Hypertensive nephropathy treatment by heart-protecting musk pill: a study of anti-inflammatory therapy for target organ damage of hypertension.

This study was designed to investigate the protective effect of the heart-protecting musk pill (HMP) on inflammatory injury of kidney from spontaneously hypertensive rat (SHR). Male SHRs aged 4 weeks were divided into SHR model group, HMP low-dosage group (13.5 mg/kg), and HMP high-dosage group (40 mg/kg). Age-matched Wistar-Kyoto rats were used as normal control. All rats were killed at 12 weeks of age. Tail-cuff method and enzyme-linked immunosorbent assay were used to determine rat systolic blood pressure and angiotensin II (Ang II) contents, respectively. Renal inflammatory damage was evaluated by the following parameters: protein expressions of inflammatory cytokines, carbonyl protein contents, nitrite concentration, infiltration of monocytes/macrophages in interstitium and glomeruli, kidney pathological changes, and excretion rate of urinary protein. HMP did not prevent the development of hypertension in SHR. However, this Chinese medicinal compound decreased renal Ang II content. Consistent with the change of renal Ang II, all the parameters of renal inflammatory injury were significantly decreased by HMP. This study indicates that HMP is a potent suppressor of renal inflammatory damage in SHR, which may serve as a basis for the advanced preventive and therapeutic investigation of HMP in hypertensive nephropathy.

DYSREGULATION OF MEOX2 FOLLOWING WT1 MUTATION IN KIDNEY DEVELOPMENT AND WILMS TUMORIGENESIS

Wilms tumor (WT) is a childhood tumor of the kidney and a productive model for understanding the role of genetic alteration and interactions in tumorigenesis. The Wilms tumor gene 1 (WT1) is a transcriptional factor and one of the few genes known to have genetic alterations in WT and has been shown be inactivated in 20% of WTs. However, the mechanisms of how WT1 mutations lead to Wilms tumorigenesis and its influence on downstream genes are unknown. Since it has been established that WT1 is a transcriptional regulator, it has been hypothesized that the loss of WT1 leads to the dysregulation of downstream genes, in turn result in the formation of WTs. To identify the dysregulated downstream genes following WT1 mutations, an Affymetrix GeneChip Human Genome Array was previously conducted to assess the differentially expressed genes in the WT1-wildtype human and WT1-mutant human WTs. Approximately 700 genes were identified as being significantly dysregulated. These genes were further prioritized based on their statistical significance, fold change, chromosomal region, spatial pattern of gene expression and known or putative cellular functions. Mesenchyme homeobox 2 (MEOX2) was one of the most significantly upregulated genes in WT1-mutant WT. MEOX2 is known to play a role in cell proliferation, apoptosis, and differentiation. In addition to its biological roles, it is expressed during early kidney development in the condensed mesenchyme similar to WT1. Furthermore, the use of the Match® web-based tool from the BIOBASE Biological Data base identified a significant predicted WT1 binding site within the first intron of MEOX2. The similarity in spatial gene expression in the developing kidney and the significant predicted WT1 binding site found in the first intron of MEOX2 lead to the development of my hypothesis that MEOX2 is upregulated via a WT1-dependent manner. Here as a part of my master’s work, I have validated the Affymetrix GeneChip Human Genome Array data using an independent set of Wilms tumors. MEOX2 remained upregulated in the mutant WT1 Wilms tumor by 41-fold. Wt1 and Meox2 gene expression were assessed in murine newborn kidney; both Wt1 and Meox2 were expressed in the condensed, undifferentiated metanephric mesenchyme. I have shown that the in vivo ablation of Wt1 during embryonic development at embryonic day (E) 13.5 resulted in the slight increase of Meox2 gene expression by two fold. In order to functionally demonstrate the effect of the loss of Wt1 on Meox2 gene expression in undifferentiated metanephric mesenchyme, I have generated a kidney mesenchymal cell line to genetically ablate Wt1 in vitro by adenoviral infection. The ablation of Wt1 in the kidney mesenchymal cell line resulted in the upregulation of Meox2 by 61-fold. Moreover, the upregulation of Meox2 resulted in the significant induction of p21 and Itgb5. In addition to the dysregulation of these genes the ablation of Wt1 in the kidney mesenchymal cells resulted in decrease in cell growth and loss of cellular adherence. However, it is uncertain whether the upregulation of Meox2 caused this particular cellular phenotype. Overall, I have demonstrated that the upregulation of Meox2 is Wt1-dependent during early kidney development.

