Hypertension and aging in rural Haiti: results from a preliminary survey.

Cross-sectional studies in the developed countries document strong relationships among age, systolic blood pressure (SBP) and pulse pressure (PP). There is little information about these trends and their impact in underdeveloped countries with different socioeconomic and lifestyle characteristics. We studied a convenience sample of 572 residents of rural Fontaine, Haiti: 193 males and 379 females (mean, s.d.) age 40.2 (17.1) years and performed intake questionnaires and BP measurements in participants' homes. Income and educational achievement were very low but most-recommended lifestyle factors were very favorable: very high physical activity, low dietary fat, virtually no obesity (body mass index 21.8 (4.9)), and low smoking prevalence. Rough estimates of salt intake were high (~13 g per day) as was the overall prevalence of hypertension: 34.4% (23.4% in males, 40.2% in females). SBP and PP were related closely to age (r2=0.28, P<0.001 and r2=0.22, P<0.001); for each decade of age, SBP increased by 7.6 mm Hg. Diastolic BP peaked in the 6th decade (polynomial r2=0.22, P<0.001) and the nadir of PP occurred in the 3rd decade. We conclude that, despite a favorable profile of lifestyle characteristics and no obesity, the prevalence of hypertension and rate of increase in SBP and PP with age in Haiti are at least as high as those of developed countries.

Office and ambulatory pulse pressure--association with clinical characteristics and cardiovascular risk factors in normoalbuminuric patients with type 2 diabetes (ROADMAP study).

To investigate the association of office and ambulatory 24-h pulse pressure (PP) with clinical characteristics and cardiovascular risk factors in normoalbuminuric type 2 diabetic patients enrolled to the Randomised Olmesartan and Diabetes Microalbuminuria Prevention study, 4449 patients (2054 male and 2395 female; mean age 57.7±8.7 years) with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor were included into the analysis. After adjustment by age, there were significant correlations between office PP and presence of hypertension (r=0.24; P<0.001), presence of cardiac and vascular disorders (r=0.17; P<0.001), metabolic syndrome (r=0.10; P<0.001), duration of diabetes (r=0.09; P<0.001), fasting blood glucose (r=0.08; P<0.001), albumin/creatinine ratio (r=0.07; P<0.001), insulin treatment, glycosylated haemoglobin (HbA1c), male gender and current smoking. In the subgroup of 1234 patients with ambulatory blood pressure measurement performed, ambulatory PP adjusted for office PP correlated with fasting blood glucose (r=0.16; P<0.001), metabolic syndrome (r=0.14; P<0.001), albumin/creatinine ratio (r=0.11; P<0.001) and indices of glycemic control (HbA1c: r=0.11; P<0.001). In this group of normoalbuminuric type 2 diabetic patients, office and ambulatory PP were associated with duration of diabetes, indices of glycemic control and cardiovascular risk factors. There was relationship between office and ambulatory PP and albuminuria even within normal albuminuria range.

Seasonal variation in haemodynamics and blood pressure-regulating hormones.

Seasonal variation in blood pressure (BP) has been described in some people, although the variation is small for both systolic and diastolic BPs. The aim of this study was to elucidate underlying haemodynamic and hormonal mechanisms that may occur to defend seasonal changes in BP. Participants were 27 men and 7 women with either normal BP or early hypertension. Measurements of haemodynamics (cardiac output by dual-gas rebreathing) and hormones (resting catecholamines, renin activity, and aldosterone by radioenzymatic assay or radioimmunoassay) were performed during the summer, fall, winter, and spring seasons. Student's paired t-test with Bonferroni modification and regression analyses were used to examine the data with a significance level of P<0.05. Systolic and diastolic BP remained relatively constant across seasons. Cardiac output and stroke volume significantly decreased 10 and 15%, respectively, from summer to winter, whereas heart rate and systemic vascular resistance significantly increased 5 and 11%, respectively. Plasma aldosterone (PA) significantly increased 59% from summer to winter, whereas plasma norepinephrine (PNE), plasma epinephrine, and plasma renin activity (PRA) increased 19, 2, and 17%, respectively (pNS for each). Across the four seasons, mean arterial pressure significantly correlated with PRA and PA, whereas systemic vascular resistance significantly correlated with PNE and PRA. There are dramatic counterregulatory haemodynamic and hormonal adaptations to maintain a relatively constant BP. Norepinephrine, PRA, and aldosterone have a function in mediating the changes in haemodynamics.

