Brain fiber tract plasticity in experimental spinal cord injury: diffusion tensor imaging.

Diffusion tensor imaging (DTI) and immunohistochemistry were performed in spinal cord injured rats to understand the basis for activation of multiple regions in the brain observed in functional magnetic resonance imaging (fMRI) studies. The measured fractional anisotropy (FA), a scalar measure of diffusion anisotropy, along the region encompassing corticospinal tracts (CST) indicates significant differences between control and injured groups in the 3 to 4 mm area posterior to bregma that correspond to internal capsule and cerebral peduncle. Additionally, DTI-based tractography in injured animals showed increased number of fibers that extend towards the cortex terminating in the regions that were activated in fMRI. Both the internal capsule and cerebral peduncle demonstrated an increase in GFAP-immunoreactivity compared to control animals. GAP-43 expression also indicates plasticity in the internal capsule. These studies suggest that the previously observed multiple regions of activation in spinal cord injury are, at least in part, due to the formation of new fibers.

Mutation and association analysis of the PVR and PVRL2 genes in patients with non-syndromic cleft lip and palate.

Orofacial clefts (OFC; MIM 119530) are among the most common major birth defects. Here, we carried out mutation screening of the PVR and PVRL2 genes, which are both located at an OFC linkage region at 19q13 (OFC3) and are closely related to PVRL1, which has been associated with both syndromic and non-syndromic cleft lip and palate (nsCLP). We screened a total of 73 nsCLP patients and 105 non-cleft controls from the USA for variants in PVR and PVRL2, including all exons and encompassing all isoforms. We identified four variants in PVR and five in PVRL2. One non-synonymous PVR variant, A67T, was more frequent among nsCLP patients than among normal controls, but this difference did not achieve statistical significance.

Identification of a novel tumor suppressor gene on human chromosome 3p14-p12 involved in renal cell carcinoma

Nonpapillary renal cell carcinoma (RCC) is an adult cancer of the kidney which occurs both in familial and sporadic forms. The familial form of RCC is associated with translocations involving chromosome 3 with a breakpoint at 3p14-p13. Studies focused on sporadic RCC have shown two commonly deleted regions at 3p14.3-p13 and 3p21.3. In addition, a more distal region mapping to 3p26-p25 has been linked to the Von Hippel Lindau (VHL) disease gene. A large proportion of VHL patients develop RCC. The short arm of human chromosome 3 can, therefore, be dissected into three distinct regions which could encode tumor suppressor genes for RCC. Loss or inactivation of one or more of these loci may be an important step in the genesis of RCC.^ I have used the technique of microcell-mediated chromosome transfer to introduce an intact, normal human chromosome 3 and defined fragments of 3p, dominantly marked with pSV2neo, into the highly malignant RCC cell line SN12C.19. The introduction of chromosome 3 and of a centric fragment of 3p, encompassing 3p14-q11, into SN12C.19 resulted in dramatic suppression of tumor growth in nude mice. Another defined deletion hybrid contained the region 3p12-q24 of the introduced human chromosome and failed to suppress tumorigenicity. These data define the region 3p14-p12, the most proximal region of high frequency allele loss in sporadic RCC as well as the region containing the translocation breakpoint in familial RCC, to contain a novel tumor suppressor locus involved in RCC. We have designated this locus nonpapillary renal cell carcinoma-1 (NRC-1). Furthermore, we have functional evidence that NRC-1 controls the growth of RCC cells by inducing rapid cell death in vivo. ^

The door of the tomb is open: Participatory action research to assess the impact of strengthened community capacity on maternal health care in rural Mali

