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The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR) plays a central role in the molecular basis of cystic fibrosis (CF). The misfolding of the most common CF variant (ΔF508) remodels both the translational regulation and quality control of CFTR. Nevertheless, it is unclear how the misassembly of the nascent polypeptide influences the activity of the translation machinery. In this work, we identify a structural motif within the CFTR transcript that stimulates efficient -1 ribosomal frameshifting and triggers the premature termination of translation. Though this motif does not appear to impact the wild-type CFTR interactome, silent mutations that disrupt this RNA structure alter how ΔF508 CFTR interacts with numerous translation and quality control proteins. Moreover, disrupting this RNA structure enhances both the expression and function of ΔF508 CFTR with no impact on wild-type. Finally, we show that disrupting this motif enhances the pharmacological rescue of ΔF508 by Trikafta, which implies ribosomal frameshifting antagonizes the effects of leading CF therapeutics. Together, our results reveal that ribosomal frameshifting selectively reduces the expression and assembly of a misfolded CFTR variant. These findings suggest cotranslational misfolding alters the processivity of translation and potentially the stability of the mRNA transcript through the dynamic modulation of ribosomal frameshifting.

Background/Objective: Cachexia is a systemic wasting syndrome characterized by skeletal muscle mass loss and is estimated to affect 80% of lung cancer patients. Previous studies haveshown that metastatic bone disease may have a role in inducing cachexia, which is mediated bycytokines such as IL-6, TNF-α, and TGF-β. To develop therapies for cachexia, a better understanding of the impact of metastatic bone disease and these cytokines on cachexia is needed. Methods: Patients diagnosed with lung cancer were identified from an institutional database and were designated to one of three cohorts: local disease (n=63), osseous metastatic disease(n=39), and extraosseous metastatic disease (n=39). Body mass index (BMI) at diagnosis and follow up were collected. Change in BMI per year was calculated and the Kruskal-Wallis Test was used to compare groups. In a parallel study, ELISA was performed for IL-6, TNF-α, and TGF-β on supernatant collected after 48 hours from the cell lines BEAS-2B (normal lung epithelia), H1299 (lung cancer), and A549 (lung cancer). These groups were compared using a one-way ANOVA. Results: Median change in BMI was not statistically different (P=.79) among any cohort. The cytokine level varied by cell line. H1299 had significantly increased levels of TGF-β as compared to BEAS-2B (P=.004). A549 had elevated, but not a statistically significant differentlevel of IL-6 as compared to BEAS-2B (P=.17). TNF-α was not present in any cell line. Conclusion:BMI was not associated with disease state with the numbers available. The parallel study showed cell line specific elevation of TGF-β and IL-6 in lung cancer compared to noncancerous tissues. Together, these findings are inconclusive but support continued investigation into the pathogenesis of cachexia in lung cancer. Future studies will employ imaging-based body composition measurements in these disease cohorts and explore int eractions between tumor, bone, and muscle in vitro.

Hypertension Canada provides annually-updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately. For 2018, 5 new guidelines were introduced, and one existing guideline on the blood pressure thresholds and targets in the setting of thrombolysis for acute ischemic stroke was revised. The use of validated wrist devices for the estimation of blood pressure in individuals with large arm circumference is now included. Guidance is provided for the follow-up measurements of blood pressure, with the use of standardized methods and electronic (oscillometric) upper arm devices in individuals with hypertension, and either ambulatory blood pressure monitoring or home blood pressure monitoring in individuals with white coat effect. We specify that all individuals with hypertension should have an assessment of global cardiovascular risk to promote health behaviours that lower blood pressure. Finally, an angiotensin receptor-neprilysin inhibitor combination should be used in place of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in individuals with heart failure (with ejection fraction < 40%) who are symptomatic despite appropriate doses of guideline-directed heart failure therapies. The specific evidence and rationale underlying each of these guidelines are discussed.

In Canada, the multiple chronic conditions and cardiovascular risk factors of our aging population continue to challenge health care providers and burden health systems. Cardiovascular disease is a major contributor to chronic illness, with four in five Canadians having at least one risk factor for

SummaryThe UAS/GAL4 system is the most used method InDrosophila melanogasterfor directing the expression of a gene of interest to a specific tissue. However, the ability to control the temporal activity of GAL4 with this system is very limited. This study constructed and characterized Tet-off GAL80 transgenes designed to allow temporal control of GAL4 activity in aging adults. By placing GAL80 under the control of a Tet-off promoter, GAL4 activity is regulated by the presence or absence of tetracycline in the diet. Almost complete inhibition of the expression of UAS transgenes during the pre-adult stages of the life cycle is obtained by using four copies and two types of Tet-off GAL80 transgenes. Upon treatment of newly emerged adults with tetracycline, induction of GAL4 activity is observed but the level of induction is influenced by the concentration of the inducer, the age, the sex and the anatomical location of the expression. The inhibition of GAL4 activity and the maintenance of induced expression is altered in old animals. This study reveals that the repressive ability of GAL80 is affected by the age and sex of the animal which is a major limitation to regulate gene expression with GAL80 in agedDrosophila.