Determinants of urinary albumin excretion within the normal range in patients with type 2 diabetes: the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.

AIMS/HYPOTHESIS: In contrast to microalbuminuric type 2 diabetic patients, the factors correlated with urinary albumin excretion are less well known in normoalbuminuric patients. This may be important because even within the normoalbuminuric range, higher rates of albuminuria are known to be associated with higher renal and cardiovascular risk. METHODS: At the time of screening for the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Study, the urinary albumin/creatinine ratio (UACR) was 0.44 mg/mmol in 4,449 type 2 diabetic patients. The independent correlates of UACR were analysed. RESULTS: Independent correlates of UACR during baseline were (in descending order): night-time systolic BP (r(s) = 0.19); HbA(1c) (r(s) = 0.18); mean 24 h systolic BP (r(s) = 0.16); fasting blood glucose (r(s) = 0.16); night-time diastolic BP (r(s) = 0.12); office systolic BP, sitting (r(s) = 0.11), standing (r(s) = 0.10); estimated GFR (r(s) = 0.10); heart rate, sitting (r(s) = 0.10); haemoglobin (r(s) = -0.10); triacylglycerol (r(s) = 0.09); and uric acid (r(s) = -0.08; all p

Comparative efficacy and safety of amlodipine/benazepril combination therapy and amlodipine monotherapy in severe hypertension.

This multicentre, double-blind, trial in subjects with severe hypertension compared the efficacy and tolerability of two parallel drug regimens: A/B (amlodipine/benazepril: 5/20 or 10/40 mg daily, if necessary) with A (amlodipine: 5 or 10 mg daily, if necessary). The principal dependent variable was the proportion of patients achieving goal blood pressures (BP<140/90 mm Hg or BP<130/80 mm Hg in diabetes or chronic kidney disease) in the two groups within 6 weeks. In the 259 randomized subjects, BP control rates were higher with A/B at 2, 4 and 6 weeks (10.5, 22, and 33.6%, respectively) compared with A (5.7, 16, and 25.8 %, respectively). Corresponding trended BP reductions from baseline at 2, 4 and 6 weeks were about 5 mm Hg greater with A/B (-21+/-16, -26+/-17 and -30+/-17 mm Hg, respectively, compared with A (-16+/-17, -23+/-18 and 25+/-19 mm Hg, respectively, P<0.01). Both regimens were well tolerated; incidences of peripheral oedema at weeks 4 and 6 were similar (A/B: 13 and 20% versus A: 20 and 22%, P=not significant). We conclude that titration of amlodipine and benazepril in single-pill combinations is more effective than titration of amlodipine alone for rapid BP control in patients with severe hypertension.

Therapy-induced expression of NF-kappaB portends poor prognosis in patients with localized esophageal cancer undergoing preoperative chemoradiation.