Cultural beliefs and hypertension in rural Philippines

Hypertension (HTN), the major risk factor for cardiovascular disease (CVD), is emerging as a major public health problem in the Philippines. CVD has been the leading cause of mortality in the Philippines since 1990. ^ Although research has shown that certain populations have a greater propensity for HTN, and that culture may be a factor, empirical investigations of the influence of cultural beliefs on HTN are lacking. ^ The operational aims of this study were to: (a) develop and examine the reliability (test-retest, internal consistency) and validity (content) of a questionnaire which measures factors related to HTN; (b) administer the questionnaire; and (c) measure blood pressure, height, and weight of the ≥ 30 year old residents of San Antonio, Nueva Ecija, Philippines. ^ The analytic aims were to determine the: (a) cultural beliefs relating to HTN; (b) associations between cultural beliefs and HTN; and (c) extent to which cultural beliefs versus biological, behavioral, socioeconomic, and access factors are associated with HTN. ^ A cluster survey was conducted among 336 residents ≥ 30 years old in May, 1998. Sixty clusters of households were derived using probability proportionate to size sampling technique. Seven households per cluster were visited and one respondent per household was randomly chosen for interview and measurement of blood pressure, height and weight. A response rate of 84% (336/400) was achieved. ^ Results showed that the test-retest reliability of cultural belief items was 0.69–0.96. Internal consistency reliability was 0.74. ^ HTN (SBP ≥ 140; or DBP ≥ 90 mmHg; or currently taking anti-hypertensive medication) prevalence was 23/100. Univariate logistic regression showed cultural beliefs to be significantly associated (p < 0.037) with HTN. However, multivariate analysis showed that only age ≥ 50 (p = 0.000), family history of HTN (p = 0.004) and body mass index ≥ 25 (p = 0.003) were significant predictors. ^ In the absence of fully implemented programs to prevent and control HTN, the current prevalence is only expected to increase, leading to substantial increases in morbidity and mortality and health care cost. It is recommended that research which focuses on designing, implementing, and evaluating culturally appropriate community-wide programs on HTN prevention and control be undertaken in this community. ^

Hypertension control and related variables among urban and rural adults in Taiwan

Literature on hypertension treatment has demonstrated that a healthy life style is one of the best strategies for hypertension control. In exploring the mechanisms of behavioral change for hypertension control, a comprehensive study based on the Transtheoretical Model was carried out in Taiwan during the summer of 2000 with a sample of 350 hypertensive adults living in Taipei urban and rural areas. ^ The relationships among stages of change, processes of change and demographic factors were analyzed for six health behaviors—low fat food consumption, alcohol use, smoking, physical activity, weight control, and routine blood pressure checkups. In addition, differences were assessed between urban and rural populations in changing their behavior for hypertension control. ^ The results showed that rural populations had more difficulties than urban populations in avoiding smoking and engaging in physical activity, and the processes of change being used by urban populations were significantly greater than rural populations. The study findings support a strong association between processes and stages of change. ^ Individuals who use more processes of change will be more inclined to move from precontemplation stage to maintenance stage. Counterconditioning, which is the substitution of alternatives for the problem behaviors, in this study, significantly helped people to change diet, engage in physical activity, and check blood pressure regularly. For example, counterconditioning is eating more vegetables instead of meat, or engaging in physical activity as a time to relax rather than another task to accomplish. ^ In addition, self-reevaluation was the most important process for helping people to engage in physical activity; and social liberation was the most important process for changing diet behavior. The findings in this study may be applied to improve health behaviors among rural populations with low income and low education; however, at the same time, the obesity problems among urban populations should be prevented to control hypertension in Taiwan. ^

