimate associations between complete vaccination status and health care access and sociodemographic variables using backwards stepwise regression. Vaccination varied significantly by country. In all countries, the majority of children received at least one dose of a WHO recommended vaccine; however, in Ethiopia, Tanzania, and Uganda less than 50% of children received a complete schedule of recommended vaccines. Being delivered in a public or private institution compared with being delivered at home was associated with increased odds of complete vaccination status. Sociodemographic covariates were not consistently associated with complete vaccination status across countries. Although no consistent set of predictors accounted for complete vaccination status, we observed differences based on region and the location of delivery. These differences point to the need to examine the historical, political, and economic context of each country in order to maximize vaccination coverage. Vaccination against these childhood diseases is a critical step towards reaching the Millennium Development Goal of reducing under-five mortality by two-thirds by 2015 and thus should be a global priority

The need for international perspectives to solve global biosecurity challenges

Global biosecurity presents international challenges because the majority of instances of novel organism introductions are due to international movements of goods, food and people and the likelihood of introduced agents crossing political boundaries. The inherent vulnerability of environments to introductions of alien, or non-indigenous, biological agents is due to the greater ecological vulnerability to these exotic entrants in the receiving environment. Agencies and individuals responsible for approving intentional introductions of beneficial organisms recognize this relationship and consider potential impacts in risk assessments prior to release of the organisms. However, some of those responsible for detection and control of novel pathogens and pests, introduced either inadvertently or intentionally, lack extensive training in ecology, environmental biology, and pathology, and may therefore underestimate the risk from such events. The latter is a key factor in the case of food safety. Europe is particularly vulnerable to cross-border movement of introduced agents, and one response to this has been the recent revision of plant health regimes throughout the European Union. Other responses include project-based initiatives, such as PLANTFOODSEC

A proteomic approach to investigating gene cluster expression and secondary metabolite functionality in Aspergillus fumigatus.

A combined proteomics and metabolomics approach was utilised to advance the identification and characterisation of secondary metabolites in Aspergillus fumigatus. Here, implementation of a shotgun proteomic strategy led to the identification of non-redundant mycelial proteins (n = 414) from A. fumigatus including proteins typically under-represented in 2-D proteome maps: proteins with multiple transmembrane regions, hydrophobic proteins and proteins with extremes of molecular mass and pI. Indirect identification of secondary metabolite cluster expression was also achieved, with proteins (n = 18) from LaeA-regulated clusters detected, including GliT encoded within the gliotoxin biosynthetic cluster. Biochemical analysis then revealed that gliotoxin significantly attenuates H2O2-induced oxidative stress in A. fumigatus (p>0.0001), confirming observations from proteomics data. A complementary 2-D/LC-MS/MS approach further elucidated significantly increased abundance (p<0.05) of proliferating cell nuclear antigen (PCNA), NADH-quinone oxidoreductase and the gliotoxin oxidoreductase GliT, along with significantly attenuated abundance (p<0.05) of a heat shock protein, an oxidative stress protein and an autolysis-associated chitinase, when gliotoxin and H2O2 were present, compared to H2O2 alone. Moreover, gliotoxin exposure significantly reduced the abundance of selected proteins (p<0.05) involved in de novo purine biosynthesis. Significantly elevated abundance (p<0.05) of a key enzyme, xanthine-guanine phosphoribosyl transferase Xpt1, utilised in purine salvage, was observed in the presence of H2O2 and gliotoxin. This work provides new insights into the A. fumigatus proteome and experimental strategies, plus mechanistic data pertaining to gliotoxin functionality in the organism

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

Laminin γ1 chain peptide, C-16 (KAFDITYVRLKF), promotes migration, MMP-9 secretion, and pulmonary metastasis of B16–F10 mouse melanoma cells

Laminin-1, a heterotrimer of α1, β1, and γ1 chains specific to basement membrane, promotes cell adhesion and migration, proteinase secretion and metastases of tumour cells. Several active sites on the α1 chain have been found to promote B16–F10 melanoma lung colonisation and here we have determined whether additional tumour promoting sites exist on the β1 and γ1 chains. Recently, we have identified novel cell adhesive peptides derived from laminin β1 and γ1 chains by systematic screening of synthetic peptides. Nine β1 peptides and seven γ1 peptides active for cell adhesion were tested for their effects on experimental pulmonary metastases of B16–F10 mouse melanoma cells in vivo. The most active adhesive peptide derived from the γ1 chain globular domain, C-16 (KAFDITYVRLKF), significantly enhanced pulmonary metastases of B16–F10 cells, whereas no other peptides showed enhancement. C-16 also stimulated migration of B16–F10 cells in the Boyden chamber assay in vitro. Furthermore, C-16 significantly induced the production of MMP-9 from B16–F10 cells. These results suggest that this specific laminin γ1 chain peptide has a metastasis-promoting activity and might be a new molecular target of anti-cancer treatment

PRNP Haplotype Associated with Classical BSE Incidence in European Holstein Cattle

Background: Classical bovine spongiform encephalopathy (BSE) is an acquired prion disease of cattle. The bovine prion gene (PRNP) contains regions of both high and low linkage disequilibrium (LD) that appear to be conserved across Bos taurus populations. The region of high LD, which spans the promoter and part of intron 2, contains polymorphic loci that have been associated with classical BSE status. However, the complex genetic architecture of PRNP has not been systematically tested for an association with classical BSE. Methodology/Principal Findings: In this study, haplotype tagging single nucleotide polymorphisms (htSNPs) within PRNP were used to test for association between PRNP haplotypes and BSE disease. A combination of Illumina goldengate assay, sequencing and PCR amplification was used to genotype 18 htSNPs and 2 indels in 95 BSE case and 134 control animals. A haplotype within the region of high LD was found to be associated with BSE unaffected animals (p-value = 0.000114). Conclusion/Significance: A PRNP haplotype association with classical BSE incidence has been identified. This result suggests that a genetic determinant in or near PRNP may influence classical BSE incidence in cattle

Race/ethnicity and potential suicide misclassification: window on a minority suicide paradox?

