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.

Diagnosis of sexually transmitted infections in developing nations using syndromic management: Is it working?

Sexually transmitted infections (STIs) are a major public health problem, and controlling their spread is a priority. According to the World Health Organization (WHO), there are 340 million new cases of treatable STIs among 15–49 year olds that occur yearly around the world (1). Infection with STIs can lead to several complications such as pelvic inflammatory disorder (PID), cervical cancer, infertility, ectopic pregnancy, and even death (1). Additionally, STIs and associated complications are among the top disease types for which healthcare is sought in developing nations (1), and according to the UNAIDS report, there is a strong connection between STIs and the sexual spread of HIV infection (2). In fact, it is estimated that the presence of an untreated STI can increase the likelihood of contracting and spreading HIV by a factor up to 10 (2). In addition, developing countries are poorer in resources and lack inexpensive and precise diagnostic laboratory tests for STIs, thereby exacerbating the problem. Thus, the WHO recommends syndromic management of STIs for delivering care where lab testing is scarce or unattainable (1). This approach utilizes the use of an easy to use algorithm to help healthcare workers recognize symptoms/signs so as to provide treatment for the likely cause of the syndrome. Furthermore, according to the WHO, syndromic management offers instant and legitimate treatment compared to clinical diagnosis, and that it is also more cost-effective for some syndromes over the use of laboratory testing (1). In addition, even though it has been shown that the vaginal discharge syndrome has low specificity for gonorrhea and Chlamydia and can lead to over treatment (1), this is the recommended way to manage STIs in developing nations. Thus, the purpose of this paper is to specifically address the following questions: is syndromic management working to lower the STI burden in developing nations? How effective is it, and should it still be recommended? To answer these questions, a systematic literature review was conducted to evaluate the current effectiveness of syndromic management in developing nations. This review examined published articles over the past 5 years that compared syndromic management to laboratory testing and had published sensitivity, specificity, and positive predicative value data. Focusing mainly on vaginal discharge, urethral discharge, and genital ulcer algorithms, it was seen that though syndromic management is more effective in diagnosing and treating urethral and genial ulcer syndromes in men, there still remains an urgent need to revise the WHO recommendations for managing STIs in developing nations. Current studies have continued to show decreased specificity, sensitivity and positive predicative values for the vaginal discharge syndrome, and high rates of asymptomatic infections and healthcare workers neglecting to follow guidelines limit the usefulness of syndromic management. Furthermore, though advocate d as cost-effective by the WHO, there is a cost incurred from treating uninfected people. Instead of improving this system, it is recommended that better and less expensive point of care and the development of rapid test diagnosis kits be the focus and method of diagnosis and treatment in developing nations for STI management. ^

Syndromic surveillance at a long term shelter for persons displaced by hurricanes Katrina and Rita conducted by the San Antonio Metropolitan Health District

Background. Beginning September 2, 2005, San Antonio area shelters received approximately 12,700 evacuees from Hurricane Katrina. Two weeks later, another 12,000 evacuees from Hurricane Rita arrived. By mid-October, 2005, the in-shelter population was 1,000 people. There was concern regarding the potential for spread of infectious diseases in the shelter. San Antonio Metropolitan Health District (SAMHD) established a syndromic surveillance system with Comprehensive Health Services (CHS) who provided on-site health care. CHS was in daily contact with SAMHD to report symptoms of concern until the shelter closed December 23, 2005. ^ Study type. The objective of this study was to assess the methods used and describe the practical considerations involved in establishing and managing a syndromic surveillance system, as established by the SAMHD in the long-term shelter clinic maintained by CHS for the hurricane evacuees. ^ Methods. Information and descriptive data used in this study was collected from multiple sources, primarily from the San Antonio Metropolitan Health District’s 2006 Report on Syndromic Surveillance of a Long-Term Shelter by Hausler & Rohr-Allegrini. SAMHD and CHS staff ensured that each clinic visit was recorded by date, demographic information, chief complaint and medical disposition. Logs were obtained daily and subsequently entered into a Microsoft Access database and analyzed in Excel. ^ Results. During a nine week period, 4,913 clinic visits were recorded, reviewed and later analyzed. Repeat visits comprised 93.0% of encounters. Chronic illnesses contributed to 21.7% of the visits. Approximately 54.0% were acute care encounters. Of all encounters, 17.3% had infectious disease potential as primarily gastrointestinal and respiratory syndromes. Evacuees accounted for 86% and staff 14% of all visits to the shelter clinic. There were 782 unduplicated individuals who sought services at the clinic, comprised of 63% (496) evacuees and 36% (278) staff members. Staff were more likely to frequent the clinic but for fewer visits each. ^ Conclusion. The presence of health care services and syndromic surveillance provided the opportunity to recognize, document and intervene in any disease outbreak at this long-term shelter. Constant vigilance allowed SAMHD to inform and reassure concerned people living and working in the shelter and living outside the shelter.^

