Impact of primary platinum-free interval and BRCA1/2 mutation status on treatment and survival in patients with recurrent ovarian cancer.

OBJECTIVE: To understand the relationship between primary platinum-free interval (PFI), BRCA mutation status, and overall survival (OS) in patients with recurrent ovarian cancer receiving multiple lines of therapy in a multicenter, community-based, retrospective observational cohort study of adult patients with stage III-IV high-grade ovarian cancer. METHODS: Data were retrospectively obtained from the electronic health record (EHR) of a US community oncology network, including patient characteristics, subsequent treatments, primary PFI, and BRCA status. OS was analyzed by the Kaplan-Meier method, stratified by primary PFI and BRCA status. RESULTS: 750 patient charts were reviewed. BRCA testing status was known in 267 patients (16% BRCA mutation). Among patients with identified recurrent disease, 41% had a primary PFI <6months and 59% had a primary PFI ≥6months. Of second-line patients, 59% received third-line therapy, and 60% of third-line patients received fourth-line therapy within the period of observation. Median OS from the start of primary treatment for the entire population was 41.4months (95% CI, 39.0-48.3months). Median OS was significantly increased in patients with primary PFI ≥6months at second-line and third-line (P<0.0001 and P=0.002, respectively). Survival was observed to be increased among patients with BRCA mutations across multiple treatment lines, although this was not statistically significant. CONCLUSIONS: Patients with a primary PFI ≥6months demonstrated improved outcomes over multiple lines of therapy. BRCA status was known in 36% of patients, and those patients with a BRCA mutation demonstrated a trend toward delayed primary recurrence and improved clinical outcomes.

Does the association between adherence to statin medications and mortality depend on measurement approach? A retrospective cohort study.

BACKGROUND: The aim of this study was to examine the relationship between mortality and statin adherence using two different approaches to adherence measurement (summary versus repeated-measures). METHODS: A retrospective cohort study was conducted using administrative data from Saskatchewan, Canada between 1994 and 2008. Eligible individuals received a prescription for a statin following hospitalization for acute coronary syndrome (ACS). Adherence was measured using proportion of days covered (PDC) expressed either as: 1) a fixed summary measure, or 2) as a repeatedly measured covariate. Multivariable Cox-proportional hazards models were used to estimate the association between adherence and mortality. RESULTS: Among 9,051 individuals, optimal adherence (≥80%) modeled with a fixed summary measure was not associated with mortality benefits (adjusted HR 0.97, 95% CI 0.86 to 1.09, p = 0.60). In contrast, repeated-measures approach resulted in a significant 25% reduction in the risk of death (adjusted HR 0.75, 95% CI 0.67 to 0.85, p < 0.01). CONCLUSIONS: Unlike the summary measure, the repeated measures approach produces a significant reduction of all-cause mortality with optimal adherence. This effect may be a result of the repeated measures approach being more sensitive, or more prone to survival bias. Our findings clearly demonstrate the need to undertake (and report) multiple approaches when assessing the benefits of medication adherence.

Multiple-domain Versus Single-domain Measurements of Socioeconomic Status (SES) for Predicting Nonadherence to Statin Medications: An Observational Population-based Cohort Study.