<p>Abstract</p> <p>Background</p> <p>Suicide officially kills approximately 30,000 annually in the United States. Analysis of this leading public health problem is complicated by undercounting. Despite persisting socioeconomic and health disparities, non-Hispanic Blacks and Hispanics register suicide rates less than half that of non-Hispanic Whites.</p> <p>Methods</p> <p>This cross-sectional study uses multiple cause-of-death data from the US National Center for Health Statistics to assess whether race/ethnicity, psychiatric comorbidity documentation, and other decedent characteristics were associated with differential potential for suicide misclassification. Subjects were 105,946 White, Black, and Hispanic residents aged 15 years and older, dying in the US between 2003 and 2005, whose manner of death was recorded as suicide or injury of undetermined intent. The main outcome measure was the relative odds of potential suicide misclassification, a binary measure of manner of death: injury of undetermined intent (includes misclassified suicides) versus suicide.</p> <p>Results</p> <p>Blacks (adjusted odds ratio [AOR], 2.38; 95% confidence interval [CI], 2.22-2.57) and Hispanics (1.17, 1.07-1.28) manifested excess potential suicide misclassification relative to Whites. Decedents aged 35-54 (AOR, 0.88; 95% CI, 0.84-0.93), 55-74 (0.52, 0.49-0.57), and 75+ years (0.51, 0.46-0.57) showed diminished misclassification potential relative to decedents aged 15-34, while decedents with 0-8 years (1.82, 1.75-1.90) and 9-12 years of education (1.43, 1.40-1.46) showed excess potential relative to the most educated (13+ years). Excess potential suicide misclassification was also apparent for decedents without (AOR, 3.12; 95% CI, 2.78-3.51) versus those with psychiatric comorbidity documented on their death certificates, and for decedents whose mode of injury was "less active" (46.33; 43.32-49.55) versus "more active."</p> <p>Conclusions</p> <p>Data disparities might explain much of the Black-White suicide rate gap, if not the Hispanic-White gap. Ameliorative action would extend from training in death certification to routine use of psychological autopsies in equivocal-manner-of-death cases.</p

Molecular, Biochemical and Genetic Characteristics of BSE in Canada

The epidemiology and possibly the etiology of bovine spongiform encephalopathy (BSE) have recently been recognized to be heterogeneous. In particular, three types [classical (C) and two atypical (H, L)] have been identified, largely on the basis of characteristics of the proteinase K (PK)-resistant core of the misfolded prion protein associated with the disease (PrPres). The present study was conducted to characterize the 17 Canadian BSE cases which occurred prior to November 2009 based on the molecular and biochemical properties of their PrPres, including immunoreactivity, molecular weight, glycoform profile and relative PK sensitivity. Two cases exhibited molecular weight and glycoform profiles similar to those of previously reported atypical cases, one corresponding to H-type BSE (case 6) and the other to L-type BSE (case 11). All other cases were classified as C-type. PK digestion under mild and stringent conditions revealed a reduced protease resistance in both of these cases compared to the C-type cases. With Western immunoblotting, N-terminal-specific antibodies bound to PrPres from case 6 but not to that from case 11 or C-type cases. C-terminal-specific antibodies revealed a shift in the glycoform profile and detected a fourth protein fragment in case 6, indicative of two PrPres subpopulations in H-type BSE. No mutations suggesting a genetic etiology were found in any of the 17 animals by sequencing the full PrP-coding sequence in exon 3 of the PRNP gene. Thus, each of the three known BSE types have been confirmed in Canadian cattle and show molecular characteristics highly similar to those of classical and atypical BSE cases described from Europe, Japan and the USA. The occurrence of atypical cases of BSE in countries such as Canada with low BSE prevalence and transmission risk argues for the occurrence of sporadic forms of BSE worldwide

The Use of Sexually Explicit Internet Material and Its Antecedents: A Longitudinal Comparison of Adolescents and Adults

An implicit assumption in research on adolescents’ use of sexually explicit internet material (SEIM) is that they may feel more attracted to such material than adults, given the “forbidden” character of SEIM for minors. However, systematic comparisons between adolescents’ and adults’ SEIM use and of its antecedents are missing. We conducted a two-wave panel survey among a nationally representative sample of 1,445 Dutch adolescents and a nationally representative sample of 833 Dutch adults. Adolescents’ and adults’ SEIM use was similar. When significant differences in the SEIM use occurred, they indicated that adults used SEIM more often than adolescents. Male adults were the most frequent users of SEIM. No difference in the antecedent structure of SEIM use emerged between adolescents and adults. In both groups, males, sensation seekers, as well as people with a not exclusively heterosexual orientation used SEIM more often. Among adolescents and adults, lower life satisfaction increased SEIM use. Our findings suggest that the frequency of SEIM use and its antecedents are largely the same among adolescents and adults