Activated nuclear factor-kappa B (NF-kappaB) in the pretreatment cancer tissue of patients with localized esophageal adenocarcinoma (LEA) undergoing preoperative chemoradiation is associated with poor prognosis. It is known that constitutively activated NF-kappaB prior to any therapy portends poor prognosis, and it is also known that activated NF-kappaB in the treated specimen is associated with poor prognosis. However, the prognosis of patients who have treatment-induced activation of NF-kappaB (meaning their cancers activate NF-kappaB during or after therapy) is not been reported. We hypothesized that the treatment-induced activation of NF-kappaB would impart poor prognosis similar to that imparted by constitutively activated NF-kappaB cancer. Patients with LEA who had undergone preoperative chemoradiation plus surgery and had pre- and post-therapy cancer tissue available were selected. Pre- and post-therapy cancer tissues were stained by immunohistochemistry for nuclear staining of NF-kappaB. The overall survival (OS) and disease-free survival were assessed and compared for patients who had intrinsic constitutively activated NF-kappaB cancer with those who had induced activation of NF-kappaB only post-therapy. A total of 41 patients with LEA were investigated. Twenty-five patients had NF-kappaB positive cancer at baseline, and 16 had NF-kappaB negative cancer at baseline but became positive post-therapy. There was no difference in the location, histology grade, clinical stage, or the curative resection (RO) resection rate in the two populations. OS (P = 0.71), disease-free survival (P = 0.86), and median survivals (Converters: 24 months [95% confidence intervals: 7.78 to 40.22]vs. Nonconverters: 34.13 months [95% confidence intervals: 3.54 to 64.27]) were not different between the two groups. Our data suggest that activation of NF-kappaB in response to stress/injury of therapy leads to poor OS. These results need to be confirmed in a larger number of patients. It may be that only pre-therapy evaluation of NF-kappaB is insufficient to assess prognosis of patients with LEA. Additional implications include that when effective anti-NF-kappaB therapies become available, they may have to be considered in patients whose cancers do not have constitutively activated NF-kappaB or cancer may have to be monitored during therapy with biomarker assessments.

Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport.

A major obstacle to successful chemotherapy is intrinsic or acquired multi-drug resistance (MDR). The most common cause of MDR involves increased drug efflux from cancer cells mediated by members of the ATP-binding cassette (ABC) transporter family. The regulation of ABC transporters in the context of cancer is poorly understood, and clinical efforts to inhibit their function have not been fruitful. Constitutive activation of the Hedgehog (Hh) pathway has been shown to contribute to the growth and maintenance of various cancers. Here, we show that inhibition of Hh signaling increases the response of cancer cells to multiple structurally unrelated chemotherapies. We further show that Hh pathway activation induces chemoresistance in part by increasing drug efflux in an ABC transporter-dependent manner. We found that Hh signaling regulates the expression of the ABC transporter proteins multi-drug resistance protein-1 (MDR1, ABCB1, P-glycoprotein) and (BCRP, ABCG2), and that targeted knockdown of MDR1 and BCRP expression by small interfering RNA partially reverses Hh-induced chemoresistance. These results suggest that the Hh pathway may be a target to overcome MDR and increase chemotherapeutic response.

Office blood pressures, arterial compliance characteristics, and estimated cardiac load.

Because of rising interest in new methods to detect arterial diseases, we compared data from 3 different compliance-related techniques to measure arterial stiffness: systolic pulse contour analysis, diastolic pulse contour analysis (modified Windkessel model), and muscular (brachial) artery compliance by cuff plethysmography. Variables measured in the sitting position were compared with each other, with clinic blood pressures (BPs), and with the cardiac time-tension integral (CTTI) in 63 established hypertensive and 28 age-matched normotensive subjects. Hypertensives demonstrated marginal reductions in C(1) (thought to represent reduced large vessel compliance) and increased central systolic BP augmentation. In contrast, muscular artery compliance tended to be greater in the hypertensives despite normal brachial arterial diameters. C(2), suggested to be an indicator of small artery properties, was similar in both groups. CTTI was strongly related to systolic pressure (r=0.81), integrated mean arterial pressure (r=0.83), and systolic pressure-heart rate product (r=0.85) and was less strongly related to diastolic (r=0.71) or pulse pressure (r=0.57). Weak correlations were observed between CTTI and measured compliance-related variables, which also showed absent or weak correlations among themselves. We conclude that the weak relationships among BP and compliance-related variables could be due to intrinsic differences in the properties of large and small arteries, theoretical methodological weaknesses, measurement artifacts, or intrinsic hemodynamic differences of the sitting position. At present, compliance-related variables provide little additional advantage over cuff BP in the office estimation of cardiac work.

Characterization and drug sensitivity of four newly established colon adenocarcinoma cell lines to antifolate inhibitors of thymidylate synthase.