INTRODUCTION: Low socioeconomic status (SES) should be a robust predictor of medication nonadherence because it shares key features with the theoretical origins of this phenomenon. However, population-based studies have demonstrated weak associations overall, possibly because SES is inadequately represented. We compared the performance of multiple versus single-domain measures of SES as predictors of statin adherence. METHODS: This retrospective cohort study used population-based administrative data mapped to area-level census information of individuals who received a statin medication following a hospitalization for coronary heart disease. One-year adherence was calculated by dividing the sum of all tablets dispensed by the total number of days in the observation period (365 d following the first statin dispensation). Logistic regression models were constructed and the relative impact of each SES measure was assessed by its adjusted odds ratio (OR) and improvement over the predictive accuracy of a reference model that included non-SES factors only. RESULTS: More than two thirds (ie, 68.8%; 6517/9478) of eligible individuals exhibited optimal adherence (ie, ≥80%). The estimated impact of SES on optimal adherence differed depending on the SES measure tested. The highest performing single-domain measure, household income (OR=0.75; 95% confidence interval, 0.63-0.90; model c-statistic improvement 0.5%, P=0.04) generated a similar result to the multiple-domain measure (adjusted OR=0.74; 95% confidence interval, 0.62-0.88; model c-statistic improvement 0.7%, P=0.01). CONCLUSION: Multidomain measurements of SES using administrative databases mapped to census data are not associated with better performance in predicting statin medication adherence compared with single-domain measures such as household income.

Residents' and attendings' perceptions of a night float system in an internal medicine program in Canada.

BACKGROUND: The Night Float system (NFS) is often used in residency training programs to meet work hour regulations. The purpose of this study was to examine resident and attendings' perceptions of the NFS on issues of resident learning, well-being, work, non-educational activities and the health care system (patient safety and quality of care, inter-professional teams, workload on attendings and costs of on-call coverage). METHODS: A survey questionnaire with closed and open-ended questions (26 residents and eight attendings in an Internal Medicine program), informal discussions with the program and moonlighting and financial data were collected. RESULTS AND DISCUSSION: The main findings included, (i) an overall congruency in opinions between resident and attendings across all mean comparisons, (ii) perceptions of improvement for most aspects of resident well-being (e.g. stress, fatigue) and work environment (e.g. supervision, support), (iii) a neutral effect on the resident learning environment, except resident opinions on an increase in opportunities for learning, (iv) perceptions of improved patient safety and quality of care despite worsened continuity of care, and (v) no increases in work-load on attendings or the health care system (cost-neutral call coverage). Patient safety, handovers and increased utilization of moonlighting opportunities need further exploration.

Socioeconomic status and nonadherence to antihypertensive drugs: a systematic review and meta-analysis.

BACKGROUND: Although conventional wisdom suggests that low socioeconomic status (SES) is a robust predictor of medication nonadherence, the strength of this association remains unclear. OBJECTIVES: 1) To estimate the proportion of studies that identified SES as a potential risk indicator of nonadherence, 2) to describe the type of SES measurements, and 3) to quantify the association between SES and nonadherence to antihypertensive pharmacotherapy. METHODS: A systematic review and meta-analysis research design was used. We searched multiple electronic databases for studies in English or French examining nonadherence to antihypertensive medications measured by electronic prescription databases where explanatory factors were considered. Two authors independently assessed quality, described the SES measure(s), and recorded its association with nonadherence to antihypertensives. A random-effects model meta-analysis was performed, and heterogeneity was examined by using the I(2) statistic. RESULTS: Fifty-six studies with 4,780,293 subjects met the inclusion criteria. Twenty-four of these studies (43%) did not report any SES measures. When it was reported (n = 32), only seven (13%) examined more than one component but none performed a multidimensional assessment. Most of the studies relied on income or income-related measures (such as prescription-drug benefits or co-payments) (27 of 32 [84%]). Meta-analysis could be quantified in 40 cohorts reported in 30 studies. Overall, the pooled adjusted risk estimate for nonadherence according to SES (high vs. low) was 0.89 (95% confidence interval 0.87-0.92; I(2) = 95%; P < 0.001). Similar patterns were observed in all subgroups examined. CONCLUSIONS: Published studies have not found a strong association between low SES and nonadherence to antihypertensive medications. However, important limitations in the assessment of SES can be identified in virtually all studies. Future studies are required to ascertain whether a stronger association is observed when SES is determined by comprehensive measures.

Dress and deportment of medical residents: formal or informal?

