The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci

Thoracic aortic aneurysms leading to aortic dissections (TAAD) are a major cause of morbidity and mortality in the United States. TAAD is a complication of some known genetic disorders, such as Marfan syndrome and Turner syndrome, but the majority of familial cases are not due to a known genetic syndrome. Previous studies by our group have established that nonsyndromic, familial TAAD is inherited in an autosomal dominant manner with decreased penetrance and variable expression. Using one large family with multiple members with TAAD for the genome wide scan, a major locus for familial TAAD was mapped to 5q13–14 (TAAD1). Nine out of 15 families studied were linked to this locus, establishing that TAAD1 was a major locus, and that there was genetic heterogeneity for the condition. Mapping of TAAD2 locus was accomplished using a single large family with multiple members with TAAD not linked to known loci of aneurysm formation. This established a second novel locus for familial TAAD on 3p24–25 (LOD score of 4.3), termed the TAAD2 locus. Two putative loci with suggestive LOD scores were mapped on 4q and 12q through a genome scan carried out using three families. TAAD phenotype in 12 families did not segregate with known loci, indicating further genetic heterogeneity. An STS-tagged BAC based contig was constructed for 7.8Mb and 25Mb critical interval of TAAD1 and TAAD2 respectively and characterized to identify the defective gene. The hypothesis that the defective genes responsible for the TAAD1 and TAAD2 encoded extracellular matrix (ECM) proteins, the major components of the elastic fiber system in the aortic media was tested. Four genes encoding ECM proteins, versican, thrombospondin-3, CRTL1, on TAAD1 and FBLN2 at TAAD2 were sequenced, but no disease-causing mutations were identified. Studies to identify the defective gene are initiated through the positional candidate gene approach using combination of bioinformatics and expression studies. The identification of the TAAD susceptibility genes will allow for presymptomatic diagnosis of individuals at risk for this life threatening disease. The identification of the molecular defects that contribute to TAAD will also further our understanding of the proteins that provide structural integrity to the aortic wall. ^

Cost-effectiveness analysis of a 2-stage community-based hepatocellular carcinoma screening program in Taiwan

Hepatocellular carcinoma (HCC) has been ranked as the top cause of death due to neoplasm malignancy in Taiwan for years. The high incidence of HCC in Taiwan is primarily attributed to high prevalence of hepatitis viral infection. Screening the subjects with liver cirrhosis for HCC was widely recommended by many previous studies. The latest practice guideline for management of HCC released by the American Association for the Study of Liver Disease (AASLD) in 2005 recommended that the high risk groups, including cirrhotic patients, chronic HBV/HCV carriers, and subjects with family history of HCC and etc., should undergo surveillance.^ This study aims to investigate (1) whether the HCC screening program can prolong survival period of the high risk group, (2) what is the incremental cost-effectiveness ratio of the HCC screening program in Taiwan, as compared with a non-screening strategy from the payer perspective, (3) which high risk group has the lowest ICER for the HCC screening program from the insurer's perspective, in comparison with no screening strategy of each group, and (4) the estimated total cost of providing the HCC screening program to all high risk groups.^ The high risk subjects in the study were identified from the communities with high prevalence of hepatitis viral infection and classified into three groups (cirrhosis group, early cirrhosis group, and no cirrhosis group) at different levels of risk to HCC by status of liver disease at the time of enrollment. The repeated ultrasound screenings at an interval of 3, 6, and 12 months were applied to cirrhosis group, early cirrhosis group, and no cirrhosis group, respectively. The Markov-based decision model was constructed to simulate progression of HCC and to estimate the ICER for each group of subjects.^ The screening group had longer survival in the statistical results and the model outcomes. Owing to the low HCC incidence rate in the community-based screening program, screening services only have limited effect on survival of the screening group. The incremental cost-effectiveness ratio of the HCC screening program was $3834 per year of life saved, in comparison with the non-screening strategy. The estimated total cost of each group from the screening model over 13.5 years approximately consumes 0.13%, 1.06%, and 0.71% of total amount of adjusted National Health Expenditure from Jan 1992 to Jun 2005. ^ The subjects at high risk of developing HCC to undergo repeated ultrasound screenings had longer survival than those without screening, but screening was not the only factor to cause longer survival in the screening group. The incremental cost-effectiveness ratio of the 2-stage community-based HCC screening program in Taiwan was small. The HCC screening program was worthy of investment in Taiwan. In comparison with early cirrhosis group and no cirrhosis group, cirrhosis group has the lowest ICER when the screening period is less than 19 years. The estimated total cost of providing the HCC screening program to all high risk groups consumes approximately 1.90% of total amount of adjusted 13.5-year NHE in Taiwan.^

