Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

BENCHMARKING AND IMPLEMENTATION OF A NEW INDEPENDENT MONTE CARLO DOSE CALCULATION QUALITY ASSURANCE AUDIT TOOL FOR CLINICAL TRIALS

Introduction Commercial treatment planning systems employ a variety of dose calculation algorithms to plan and predict the dose distributions a patient receives during external beam radiation therapy. Traditionally, the Radiological Physics Center has relied on measurements to assure that institutions participating in the National Cancer Institute sponsored clinical trials administer radiation in doses that are clinically comparable to those of other participating institutions. To complement the effort of the RPC, an independent dose calculation tool needs to be developed that will enable a generic method to determine patient dose distributions in three dimensions and to perform retrospective analysis of radiation delivered to patients who enrolled in past clinical trials. Methods A multi-source model representing output for Varian 6 MV and 10 MV photon beams was developed and evaluated. The Monte Carlo algorithm, know as the Dose Planning Method (DPM), was used to perform the dose calculations. The dose calculations were compared to measurements made in a water phantom and in anthropomorphic phantoms. Intensity modulated radiation therapy and stereotactic body radiation therapy techniques were used with the anthropomorphic phantoms. Finally, past patient treatment plans were selected and recalculated using DPM and contrasted against a commercial dose calculation algorithm. Results The multi-source model was validated for the Varian 6 MV and 10 MV photon beams. The benchmark evaluations demonstrated the ability of the model to accurately calculate dose for the Varian 6 MV and the Varian 10 MV source models. The patient calculations proved that the model was reproducible in determining dose under similar conditions described by the benchmark tests. Conclusions The dose calculation tool that relied on a multi-source model approach and used the DPM code to calculate dose was developed, validated, and benchmarked for the Varian 6 MV and 10 MV photon beams. Several patient dose distributions were contrasted against a commercial algorithm to provide a proof of principal to use as an application in monitoring clinical trial activity.

Progressive multifocal leukoencephalopathy in a patient without apparent immunosuppression.

An 80-year-old man with no history of an immune-compromising disorder was diagnosed with progressive multifocal leukoencephalopathy (PML). He presented with dysphagia and left-sided weakness; magnetic resonance imaging demonstrated marked signal abnormality in the subcortical white matter of the left frontal lobe and in the posterior limb of the right internal capsule. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) was negative for John Cunningham (JC) virus. On brain biopsy, foamy macrophages infiltrating the white matter were identified, staining positive for anti-simian virus 40 antibodies. Postoperatively, PCR for JC viral DNA in the CSF was positive, establishing the diagnosis of PML. Extensive investigation for an occult immunocompromising disorder was negative. The patient's neurologic deficits rapidly increased throughout his hospital stay, and he died 3.5 months after his diagnosis.

A study of the impact of cigarette advertising on adolescent susceptibility to smoking among 5th-, 8th-, and 12th-grade students in Hempstead and Hitchcock Independent School Districts

This study assessed the impact of cigarette advertising on adolescent susceptibility to smoking in the Hempstead and Hitchcock Independent School Districts. A convenience sample of 217 youths, 10-19 years of age was recruited in the study. Students completed both a paper-and-pencil and a computer-aided questionnaire in April 1996. Adolescents were defined as susceptible to smoking if they could not definitely rule out the possibility of future smoking. For the analysis, an index was devised: a 5-point index of an individual's receptivity to cigarette advertising. The index is determined by the number of positive responses to five survey items (recognizing cigarette brand logos, recognizing cigarette advertisement's pictures, recognizing cigarette brand slogans, evaluating adolescent attitudes toward cigarette advertising, and the degree to which adolescents were exposed to cigarette advertisements). Using logistic regression, we assessed the independent importance of the index in predicting susceptibility to smoking and ever smoking after adjusting for sociodemographic variables, perceived school performance and family composition. Of students surveyed, 54.4% of students appeared to have started the smoking uptake process as measured by susceptibility to smoking. Camel was recognized by the majority of students (88%), followed by Marlboro (41.5%) and Newport (40.1%). The pattern for recognition of the cigarette advertisements was the same as the pattern of market for cigarette. Advertisement featuring the cartoon character Joe Camel was significantly more appealing to adolescents than were advertisements with human models, with animal models, and with text only (p $<$ 0.001). Text only advertisement was significantly less appealing than other types of advertisements. The cigarette advertisement with White models (Marlboro) had significantly higher appeal to White students than to African-American students (p $<$ 0.001). The cigarette advertisement featuring African-American models (Virginia Slims) was significantly more appealing to African-American students than other ethnic groups (p $<$ 0.001). Receptivity to cigarette advertising was to be an important concurrent predictor of past smoking experience and intention to smoke in the future. Adolescents who scored in the fourth quartile of the Index of Receptivity to Cigarette Advertising were 7.54 (95% confidence interval (CI) = 1.92-29.56) times as likely to be susceptible to smoking, and were 4.56 (95% CI = 1.55-13.38) times as likely to have tried smoking, as those who scored in the first quartile of the Index. The findings confirmed the hypothesis that cigarette advertising may be a strong current influence in encouraging adolescents to initiate the smoking uptake process than sociodemographic variables, perceived school performance and family composition. ^