PURPOSE: Health care workers, including physicians, have adopted more casual dress. The appearance of a physician may influence patients' opinion of physician knowledge, competence and trustworthiness. We hypothesized that medical inpatients and outpatients would rate these attributes higher in residents who dressed and acted in a more formal manner. METHODS: Prospective cohort included both inpatients and outpatients. One hundred thirty three patients, aged 62.3 ± 16 years, 49% of whom were female, were surveyed. One of two male resident physicians approached each patient, ostensibly to obtain consent to a brief mini-mental status examination. The physician was dressed, and acted, either "formally" (F) or "informally" (I). Patients then completed a six item questionnaire, using a 5 point Likert scale, to assess their confidence in the resident. Total scores could be 6 to 30. Total scores were compared using one-way ANOVA. RESULTS: Patients' perceptions were high for both F and I: 25.5 ± 3.1 vs. 24.1 ± 3.0, respectively (p=0.013). This difference was driven by the "lab coat" question: patients generally preferred physicians to wear a lab coat (3.9 ± 1.0 vs. 2.8 ± 1.3, p < 0.0001). Responses to four of the other five questions were numerically, but not statistically, higher in F. There was no difference in preference between the two residents: 24.6 ± 2.8 vs. 24.9 ± 3.5, p=0.56. CONCLUSION: More formal dress and demeanor by residents leads to a modest, but significant, increase in patient perception of the resident's value. Wearing a white lab coat, in particular, has a positive effect.

Comparing health behaviours of internal medicine residents and medical students: an observational study.

PURPOSE: During residency, many physicians find it difficult to maintain a healthy lifestyle; however, there is little objective data available. In this study, residents' health behaviours and cardiovascular risk status were compared with those of medical students. METHODS: Medical residents (n=55, postgraduate years 1 to 4) were compared with medical students (n=62, years 1-4). The main dependent variable was the average number of steps per day (assessed using a pedometer) at work and leisure over three days, during which subjects were not on call or post-call. In addition, all subjects completed a three day food log. Frequency of vigorous exercise was assessed by a single question. Body mass index (BMI), waist circumference, blood pressure, total and high-density lipoprotein cholesterol, smoking habits and random blood glucose were measured, and Framingham Risk Score coronary artery disease 10 year probabilities (FRS) were calculated. RESULTS: Residents recorded 8344±3520 steps per day while students recorded 10703±3986 (p < 0.002). 35% of residents and 52% of students averaged more than 10,000 steps per day and senior residents took fewer steps than junior residents. Both groups frequently failed to achieve the recommended daily servings of fruits and vegetables; on average, 3.5±2.0 servings for residents and 5.4±2.2 for students (p < 0.0001). BMI and FRS were higher among the residents in comparison with the students. CONCLUSION: Medical residents at our institution appear less active and consume fewer servings of fruits and vegetables than undergraduate medical students. These differences are associated with higher BMI, waist circumference and cardiovascular risk.

Vitamin D and hypertension in pregnancy.

PURPOSE: Vitamin D Deficiency is common, particularly in northern latitudes. We examined the association between vitamin D status and hypertension in late pregnancy. METHODS: A case-control study was conducted during two time periods: September-October, 2008, and January-March, 2009, in women near term. A case was defined as having two or more documented blood pressure readings above 140/90 (either/or) at any time during pregnancy (n=78). Controls had at least two blood pressure readings, with none above 140/90 during pregnancy (n=109). Serum 25-hydroxyvitamin D (25(OH)D) was measured in all participants. RESULTS: In the summer, 13% of controls and 29% of the cases had 25(OH) D levels < 50 nmol/L. During the winter, these numbers rose to 44% and 49% respectively. Both cases and controls were more likely to be vitamin D deficient in the winter (p=0.002). There was a negative correlation between BMI and 25(OH)D (r=-0.202, p=0.002). In univariate analysis, cases had lower 25(OH)D (p=0.046), but also higher body mass index, so that in multivariate analysis 25(OH)D status was no longer significant. There was no difference in mean oral daily vitamin D intake (dietary intake and supplements, 746 and 785 IU respectively). Controls gained less weight in pregnancy. There was a negative correlation between the highest blood pressure measured in pregnancy and 25(OH)D levels (r= -0.118; p=0.012). CONCLUSION: There is a high prevalence of vitamin D deficiency in pregnant women recruited in Saskatoon, Saskatchewan. Women with low circulating vitamin D concentrations are more likely to have hypertension.

