Struggling to a monumental triumph : Re-assessing the final stages of the smallpox eradication program in India, 1960-1980

The global smallpox program is generally presented as the brainchild of a handful of actors from the WHO headquarters in Geneva and at the agency's regional offices. This article attempts to present a more complex description of the drive to eradicate smallpox. Based on the example of India, a major focus of the campaign, it is argued that historians and public health officials should recognize the varying roles played by a much wider range of participants. Highlighting the significance of both Indian and international field officials, the author shows how bureaucrats and politicians at different levels of administration and society managed to strengthen—yet sometimes weaken—important program components. Centrally dictated strategies developed at WHO offices in Geneva and New Delhi, often in association with Indian federal authorities, were reinterpreted by many actors and sometimes changed beyond recognition

Multifaceted contributions : health workers and smallpox eradication in India

Smallpox eradication in South Asia was a result of the efforts of many grades of health-workers. Working from within the confines of international organisations and government structures, the role of the field officials, who were of various nationalities and also drawn from the cities and rural enclaves of the countries in these regions, was crucial to the development and deployment of policies. However, the role of these personnel is often downplayed in official histories and academic histories, which highlight instead the roles played by a handful of senior officials within the World Health Organization and the federal governments in the sub-continent. This article attempts to provide a more rounded assessment of the complex situation in the field. In this regard, an effort is made to underline the great usefulness of the operational flexibility displayed by field officers, wherein lessons learnt in the field were made an integral part of deploying local campaigns; careful engagement with the communities being targeted, as well as the employment of short term workers from amongst them, was an important feature of this work

Prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma in Bhaktapur district of Nepal: The Bhaktapur Glaucoma Study

<p>Abstract</p> <p>Background</p> <p>Cataract and glaucoma are the major causes of blindness in Nepal. Bhaktapur is one of the three districts of Kathmandu valley which represents a metropolitan city with a predominantly agrarian rural periphery. This study was undertaken to determine the prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma among subjects residing in this district of Nepal.</p> <p>Methods</p> <p>Subjects aged 40 years and above was selected using a cluster sampling methodology and a door to door enumeration was conducted for a population based cross sectional study. During the community field work, 11499 subjects underwent a structured interview regarding awareness (heard of) and knowledge (understanding of the disease) of cataract and glaucoma. At the base hospital 4003 out of 4800 (83.39%) subjects underwent a detailed ocular examination including log MAR visual acuity, refraction, applanation tonometry, cataract grading (LOCSΙΙ), retinal examination and SITA standard perimetry when indicated.</p> <p>Results</p> <p>The age-sex adjusted prevalence of blindness (best corrected <3/60) and low vision (best corrected <6/18 ≥3/60) was 0.43% (95%C.I. 0.25 - 0.68) and 3.97% (95% C.I. 3.40 - 4.60) respectively. Cataract (53.3%) was the principal cause of blindness. The leading causes of low vision were cataract (60.8%) followed by refractive error (12%). The cataract surgical coverage was 90.36% and was higher in the younger age group, females and illiterate subjects. Pseudophakia was seen in 94%. Awareness of cataract (6.7%) and glaucoma (2.4%) was very low. Among subjects who were aware, 70.4% had knowledge of cataract and 45.5% of glaucoma. Cataract was commonly known to be a 'pearl like dot' white opacity in the eye while glaucoma was known to cause blindness. Awareness remained unchanged in different age groups for cataract while for glaucoma there was an increase in awareness with age. Women were significantly less aware (odds ratio (OR): 0.63; 95%, confidence interval (CI): 0.54 - 0.74) for cataract and (OR: 0.64; 95% CI: 0.50 - 0.81) for glaucoma. Literacy was also correlated with awareness.</p> <p>Conclusion</p> <p>The low prevalence of visual impairment and the high cataract surgical coverage suggests that cataract intervention programs have been successful in Bhaktapur. Awareness and knowledge of cataract and glaucoma was very poor among this population. Eye care programs needs to be directed towards preventing visual impairment from refractive errors, screening for incurable chronic eye diseases and promoting health education in order to raise awareness on cataract and glaucoma among this population.</p