Analysis of Variation in Clubfoot Candidate Genes

Isolated clubfoot, a common birth defect occurring in more than 135,000 livebirths worldwide each year, is associated with significant health care and financial burdens. Clubfoot is defined by forefoot adduction, hindfoot varus, midfoot cavus and hindfoot equinus. Isolated clubfoot, which is the focus of these studies, is distinct from syndromic clubfoot because there are no other associated malformations. Population, family, twin and segregation analysis studies provide evidence that genetic and environmental factors play an etiologic role in isolated clubfoot. The studies described in this thesis were performed to define the role of genetic variation in isolated clubfoot. Interrogation of a deletion region associated with syndromic clubfoot, suggested that CASP8 and CASP10, two apoptotic genes, play a role in isolated clubfoot. To explore the role of apoptotic genes in clubfoot, SNPs spanning genes involved in the apoptotic pathway in the six chromosomal deletion regions, and limb patterning genes, HOXD and HOXA, were interrogated. SNPs in mitochondrial mediated apoptotic genes and several SNPs in HOXA and HOXD genes were modestly associated with clubfoot with the most significant SNP, rs3801776, located in the basal promoter of HOXA9. Several significant associations were found with SNPs in NFAT2 and TNIP2. Significant gene interactions were detected between SNPs in HOX and apoptotic genes. These findings suggest a model for clubfoot in which variation in one gene is not sufficient to cause the malformation but requires variation several genes to perturb protein expression sufficiently to alter muscle and foot development. These results significantly impact our knowledge base by delineating underlying mechanisms causing clubfoot.

Novel molecular insights into human tooth agenesis

The development of dentition is a fascinating process that involves a complex series of epithelial-mesenchymel signaling interactions. That such a precise process frequently goes awry is not surprising. Indeed, tooth agenesis is one of the most commonly inherited disorders in humans that affects up to twenty percent of the population and imposes significant functional, emotional and financial burdens on patients. Mutations in the paired box domain containing transcription factor PAX9 result in autosomal dominant tooth agenesis that primarily involves posterior dentition. Despite these advances, little is known about how PAX9 mediates key signaling actions in tooth development and how aberrations in PAX9 functions lead to tooth agenesis. As an initial step towards providing evidence for the pathogenic role of mutant PAX9 proteins, I performed a series of molecular genetic analyses aimed at resolving the structural and functional defects produced by a number of PAX9 mutations causing non-syndromic posterior tooth agenesis. It is likely that the pathogenic mechanism underlying tooth agenesis for the first two mutations studied (219InsG and IIe87Phe) is haploinsufficiency. For the six paired domain missense mutations studied, the lack of functional defects observed for three of the mutant proteins suggests that these mutations altered PAX9 function through alternate mechanisms. Next, I explored further the nature of the partnership between Pax9 and the Msx1 homeoprotein and their role in the expression of a downstream effector molecule, Bmp4. When viewed in the context of events occurring in dental mesenchyme, the results of these studies indicate that the Pax9-Msx1 protein interaction involves the localized up-regulation of Bmp4 activity that is mediated by synergistic interactions between the two transcription factors. Importantly, these assays corroborate in vivo data from mouse genetic studies and support reports of Pax9-dependent expression of Bmp4 in dental mesenchyme. Taken together, these results suggest that PAX9 mutations cause an early developmental defect due to an inability to maintain the inductive potential of dental mesenchyme through involvement in a pathway involving Msx1 and Bmp4. ^

Birth prevalence of isolated congenital limb reduction defects in Texas 1999--2001