After the 2016 guidelines for blood pressure measurement, diagnosis, and investigation of pediatric hypertension, we now present evidence-based guidelines for the prevention and treatment of hypertension in children. These guidelines were developed by Hypertension Canada's Guideline Committee pediatric subgroup after thorough evaluation of the available literature. Included are 10 guidelines specifically addressing health behaviour management, indications for drug therapy in children with hypertension, choice of therapy for children with primary hypertension, and goals of therapy for children with hypertension. Although the pediatric literature is inherently limited by small numbers of participants, fewer trials, and a prolonged latency to the development of vascular outcomes, this report reflects the current and highest level of evidence and provides guidance for primary care practitioners on the management of pediatric hypertension. Studies of therapeutic lifestyle modifications in children are available to guide current management and more antihypertensive drugs have been studied in children since the Food and Drug Administration Modernization Act. Consistent with Hypertension Canada's guideline policy, diagnostic and therapeutic algorithm tools will be developed and the guidelines will be reviewed annually and updated according to new evidence.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This year's update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be150 mm Hg (Grade C) rather than140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.

Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force provides annually updated, evidence-based recommendations to guide the diagnosis, assessment, prevention, and treatment of hypertension. This year, we present 4 new recommendations, as well as revisions to 2 previous recommendations. In the diagnosis and assessment of hypertension, automated office blood pressure, taken without patient-health provider interaction, is now recommended as the preferred method of measuring in-office blood pressure. Also, although a serum lipid panel remains part of the routine laboratory testing for patients with hypertension, fasting and nonfasting collections are now considered acceptable. For individuals with secondary hypertension arising from primary hyperaldosteronism, adrenal vein sampling is recommended for those who are candidates for potential adrenalectomy. With respect to the treatment of hypertension, a new recommendation that has been added is for increasing dietary potassium to reduce blood pressure in those who are not at high risk for hyperkalemia. Furthermore, in selected high-risk patients, intensive blood pressure reduction to a target systolic blood pressure ≤ 120 mm Hg should be considered to decrease the risk of cardiovascular events. Finally, in hypertensive individuals with uncomplicated, stable angina pectoris, either a β-blocker or calcium channel blocker may be considered for initial therapy. The specific evidence and rationale underlying each of these recommendations are discussed. Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force will continue to provide annual updates.

Reactive oxygen species (ROS) modulate aging and aging-related diseases. Dietary composition is critical in modulating lifespan. However, how ROS modulate dietary effects on lifespan remains poorly understood. Superoxide dismutase 1 (SOD1) is a major cytosolic enzyme responsible for scavenging superoxides. Here we investigated the role of SOD1 in lifespan modulation by diet in Drosophila. We found that a high sugar-low protein (HS-LP) diet or low-calorie diet with low-sugar content, representing protein restriction, increased lifespan but not resistance to acute oxidative stress in wild-type flies, relative to a standard base diet. A low sugar-high protein diet had an opposite effect. Our genetic analysis indicated that SOD1 overexpression or dfoxo deletion did not alter lifespan patterns of flies responding to diets. However, sod1 reduction blunted lifespan extension by the HS-LP diet but not the low-calorie diet. HS-LP and low-calorie diets both reduced target-of-rapamycin (TOR) signaling and only the HS-LP diet increased oxidative damage. sod1 knockdown did not affect phosphorylation of S6 kinase, suggesting that SOD1 acts in parallel with or downstream of TOR signaling. Surprisingly rapamycin decreased lifespan in sod1 mutant but not wild-type males fed the standard, HS-LP and low calorie diets, whereas antioxidant N-acetylcysteine only increased lifespan in sod1 mutant males fed the HS-LP diet, when compared to diet-matched controls. Our findings suggest that SOD1 is required for lifespan extension by protein restriction only when dietary sugar is high, and support the context-dependent role of ROS in aging and caution the use of rapamycin and antioxidants in aging interventions.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2012. The new recommendations are: (1) use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome; (2) mineralocorticoid receptor antagonists may be used in selected patients with hypertension and systolic heart failure; (3) a history of atrial fibrillation in patients with hypertension should not be a factor in deciding to prescribe an angiotensin-receptor blocker for the treatment of hypertension; and (4) the blood pressure target for patients with nondiabetic chronic kidney disease has now been changed to < 140/90 mm Hg from < 130/80 mm Hg. We also reviewed the recent evidence on blood pressure targets for patients with hypertension and diabetes and continue to recommend a blood pressure target of less than 130/80 mm Hg.

