Dysregulation of alternative splicing of coagulation factor V results in bleeding disorder, east Texas type and other disorders of hemostasis

The studies completed herein explore different phenotypes related to the genetic defects that predispose individuals to a disruption of normal hemostasis. In the first study, a novel autosomal dominant bleeding disorder, which is characterized by excessive bleeding with trauma or surgery and menorrhagia in affected women, was studied in a large family (16 affected individuals) from east Texas. Affected members had a prolongation of their PT and/or aPTT, but normal clinical coagulation studies. Previous linkage analysis by Kuang et. al. (2001) mapped the defective gene to 1g23-24 (LODmax 7.22), which contains the gene for coagulation factor V (FV). I identified an alteration (A2440G) in the FV gene in exon 13 that segregated with the disease and was not present in 62 controls. Interestingly, this alteration resulted in a 22-fold up-regulation of a novel alternative splicing variant in patients' RNA versus controls. This translated into a similar fold increase in a 250-kDa isoform of FV seen in patients' plasma versus controls. A recombinant of this splicing event exhibited an increased sensitivity to cleavage by activated protein C (APC) that was more striking in the presence of PS. In addition, this novel isoform had increased APC cofactor activity, thus increasing the degradation of FVIIIa. These data indicated that A2440G up-regulates an alternatively spliced transcript of FV, and increases a FV isoform that hinders coagulation as opposed to promoting it like its wild-type counterpart. ^ The second study reports the largest screening to date of African Americans in two independent cohorts for a rare prothrombin variant, C20209T, which is suspected to be associated with thrombotic disease. The Texas Medical Center Genetics Resource (TexGen) Stroke DNA repository revealed 1.67% (Fisher p=0.27) of African American stroke patients were heterozygous for the 20209*T allele. Screening of the Atherosclerosis Risk in Communities Study (ARIC) cohort (n=3470) for the 20209*T allele revealed a population prevalence of 0.58% in individuals of African American descent; however, all associations with thrombotic disease were negative. Analysis of these two independent cohorts revealed that, unlike its neighbor G20210A, the C20209T variant does not increase the risk of thrombotic events in the African American population. ^

Health, education and community: Assets and needs of a small urban community in north east Tamaulipas, Mexico: A community based participatory research assessment

This study explored the health, education, social assets, needs, attitudes, and behaviors of residents of Ferrocarril #4, a small urban community in Tamaulipas, Mexico. A collaborative Participatory Action Research approach was used to emphasize community involvement. Using Triangulation to ensure validity, qualitative methods included key informant in depth interviews, participant observation and participatory discussion groups with women and men. A personal interview with a probability sample of women was done. The median age of interviewees was 37 years. The majority was married or had a partner. Over half of respondents completed grades 6-9. Employed women (25%) earned a median weekly salary equivalent to ∼56 USD. Women with health insurance (67.7%) were covered mainly through Social Security and Seguro Popular. One in 5 reported bad health. Barriers to care were primarily money and transportation. To improve health care, women wanted a full service clinic in or close to the community and affordable health care. Socially, 28% of respondents had no close friends in the community and most did not participate in beneficial community activities. Many women did not socialize with others and help from neighbors was situational. Primary school teachers lacked parental support and it interfered with classroom efforts. Healthy community discussion groups focused on personal and environmental hygiene and safety. Valuable assets exist in the community. To date, collaborative efforts resulted in a school First Aid station, a school nurse visit weekly, posting of emergency contact phone numbers in the school and community center, and development of a student health information form. ^

Characterization of the East Houston particulate matter <2.5 atmosphere; a novel method for desorbing organic constituents from airborne particulates

I have developed a novel approach to test for toxic organic substances adsorbed onto ultra fine particulate particles present in the ambient air in Northeast Houston, Texas. These particles are predominantly carbon soot with an aerodynamic diameter (AD) of <2.5 μm. If present in the ambient air, many of the organic substances will be absorbed to the surface of the particles (which act just like a charcoal air filter), and may be adducted into the respiratory system. Once imbedded into the lungs these particles may release the adsorbed toxic organic substances with serious health consequences. I used a Airmetrics portable Minivol air sampler time drawing the ambient air through collection filters samples from 6 separate sites in Northeast Houston, an area known for high ambient PM 2.5 released from chemical plants and other sources (e.g. vehicle emissions).(1) In practice, the mass of the collected particles were much less than the mass of the filters. My technique was designed to release the adsorbed organic substances on the fine carbon particles by heating the filter samples that included the PM 2.5 particles prior to identification by gas chromatography/mass spectrometry (GCMS). The results showed negligible amounts of target chemicals from the collection filters. However, the filters alone released organic substances and GCMS could not distinguish between the organic substances released from the soot particles from those released from the heated filter fabric. However, an efficacy tests of my method using two wax burning candles that released soot revealed high levels of benzene. This suggests that my method has the potential to reveal the organic substances adsorbed onto the PM 2.5 for analysis. In order to achieve this goal, I must refine the particle collection process which would be independent of the filters; the filters upon heating also release organic substances obscuring the contribution from the soot particles. To obtain pure soot particles I will have to filter more air so that the soot particles can be shaken off the filters and then analyzed by my new technique. ^