A case comparison study of dietary factors and risk of colorectal polyps

Little is known about the etiology of colorectal adenomatous polyps, although they are generally considered to be precursor lesions to colorectal carcinoma. To investigate the associations of colorectal adenomatous polyps with dietary intake of calcium, total fat and fiber, a case comparison study was conducted among 98 persons who had first occurrences of adenomatous polyps and 408 persons who did not have colorectal polyps.^ The study population comprised Black, White and Hispanic males and females ages 35 to 80 inclusive, who underwent a sigmoidoscopy or total colonoscopy at collaborating clinics in the Texas Medical Center at Houston between September 1991 and November 1992, and met the eligibility criteria. Case participants were those who had a first-time diagnosis of adenomatous polyps. Comparison participants were individuals who underwent the same diagnostic procedure as the cases and met the same eligibility criteria but had no colorectal polyps. A food frequency questionnaire was administered by interview to obtain information about diet during the 28 days preceding the interview.^ Dietary intake of total fiber was inversely associated with risk of adenomatous polyps. An increment of 15 gm/day in energy-adjusted intake of fiber was associated with a relative odds of 0.39 with a 95% confidence interval of 0.20 to 0.79, after adjustment for age, sex, ethnicity, body mass index, cigarette smoking, family history of colorectal cancer and intake of nonsteroidal anti-inflammatory drugs. No association between dietary intake of total fat and risk of adenomatous polyps was observed. When total fat was analyzed as percent of energy, an increment of 15.3% in intake was associated with a relative odds of 0.98 with a 95% confidence interval of 0.53 to 1.80. However, few persons in the study group had intakes below 25% of energy from total fat. An inverse association was observed between energy-adjusted intake of dietary calcium and risk of adenomatous polyps, but this was not statistically significant; an increment of 638 mg/day was associated with a relative odds of 0.77 with a 95% confidence interval of 0.41 to 1.38. Intake of calcium did not appear to strongly modify the association between intake of fat and risk of adenomatous polyps, perhaps because the study group included few people with calcium intake below 400 mg/day.^ These results support the idea that dietary fiber decreases risk of adenomatous polyps. Further studies are needed on the association of dietary calcium and fat with risk of colorectal adenomatous polyps in populations where individuals vary widely in intake of these nutrients. ^

The response of Texas public health agencies and workers to the emergency preparedness initiatives after 9/11

The purpose of this research was to better understand the impact of the terrorist attacks in 2001 on public health, particularly for Texas public health. This study employed mixed methods to examine changes to public health culture within Texas local public health agencies, important attitudes of public health workers toward responding to a disaster, and the funding policies that might ensure our investment in public health emergency preparedness is protected. ^ A qualitative analysis of interviews conducted with a large sample of public health officials in Texas found that all the constituent parts of a peculiar culture for public health preparedness existed that spanned the state's local health departments regardless of size, or funding level. The new preparedness culture in Texas had the hallmarks necessary for a robust public health preparedness and emergency response system. ^ The willingness of public health workers, necessary to make these kinds of changes and mount a disaster response was examined in one of Texas' most experienced disaster response teams—the public health workers for the City of Houston. A hypothesized latent variable model showed that willingness mediated all other factors in the model (self-efficacy, knowledge, barriers, and risk perception) for self-reported likelihood of reporting to work for a disaster. The RMSEA for the final model was 0.042 with a confidence interval of 0.036—0.049 and the chi-squared difference test was P=0.08, indicating a well-fitted model that suggests willingness is an important factor for consideration by preparedness planners and researchers alike. ^ Finally, with disasters on the rise and federal funding for preparedness dwindling, a review of states' policies for the distribution of these funds and their advantages and disadvantages were examined through a review of current literature and public documents, and a survey of state-level public health officials, emergency management professionals and researchers. Although the base plus per-capita method is the most common, it is not necessarily perceived to be the most effective. No clear "optimal" method emerged from the study, but recommendations for a strategic combination of three methods were made that has the potential to maximize the benefits of each method, while minimizing the weaknesses.^