Candidate gene identification following linkage: Search for hypertension susceptibility genes

Following up genetic linkage studies to identify the underlying susceptibility gene(s) for complex disease traits is an arduous yet biologically and clinically important task. Complex traits, such as hypertension, are considered polygenic with many genes influencing risk, each with small effects. Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contribute to blood pressure levels and hypertension status. Using combined positional candidate gene methods, the Family Blood Pressure Program has concentrated efforts in investigating this region of chromosome 2 in an effort to identify underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in eight positional candidate genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. To adjust for multiple comparisons, resampling-based false discovery adjustment was applied, extending traditional resampling methods to sibship samples. Following this adjustment for multiple comparisons, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two populations of African Americans (N = 461; N = 778) and two of whites (N = 550; N = 967). Again, SNPs within SLC4A5 were significantly associated with blood pressure levels and hypertension status. While not identifying a single causal DNA sequence variation that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene, validating previous evidence for one or more genes on chromosome 2 that influence hypertension related phenotypes in the population-at-large. The methodology and results reported provide a case study of one approach for following up the results of genetic linkage analyses to identify genes influencing complex traits. ^

Characterization of glucocorticoid receptor (NR3C1) gene polymorphisms and a family-based association study with hypertension

Hypertension is usually defined as having values of systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg. Hypertension is one of the main adverse effects of glucocorticoid on the cardiovascular system. Glucocorticoids are essential hormones, secreted from adrenal glands in circadian fashion. Glucocorticoid's effect on blood pressure is conveyed by the glucocorticoid receptor (NR3C1), an omnipresent nuclear transcription factor. Although polymorphisms in this gene have long been implicated to be a causal factor for cardiovascular diseases such as hypertension, no study has yet thoroughly interrogated the gene's polymorphisms for their effect on blood pressure levels. Therefore, I have first resequenced ∼30 kb of the gene, encompassing all exons, promoter regions, 5'/3' UTRs as well as at least 1.5 kb of the gene's flanking regions from 114 chromosome 5 monosomic cell lines, comprised of three major American ethnic groups—European American, African American and Mexican American. I observed 115 polymorphisms and 14 common molecularly phased haplotypes. A subset of markers was chosen for genotyping study populations of GENOA (Genetic Epidemiology Network of Atherosclerosis; 1022 non-Hispanic whites, 1228 African Americans and 954 Mexican Americans). Since these study populations include sibships, the family-based association test was performed on 4 blood pressure-related quantitative variables—pulse, systolic blood pressure, diastolic blood pressure and mean arterial pressure. Using these analyses, multiple correlated SNPs are significantly protective against high systolic blood pressure in non-Hispanic whites, which includes rsb198, a SNP formerly associated with beneficial body compositions. Haplotype association analysis also supports this finding and all p-values remained significant after permutation tests. I therefore conclude that multiple correlated SNPs on the gene may confer protection against high blood pressure in non-Hispanic whites. ^

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. ^

A case-control study of medication-associated acute kidney injuries in hospitalized pediatric patients