Comparison of two oscillometric blood pressure monitors in subjects with atrial fibrillation.

OBJECTIVE: To compare blood pressure readings obtained with two commonly used oscillometric monitors: Omron HEM 711 AC (OM) and Welch-Allyn 52000 series NIBP/oximeter (WA) with mercury sphygmomanometers (Merc) in subjects with atrial fibrillation. METHODS: We recruited 51 hemodynamically stable subjects with atrial fibrillation. Fifty four subjects in normal sinus rhythm served as controls. Supine blood pressure readings in each arm were recorded simultaneously using one monitor and Merc. The second monitor then replaced the first and readings were repeated. Merc was then switched to the opposite arm, and both monitors retested. Apical heart rates were ascertained with a stethoscope. We used the averaged, same arm Merc readings as "gold standard". RESULTS: Automated blood pressure readings were obtained in all control subjects and in all but three of those with atrial fibrillation. Both monitors, and operators, noted a difference between apical and radial/brachial pulse rates: apical-recorded: Merc 6.1 + or - 15.0; OM 5.5 + or - 13.7; WA 10.0 + or - 21.2 beats per minute. Both monitors were accurate in controls: over 90% of readings were within 10 mmHg of averaged Merc, and both achieved European Hypertension Society standards. In subjects with atrial fibrillation, about one quarter of all oscillometric readings differed from Merc by more than 10 mmHg. Both falsely high and falsely low readings occurred, some up to 30 mmHg. There was no relation between accuracy and heart rate. CONCLUSIONS: Single blood pressure readings, taken with oscillometric monitors in subjects with atrial fibrillation differ, often markedly, from those taken manually. Health care professionals should record multiple readings manually, using validated instruments when making therapeutic decisions.

Prevalence and duration of exercise induced albuminuria in healthy people.

PURPOSE: Vigorous exercise increases urine protein excretion. However, whether exercise increases urine albumin enough to reach the threshold for microalbuminuria (2.8 and 2.0 mg/mmol creatinine in women and men respectively) is uncertain. Furthermore, the duration of such albuminuria is unknown. We aimed to estimate the prevalence and duration of exercise induced microalbuminuria in normal healthy volunteers. METHODS: Thirty normal subjects provided a urine sample, then exercised to maximal heart rate, or exhaustion, using the standard Bruce Treadmill protocol. Further urine samples were collected within 15 min of completing exercise, and 24 and 48 hr later. Urine creatinine was measured by the Jaffé method and albumin via immunoturbidometry. RESULTS: Baseline urine albumin: creatinine ratio (A/C) was 0.5 +/- 0.3 (SD) in women (n=14) and 0.4 +/- 0.1 mg/mmol in men (n=16). Immediately after exercise A/C increased to 5.6 +/- 9.7 (in women) and 7.6 +/- 17.6 (in men). Twelve of 30 subjects reached the threshold for microalbuminuria and 2 that for macroalbuminuria. By 24 hr all had returned to baseline and there was no further change at 48 hours. CONCLUSIONS: A short period, 15-20 min, of maximal exercise leads to A/C ratios above the microalbuminuria threshold in a substantial proportion of normal subjects. Physicians should not measure urine albumin in patients who give a history of such activity in the past 24 hr.

Chronic clofibrate administration prevents saline-induced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats.