Four new cell lines were established from the primary tumors of patients with untreated colorectal adenocarcinoma. Drug sensitivity and characterization of these cell lines was performed. Three of the four cell lines formed colonies in soft agar and all were tumorigenic in nude mice. The cell lines were morphologically similar but had differences in growth characteristics. Two of the cell lines, C18 (CCCL-4) and C29 (CCCL-6), had a longer doubling time compared with C85 (CCCL-1) and C86 (CCCL-2). The C18 and C29 cell lines had chromosome 17 abnormalities and evidence by immunohistochemistry of a mutant p53 and had decreased levels of thymidylate synthase and dihydrofolate reductase proteins, associated with decreased thymidylate synthase catalytic activity in C18 and no detectable activity in C29. Raltitrexed and GW1843U89 showed potent cytotoxic activity and all four cell lines displayed similar cytotoxicity to these folate thymidylate synthase inhibitors. The C18 and C29 cell lines were in general resistant to the other agents tested (methotrexate, 5-fluorouracil, nolatrexed) when compared with the C85 and C86 cell lines. These new cell lines may be useful for the study of colorectal adenocarcinoma and for evaluating new drugs or treatment schedules.

Pet ownership, but not ace inhibitor therapy, blunts home blood pressure responses to mental stress.

In the present study, we evaluated the effect of a nonevaluative social support intervention (pet ownership) on blood pressure response to mental stress before and during ACE inhibitor therapy. Forty-eight hypertensive individuals participated in an experiment at home and in the physician's office. Participants were randomized to an experimental group with assignment of pet ownership in addition to lisinopril (20 mg/d) or to a control group with only lisinopril (20 mg/d). On each study day, blood pressure, heart rate, and plasma renin activity were recorded at baseline and after each mental stressor (serial subtraction and speech). Before drug therapy, mean responses to mental stress did not differ significantly between experimental and control groups in heart rate (94 [SD 6.8] versus 93 [6.8] bpm), systolic blood pressure (182 [8.0] versus 181 [8.3] mm Hg), diastolic blood pressure (120 [6.6] versus 119 [7.9] mm Hg), or plasma renin activity (9.4 [0.59] versus 9.3 [0.57] ng. mL(-1). h(-1)). Lisinopril therapy lowered resting blood pressure by approximately 35/20 mm Hg in both groups, but responses to mental stress were significantly lower among pet owners relative to those who only received lisinopril (P<0.0001; heart rate 81 [6.3] versus 91 [6.5] bpm, systolic blood pressure 131 [6.8] versus 141 [7.8] mm Hg, diastolic blood pressure 92 [6.3] versus 100 [6.8] mm Hg, and plasma renin activity 13.9 [0.92] versus 16.1 [0.58] ng. mL(-1). h(-1)). We conclude that ACE inhibitor therapy alone lowers resting blood pressure, whereas increased social support through pet ownership lowers blood pressure response to mental stress.

Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: role in response to chemoprevention and cancer development.

PURPOSE: To better understand the role of G(1)-S transition regulator abnormalities in the pathogenesis of advanced premalignant lesions of the upper aerodigestive tract and the biological effects of chemoprevention, we studied biopsies obtained sequentially from participants in a prospective trial using 13-cis retinoic acid, IFN-alpha, and alpha-tocopherol for 12 months. EXPERIMENTAL DESIGN: Cyclin D1 and p16 expression were analyzed by immunohistochemistry, loss of heterozygosity by polymerase chain reacting amplification, and then electrophoretic separation of the products, methylation of the p16 promoter by methylation-specific polymerase chain reacting, and cyclin D1 gene amplification by fluorescence in situ hybridization. RESULTS: Baseline dysregulation of cyclin D1 expression was found in 50% (14 of 28) and was reversed in 6 of 14 cases, whereas p16 expression was lost in 46% (13 of 28) and regained in 2 of 13 cases. Loss of heterozygosity at 9p21 occurred in 68% and p16(INK4a) promoter methylation occurred in 75% of cases, with increasing frequency from mild to severe dysplasia. Cyclin D1 gene amplification was identified in two cases. Cyclin D1 protein dysregulation at last follow-up alone and in combination with p16 loss was associated with histological progression and cancer development (P < 0.01). CONCLUSIONS: Additional study of these alterations in a larger sample and exploration of the upstream signaling partners of these cell cycle regulators in vivo is warranted to identify cancer risk profiles that would be meaningful targets for chemopreventive intervention.