ANTIBODY-DEPENDENT AND ANTIBODY-INDEPENDENT CELLULAR CYTOTOXICITY AGAINST SHIGELLA

Diarrhea is a major cause of morbidity and mortality worldwide. Shigella causes up to 20% of all diarrhea. Gut-level immunity and breast-feeding of infants are important factors in protection against shigellosis. The lumen of the gut is lined with lymphocytes which mediate natural killer cytotoxicity, NKC, and antibody-dependent cellular cytotoxicity, ADCC. NKC and ADCC are extracellular, nonphagocytic leukocyte killing mechanisms, which occur in the absence of complement, without prior antigen stimulation, and without regard to the major histocompatibility complex. In this study, virulent and avirulent shigellae were used as the target cells. Leukocytes from peripheral blood, breast milk, and guinea pig gut-associated tissues were used as effector cells. Adult human peripheral blood mononuclear cells and lymphocytes, but not macrophages or polymorphonuclear leukocytes, mediated NKC and ADCC at an optimal effector to target cell ratio of 100:1 in a 60 minute bactericidal assay. An antiserum dilution of 1:10 was optimal for ADCC. Whole, viable lymphocytes were necessary for cytotoxicity. Lymphocyte NKC, but not ADCC, was greatly enhanced by interferon. Lymphocyte NKC occurred against several virulent strains of S. sonnei and a virulent strain of S. flexneri. ADCC (using immune serum directed against S. sonnei) occurred against virulent S. sonnei, but not against avirulent S. sonnei or virulent S. flexneri. Lymphocyte ADCC was not inhibited by the presence of phenylbutazone or by pretreatment of lymphocytes with anti-HNK serum plus complement. Both adherent and non-adherent breast milk leukocytes mediated NKC and ADCC. Mononuclear cells from young children demonstrated normal ADCC, when compared to ADCC of adult cells. Neonatal cord blood and a CGD patient's peripheral blood mononuclear and ploymorphonuclear cells demonstrated high ADCC compared to adult cells. Intraepithelial lymphocytes, spleen cells, and peritoneal cells from normal guinea pigs demonstrated NKC and ADCC. Animals which had been starved and opiated were made susceptible to infection by Shigella. The susceptible animals demonstrated deficient NKC and ADCC with all three leukocyte populations. High NKC and ADCC activity of gut-associated leukocytes from human breast milk and guinea pig tissues may correlate with resistance to infection. ^

The characterization of PKC-isozyme specific EGFR-dependent Erk1/2 activation in androgen-independent prostate cancer cell lines

One growth factor receptor commonly altered during prostate tumor progression is the epidermal growth factor receptor (EGFR). EGFR signaling regulates Erk1/2 phosphorylation through multiple mechanisms. We hypothesized that PKC isozymes play a role in EGFR-dependent signaling, and that through PKC isozyme selective inhibition, EGFR-dependent Erk1/2 activation can be attenuated in AICaP cells. ^ To test the hypothesis, PKC activation was induced by 12-O-tetradecanoyi-phorbol-13-acetate (TPA) in PC-3 cells. As a result, Erk1/2 was activated similarly to what was observed upon EGF stimulation. EGF-induced Erk1/2 activation in PC-3 cells was PKC-dependent, as demonstrated through use of a selective PKC inhibitor, GF109203X. This provides evidence for PKC regulatory control over Erk1/2 signaling downstream of EGFR. Next, we demonstrated that when PKC was inhibited by GF109203X, EGF-stimulated Erk1/2 activation was inhibited in PC-3, but not DU145 cells. TPA-stimulated Erk1/2 activation was EGFR-dependent in both DU145 and PC-3 cells, demonstrated through abrogation of Erk1/2 activation by a selective EGFR inhibitor AG1478. These data support PKC control at or upstream of EGFR in AICaP cells. We observed that interfering with ligand/EGFR binding abrogated Erk1/2 signaling in TPA-stimulated cells, revealing a role for PKC upstream of EGFR. ^ Next, we determined which PKC isozymes might be responsible for Erk1/2 regulation. We first determined that human AICaP cell lines express the same PKC isozymes as those observed in clinical prostate cancer specimens (α, ϵ, &zgr;, ι and PKD). Isozyme-selective methods were employed to characterize discrete PKC isozyme function in EGFR-dependent Erk1/2 activation. Pharmacologic inhibitors implicated PKCα in TPA-induced EGFR-dependent Erk1/2 activation in both PC-3 and DU145 cells. Further, the cPKC-specific inhibitor, Gö6976 decreased viablilty of DU145 cells, providing evidence that PKCα is necessary for growth and survival. Finally, resveratrol, a phytochemical with strong cancer therapeutic potential inhibited Erk1/2 activation, and this correlated with selective inhibition of PKCα. These results demonstrate that PKC regulates pathways critical to progression of CaP cells, including those mediated by EGFR. Thus, PKC isozyme-selective targeting is an attractive therapeutic strategy, and understanding the role of specific PKC isozymes in CaP cell growth and survival may aid in development of effective, non-toxic PKC-targeted therapies. ^