Acute kidney Injury (AKI) in hospitalized pediatric patients can be a significant event that can result in increased patient morbidity and mortality. The incidence of medication associated AKI is increasing in the pediatric population. Currently, there are no data to quantify the risks of developing AKI for various potentially nephrotoxic medications. The primary objective of this study was to determine the odds of nephrotoxic medication exposure in hospitalized pediatric patients with AKI as defined by the pediatric modified pRIFLE criteria. A retrospective case-control study was performed with patients that developed AKI, as defined by the pediatric pRIFLE criteria, as cases, and patients without AKI as controls that were matched by age category, gender, and disease state. Patients between 1 day and 18 years of age, admitted to a non-intensive care unit at Texas Children's Hospital for at least 3 days, and had at least 2 serum creatinine values drawn were included. Patient data was analyzed with Student's t test, Mann-Whitney U test, Chi square analysis, ANOVA, and conditional logistic regression. ^ Out of 1,660 patients identified for inclusion, 561 (33.8%) patients had AKI, and 357 cases were matched with 357 controls to become pairs. Of the cases, 441 were category 'R', 117 category 'I', 3 patients were category 'F', and no patient died. Cases with AKI were significantly younger than controls (p < 0.05). Significantly longer hospital length of stays, increased hospital costs, and exposure to more nephrotoxic medications for a longer period of time were characteristics of patients with AKI compared to patient without AKI. Patients with AKI had greater odds of exposure to one or more nephrotoxic medication than patients without AKI (OR 1.3, 95% CI 1.1–1.4, p < 0.05). Percent changes in estimated creatinine clearance (eCCl) from baseline were greatest with increased number of nephrotoxic medication exposures. ^ Exposure to potentially nephrotoxic medications may place pediatric patients at greater risk of acute kidney injury. Multiple nephrotoxic medication exposure may confer a greater risk of development of acute kidney injury, and result in increased hospital costs and patient morbidity. Due to the high percentage of patients that were exposed to potentially nephrotoxic medications, monitoring and medication selection strategies may need to be altered to prevent or minimize risk.^

THE RELATIONSHIP BETWEEN DEGREE OF BLOOD PRESSURE REDUCTION AND MORTALITY AMONG HYPERTENSIVES IN THE HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM

The relationship between degree of diastolic blood pressure (DBP) reduction and mortality was examined among hypertensives, ages 30-69, in the Hypertension Detection and Follow-up Program (HDFP). The HDFP was a multi-center community-based trial, which followed 10,940 hypertensive participants for five years. One-year survival was required for inclusion in this investigation since the one-year annual visit was the first occasion where change in blood pressure could be measured on all participants. During the subsequent four years of follow-up on 10,052 participants, 568 deaths occurred. For levels of change in DBP and for categories of variables related to mortality, the crude mortality rate was calculated. Time-dependent life tables were also calculated so as to utilize available blood pressure data over time. In addition, the Cox life table regression model, extended to take into account both time-constant and time-dependent covariates, was used to examine the relationship change in blood pressure over time and mortality.^ The results of the time-dependent life table and time-dependent Cox life table regression analyses supported the existence of a quadratic function which modeled the relationship between DBP reduction and mortality, even after adjusting for other risk factors. The minimum mortality hazard ratio, based on a particular model, occurred at a DBP reduction of 22.6 mm Hg (standard error = 10.6) in the whole population and 8.5 mm Hg (standard error = 4.6) in the baseline DBP stratum 90-104. After this reduction, there was a small increase in the risk of death. There was not evidence of the quadratic function after fitting the same model using systolic blood pressure. Methodologic issues involved in studying a particular degree of blood pressure reduction were considered. The confidence interval around the change corresponding to the minimum hazard ratio was wide and the obtained blood pressure level should not be interpreted as a goal for treatment. Blood pressure reduction was attributed, not only to pharmacologic therapy, but also to regression to the mean, and to other unknown factors unrelated to treatment. Therefore, the surprising results of this study do not provide direct implications for treatment, but strongly suggest replication in other populations. ^