This participatory action-research project addressed the hypothesis that strengthened community and women's capacity for self-development will lead to action to address maternal health problems and the prevention of maternal morbidity and mortality in Mali. Research objectives were: (1) to undertake a comparative cross-sectional study of the association of community capacity with improved maternal health in rural areas of Sanando, Mali, where capacity building interventions have taken place in some villages but not in others. (2) to describe women's maternal health status, access to and use of maternal health services given their residence in program or comparison communities.^ The participatory action research project was an integrated qualitative and quantitative study using participatory rural appraisal exercises, semi-structured group interviews and a cross-sectional survey.^ Factors related to community capacity for self-development were identified: community harmony; an understanding of the benefits of self-development; dynamic leadership; and a structure to implement collective activities.^ A distinct difference between the program and comparison villages was the commitment to train and support traditional birth attendants (TBAs). The TBAs in the program villages work in the context of the wider, integrated self-development program and, 10 years after their initial training, the TBAs continue to practice.^ Many women experience labor and childbirth alone or are attended by an untrained relative in both program and comparison villages. Nevertheless a significant change is apparent, with more women in program villages than in comparison villages being assisted by the TBAs. The delivery practices of the TBAs reveal the positive impact of their training in the "three cleans" (clean hands of the assistant, clean delivery surface and clean cord-cutting). The findings of this study indicate a significant level of unmet need for child spacing methods in all villages.^ The training and support of TBAs in the program villages yielded significant improvements in their delivery practices, and resulting outcomes for women and infants. However, potential exists for further community action. Capacities for self-development have not yet been directed toward an action plan encompassing other Safe Motherhood interventions, including access to family planning services and emergency obstetric care services. ^

Studies of the structure and function of a fibrinogen binding MSCRAMM(RTM) from Staphylococcus epidermidis

Coagulase-negative staphylococci (CNS) are recognized as important pathogens and are particularly associated with foreign body infections. S. epidermidis accounts for approximately 75% of the infections caused by CNS. Three genes, sdrF, sdrG, and sdrH, were identified by screening a S. epidermidis genomic library with a probe encompassing the serine-aspartate dipeptide repeat-encoding region (region R) of clfA from S. aureus. SdrG has significant amino acid identity to ClfA, ClfB and other surface proteins of S. aureus. SdrG is also similar to a protein (Fbe) recently described by Nilsson, et al. (Infection and Immunity, 1998, 66:2666–73) from S. epidermidis. The N-terminal domain (A region) of SdrG was expressed as a his-tag fusion protein in E. coli. In an ELISA, this protein, rSdrG(50-597) was shown to bind specifically to fibrinogen (Fg). Western ligand blot analysis showed that SdrG binds the Bβ chain of Fg. To further characterize the rSdrG(50-597)-Fg interaction, truncates of the Fg Bβ chain were made and expressed as recombinant proteins in E. coli. SdrG was shown to bind the full-length Bβ chain (1462), as well as the N-terminal three-quarters (1-341), the N-terminal one-half (1-220) and the N-terminal one-quarter (1-95) Bβ chain constructs. rSdrG(50-597) failed to bind to the recombinant truncates that lacked the N-terminal 25 amino acid residues of this polypeptide suggesting that SdrG recognizes a site within this region of the Bβ chain. Inhibition ELISAs have shown that peptide mimetics, including β1–25, and β6–20, encompassing this 25 residue region can inhibit binding of rSdrG(50-597) to Fg coated wells. Using fluorescence polarization we were able to determine an equilibrium constant (KD) for the interaction of rSdrG(50-597) with the Fg Bβ chain peptide β1–25. The labeled peptide was shown to bind to rSdrG(50-597) with a KD of 0.14 ± 0.01μM. Because rSdrG(50-597) recognizes a site in the Fg Bβ chain close to the thrombin cleavage site, we investigated the possibility of the rSdrG(50-597) site either overlapping or lying close to this cleavage site. An ELISA showed that rSdrG(50-597) binding to thrombin-treated Fg was significantly reduced. In a clot inhibition assay rSdrG(50-597) was able to inhibit fibrin clot formation in a concentration dependent manner. Furthermore, rSdrG(50-597) was able to inhibit clot formation by preventing the release of fibrinopeptide B as determined by HPLC. To further define the interaction between rSdrG(50-597) and peptide β6–20, we utilized an alanine amino acid replacement strategy. The residues in β6–20 that appear to be important in rSdrG(50-597) binding to Fg, were confirmed by the rSdrG(273-597)-β6–20 co-crystal structure that was recently solved by our collaborators at University of Alabama-Birmingham. Additionally, rSdrG(50-597) was not able to bind to Fg from different animal species, rather it bound specifically to human Fg in an ELISA. This suggests that the sequence variation between Fg Bβ chains of different species, specifically with in the N-terminal 25 residues, affects the ability of rSdrG(50-597) binding to Fg, and this may explain why S. epidermidis is primarily a human pathogen. ^