Evaluation of the city of Houston HIV/STD prevention program in Houston Independent School District (HISD) high schools

This cross-sectional study was undertaken to evaluate the impact in terms of HIV/STD knowledge and sexual behavior that the City of Houston HIV/STD prevention program in HISD high schools has had on students who have participated in it by comparing them with their peers who have not, based on self reports. The study further evaluated the program cost-effectiveness for averting future HIV infections by computing Cost-Utility Ratios based on reported sexual behavior. ^ Mixed results were obtained, indicating a statistically significant difference in knowledge with the intervention group having scored higher (p-value 0.001) but not for any of the behaviors assessed. The knowledge score outcome's overall p-value after adjusting for each stratifying variable (age, grade, gender and ethnicity) was statistically significant. The Odds Ratio of intervention group participants aged 15 years or more scoring 70% or higher was 1.86 times; that of intervention group female participants was 2.29 times; and that of intervention group Black/African American participants was 2.47 times relative to their comparison group counterparts. The knowledge score results remained statistically significant in the logistic regression model, which controlled for age, grade level, gender and ethnicity. The Odds Ratio in this case was 1.74. ^ Three scenarios based on the difference in the risk of HIV infection between the intervention and comparison group were used for computation of Cost-Utility Ratios: Base, worst and best-case scenario. The best-case scenario yielded cost-effective results for male participants and cost-saving results for female participants when using ethnicity-adjusted HIV prevalence. The scenario remained cost-effective for female participants when using the unadjusted HIV prevalence. ^ The challenge to the program is to devise approaches that can enhance benefits for male participants. If it is a threshold problem implying that male participants require more intensive programs for behavioral change, then programs should first be piloted among boys before being implemented across the board. If it is a reflection of gender differences, then we might have to go back to the drawing board and engage boys in focus group discussions that will help formulate more effective programs. Gender-blind approaches currently in vogue do not seem to be working. ^

Incident hypertension among pre-hypertensive adolescents: Evaluation of pre-hypertension as an independent risk factor among secondary school students in the Houston area

Cardiovascular disease has been the leading cause of death in the United States for over fifty years. While multiple risk factors for cardiovascular disease have been identified, hypertension is one of the most commonly recognized and treatable. Recent studies indicate that the prevalence of hypertension among children and adolescents is between 3-5%, much higher than originally estimated and likely rising due to the epidemic of obesity in the U.S. In 2004, the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents published new guidelines for the diagnosis and treatment of hypertension in this population. Included in these recommendations was the creation of a new diagnosis, pre-hypertension, aimed at identifying children at-risk for hypertension to provide early lifestyle interventions in an effort to prevent its ultimate development. In order to determine the risk associated with pre-hypertension for the development of incident HTN, a secondary analysis of a repeated cross-sectional study measuring blood pressure in Houston area adolescents from 2000 to 2007 was performed. Of 1006 students participating in the blood pressure screening on more than one occasion not diagnosed with hypertension at initial encounter, eleven were later found to have hypertension providing an overall incident rate of 0.5% per year. Incidence rates were higher among overweight adolescents–1.9% per year [IRR 8.6 (1.97, 51.63)]; students “at-risk for hypertension” (pre-hypertensive or initial blood pressure in the hypertensive range but falling on subsequent measures)–1.4% per year [IRR 4.77 (1.21, 19.78)]; and those with blood pressure ≥90th percentile on three occasions–6.6% per year [IRR 21.87 (3.40, 112.40)]. Students with pre-hypertension as currently defined by the Task Force did have an increased rate of hypertension (1.1% per year) but it did not reach statistical significance [IRR 2.44 (0.42, 10.18)]. Further research is needed to determine the morbidity and mortality associated with pre-hypertension in this age group as well as the effectiveness of various interventions for preventing the development of hypertensive disease among these at-risk individuals. ^