PURPOSE: High salt intake causes hypertension and endothelial dysfunction in young Sprague-Dawley rats. Clofibrate (clof) prevents this salt induced hypertension. We asked whether clof can prevent salt-induced endothelial dysfunction, and if so, its mechanism. We also questioned whether high salt intake can induce endothelial dysfunction without hypertension in older animals. METHODS: Young (Y, 5 weeks) and old (O, 53 weeks) male Sprague-Dawley rats were given either vehicle (Con, 20 mM Na2CO3) or 0.9% NaCl (Sal) to drink for three weeks. Some young rats received clof (80 mg/d) in their drinking fluid. After three weeks, we measured mean arterial pressure (MAP), endothelial function, by comparing hypotensive responses to acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent), plasma total nitrite+nitrate levels (PNOx), by the Griess reaction, and aortic superoxide production by lucigenin chemiluminescence. RESULTS: Carotid artery MAP did not change in O. Sal-Y developed hypertension: 133+/-3 vs. 114+/-2 mmHg, P < 0.001, which was prevented by clof: 105+/-2 mmHg. ACh induced a similar dose dependent hypotensive response in Con-O and Sal-O that was inhibited by L-NAME (100mg/kg i.v.). Responses to ACh were blunted in Sal-Y but not in Con-Y. Further, L-NAME inhibited ACh responses only in Con-Y. The response to SNP was similar in all animals. Importantly, the ACh-induced hypotensive response was potentiated in clof+Sal-Y, an effect which was attenuated by blocking calcium-activated potassium channels (KCa) with a combination of apamin (50 ug/kg i.v.) + charybdotoxin (50 ug/kg i.v.), but not by L-NAME. PNOx was reduced in Sal-Y compared to Con-Y (2.09+/-0.26 vs. 4.8+/-0.35 microM, P < 0.001), but not in Sal-O. Aortic superoxide production was higher (P < 0.001) in Sal-Y (2388+/-40 milliunits/mg/min) than Sal-O (1107+/-159 milliunits/mg/min), but was reduced by clof (1378+/-64 milliunits/mg/min; P < 0.001). CONCLUSIONS: High salt intake increases oxidative stress in young animals, leading to impaired nitric oxide activity and endothelial dysfunction. Clofibrate prevents endothelial dysfunction partly through reduced O2 - formation but mainly via selective activation of KCa channels. Older animals are resistant to both salt induced hypertension and oxidative stress.

Clinical Outcomes with First-Line Chemotherapy in a Large Retrospective Study of Patients with Metastatic Pancreatic Cancer Treated in a US Community Oncology Setting.

BACKGROUND: The combination chemotherapy regimens of nab-paclitaxel plus gemcitabine (nab-p + G) and FOLFIRINOX (FFX) have each demonstrated improved survival compared with gemcitabine monotherapy in clinical trials for metastatic pancreatic cancer; however, limited comparative data exist. OBJECTIVE: The objective of this study was to compare patient characteristics and clinical outcomes including time to treatment failure and overall survival in patients with metastatic pancreatic cancer receiving first-line chemotherapy in the community. METHODS: We conducted a retrospective, multi-site, observational cohort study of patients with metastatic pancreatic cancer receiving first-line nab-p + G, FFX, or gemcitabine monotherapy between April 2013 and October 2015, using data from the iKnowMed electronic health record database. Patients on clinical trials or with other cancer diagnoses were excluded. Time to treatment failure and overall survival were assessed by Kaplan-Meier methods. RESULTS: Four hundred and eighty-six patients met selection criteria, 255 nab-p + G, 159 FFX, and 72 gemcitabine patients. Median age was 61, 68, and 73 years for FFX, nab-p + G, and gemcitabine patients, respectively (p < 0.01 for nab-p + G vs. FFX). Eastern Cooperative Oncology Group performance status of 0-1 was 91% for FFX, 77% for nab-p + G, and 68% for gemcitabine patients (p < 0.01 for nab-p + G vs. FFX). For the nab-p + G vs. FFX cohorts, respectively, time to treatment failure was 3.7 vs. 4.3 months (log-rank p = 0.25); and OS was 9.8 vs. 11.4 months (log-rank p = 0.38). Among patients with Eastern Cooperative Oncology Group performance status 0-1, time to treatment failure was 4.2 vs. 4.3 months (log-rank p = 0.47); and overall survival was 12.1 vs 11.4 months (log-rank p = 0.68). CONCLUSIONS: The nab-p + G patients were older and had worse performance status than FFX patients. Time to treatment failure and overall survival were not observed to be significantly different in first-line nab-p + G and FFX patients. Results were similar after stratifying by performance status.

