CHARACTERIZING A NOVEL GENETIC LOCUS ASSOCIATED WITH FAMILIAL CO-OCCURRENCE OF THORACIC AORTIC ANEURYSMS AND INTRACRANIAL ANEURYSMS

The Mendelian inheritance of genetic mutations can lead to adult-onset cardiovascular disease. Several genetic loci have been mapped for the familial form of Thoracic Aortic Aneurysms (TAA), and many causal mutations have been identified for this disease. Intracranial Aneurysms (ICA) also show linkage heterogeneity, but no mutations have been identified causing familial ICA alone. Here, we characterized a large family (TAA288) with an autosomal dominant pattern of inherited aneurysms. It is intriguing that female patients predominantly present with ICA and male patients predominantly with TAA in this family. To identify a causal mutation in this family, a genome-wide linkage analysis was previously performed on nine members of this family using the 50k GenChips Hind array from Affymetrix. This analysis eventually identified a single disease-segregating locus, on chromosome 5p15. We build upon this previous analysis in this study, hypothesizing that a genetic mutation inherited in this locus leads to the sex-specific phenotype of TAA and ICA in this family First we refined the boundaries of the 5p15 disease linked locus down to the genomic coordinates 5p15: 3,424,465- 6,312,925 (GRCh37/hg19 Assembly). This locus was named the TAA288 critical interval. Next, we sequenced candidate genes within the TAA288 critical interval. The selection of genes was simplified by the relatively small number of well-characterized genetic elements within the region. Seeking novel or rare disease-segregating variants, we initially observed a single point alteration in the metalloproteinase gene ADAMTS16 fulfilling this criteria. This variant was later classified as a low-frequency population polymorphism (rs72647757), but we continued to explore the potential role of the ADAMTS16 as the cause of disease in TAA288. We observed that fibroblasts cultured from TAA288 patients consistently upregulated the expression of this gene more strongly compared to matched control fibroblasts when treated with the cytokine TGF-β1, though there was some variation in the exact nature of this expression. We also observed evidence that this protein is expressed at elevated levels in aortic aneurysm tissue from patients with mutations in the gene TGFBR2 and Marfan syndrome, shown by immunohistochemical detection of this protein.

The effects of population density on the spread of disease

The objective of this study is to identify the relationship between population density and the initial stages of the spread of disease in a local population. This study proposes to concentrate on the question of how population density affects the distribution of the susceptible individuals in a local population and thus affects the spread of the disease, measles. Population density is measured by the average of the number of contacts with susceptible individuals by each individual in the population during a fixed-length time period. The term “contact with susceptible individuals” means sufficient contact between two people for the disease to pass from an infectious person to a susceptible person. The fixed-length time period is taken to be the average length of time an infected person is infectious without symptoms of the disease. For this study of measles, the time period will be seven days. ^ While much attention has been given to modeling the entire epidemic process of measles, attempts have not been made to study the characteristics of contact rates required to initiate an epidemic. This study explores the relationship between population density, given a specific herd immunity rate in the population, and initial rate of the spread of the disease by considering the underlying distribution of contacts with susceptibles by the individuals in the population. ^ This study does not seek to model an entire measles epidemic, but to model the above stated relationship for the local population within which the first infective person is introduced. This study describes the mathematical relationship between population density parameters and contact distribution parameters. ^ The results are displayed in graphs that show the effects of different population densities on the spread of disease. The results support the idea that the number of new infectives is strongly related to the distribution of susceptible contacts. The results also show large differences in the epidemic measures between populations with densities equal to four versus three. ^

TUMOR PROGRESSION: ANALYSIS OF THE INSTABILITY OF THE METASTATIC PHENOTYPE, SENSITIVITY TO RADIATION AND CHEMOTHERAPY (PHENOTYPIC DRIFT, BREAST CANCER)