The emergence of the social determinants of health on the policy agenda in Britain: A case study, 1980--2003

Numerous theories have been advanced in the effort to explain how a given policy issue manages to take root in the public sphere and subsequently move forward on the public legislative agenda—or not. This study examined how the social determinants of health (SDOH) came to be part of the legislative policy agenda in Britain from 1980 to 2003. ^ The specific objectives of the research were: (1) to conduct a sociopolitical analysis grounded in alternative agenda-setting theories to identify the factors responsible for moving the social determinants health perspective onto the British policy agenda; and (2) to determine which of the theories and related dimensions best accounted for the emergence of this perspective. ^ A triangulated content and context analysis of British news articles, historical accounts, and research commentaries of the SDOH movement was conducted guided by relevant agenda-setting theories set within a social movement framework to chronicle the emergence of the SDOH as a significant policy issue in Britain. ^ The most influential social movement and agenda setting elements in the emergence of the SDOH in Britain were issue generation tactics, framing efforts, mobilizing structures, and political opportunities grounded in social movement and agenda setting theories. Policy content or the details of the policy had comparatively little impact on the successful emergence of the SDOH. Despite resistance by the government, from 1980 to 1996 interest groups created a political understanding of the SDOH utilizing a framing package encompassing notions of inequality, fairness, and justice. This frame transmitted a powerful idea connected to a core set of British values and beliefs. After 1996, a shift in political opportunities cemented the institutional arrangements needed to sustain an environment conducive to the development and implementation of SDOH policies and programs. ^ This research demonstrates that the U.S. emergence of the SDOH on the policy agenda will depend upon: (1) U.S. ideals and values regarding poverty, inequality, race, health, and health care that will determine issue framing; (2) political opportunities that will emerge—or not—to advance the SDOH policy agenda; and (3) the mobilizing structures that support or oppose the issue. ^

Characterization of glucocorticoid receptor (NR3C1) gene polymorphisms and a family-based association study with hypertension

Hypertension is usually defined as having values of systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg. Hypertension is one of the main adverse effects of glucocorticoid on the cardiovascular system. Glucocorticoids are essential hormones, secreted from adrenal glands in circadian fashion. Glucocorticoid's effect on blood pressure is conveyed by the glucocorticoid receptor (NR3C1), an omnipresent nuclear transcription factor. Although polymorphisms in this gene have long been implicated to be a causal factor for cardiovascular diseases such as hypertension, no study has yet thoroughly interrogated the gene's polymorphisms for their effect on blood pressure levels. Therefore, I have first resequenced ∼30 kb of the gene, encompassing all exons, promoter regions, 5'/3' UTRs as well as at least 1.5 kb of the gene's flanking regions from 114 chromosome 5 monosomic cell lines, comprised of three major American ethnic groups—European American, African American and Mexican American. I observed 115 polymorphisms and 14 common molecularly phased haplotypes. A subset of markers was chosen for genotyping study populations of GENOA (Genetic Epidemiology Network of Atherosclerosis; 1022 non-Hispanic whites, 1228 African Americans and 954 Mexican Americans). Since these study populations include sibships, the family-based association test was performed on 4 blood pressure-related quantitative variables—pulse, systolic blood pressure, diastolic blood pressure and mean arterial pressure. Using these analyses, multiple correlated SNPs are significantly protective against high systolic blood pressure in non-Hispanic whites, which includes rsb198, a SNP formerly associated with beneficial body compositions. Haplotype association analysis also supports this finding and all p-values remained significant after permutation tests. I therefore conclude that multiple correlated SNPs on the gene may confer protection against high blood pressure in non-Hispanic whites. ^