A cohort study of body fatness and coronary mortality in middle -aged men

Data from the Chicago Western Electric Study were used to investigate whether central fat distribution, as estimated by the ratio of subscapular-to-triceps skinfold, was associated with 25-year risk of death from coronary heart disease in a cohort of 1,945 middle-aged employed men. Subscapular-triceps skinfold ratio was found positively and significantly associated with risk of coronary death after adjustment for age and body mass index. The age-adjusted proportional hazards regression coefficient was 0.2078 with 95% confidence interval of 0.0087 to 0.4069. A difference of 1.1 in the subscapular-triceps skinfold ratio (the difference between the mean of the fifth quintile and of the first and second quintiles combined) was associated with a relative risk of 1.31 with 95% confidence interval of 1.06 to 1.62. The coefficient was decreased to 0.1961 (95% confidence interval of ($-$0.0028 to 0.3950) after adjustment for diastolic blood pressure, serum cholesterol and cigarette smoking as well as age and body mass index. At least some of the effect of central fat on coronary risk is probably mediated by blood pressure and serum lipids, but whether all of the effect can be accounted for blood pressure and serum lipids is uncertain.^ This study supports the concept that central fat distribution is a risk factor for 25-year risk of coronary death in middle-aged men. ^

MYELINATION IN UNDERNOURISHED RAT BRAIN

Several interactive parameters of protein-calorie malnutrition imposed during postnatal ontogeny on the myelination of rat brain wre investigated. Postnatal starvation depresses the rate of myelin protein synthesis to approximately the same extent in all major brain regions examined (cerebral cortex, cerebellum, striatum, hippocampus, hypothalamus, midbrain and medulla), indicating a relatively uniform reduction in myelination throughout the brain. Early starvation from birth through 8 days, as well as starvation occurring late, from 14 to 30 days, produced no lasting deficit in myelin accumulation. Starvation from birth through 14 days or from birth through 20 days produces lasting, significant myelin deficits in all brain regions when examined following ad libitum feeding to 60 days of age. These data, in combination with the metabolic studies of myelin synthesis, show that severe starvation occurring during the 2nd and 3rd weeks of postnatal life produces an immediate reduction in myelin synthesis, and that the subsequent deficit in myelin accumulation is irreversible by nutritional rehabilitation. With respect to the relative severity of nutritional restriction occurring during this "critical" interval of brain ontogeny, additional studies showed that mild undernourishment (producing less than 20 percent growth lag) produces no myelin deficit. There appears to be a threshold effect such that undernutrition producing a growth lag of between 20 to 30 percent first produces a measurable deficit. Increasingly severe regimens of nutritional restriction which produce approximately 30, 40 and 50 percent body weight lags result in initial myelin deficits of 25, 55 and 60 percent, respectively. Initial myelin deficits do not recover following nutritional rehabilitation, although myelin continues to increase in both normal and all undernourished populations. At the cellular level, severe postnatal nutritional restriction appears to depress both the initial synthesis of myelin precursor proteins (as demonstrated for proteolipid protein) as well as their subsequent assembly into myelin membrane. All of the findings of the present studies are consistent with a hypothetical model of undernutrition-induced brain hypomyelination in which the primary defect consists of a failure of oligodendroglia to myelinate a substantial percentage of axons, resulting in a greatly decreased ratio of myelinated to unmyelinated axons. ^

A novel myeloid leukemia suppressor locus at human chromosome 5q13.3

Molecular mechanisms that underlie preleukemic myelodysplasia (MDS) and acute myelogenous leukemia (AML) are poorly understood. In MDS or AML with a refractory clinical course, more than 30% of patients have acquired interstitial or complete deletions of chromosome 5. The 5q13.3 chromosomal segment is commonly lost as the result of 5q deletion. Reciprocal and unbalanced translocations of 5q13.3 can also occur as sole anomalies associated with refractory AML or MDS. This study addresses the hypothesis that a critical gene at 5q13.3 functions either as a classical tumor suppressor or as a chromosomal translocation partner and contributes to leukemogenesis. ^ Previous studies from our laboratory delineated a critical region of loss to a 2.5–3.0Mb interval at 5q13.3 between microsatellite markers D5S672 and GATA-P18104. The critical region of loss was later resolved to an interval of approximately 2Mb between the markers D5S672 and D5S2029. I, then generated a long range physical map of yeast artificial chromosomes (YACs) and developed novel sequence tagged sites (STS). To enhance the resolution of this map, bacterial artificial chromosomes (BACs) were used to construct a triply linked contig across a 1 Mb interval. These BACs were used as probes for fluorescent in situ hybridization (FISH) on an AML cell line to define the 5q13.3 critical region. A 200kb BAC, 484a9, spans the translocation breakpoint in this cell line. A novel gene, SSDP2 (single stranded DNA binding protein), is disrupted at the breakpoint because its first four exons are encoded within 140kb of BAC 484a9. This finding suggests that SSDP2 is the critical gene at 5q13.3. ^ In addition, I made an observation that deletions of chromosome 5q13 co-segregate with loss of the chromosome 17p. In some cases the deletions result from unbalanced translocations between 5q13 and 17p13. It was confirmed that the TP53 gene is deleted in patients with 17p loss, and the remaining allele harbors somatic mutation. Thus, the genetic basis for the aggressive clinical course in AML and MDS may be caused by functional cooperation between deletion or disruption of the 5q13.3 critical gene and inactivation of TP53. ^