The major complications for tumor therapy are (i) tumor spread (metastasis); (ii) the mixed nature of tumors (heterogeneity); and (iii) the capacity of tumors to evolve (progress). To study these tumor characteristics, the rat 13762NF mammary adenocarcinoma was cloned and studied for metastatic properties and sensitivities to therapy (chemotherapy, radiation and hyperthermia). The cell clones were heterogeneous and no correlation between metastatic potential and therapeutic sensitivities was observed. Further, these phenotypes were unstable during passage in vitro; yet, the changes were clone dependent and reproducible using different cryoprotected cell stocks. To understand the phenotypic instability, subclones were isolated from low and high passage cell clones. Each subclone possessed a unique composite phenotype. Again, no apparent correlation was seen between metastatic potential and sensitivity to therapy. The results demonstrated that (1) tumor cells are heterogeneous for multiple phenotypes; (2) tumor cells are unstable for multiple phenotypes; (3) the magnitude, direction and time of occurrence of phenotypic drift is clone dependent; (4) the sensitivity of cell clones to ionizing radiation (gamma or heat) and chemotherapy agents is independent of their metastatic potential; (5) shifts in metastatic potential and sensitivity to therapy may occur simultaneously but are not linked; and (6) tumor cells independently diverge to form several subpopulations with unique phenotypic profiles. ^

Using GIS methods to assess the occurrence of neural tube defect births by residential proximity at conception to hazardous waste sites

In the United States, approximately 4,000 pregnancies each year are affected by the two most common birth defects, spina bifida and anencephaly. Studies have shown that exposure to environmental chemicals before and after conception may adversely affect reproduction by inducing cell death or dysfunction, which leads to infertility, fetal loss, lowered weight at birth, or birth anomalies in the offspring. The objective of the study was to evaluate the relationship between Neural Tube Defect births and residence at conception in proximity to hazardous waste sites in the Texas-Mexico border region between 1993 and 2000. ^ The study design was a nested matched case-control and utilized secondary data from a project, “The role of chemical and biological factors in the etiology of neural tube birth defects births along the Texas-Mexico Border” (Irina Cech, Principal Investigator). Geographic Information Systems (GIS) database methods were used to compare Neural Tube Defects cases to controls on status of conception residence occurring within a one-mile radius from hazardous waste sites, as compared to conception residence further away. Information on the exposures was obtained from the OnTarget Database and Environment Protection Agency website. Conditional logistic regression was used for the matched case-control study to investigate the relationship between an outcome of being a case or a control and proximity to hazardous waste sites. ^ The result of the study showed a 36 percent non-significant increased risk of having an NTD birth associated with maternal proximity to abandoned hazardous waste sites (95% CI = 0.62–3.02). In addition, there was a 24% non-significant elevated risk of having an NTD birth when living in proximity to air pollutant sites than when living further away (95% CI = 0.67–2.32). Although this study did not find statistically significant associations, it will expand on the existing knowledge of the relationship between NTD and proximity to hazardous waste sites. ^

The association between smoking marijuana and the occurrence of lung cancer

It is still unclear if an association exists between the smoking of marijuana and the occurrence of lung cancer although one clearly exists between cigarette smoking and lung cancer. The objective of this study was to systematically review the literature in order to assess the impact of marijuana smoking, which is increasingly becoming a significant public health issue, on the occurrence of the number one killing cancer, lung cancer. ^ Method. Selected studies in the English language conducted on humans that assess the impact of marijuana smoking on lung cancer were identified from EBSCO MEDLINE, PUBMED, and GOOGLE databases. The search keywords were marijuana, cannabis, hashish, kif, and lung cancer with selection criteria including studies in the English language identified from 1950 to April 2008. Excluded were non-research studies such as editorials, letters, and reviews. Also excluded were studies that did not involve humans with direct intentional marijuana smoking or in vivo studies with mice. Case report studies or case series studies involving less than 10 patients were also excluded as well as studies that did not examine lung conditions related to premalignant or cancerous changes. ^ Results. Ten studies met the selection criteria and were analyzed. The ten studies in this review overall offer biological evidence of the potential association between marijuana smoking and premalignant lung findings but no overwhelming conclusive evidence for the association between marijuana smoking and the occurrence of lung cancer. Two of the observational studies [1, 2] failed to demonstrate an association between marijuana and lung cancer, but the remaining studies supported an association between marijuana smoking and premalignant or malignant lung findings. ^ Conclusion. It must, therefore, be concluded that no convincing evidence exists, based on the existing data, for an association between marijuana smoking and the occurrence of lung cancer even though the few observational studies failing to report such an association may be due to certain limitations particularly the relative young age of the participants precluding sufficient lag time for the identification of lung cancer outcome as explained in other sections of this paper. ^ Further research is, therefore, necessary to better evaluate this critical issue, while recommendations against smoking marijuana because of its potential harmful effects, including the potential for premalignant lung changes as noted in this review, should continue to be made. ^ In the future, large prospective studies with study participants representing a much wider spectrum of ages, and longer follow-up periods, with detailed assessment of marijuana exposure and definitive pathologic diagnosis of lung cancer are necessary^