A GWAS Study on Liver Function Test Using eMERGE Network Participants

Introduction: Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations. Methods: The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC). Results: Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10−8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10-15). Conclusions: Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations

The Transmembrane Domain of CEACAM1-4S Is a Determinant of Anchorage Independent Growth and Tumorigenicity

CEACAM1 is a multifunctional Ig-like cell adhesion molecule expressed by epithelial cells in many organs. CEACAM1-4L and CEACAM1-4S, two isoforms produced by differential splicing, are predominant in rat liver. Previous work has shown that downregulation of both isoforms occurs in rat hepatocellular carcinomas. Here, we have isolated an anchorage dependent clone, designated 253T-NT that does not express detectable levels of CEACAM1. Stable transfection of 253-NT cells with a wild type CEACAM1-4S expression vector induced an anchorage independent growth in vitro and a tumorigenic phenotype in vivo. These phenotypes were used as quantifiable end points to examine the functionality of the CEACAM1-4S transmembrane domain. Examination of the CEACAM1 transmembrane domain showed N-terminal GXXXG dimerization sequences and C-terminal tyrosine residues shown in related studies to stabilize transmembrane domain helix-helix interactions. To examine the effects of transmembrane domain mutations, 253-NT cells were transfected with transmembrane domain mutants carrying glycine to leucine or tyrosine to valine substitutions. Results showed that mutation of transmembrane tyrosine residues greatly enhanced growth in vitro and in vivo. Mutation of transmembrane dimerization motifs, in contrast, significantly reduced anchorage independent growth and tumorigenicity. 253-NT cells expressing CEACAM1-4S with both glycine to leucine and tyrosine to valine mutations displayed the growth-enhanced phenotype of tyrosine mutants. The dramatic effect of transmembrane domain mutations constitutes strong evidence that the transmembrane domain is an important determinant of CEACAM1-4S functionality and most likely by other proteins with transmembrane domains containing dimerization sequences and/or C-terminal tyrosine residues

Regulation of RKIP Function by Helicobacter pylori in Gastric Cancer

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that infects more than half of the world’s population and is a major cause of gastric adenocarcinoma. The mechanisms that link H. pylori infection to gastric carcinogenesis are not well understood. In the present study, we report that the Raf-kinase inhibitor protein (RKIP) has a role in the induction of apoptosis by H. pylori in gastric epithelial cells. Western blot and luciferase transcription reporter assays demonstrate that the pathogenicity island of H. pylori rapidly phosphorylates RKIP, which then localizes to the nucleus where it activates its own transcription and induces apoptosis. Forced overexpression of RKIP enhances apoptosis in H. pylori-infected cells, whereas RKIP RNA inhibition suppresses the induction of apoptosis by H. pylori infection. While inducing the phosphorylation of RKIP, H. pylori simultaneously targets non-phosphorylated RKIP for proteasome-mediated degradation. The increase in RKIP transcription and phosphorylation is abrogated by mutating RKIP serine 153 to valine, demonstrating that regulation of RKIP activity by H. pylori is dependent upon RKIP’s S153 residue. In addition, H. pylori infection increases the expression of Snail, a transcriptional repressor of RKIP. Our results suggest that H. pylori utilizes a tumor suppressor protein, RKIP, to promote apoptosis in gastric cancer cells

DNA Copy Number Variants of Known Glaucoma Genes in Relation to Primary Open-Angle Glaucoma

We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG)

Altered Ultrasonic Vocalization and Impaired Learning and Memory in Angelman Syndrome Mouse Model with a Large Maternal Deletion from Ube3a to Gabrb3

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11–q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11–q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m−/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m−/p+), but not paternal (m+/p−), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H