Gender differences in tuberculosis notification in Pakistan

Worldwide the male:female ratio of new smear-positive TB cases is estimated to be roughly 2:1. However in Pakistan this is not the case. Rates of notified TB cases are 20–30% higher in young females compared with males and female rates remain high regardless of increasing age. This is in stark contrast to neighboring India which is characterized by a huge excess of male TB cases. It is currently unknown why rates of notified TB are so high in females in Pakistan, but it is clear this epidemiology is a public health issue of great importance that impacts transmission dynamics and disease control initiatives.^

Policy analysis of iron micronutrient programs at USAID: The FANTA program in East Africa and the micronutrient initiative in Bihar region of India, using comparative cost effective and cost benefit analysis

It is the aim of this paper to examine iron supplementation programs which receive funding from United States Agency for International Development (USAID) but approach combating iron deficiency anemia in two vastly different ways. A brief literature review and background information on iron deficiencies and the differences between supplementation programs and micronutrient fortification were reviewed. Two non-governmental organizations (NGO's) were examined for this paper: the Food and Nutrition Technical Assistance II (FANTA) and the MicroNutrient Initiative. The FANTA program included an educational component to their supplementation program while the MicroNutrient Initiative solely used supplementation of micronutrients to their population. Methods used were cost-benefit analysis and cost-effectiveness analysis to determine the overall effectiveness of each program in reducing iron deficiency anemia in each population, if the added costs of the incentives in the FANTA program changed the cost-effectiveness of the program compared to the MicroNutrient Initiative program and to determine which program imparted the greatest benefit to each population by reducing the disease burden in Disability Adjusted Life Years (DALY). Results showed that the unit cost of the FANTA program per person was higher than the MicroNutrient Initiative program due to the educational component. The FANTA program reduced iron deficiency anemia less overall but cost less for each percentage point of anemia decreased in their respective populations. The MicroNutrient Initiative program had a better benefit cost ratio for the populations it served. The MicroNutrient Initiative's large scale program imparted many advantages by reducing unit cost per person and decreasing iron deficiency anemia. The FANTA program was more effective at decreasing iron deficiency anemia with less money: $5,660 per 1% decrease in iron deficiency anemia versus $18,450 per 1% decrease in iron deficiency anemia for the MicroNutrient Initiative program. ^ In conclusion, economic analysis cannot measure all of the benefits associated with programs that contain an educational component or large scale supplementation. More information needs to be gathered by NGOs and reported to USAID, such as detailed prevalence rates of iron deficiency anemia among the populations served. Further research is needed to determine the effects an educational supplementation program has on compliance rates of participants and motivation to participate in supplementation programs whose aim is to decrease iron deficiency anemia in a targeted population.^

Evidence of hepatitis C transmission in healthcare settings in Karachi, Pakistan

Transmission of Hepatitis C (HCV) in Pakistan is a continuing public health problem. Several cultural and behavioral practices promote HCV transmission through the use of unsafe needles and blood products. This study aimed to determine the prominent risk factors associated with HCV transmission in the Indus Hospital catchment population. A case-control study design was implemented to enroll 300 laboratory confirmed HCV+ participants from consulting clinics at Indus Hospital and 300 laboratory confirmed HCV− participants from both the consulting clinics and the surrounding community. Odds ratios and their 95% were calculated for each risk factor to create a two gender specific multivariable models and a combined multivariable model. Participants who received 12 or more injections in the past year, ever received a blood transfusion, or ever had dental work performed were all independently significant more likely to be HCV+ when compared to those who received 1–4 injections in the past year, never received a blood transfusion, or never had dental work performed. Female participants who received 12 or more injections in the past year, had a blood transfusion while pregnant, or ever had dental work performed were all significantly more likely to be HCV+ while males who received 12 or more injections in the past year were also significantly more likely to be HCV+. Participants who brought their own needles to their injections or infusions along with those who were born in the Sindh province were significantly less likely to be HCV+ when compared to those who did not bring their own needles or born in the Punjab province. ^ Clearly transmission in healthcare settings are implicated for HCV transmission. A population level preventative approach must be taken to educate both the population and healthcare practitioners to prevent further transmission in the Pakistani healthcare system. Participants should also be followed and re-interviewed to ask where they received their various treatments as well as assess their knowledge and attitudes towards injections, infusions, and other unsafe medical procedures.^

Feminism, gender equity and sexual/reproductive health in the Middle East and North Africa (MENA) region

Sexual/reproductive/health and rights are crucial public health concerns that have been specifically integrated into the Millennium Development Goals to be accomplished by 2015. These issues are related to several health outcomes, including HIV/AIDS and gender-based violence (GBV) among women. The Middle East and North Africa (MENA) region comprises Algeria, Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunisia, United Arab Emirates (UAE), West Bank and Gaza (WBG), and Yemen. This region is primarily Arabic speaking (except for Israel and Iran), and primarily Muslim (except for Israel). Some traditional and cultural views and practices in this region engender gender inequalities, which manifest themselves in the economic, political and social spheres. HIV and gender-based violence in the region may be interlinked with gender inequalities which breed justification for partner violence and honour killings, and increase the chance that HIV will transform into an epidemic in the region if not addressed. A feminist framework, focused on economic, political and social empowerment for women would be useful to consider applying to sexual/reproductive health in the region.^