Comparison of hand hygiene evaluations: A literature review

Background. Because our hands are the most common mode of transmission for bacteria causing hospital acquired infections, hand hygiene practices are the most effective method of preventing the spread of these pathogens, limiting the occurrence of healthcare-associated infections and reducing transmission of multi-drug resistant organisms. Yet, compliance rates are below 40% on the average. ^ Objective. This culminating experience project is primarily a literature review on hand hygiene to help determine the barriers to hand hygiene compliance and offer solutions on improving these rates and to build on a hand hygiene evaluation performed during my infection control internship completed at Memorial Hermann Hospital during the fall semester of 2005. ^ Method. A review of peer-reviewed literature using Ovid Medline, Ebsco Medline and PubMed databases using keywords: hand hygiene, hand hygiene compliance, alcohol based handrub, healthcare-associated infections, hospital-acquired infections, and infection control. ^ Results. A total of eight hand hygiene studies are highlighted. At a children's hospital in Seattle, hand hygiene compliance rates increases from 62% to 81% after five periods of interventions. In Thailand, 26 nurses dramatically increased compliance from 6.3% to 81.2% after just 7 months of training. Automated alcohol based handrub dispensers improved compliance rates in Chicago from 36.3% to 70.1%. Using education and increased distribution of alcohol based handrubs increased hand hygiene rates from 59% to 79% for Ebnother, from 54% to 85% for Hussein and from 32% to 63% for Randle. Spartanburg Regional Medical Center increased their rates from 72.5% to 90.3%. A level III NICU achieved 100% compliance after a month long educational campaign but fell back down to its baseline rate of 89% after 3 months. ^ Discussion. The interventions used to promote hand hygiene in the highlighted studies varied from low tech approaches such as printed materials to advanced electronic gadgets that alerted individuals automatically to perform hand hygiene. All approaches were effective and increased compliance rates. Overcoming hand hygiene barriers, receiving and accepting feedback is the key to maintaining consistently high hand hygiene adherence. ^

Identfying predictors of St. Louis encephalitis activity in Houston Texas

Generalized linear Poisson and logistic regression models were utilized to examine the relationship between temperature and precipitation and cases of Saint Louis encephalitis virus spread in the Houston metropolitan area. The models were investigated with and without repeated measures, with a first order autoregressive (AR1) correlation structure used for the repeated measures model. The two types of Poisson regression models, with and without correlation structure, showed that a unit increase in temperature measured in degrees Fahrenheit increases the occurrence of the virus 1.7 times and a unit increase in precipitation measured in inches increases the occurrence of the virus 1.5 times. Logistic regression did not show these covariates to be significant as predictors for encephalitis activity in Houston for either correlation structure. This discrepancy for the logistic model could be attributed to the small data set.^ Keywords: Saint Louis Encephalitis; Generalized Linear Model; Poisson; Logistic; First Order Autoregressive; Temperature; Precipitation. ^

A comprehensive review of the environmental impacts and human health risks associated with the occurrence of waste pharmaceuticals in water sources of the United States, and policy implications