Objective. Congenital limb defects are common birth defects occurring in approximately 2-7/10,000 live births. Because congenital limb defects are pervasive throughout all populations, and the conditions profoundly affect quality of life, they represent a significant public health concern. Currently there is a paucity of etiologic information in the literature regarding congenital limb reduction defects which represents a major limitation in developing treatment strategies as well as identifying high risk pregnancies. ^ Additionally, despite the fact that the majority of congenital limb reduction defects are isolated, most previous studies have not separated them from those occurring as part of a known syndrome or with multiple additional congenital anomalies of unknown etiology. It stands to reason that factors responsible for multiple congenital anomalies that happen to include congenital limb reduction defects may be quite different from those factors leading to an isolated congenital limb reduction defect. ^ As a first step toward gaining etiologic understanding, this cross-sectional study was undertaken to determine the birth prevalence and obtain demographic information about non-syndromic (isolated) congenital limb reduction defects that occurred in Texas from 1999-2001. ^ Methods. The study population included all infants/fetuses with isolated congenital limb reduction defects born in Texas during 1999-2001; the comparison population was all infants who were born to mothers who were residents of Texas during the same period of time. The overall birth prevalence of limb reduction defects was determined and adjusted for ethnicity, gender, site of defect (upper limb versus lower limb), county of residence, maternal age and maternal education. ^ Results. In Texas, the overall birth prevalence of isolated CLRDs was 2.1/10,000 live births (1.5 and 0.6/10,000 live births for upper limb and lower limb, respectively). ^ The risk of isolated lower limb CLRDs in Texas was significantly lower in females when gender was examined individually (crude prevalence odds ratio of 0.57, 95% CI of 0.36-0.91) as well as in relation to all other variables used in the analysis (adjusted prevalence odds ratio of 0.58, 95% CI of 0.36-0.93). ^ Harris County (which includes the Houston metropolitan area) had significantly lower risks of all (upper limb and lower limb combined) isolated CLRDs when examined in relation to other counties in Texas, with a crude prevalence odds ratio of 0.4 (95% CI: 0.29-0.72) and an adjusted prevalence odds ratio of 0.50 (95% CI: 0.31-0.80). The risk of isolated upper limb CLRDs was significantly lower in Harris County (crude prevalence odds ratio of 0.45, CI of 0.26-0.76 and adjusted prevalence odds ratio of 0.49, CI of 0.28-0.84). This trend toward decreased risk in Harris County was not observed for isolated lower limb reduction defects (adjusted prevalence odds ratio of 0.50, 95% confidence interval: 0.22-1.12). ^ Conclusions. The birth prevalence of isolated congenital limb reduction defects in Texas is in the lower limits of the range of rates that have been reported by other authors for other states (Alabama, Arkansas, California, Georgia, Hawaii, Iowa, Maryland, Massachusetts, North Carolina, Oklahoma, Utah, Washington) and other countries (Argentina, Australia, Austria, Bolivia, Brazil, Canada, Chile, China, Colombia, Costa Rica, Croatia, Denmark, Ecuador, England, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Lithuania, Mexico, Norway, Paraguay, Peru, Spain, Scotland, Sweden, Switzerland, Uruguay, and Venezuela). In Texas, the birth prevalence of isolated congenital lower limb reduction defects was greater for males than females, while the birth prevalence of isolated congenital upper limb reduction defects was not significantly different between males and females. The reduced rates of limb reduction defects in Harris County warrant further investigation. This study has provided an important first step toward gaining etiologic understanding in the study of isolated congenital limb reduction defects. ^

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.^

Maternal exposure to hazardous air pollutants and oral clefts among offspring: Texas, 1999-2008

Birth defects are a leading cause of infant mortality in the United States. About one in 33 births in the United States is diagnosed with birth defects. Common birth defects include neural tube defects, Down syndrome and oral clefts. The present study focused on oral clefts. ^ Oral clefts refer to the malformation of lip, mouth or both. Birth prevalence of oral clefts in Texas is about 11 per 10,000 births. Etiologically, oral clefts have been classified into two groups, cleft lip with or without cleft palate (CL±P) and isolated cleft palate (CP). In spite of their high prevalence and clinical significance, the etiology of oral clefts in humans has not been well understood. Though a number of risk factors have been identified in epidemiological studies, most of them do not explain the majority of the cases. The need to identify novel risk factors associated with oral clefts provided the motivation for this study. The present study focused on maternal exposure to several hazardous air pollutants. A common subgroup of hazardous air pollutants is the volatile organic compounds found in petroleum derivatives. Four important hydrocarbons in this group are benzene, toluene, ethyl benzene and xylenes (BTEX). ^ The specific aim of this study was to evaluate the association between maternal exposure to environmental levels of BTEX and oral clefts among offspring in Texas for the period 1999-2008. ^ A case-control study design was used to assess if maternal exposure to BTEX increased the risk of oral clefts. The Texas Birth Defects Registry provided data on cases of non-syndromic oral clefts delivered in Texas during the period 1999-2008. Census tract level maternal exposure to BTEX concentrations were obtained from the Hazardous Air Pollutant Exposure Model (HAPEM) developed by the U.S. Environmental Protection Agency. Unconditional logistic regression was used to assess the relationship between maternal exposure to BTEX levels and risk of oral clefts in offspring. ^ In the selected population, mothers who had high estimated exposure to any of the BTEX compounds were not more likely to deliver an offspring with oral clefts. Future research efforts will focus on additional birth defects and thorough assessment of additional potential confounders.^