Mexican Americans' awareness, knowledge, and beliefs of hypertension

Cardiovascular disease (CVD) is the number one cause of death for people in Texas as well as Mexico. The progressive morbidity and mortality of CVD can be prevented initially and controlled through regular health screenings or visits to the physician where health markers such as hypertension can be detected and treated. Yet, many people go unaware of existing hypertension not only due to lack of access to health care but to their own personal beliefs, ideas, or perceived barriers that prevent them from seeking preventative health care. ^ The main purpose of this study was to evaluate whether individuals of Mexican origin, who have some form of medical coverage, posses more knowledge, more perceived severity, less perceived barriers, and greater self-efficacy in regards to hypertension than those individuals who have no medical coverage. This was done by addressing the following specific aims: 1.To evaluate the association between individuals who have health care coverage and those who do not have health care coverage in regards to their beliefs of hypertension; 2. To evaluate if there exists a variation among the respondents demographic data and their beliefs of hypertension. ^ The total number of respondents were 150; with 75 being from Cuidad Juarez, and 75 being from El Paso, Texas. The results indicated that the individuals with some form of medical coverage perceived themselves to be more susceptible to suffering a cardiac event or developing heart disease than those who had no form of medical coverage. The individuals with some form of health care coverage also found themselves having less perceived barriers than those who had no health care coverage. The level of education seemed to have some association with individuals perceiving themselves as being susceptible to experiencing a cardiac event if they do not control their hypertension. Regarding self-efficacy, or the self-reported confidence in performing certain behaviors to controlling hypertension, those individuals who perceived themselves as having no self-efficacy had a lower level of education, compared to those who did perceive themselves as possessing self-efficacy. The findings of this study indicate that beliefs regarding hypertension and medical coverage are variables that need to be investigated further for individuals in the El Paso and Cuidad Juarez region. ^

Patient-centered medical home technology effects on hypertension and diabetes control

Background: Hypertension and Diabetes is a public health and economic concern in the United States. The utilization of medical home concepts increases the receipt of preventive services, however, do they also increase adherence to treatments? This study examined the effect of patient-centered medical home technologies such as the electronic health record, clinical support system, and web-based care management in improving health outcomes related to hypertension and diabetes. Methods: A systematic review of the literature used a best evidence synthesis approach to address the general question " Do patient-centered medical home technologies have an effect of diabetes and hypertension treatment?" This was followed by an evaluation of specific examples of the technologies utilized such as computer-assisted recommendations and web-based care management provided by the patient's electronic health record. Ebsco host, Ovid host, and Google Scholar were the databases used to conduct the literature search. Results: The initial search identified over 25 studies based on content and quality that implemented technology interventions to improve communication between provider and patient. After further assessing the articles for risk of bias and study design, 13 randomized controlled studies were chosen. All of the studies chosen were conducted in various primary care settings in both private practices and hospitals between the years 2000 and 2007. The sample sizes of the studies ranged from 42 to 2924 participants. The mean age for all of the studies ranged from 56 to 71 years. The percent women in the studies ranged from one to 78 percent. Over one-third of the studies did not provide the racial composition of the participants. For the seven studies that did provide information about the ethnic composition, 64% of the intervention participants were White. All of the studies utilized some type of web-based or computer-based communication to manage hypertension or diabetes care. Findings on outcomes were mixed, with nine out of 13 studies showing no significant effect on outcomes examined, and four of the studies showing significant and positive impact on health outcomes related to hypertension or diabetes Conclusion: Although the technologies improved patient and provider satisfaction, the outcomes measures such as blood pressure control and glucose control were inconclusive. Further research is needed with diverse ethnic and SES population to investigate the role of patient-centered technologies on hypertension and diabetes control. Also, further research is needed to investigate the effects of innovative medical home technologies that can be used by both patients and providers to increase quality of communication concerning adherence to treatments.^

Analysis of interval -censored events in hypertension studies: Evaluation of treatment of coronary heart disease

Many statistical studies feature data with both exact-time and interval-censored events. While a number of methods currently exist to handle interval-censored events and multivariate exact-time events separately, few techniques exist to deal with their combination. This thesis develops a theoretical framework for analyzing a multivariate endpoint comprised of a single interval-censored event plus an arbitrary number of exact-time events. The approach fuses the exact-time events, modeled using the marginal method of Wei, Lin, and Weissfeld, with a piecewise-exponential interval-censored component. The resulting model incorporates more of the information in the data and also removes some of the biases associated with the exclusion of interval-censored events. A simulation study demonstrates that our approach produces reliable estimates for the model parameters and their variance-covariance matrix. As a real-world data example, we apply this technique to the Systolic Hypertension in the Elderly Program (SHEP) clinical trial, which features three correlated events: clinical non-fatal myocardial infarction, fatal myocardial infarction (two exact-time events), and silent myocardial infarction (one interval-censored event). ^