The occurrence of waste pharmaceuticals has been identified and well documented in water sources throughout North America and Europe. Many studies have been conducted which identify the occurrence of various pharmaceutical compounds in these waters. This project is an extensive review of the documented evidence of this occurrence published in the scientific literature. This review was performed to determine if this occurrence has a significant impact on the environment and public health. This project and review found that pharmaceuticals such as sex hormone drugs, antibiotic drugs and antineoplastic/cytostatic agents as well as their metabolites have been found to occur in water sources throughout the United States at levels high enough to have noticeable impacts on human health and the environment. It was determined that the primary sources of this occurrence of pharmaceuticals were waste water effluent and solid wastes from sewage treatment plants, pharmaceutical manufacturing plants, healthcare and biomedical research facilities, as well as runoff from veterinary medicine applications (including aquaculture). ^ In addition, current public policies of US governmental agencies such as the Environmental Protection Agency (EPA), Food and Drug Administration (FDA), and Drug Enforcement Agency (DEA) have been evaluated to see if they are doing a sufficient job at controlling this issue. Specific recommendations for developing these EPA, FDA, and DEA policies have been made to mitigate, prevent, or eliminate this issue.^ Other possible interventions such as implementing engineering controls were also evaluated in order to mitigate, prevent and eliminate this issue. These engineering controls include implementing improved current treatment technologies such as the advancement and improvement of waste water treatment processes utilized by conventional sewage treatment and pharmaceutical manufacturing plants. In addition, administrative controls such as the use of “green chemistry” in drug synthesis and design were also explored and evaluated as possible alternatives to mitigate, prevent, or eliminate this issue. Specific recommendations for incorporating these engineering and administrative controls into the applicable EPA, FDA, and DEA policies have also been made.^

Fecal coliform contamination in child day care environments in Houston, Texas

Outbreaks of diarrhea are common among children in day care centers (DCC). Enteropathogens associated with these outbreaks are spread by the fecal-oral route through contaminated hands or environmental objects. This prospective study was undertaken to determine the prevalence of fecal coliform (FC) contamination in the DCC environment. Ten rooms in 6 DCC housing 121 children $<$2 years of age were studied for 13 weeks. Inanimate objects (1275), toy balls (724), and hands (954) were cultured 1-3 times per week. FC contamination was common during each week of study and was significantly (p $<$ 0.05) greater for objects, toy balls, and hands of children in toddler compared to infant rooms. In 5 rooms in which clothes were worn over diapers, there was a significantly lower prevalence of FC of toy balls (p $<$ 0.005), inanimate objects (p $<$ 0.05), and hands of children (p $<$ 0.001) and caregivers (p $<$ 0.05) when compared to rooms in which overclothes were not worn. Occurrence of diarrhea was significantly associated with increased contamination of caregivers' and children's hands. Using plasmid analysis of trimethoprim (TMP)-resistant Escherichia coli, stool and environmental isolates from individual DCC rooms had the same plasmid patterns, which were unique to each center. In summary, FC of environmental isolates and hands of children and caregivers in DCC is common; toy balls can serve as sentinels of contamination; FC can be significantly decreased by use of clothes worn over diapers; and plasmid analysis of E. coli strains showed the same patterns from stool and environmental isolates. ^

BENZENE TOXICITY AND THE OCCURRENCE OF BENZENE IN THE AMBIENT AIR OF THE HOUSTON AREA

This study was conducted by either literature review or actual field survey. Results are summarized as follows: (1) Long-term occupational exposure of workers to benzene vapor at levels of 3-7 ppm, 2-3 ppm and 1.6 ppm may result in a decreased level of leucocyte alkaline phosphates, an increased incidence of chromosome aberrations and an increased level of ALA in erythrocytes, respectively; (2) Benzene is capable of causing fetotoxic effects in animals at levels as low as 10 ppm by volume; (3) Exposure of animals to or less than 1 ppm benzene vapor may result in leucopenia, an inverse ratio of muscle antagonist chronaxy and a decreased level of ascorbic acid in fetus's and mother's liver as well as whole embryo; (4) Benzene is causally associated with the increased incidence of pancytopenia, including unicytopenia, bicytopenia and aplastic anemia, and chromosome aberrations in occupational exposure population, and at best benzene must also be considered as a leukemogen; (5) Since it can be emitted into the atmosphere from both man-made and natural sources, benzene in some concentrations is present everywhere in the various compartments of the environment; (6) The findings of the emission of benzene from certain natural sources indicate that reducing benzene to a zero-level of exposure is theoretically impossible; (7) The annual average of benzene concentration detected in the Houston ambient air is 2.50 ppb, which is about 2.4 times higher than the nation-wide annual average exposure level and may have been some health implications to the general public; (8) In the Houston area, stationary sources are more important than mobile sources in contributing to benzene in the ambient air. ^