Evaluation of web-based resources for pregnant and parenting teens

Current teen pregnancy and repeat pregnancy rates reveal that there is a pressing need for comprehensive care for pregnant and parenting teens to address their unique needs. The Internet has become a source of various types of information and as a result, several efforts have begun to assess the quality of health information provided on websites. The objective of this study was to assess the functionality and quality of websites containing health information and resources for pregnant and parenting teens. The three most widely used search engines currently: Google, MSN, and Yahoo were searched using three general search terms “teen pregnancy”, “pregnant teen”, and “teen parent”. The first 5 pages of each search were reviewed and categorized to yield 12 websites which met inclusion criteria for content evaluation. The 12 websites were rated using a pre-existing instrument encompassing two domains: functionality and content analysis. Within the functionality domain, this sample highlighted the need to improve accessibility and credibility for the target population. The content analysis revealed that among the topics which are recommended for pregnant and parenting teens, the topics most commonly covered were mental health and primary and preventive health care. The majority of websites neglected sexual health topics including STI’s and family planning. This study provides the first glimpse into health information and resources for pregnant and parenting teens on the Internet. Researchers, health care providers, social workers, health educators, and website sponsors can use these results to maintain and recommend websites which offer easily accessible, accurate, and practical information for pregnant and parenting teens.^

A comparative review of water disinfection methods appropriate for developing countries and their efficacy, cost-efficiency, and usability

Developing countries are heavily burdened by limited access to safe drinking water and subsequent water-related diseases. Numerous water treatment interventions combat this public health crisis, encompassing both traditional and less-common methods. Of these, water disinfection serves as an important means to provide safe drinking water. Existing literature discusses a wide range of traditional treatment options and encourages the use of multi-barrier approaches including coagulation-flocculation, filtration, and disinfection. Most sources do not delve into approaches specifically appropriate for developing countries, nor do they exclusively examine water disinfection methods.^ The objective of this review is to focus on an extensive range of chemical, physio-chemical, and physical water disinfection techniques to provide a compilation, description and evaluation of options available. Such an objective provides further understanding and knowledge to better inform water treatment interventions and explores alternate means of water disinfection appropriate for developing countries. Appropriateness for developing countries corresponds to the effectiveness of an available, easy to use disinfection technique at providing safe drinking water at a low cost.^ Among chemical disinfectants, SWS sodium hypochlorite solution is preferred over sodium hypochlorite bleach due to consistent concentrations. Tablet forms are highly recommended chemical disinfectants because they are effective and very easy to use, but also because they are stable. Examples include sodium dichloroisocyanurate, calcium hypochlorite, and chlorine dioxide, which vary in cost depending on location and availability. Among physio-chemical disinfection options, electrolysis which produces mixed oxidants (MIOX) provides a highly effective disinfection option with a higher upfront cost but very low cost over the long term. Among physical disinfection options, solar disinfection (SODIS) applications are effective, but they treat only a fixed volume of water at a time. They come with higher initial costs but very low on-going costs. Additional effective disinfection techniques may be suitable depending on the location, availability and cost.^

An evaluation of Employee Assistance Programs: An overview and case study

Methodologies for the analysis and cross-evaluations of Employee Assistance Programs (EAPs) are necessary to indicate program weaknesses and strengths for both present and future EAP services.^ As EAPs have matured from simplistic industrial alcoholism programs to all problem-encompassing, complex programs, an aggressive group of entrepreneurs has developed. Business and industrial managements need established criteria to select the most suitable professional services for their needs, as well as the best investment value for cost containments.^ Four major EAPs were compared to determine critical areas necessary for cross evaluation. Future standardization of terminology and definitions of services will facilitate both the evaluation of a specific program and its comparison to problems or successes of other EAPs.^ Past evaluation difficulties have been caused by the lack of EAP program accreditations and professional personnel licensure requirements. The Association of Labor Management Administrators and Consultants on Alcoholism (ALMACA) has recently set certification criteria for personnel, which will enhance the professional standards for EAPs. ^

Future pandemic influenza control (FPIC) related strategic management plan based on the 2009 H1N1 pandemic influenza review of health policy decisions, their practice and implications