Atenolol as initial antihypertensive therapy: an observational study comparing first-line agents.

OBJECTIVE: The role of atenolol in the management of patients with hypertension is currently under scrutiny. Our aim was to evaluate the real-world consequences of recent clinical trial findings. METHODS: We conducted a retrospective, cohort study using linked administrative data from the province of Saskatchewan, Canada. Eligible subjects were first-ever users of antihypertensive medications between 1 January 1994 and 31 December 2003 and were grouped into four cohorts: atenolol, angiotensin-converting enzyme inhibitors (ACEI), thiazide diuretics, or calcium antagonists. Patients remained eligible during monotherapy only. RESULTS: We identified 19 249 eligible individuals (mean age 60.6 years) who were followed for a mean of 2.3 years (SD 2.0). The rate of myocardial infarction, unstable angina, stroke, or death occurred in similar frequencies among all cohorts: atenolol (2.3%), ACEI (3.6%), thiazide diuretics (2.9%), and calcium antagonists (3.9%). After adjustment for potential confounders, atenolol therapy was not associated with higher event rates than the other first-line agents, with hazard ratios ranging between 1.03 [95% confidence intervals (CI) 0.72-1.46] and 1.24 (95% CI 0.91-1.68) for all cohorts compared with atenolol. Similar results were observed upon stratifying the sample into subjects above and below 60 years of age. CONCLUSION: The low event rates for all cohorts suggest that atenolol has not been associated with a significant burden of cardiovascular morbidity or mortality in its traditional role for uncomplicated hypertension. Further study is needed to identify the specific types of patients that should avoid atenolol as an antihypertensive agent.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in hypertension due to primary aldosteronism: a case for exclusion.

Aldosterone antagonists are the mainstay of therapy in patients with hypertension due to primary aldosteronism. However, in our experience, these patients are sometimes placed on angiotensin-converting enzyme (ACE) inhibitors in accordance with guidelines applying to the general hypertensive population. We believe this practice is inappropriate because of the inability of ACE inhibitors to lower blood pressure in patients with low renin levels. Furthermore, pleiotropic effects of ACE inhibitors are unlikely to provide significant benefits in the absence of blood pressure reduction. Therefore, ACE inhibitors should be discouraged for the majority of patients with primary aldosteronism, even in the face of renal or cardiac disease.

Hypertension Canada's 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults.

Hypertension Canada provides annually updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension. This year, we introduce 10 new guidelines. Three previous guidelines have been revised and 5 have been removed. Previous age and frailty distinctions have been removed as considerations for when to initiate antihypertensive therapy. In the presence of macrovascular target organ damage, or in those with independent cardiovascular risk factors, antihypertensive therapy should be considered for all individuals with elevated average systolic nonautomated office blood pressure (non-AOBP) readings ≥ 140 mm Hg. For individuals with diastolic hypertension (with or without systolic hypertension), fixed-dose single-pill combinations are now recommended as an initial treatment option. Preference is given to pills containing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in combination with either a calcium channel blocker or diuretic. Whenever a diuretic is selected as monotherapy, longer-acting agents are preferred. In patients with established ischemic heart disease, caution should be exercised in lowering diastolic non-AOBP to ≤ 60 mm Hg, especially in the presence of left ventricular hypertrophy. After a hemorrhagic stroke, in the first 24 hours, systolic non-AOBP lowering to < 140 mm Hg is not recommended. Finally, guidance is now provided for screening, initial diagnosis, assessment, and treatment of renovascular hypertension arising from fibromuscular dysplasia. The specific evidence and rationale underlying each of these guidelines are discussed.