TRANSMISSION DYNAMICS OF ENTERIC BACTERIA IN DAY-CARE CENTERS, HOUSTON, TEXAS

An investigation was undertaken to evaluate the role of fomites in the transmission of diarrhea in day-care centers (DCC) and to elucidate the paths by which enteric organisms spread within this setting.^ During a nine-month period (December 1980-August 1981) extensive culturing of inanimate objects, as well as children and staff was done routinely each month and again repeated during diarrhea outbreaks. Air was sampled from the classrooms and toilets using a Single-Stage Sieve Sampler (Ross Industries, Midland, VA.). Stool samples were collected from both ill and well children and staff in the affected rooms only during outbreaks. Environmental samples were processed for Shigella, salmonella and fecal coliforms while stools were screened for miscellaneous enteropathogens.^ A total of 11 outbreaks occurred in the 5 DCC during the study period. Enteric pathogens were recovered in 7 (64%) of the outbreaks. Multiple pathogens were identified in 3 outbreaks. The most frequently identified pathogen in stools was Giardia lamblia which was recovered in 5 (45%) of the outbreaks. Ten of the 11 (91%) outbreaks occurred in children less than 12 months of age.^ Environmental microbiology studies together with epidemiologic information revealed that enteric organisms were transmitted from person-to-person. On routine sampling, fecal coliforms were most frequently isolated from tap handles and diaper change areas. Contamination with fetal coliforms was wide-spread during diarrhea outbreaks. Fecal coliforms were recovered with significantly greater frequency from hands, toys and other classroom objects during outbreaks than during non-outbreak period. Salmonella typhimurium was recovered from a table top during an outbreak of Salmonellosis. There was no association between the level of enteric microbial contamination in the toilet areas and the occurrence of outbreaks. No evidence was found to indicate that enteric organisms were spread by the airborne route via aerosols.^ Toys, other classroom objects and contaminated hands probably play a major role in the transmission of enteropathogens during day-care center outbreaks. The presence of many enteric agents in the environment undoubtedly explains the polymicrobial etiology of the day-care center associated diarrhea outbreaks. ^

THE OCCURRENCE OF GROUP G STREPTOCOCCUS IN THE DOMESTIC CAT: COMPARISON OF THE PHYSIOLOGICAL PROPERTIES OF GROUP G STREPTOCOCCUS ISOLATED FROM HUMANS AND CATS

The occurrence of group G streptococci in cats and evaluation of the recovered organisms as potential human pathogens was investigated. Throat swabs were obtained from 89 cats (47 males and 42 females) and vaginal swabs from 39 female cats. Eighty-three of the examined cats were housed in individual cages at a University Animal Care Facility. Six cats, 2 mature males, 2 mature females and 2 young females were family pets in a rural area. Beta-hemolytic streptococci were recovered from 33 (37%) of the 89 cat throats cultured, and 27 (30.3%) were identified as group G. More males (34%) than females (24%) had throat cultures positive for group G. From the 39 vaginal cultures examined, 24 (61.5%) contained beta-hemolytic streptococci and 23 (58.9%) were identified as group G streptococci. Streptococci were not recovered from the vaginal cultures of the 5 females under 6 months of age.^ Thirty one group G streptococci isolated from cats were compared with 37 isolates of group G obtained from humans (health status or site of origin unknown). More group G cat isolates (81%) produced deoxyribonuclease (DNase) than did the human isolates (36%). The proportion of cat throat and vaginal isolates producing DNase was the same. Production of nicotinamide adenine dinucleotide glycohydrolase (NADase) by group G isolates of human origin was 70%, cat throat isolates 53% and cat vaginal isolates 37%. The Serum Opacity Factor was present in 73% of the cat throat isolates of group G, 43.7% of the cat vaginal isolates and 58.6% of the human isolates. Possession of an anti-phagocytic factor (M protein like substance) demonstrated by the ability to multiply in fresh human blood was greater in the group G from cat throats (46.7%) than from cat vagina (37.5%) or from the human isolates (13.5%). Many of the biochemical characteristics of the group G streptococci of cat origin were more similar to the biochemical characteristics of group A streptococci, than to the characteristics of group G of human origin. The group G streptococci, found in a large number of cats, could be potential human pathogens, as their physiological and biological characteristics are very similar to those of group A, a known human pathogen. ^