This cross-sectional study is based on the qualitative and quantitative research design to review health policy decisions, their practice and implications during 2009 H1N1 influenza pandemic in the United States and globally. The “Future Pandemic Influenza Control (FPIC) related Strategic Management Plan” was developed based on the incorporation of the “National Strategy for Pandemic Influenza (2005)” for the United States from the U.S. Homeland Security Council and “The Canadian Pandemic Influenza Plan for the Health Sector (2006)” from the Canadian Pandemic Influenza Committee for use by the public health agencies in the United States as well as globally. The “global influenza experts’ survey” was primarily designed and administered via email through the “Survey Monkey” system to the 2009 H1N1 influenza pandemic experts as the study respondents. The effectiveness of this plan was confirmed and the approach of the study questionnaire was validated to be convenient and the excellent quality of the questions provided an efficient opportunity to the study respondents to evaluate the effectiveness of predefined strategies/interventions for future pandemic influenza control.^ The quantitative analysis of the responses to the Likert-scale based questions in the survey about predefined strategies/interventions, addressing five strategic issues to control future pandemic influenza. The effectiveness of strategies defined as pertinent interventions in this plan was evaluated by targeting five strategic issues regarding pandemic influenza control. For the first strategic issue pertaining influenza prevention and pre pandemic planning; the confirmed effectiveness (agreement) for strategy (1a) 87.5%, strategy (1b) 91.7% and strategy (1c) 83.3%. The assessment of the priority level for strategies to address the strategic issue no. (1); (1b (High Priority) > 1a (Medium Priority) > 1c (Low Priority) based on the available resources of the developing and developed countries. For the second Strategic Issue encompassing the preparedness and communication regarding pandemic influenza control; the confirmed effectiveness (agreement) for the strategy (2a) 95.6%, strategy (2b) 82.6%, strategy (2c) 91.3% and Strategy (2d) 87.0%. The assessment of the priority level for these strategies to address the strategic issue no. (2); (2a (highest priority) > 2c (high priority) >2d (medium priority) > 2b (low priority). For the third strategic issue encompassing the surveillance and detection of pandemic influenza; the confirmed effectiveness (agreement) for the strategy (3a) 90.9% and strategy (3b) 77.3%. The assessment of the priority level for theses strategies to address the strategic Issue No. (3) (3a (high priority) > 3b (medium/low priority). For the fourth strategic issue pertaining the response and containment of pandemic influenza; the confirmed effectiveness (agreement) for the strategy (4a) 63.6%, strategy (4b) 81.8%, strategy (4c) 86.3%, and strategy (4d) 86.4%. The assessment of the priority level for these strategies to address the strategic issue no. (4); (4d (highest priority) > 4c (high priority) > 4b (medium priority) > 4a (low priority). The fifth strategic issue about recovery from influenza and post pandemic planning; the confirmed effectiveness (agreement) for the strategy (5a) 68.2%, strategy (5b) 36.3% and strategy (5c) 40.9%. The assessment of the priority level for strategies to address the strategic issue no. (5); (5a (high priority) > 5c (medium priority) > 5b (low priority).^ The qualitative analysis of responses to the open-ended questions in the study questionnaire was performed by means of thematic content analysis. The following recurrent or common “themes” were determined for the future implementation of various predefined strategies to address five strategic issues from the “FPIC related Strategic Management Plan” to control future influenza pandemics. (1) Pre Pandemic Influenza Prevention, (2) Seasonal Influenza Control, (3) Cost Effectiveness of Non Pharmaceutical Interventions (NPI), (4) Raising Global Public Awareness, (5) Global Influenza Vaccination Campaigns, (6)Priority for High Risk Population, (7) Prompt Accessibility and Distribution of Influenza Vaccines and Antiviral Drugs, (8) The Vital Role of Private Sector, (9) School Based Influenza Containment, (10) Efficient Global Risk Communication, (11) Global Research Collaboration, (12) The Critical Role of Global Public Health Organizations, (13) Global Syndromic Surveillance and Surge Capacity and (14) Post Pandemic Recovery and Lessons Learned. The future implementation of these strategies with confirmed effectiveness to primarily “reduce the overall response time’ in the process of ‘early detection’, ‘strategies (interventions) formulation’ and their ‘implementation’ to eventually ensure the following health outcomes: (a) reduced influenza transmission, (b) prompt and effective influenza treatment and control, (c) reduced influenza related morbidity and mortality.^

Genetic underpinnings of variation in brain ventricular volume: A genome-wide association study