Diameter, pressure and compliance relationships in dorsal hand veins.

The diameter-pressure characteristics of dorsal hand veins previously have not been characterized. In this study, the effects of distending pressure with and without infused norepinephrine on diameter and compliance were observed. The elevation needed for venous collapse was measured, and the effects of baseline constriction on venous reactivity were assessed. In seven supine subjects, a brachial cuff on an elevated arm was used to generate distending pressures while a linear variable displacement transformer (LVDT) measured changes in venous diameter. Arctangent functions of distending pressure were fitted to the normalized diameter, then compliance functions were calculated. In supine subjects, 5-15 cm of elevation emptied dorsal hand veins. Norepinephrine decreased the venous diameter at any distending pressure by increasing the P50 without significantly changing the midpoint slope. Compliance was a nearly single-valued function of the normalized diameter with a maximum value at about 60% distention. Reactivity depends on distending pressure and baseline P50. Percentage constriction is a function of initial and final P50 and of distending pressure.

Acid-suppressive therapy use associated with antihypertensive agents.

Nitrates and calcium channel blockers (CCBs) have been shown to decrease lower esophageal sphincter pressure and theoretically may precipitate or aggravate gastroesophageal reflux. Thus, the authors hypothesized that patients who receive these agents would have greater use of acid-suppressive drug use, defined as histamine2 antagonists or proton pump inhibitors. A retrospective cohort design was used to assess the use of acid-suppressive drug use in hypertensive patients with respect to both nitrates and antihypertensive therapy. Of 15,662 treated hypertensive patients, 20% received acid-suppressive therapy. An increased use of acid-suppressive therapy was associated with nitrate (odds ratio [OR] = 1.71), CCB (OR = 1.46), and alpha 1 antagonist (OR = 1.32) treatment, which appeared to be additive when patients received two or more of the agents. Within the class of CCBs, there was no significant difference among the individual agents. As the clinical and economic burden may be substantial, further study is warranted.

Treatment of hypertension in a managed care setting.

BACKGROUND: Based on recommendations of the Fifth and Sixth Reports of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, Health Care Plan (now Univera Healthcare) Buffalo, NY, developed a clinical guideline to improve the management of patients with hypertension. To increase awareness and utilization, the guideline was distributed as hard copy reports and made available through our electronic information system. OBJECTIVE: To determine blood pressure (BP) control rates and adherence to guideline recommendations. STUDY DESIGN: Retrospective chart review. PATIENTS AND METHODS: We randomly sampled hypertensive patients seen during 1998 to evaluate hypertension management. Computerized medical and pharmacy records were reviewed for patient demographics, antihypertensive medications, comorbid conditions, and BP readings. Patient assessment was based on antihypertensive regimen and achievement of target BP according to the recommendations of the guidelines (< 140/90 mm Hg for the general population and < 130/85 mm Hg for special populations). In addition, we assessed control rates using traditional Health Plan Employer Data and Information Set (HEDIS) measures (< 140/90 mm Hg). RESULTS: Overall, 35% of patients achieved target BP and 68% were treated with agents recommended by our JNC-based guideline. In contrast, using traditional HEDIS measures, 41% of patients achieved BP control. Of 39 patients with compelling indications (primarily diabetic patients), 13% achieved BP target and 67% were treated with recommended agents. CONCLUSIONS: The impact of our clinical guideline is reflected through the relatively high utilization of recommended drugs. However, optimal BP control continues to be problematic. In particular, patients with diabetes warrant focused attention.

[Biomarkers of carcinogenesis of the upper and lower airway epithelium and the role of chemoprevention]. / Biomarqueurs de carcinogenèse des voies aériennes et place de la chimioprévention.