Forebrain-cerebellum interactions revealed by trace eyelid conditioning

While it is commonly assumed that brain systems receive and process information from other brain systems, there are few examples of tractable behaviors that allow such interactions to be studied. With the experiments presented in this dissertation we provide evidence that trace eyelid conditioning, a simple form of associative learning, is mediated by cerebellar learning in response to the output of persistent neural activity in the prefrontal cortex (PFC) and thus may be useful in analyses of PFC-cerebellar interactions. In a series of stimulation and reversible inactivation experiments we provide evidence that trace eyelid conditioning is mediated by cerebellar learning in response to a learned forebrain-driven input. Specifically, we provide evidence that this input is driven by the medial PFC and persists through the stimulus free trace interval of trace eyelid conditioning. In the next set of experiments we show that directly presenting the cerebellum with a pattern of input that mimics the classic persistent activity of PFC neurons reconstitutes trace eyelid conditioning, as assessed by a number of stringent tests. Finally, in set of reversible inactivation experiments, we provide evidence that bidirectional learning during trace eyelid conditioning involves the omission of the persistent, PFC-driven input that the cerebellum learns and responds to during trace eyelid conditioning. Given that persistent activity in PFC is often associated with working memory, these experiments suggest that trace eyelid conditioning may be useful in analyses of working memory mechanisms, cerebellar information processing and their interaction. To facilitate future analyses, we conclude with a working hypothesis of forebrain-cerebellum interactions during trace eyelid conditioning that addresses how persistent activity in PFC is induced and how the cerebellum decodes and uses PFC-driven input. ^

Secondary left ventricular ejection fraction response to beta blocker therapy in heart failure patients

Chronic β-blocker treatment improves survival and left ventricular ejection fraction (LVEF) in patients with systolic heart failure (HF). Data on whether the improvement in LVEF after β-blocker therapy is sustained for a long term or whether there is a loss in LVEF after an initial gain is not known. Our study sought to determine the prevalence and prognostic role of secondary decline in LVEF in chronic systolic HF patients on β-blocker therapy and characterize these patients. Retrospective chart review of HF hospitalizations fulfilling Framingham Criteria was performed at the MEDVAMC between April 2000 and June 2006. Follow up vital status and recurrent hospitalizations were ascertained until May 2010. Three groups of patients were identified based on LVEF response to beta blockers; group A with secondary decline in LVEF following an initial increase, group B with progressive increase in LVEF and group C with progressive decline in LVEF. Covariate adjusted Cox proportional hazard models were used to examine differences in heart failure re-hospitalizations and all cause mortality between the groups. Twenty five percent (n=27) of patients had a secondary decline in LVEF following an initial gain. The baseline, peak and final LVEF in this group were 27.6±12%, 40.1±14% and 27.4±13% respectively. The mean nadir LVEF after decline was 27.4±13% and this decline occurred at a mean interval of 2.8±1.9 years from the day of beta blocker initiation. These patients were older, more likely to be whites, had advanced heart failure (NYHA class III/IV) more due to a non ischemic etiology compared to groups B & C. They were also more likely to be treated with metoprolol (p=0.03) compared to the other two groups. No significant differences were observed in combined risk of all cause mortality and HF re-hospitalization [hazard ratio 0.80, 95% CI 0.47 to 1.38, p=0.42]. No significant difference was observed in survival estimates between the groups. In conclusion, a late decline in LVEF does occur in a significant proportion of heart failure patients treated with beta blockers, more so in patients treated with metoprolol.^