Depolarization-dependent synaptic potentiation and hyperexcitability induced by a Ca2+-independent trigger

Despite vast research efforts since Cajal's seminal thoughts on the adaptation of the nervous system, researchers have only recently begun to understand the diversity of forms of neuronal plasticity and its mechanisms. All known forms of activity-dependent neuronal plasticity utilize alterations in [Ca 2+]i as a signal of changes in the membrane voltage. Ca 2+ sensors trigger modifications in excitability or synaptic strength that last from seconds to weeks and presumably years. Intriguingly, Kunjilwar et al., (unpublished observations) discovered in peripheral sensory axons of Aplysia that the induction of depolarization-dependent long-term axonal hyperexcitability does not require Ca2+ transients. Here we show that induction of depolarization-dependent intermediate-term and long-term synaptic potentiation in Aplysia occurs in conditions that prevent Ca2+ entry through voltage-gated channels and elevation of [Ca2+]i. We found that the intermediate-term synaptic potentiation induced under conditions expected to prevent Ca 2+ transients is associated with increased excitability of sensory neuron axons near presynaptic terminals, suggesting that the synaptic potentiation involves a presynaptic locus. The Ca2+-independent intermediate- and long-term synaptic potentiation appeared similar to previously reported Ca2+-dependent modifications in Aplysia. ^

MEETING THE NEEDS OF HANDICAPPED CHILDREN: A STUDY OF EDUCATIONAL AND HEALTH CARE SERVICES PROVIDED TO PRE-KINDERGARTEN CHILDREN IN THE HOUSTON INDEPENDENT SCHOOL DISTRICT EARLY CHILDHOOD PROGRAM FOR THE HANDICAPPED (PARENT SATISFACTION, FUNCTIONAL STATUS, PSYCHOSOCIAL DEVELOPMENT)

The Education for All Handicapped Children Act of 1975, P.L. 94-142, created a new challenge for the nation's public school systems. During 1982-1983, a national study, called the "Collaborative Study of Children with Special Needs", was conducted in 5 metropolitan school districts to evaluate the effectiveness of education and health care services of children in kindergarten to 6th grade being provided under P.L. 94-142 programs. This dissertation (the Substudy) was undertaken to augment the findings of the Collaborative Study. The purpose of this study was to develop a database to provide descriptive information on the demographic, service and health characteristics of a small group of 3 and 4 year old handicapped children served by the Houston Independent School District (HISD) during 1982-1983.^ The study involved a stratified sample of 105 three and four year old children divided into 3 groups according to type of handicapping condition.^ The results of the study gave a clearer picture of the demographic characteristics of these Pre-K children. Specifically, sex ratio was approximately one, lower than the national norm. Family and socioeconomic characteristics were assessed.^ The study used an independence/dependence index composed of 11 items on the parent questionnaire to assess the level of functional independence of each child. An association was found between index scores and parent-reported effects of the child on family activity. Parents who said that their child's condition had affected the family's job situation, housing accomodations, vacation plans, marriage, choice of friends and social activities were also more likely to report less independence in the child. In addition, many of the Substudy children had extensive care-taking needs reflected in specific components of the index such as dressing, feeding, toileting or moving about the house.^ In general the results of the Pre-K Substudy indicate that at the early childhood level, the HISD special education program is functioning well in most areas and that parents are very satisfied with the program. (Abstract shortened with permission of author.)^

Improving pregnancy prevention in the Austin Independent School District: Student participation in the development of social marketing media

Pregnancy prevention is an important goal of the Austin Independent School District (AISD), but present activity is limited to utilizing a single curriculum. To effectively prevent pregnancy, a diverse range of programs and activities is needed—including media and social marketing. This project (1) reviews literature to identify best practices and characteristics of effective pregnancy prevention programs for AISD, (2) reports on the results of meetings that gathered recommendations for effective channels and media messages for pregnancy prevention among high school students in Central Texas, and (3) presents samples of social marketing media products developed for pregnancy prevention that can be used by AISD.^