Clofibrate acutely reverses saline-induced endothelial dysfunction: role of calcium-activated potassium channels.

BACKGROUND: Endothelium-dependent vascular relaxation is impaired in various disease states including hypertension. METHODS: We investigated whether a single bolus dose of clofibrate could rapidly reverse saline-induced endothelial dysfunction, in vivo, in salt-loaded Sprague-Dawley (S-D) rats. S-D rats, 5 weeks of age, were divided into two groups. One group served as a control (Con) and was given tap water; the other group (Sal) was given normal saline (0.9% NaCl) ad libitum for 3 weeks. RESULTS: Mean arterial pressure (MAP) was significantly higher (138 +/- 2 nu 112 +/- 2 mm Hg, P < .001), whereas the total plasma nitrite/nitrate levels were lower (1.7 +/- 0.3 v 2.8 +/- 0.2 micromol/L, P < .05) in Sal. At this time, endothelial function was assessed in vivo. Sal rats had decreased hypotensive responses to acetylcholine (ACh) but maintained normal responses to sodium nitroprusside. The ACh-induced hypotensive response was significantly inhibited by the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME, 100 mg kg(-1) intraperitoneally [ip]) only in Con rats. Clofibrate (Clof, 200 mg kg(-1) ip) did not change blood pressure but increased ACh-induced hypotensive responses only in Sal, an effect that was abolished by subsequent administration of apamin (Apa, 50 microg kg(-1) iv) and charybdotoxin (ChTx, 50 microg kg(-1) iv). Apa+ChTx blocked responses to ACh in Con and Sal, as expected. A single dose of clofibrate (200 mg kg(-1) ip), given subsequently to Apa+ChTx, restored responses to ACh in both the Con and Sal groups, again without affecting baseline MAP. CONCLUSION: Clofibrate has an acute salutary effect on endothelium-dependent vasodilation in saline-treated rats, probably mediated through vascular calcium-activated potassium channels and independent of an antihypertensive effect.

Inability to upregulate cytochrome P450 4A and 2C causes salt sensitivity in young Sprague-Dawley rats.

BACKGROUND: Young Sprague-Dawley rats develop high blood pressure (BP) when exposed to a high salt intake, whereas adult ones generally do not. We investigated the role of renal cytochromes P450 4A (CYP 4A) and 2C (CYP 2C) in maintaining normal BP. METHODS: Young (age 5 weeks) and adult (age 53 weeks) Sprague-Dawley rats were given either 20 mmol sodium carbonate (vehicle for clofibrate) or 0.9% saline to drink for 3 weeks. Some young animals received the peroxisome proliferator activated receptor (PPAR)alpha agonist clofibrate (80 mg daily). We measured tail-cuff and intra-arterial BP, weight change, sodium balance, 20-hydroxyeicosatetraenoic acid (20-HETE) excretion (by high-performance liquid chromatography), and renal expression of CYP 4A and CYP 2C (by real-time reverse transcriptase-polymerase chain reaction). RESULTS: Saline-treated adult animals remained normotensive: systolic BP (SBP) 117 +/- 2 mm Hg v 117 +/- 1 mm Hg in control animals. In contrast, young rats given saline developed increased SBP: 134 +/- 2 mm Hg v 115 +/- 2 mm Hg in control animals (P < . 001). Interestingly, clofibrate lowered SBP to 102 +/- 2 mm Hg in saline-treated young rats but had no effect in control animals (114 +/- 2 mm Hg). Adult rats given saline increased renal expression of CYP 4A and 2C and excreted more 20-HETE. However, young rats given saline showed no induction, and even reduced CYP 4A and 2C, decreased urinary 20-HETE excretion, and retained sodium. Clofibrate increased renal CYP and 20-HETE excretion and prevented sodium retention. CONCLUSIONS: The products of renal CYP4A and 2C, including 20-HETE, aid in excreting salt. Animals that are unable to increase renal 20-HETE formation do not excrete sodium and are prone to hypertension.