Lung as well as head and neck cancer represent an important public health problem worldwide, with lung cancer being the leading cause of cancer death in western countries. Although early stage disease is often curable with surgery or radiotherapy, the majority of patients present with advanced disease in which despite advances in combined modality therapy the outcomes have not dramatically improved. Furthermore, patients cured of their initial early stage lung or head and neck carcinoma are at high risk for development of second primary tumors, which pose the main threat to their survival. An alternative approach in reducing the incidence and thus mortality of these cancers is chemoprevention, the use of agents to reverse, halt or delay carcinogenesis. The carcinogenesis process in lung and head and neck cancer results from a dysregulation of cellular proliferation, differentiation and cell death resulting from field-wide exposure of the upper and lower airway track to tobacco smoking. This review article presents main data regarding the actual understanding of lung and head and neck carcinogenesis, as well as results of major chemoprevention trials in this field.

Normalization of hypertensive responses during ambulatory surgical stress by perioperative music.

OBJECTIVE: The purpose of this study was to determine whether cognitive appraisals of stress level and hypertensive responses to ambulatory ophthalmic surgery can be ameliorated by patient-selected music. METHODS: We studied 40 elderly individuals requiring ophthalmic surgery, 20 in an experimental group (mean age, 74 years) and 20 in a control group (mean age, 77 years). All patients had an established resting blood pressure <140/90 mm Hg. In the experimental group self-selected music was provided by headphones throughout the preoperative, surgical, and postoperative periods. In the control group patients had neither headphones nor music. All patients received similar (weight-determined) doses of alfentanil and midazolam during surgery. Heart rate, blood pressure, and patient-reported stress and coping levels were the dependent variables. RESULTS: In both groups, blood pressure values were normal (approximately 129/82 mm Hg) during screening examinations 1 week before surgery. On the day of surgery both groups displayed increased preoperative blood pressures (approximately 159/92 mm Hg) associated with increases in heart rate (by approximately 17 beats/min). Intraoperative blood pressures in the experimental group returned quickly to screening baseline values, whereas the control group experienced persistent elevations in intraoperative blood pressure similar to preoperative levels. Over the course of the surgical experience, patients with music reported significant reductions in perceived stress and increases in coping abilities (p < .001), whereas those without music did not. CONCLUSIONS: The perceived stress of ambulatory surgery in geriatric patients is associated with a clinical hypertensive response that is ameliorated by self-selected perioperative music, which also decreases perceived stress and increases patients' sense of personal control and well-being.

Arterial stiffness: clinical relevance, measurement, and treatment.

Hardening of the pulse, first described thousands of years ago by Chinese healers, was known even then to be an adverse prognostic sign. In Western medicine, the association of aging, increased large-arterial stiffness, and systolic hypertension has been recognized for more than a century. Yet the adverse consequences of age-related arterial stiffness still receive little attention in everyday clinical practice, perhaps because clinicians assume that nothing can be done about the process. Recent developments, however, suggest that improved clinical recognition of age-related vascular stiffening will lead to better therapy and improved outcomes for patients with hypertension.

Systolic hypertension, arterial stiffness, and vascular damage: role of the renin-angiotensin system.

The field of hypertension is entering an exciting new era in which new concepts in basic and clinical science are being rapidly translated into new recommendations for clinical practice. It is now readily apparent that an age-related increase in stiffness of the walls of the large arteries causes the predominant hemodynamic characteristic of hypertension in later life: increased systolic blood pressure. Systolic hypertension is now recognized to have greater prognostic significance than diastolic hypertension, and it is also known that the effective treatment of systolic hypertension confers a proportional benefit in risk reduction. A rapidly advancing knowledge of vascular biology has revealed that the renin-angiotensin system plays a central role in the pathogenesis of vascular hypertrophy and arterial stiffness. Angiotensin-converting enzyme inhibitors have been shown to reduce arterial stiffness to a greater degree than diuretics or beta-blockers. The pharmacologic interruption of the renin-angiotensin system may therefore confer previously unrecognized benefits on age-related vascular damage, providing special benefits in systolic hypertension.