The ventricular system is a critical component of the central nervous system (CNS) that is formed early in the developmental stages and remains functional through the lifetime. Changes in the ventricular system can be easily discerned via neuroimaging procedures and most of the time it reflects changes in the physiology of the CNS. In this study we attempted to identify specific genes associated with variation in ventricular volume in humans. Methods. We conducted a genome wide association (GWA) analysis of the volume of the lateral ventricles among 1605 individuals of European ancestry from two community based cohorts, the Genetics of Microangiopathic Brain Injury (GMBI; N=814) and Atherosclerosis Risk in Communities (ARIC; N=791). Significant findings from the analysis were tested for replication in both the cohorts and then meta-analyzed to get an estimate of overall significance. Results. In our GWA analyses, no single nucleotide polymorphism (SNP) reached a genome-wide significance of p<10−8. There were 25 SNPs in GMBI and 9 SNPs in ARIC that reached a threshold of p<10 −5. However, none of the top SNPs from each cohort were replicated in the other. In the meta-analysis, no SNP reached the genome-wide threshold of 5×10−8, but we identified five novel SNPs associated with variation in ventricular volume at the p<10 −5 level. Strongest association was for rs2112536 in an intergenic region on chromosome 5q33 (Pmeta= 8.46×10−7 ). The remaining four SNPs were located on chromosome 3q23 encompassing the gene for Calsyntenin-2 (CLSTN2). The SNPs with strongest association in this region were rs17338555 (Pmeta= 5.28×10 −6), rs9812091 (Pmeta= 5.89×10−6 ), rs9812283 (Pmeta= 5.97×10−6) and rs9833213 (Pmeta= 6.96×10−6). Conclusions. This GWA study of ventricular volumes in the community-based cohorts of European descent identifies potential locus on chromosomes 3 and 5. Further characterization of these loci may provide insights into pathophysiology of ventricular involvement in various neurological diseases.^

Cloning and characterization of the full length cDNA and promoter of mouse tissue transglutaminase

Transglutaminases are a family of enzymes that catalyze the covalent cross-linking of proteins through the formation of $\varepsilon$-($\gamma$-glutaminyl)-lysyl isopeptide bonds. Tissue transglutaminase (Tgase) is an intracellular enzyme which is expressed in terminally differentiated and senescent cells and also in cells undergoing apoptotic cell death. To characterize this enzyme and examine its relationship with other members of the transglutaminase family, cDNAs, the first two exons of the gene and 2 kb of the 5$\sp\prime$ flanking region, including the promoter, were isolated. The full length Tgase transcript consists of 66 bp of 5$\sp\prime$-UTR (untranslated) sequence, an open reading frame which encodes 686 amino acids and 1400 bp of 3$\sp\prime$-UTR sequence. Alignment of the deduced Tgase protein sequence with that of other transglutaminases revealed regions of strong homology, particularly in the active site region.^ The Tgase cDNA was used to isolate and characterize a genomic clone encompassing the 5$\sp\prime$ end of the mouse Tgase gene. The transcription start site was defined using genomic and cDNA clones coupled with S1 protection analysis and anchored PCR. This clone includes 2.3 kb upstream of the transcription start site and two exons that contain the first 256 nucleotides of the mouse Tgase cDNA sequence. The exon intron boundaries have been mapped and compared with the exon intron boundaries of three members of the transglutaminase family: human factor XIIIa, the human keratinocyte transglutaminase and human erythrocyte band 4.1. Tissue Tgase exon II is similar to comparable exons of these genes. However, exon I bears no resemblance with any of the other transglutaminase amino terminus exons.^ Previous work in our laboratory has shown that the transcription of the Tgase gene is directly controlled by retinoic acid and retinoic acid receptors. To identify the region of the Tgase gene responsible for regulating its expression, fragments of the Tgase promoter and 5$\sp\prime$-flanking region were cloned into the chloramphenicol actetyl transferase (CAT) reporter constructs. Transient transfection experiments with these constructs demonstrated that the upstream region of Tgase is a functional promoter which contains a retinoid response element within a 1573 nucleotide region spanning nucleotides $-$252 to $-$1825. ^