EDHF-mediated rapid restoration of hypotensive response to acetylcholine after chronic, but not acute, nitric oxide synthase inhibition in rats.

Several in vitro studies have shown that endothelium-dependent vasodilatation is maintained by endothelium-derived hyperpolarizing factor (EDHF) or prostacyclin in vessels isolated from endothelial nitric oxide synthase knockout mice. Since this has not been addressed by in vivo studies, we sought to define the magnitude and the onset time of this compensation by recording blood pressure responses to endothelium-dependent vasodilators in rats treated acutely or chronically with the NOS inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME). Groups of male Sprague-Dawley rats were given plain water (control) or L-NAME (0.7 mg/ml) in drinking water for 1 day, 5 days, 3 wks or 6 wks. Dose-dependent hypotensive responses to acetylcholine, bradykinin and sodium nitroprusside were determined in anesthetized rats before and after acute intravenous infusion of either L-NAME or a combination of apamin plus charybdotoxin that would selectively inhibit EDHF. Acute L-NAME treatment increased the mean arterial pressure and inhibited acetylcholine- and bradykinin-induced fall in blood pressure in control but not in chronic L-NAME treated rats. The endothelium-dependent hypotensive responses to acetylcholine and bradykinin were restored in rats treated with L-NAME after a time period of 24 h along with increased sensitivity to sodium nitroprusside and reduced plasma nitrate+nitrite levels. While apamin+charybdotoxin pretreatment inhibited the responses to acetylcholine and bradykinin in both acute and chronic L-NAME treated groups, it was more pronounced in the latter group. In conclusion, chronic inhibition of nitric oxide synthase results in the development of a compensatory hypotensive response to acetylcholine within 24 h and this is mediated by EDHF.

Antihypertensive medications and blood sugar: theories and implications.

Increased rates of diabetes have been reported with thiazide diuretics and beta-blockers, but not with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or calcium channel blockers. These observations are important because significant glycemic effects of drugs may be a source of accelerated cardiovascular risk that is not detectable during restricted clinical trial follow-up periods. The extent to which diabetes is affected by these medications remains unclear, as is the precise mechanism by which diabetes is promoted. However, several plausible theories are presented herein. Although drug-induced diabetes has been a concern for several years, not enough information is available to influence prescribing for the majority of patients. The number one priority should be controlling blood pressure in a timely manner.

Bacillus Panophthalmitis with Posterior Extension to the Prechiasmatic Optic Nerve.

A rare case of Bacillus panophthlamitis with extension to the prechiasmatic optic nerve secondary to hematogenous spreading after intravenous drug use is presented. A 27-year-old man with a recent history of trauma to the left eye presented with severe left eye pain following a binge of intravenous drug use. Visual acuity (VA) was LP. On examination he had chemosis, proptosis, elevated intraocular pressure, and a complete hyphema. CT-scan identified preseptal swelling, but no evidence of any posterior extension of the anterior process or orbital fractures. Topical and systemic therapy were initiated. On follow-up clinical examination less than 12 hours after presentation he had signs of a keratitis with worsening ophthalmoplegia and repeat imaging demonstrated posterior extension to the prechiasmatic optic nerve. Shortly after the cornea ruptured with cultures growing Bacillus. The patient underwent enucleation and has had no further progression of infection. To the best of our knowledge, this is the first report of Bacillus panophthalmitis presenting with signs of trauma with posterior extension to the prechiasmatic optic nerve.