β-Adrenergic blocking agents (or β-blockers) have been widely used for the treatment of hypertension for the past 50 years, and continue to be recommended as a mainstay of therapy in many national guidelines. They have also been used in a variety of cardiovascular conditions commonly complicating hypertension, including angina pectoris, myocardial infarction (MI), acute and chronic heart failure, as well as conditions like essential tremor and migraine. Moreover, they have played a primary role in controlling blood pressure in patients with these specific comorbidities and in reducing cardiovascular risk with regard to the composite outcome of death, stroke, and MI among patients younger than 60 years of age. However, in patients 60 years of age or older, β-blockers were not associated with significantly lower rates of MI, heart failure or death, and demonstrated higher rates of stroke compared with other first-line therapies. Consequently, the Canadian Hypertension Education Program recommends the use of β-blockers as first-line therapy in hypertensive patients younger than 60 years of age but not for those age 60 and older, with the exception of patients with concomitant β-blocker-requiring cardiac diseases. Several reports suggest that the lack of consistent outcome data may relate to the use of traditional β-blockers such as atenolol and their ability only to reduce cardiac output, without beneficial effect on peripheral vascular resistance. The present report will describe the clinically relevant mechanisms of action of β-blockers, their pharmacological differences, their metabolic effects, and their usefulness in patients with hypertension.

Since 1999, the Canadian Hypertension Education Program (CHEP) has released annual recommendations on the management of hypertension. Although significant improvements in hypertension treatment and control have been made in Canada, approximately one-third of Canadians continue to have uncontrolled blood pressure.1 In 2011, we published a set of guidelines specific to pharmacists based on the CHEP recommendations.2 Since that publication, new research has been conducted that has prompted changes in the 2012 and 2013 versions of the guidelines. In this article, we will provide an update for pharmacists on these changes and their underlying evidence, as relevant to pharmacy practice.

Blood pressure (BP) control is frequently difficult to achieve in patients with predominantly elevated systolic BP. Consequently, these patients frequently require combination therapy including a thiazide diuretic such as hydrochlorothiazide (HCTZ) and an agent blocking the renin-angiotensin-aldosterone system. Current clinical practice usually limits the daily dose of HCTZ to 25 mg. This often leads to the necessity of using additional antihypertensive agents to control BP in a high proportion of patients.To compare the efficacy of two doses of losartan (LOS)⁄HCTZ combinations in patients with uncontrolled ambulatory systolic hypertension after six weeks of treatment with LOS 100 mg⁄HCTZ 25 mg (LOS100⁄HCTZ25).Following a two- to four-week washout period, subjects with a mean clinic sitting systolic BP of 160 mmHg or higher and a mean ambulatory daytime systolic BP (MDSBP) of 135 mmHg or higher on LOS100⁄HCTZ25 (n=105; 33 women and 72 men) were randomly assigned to receive LOS 150 mg⁄HCTZ 25 mg (group 1; n=53) or LOS 150 mg⁄HCTZ 37.5 mg (LOS150⁄HCTZ37.5, group 2; n=52). The primary end point was the difference in MDSBP reductions.At the end of the six-week treatment period, the respective additional decreases in MDSBP were 1.2 mmHg (P=0.335) on LOS 150 mg⁄HCTZ 25 mg and 5.6 mmHg (P0.0001) on LOS150⁄HCTZ37.5 (difference of 4.4 mmHg; P=0.011). Daytime systolic ambulatory BP goal (lower than 130 mmHg) achievement tended to be higher (25% versus 17%; P=0.313) with LOS150⁄HCTZ37.5, while it was significantly higher (65% versus 43%; P=0.024) for mean daytime diastolic BP (lower than 80 mmHg). No deleterious metabolic changes were observed.In patients with uncontrolled systolic ambulatory hypertension receiving LOS100⁄HCTZ25, increasing both HCTZ and LOS dosages simultaneously to LOS150⁄HCTZ37.5 may be an effective strategy that does not affect metabolic parameters.

Stress dipyridamole technetium‐99(m) sestamibi single photon emission computed tomographic imaging was used to study myocardial perfusion in 1116 hypertensive patients without known coronary artery disease (CAD). The test confirmed the presence of CAD in 28.9% of patients. As expected, patients with diabetes mellitus (DM) had a significantly higher prevalence of myocardial perfusion abnormalities (35.9% vs 23.9%; odds ratio, 1.79; 95% confidence interval [CI], 1.38–2.33; P

The present study investigated whether initiating therapy with a combination of losartan (L) and hydrochlorothiazide (HCTZ) allows for faster blood pressure (BP) control and fewer medications than the usual stepped-care approach in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension.Patients with a mean daytime systolic ambulatory BP (ABP) of 135 mmHg or higher were randomly assigned to receive L 50 mg plus HCTZ 12.5 mg titrated to L 100 mg plus HCTZ 25 mg versus HCTZ 12.5 mg plus atenolol 50 mg. Amlodipine 5 mg was then added, if needed, to achieve a BP goal of less than 130 mmHg. Treatment titration was based on ABP.Significantly more patients randomly assigned to L/HCTZ (63.5%) than stepped-care (37.5%; P=0.008) achieved the primary end point (daytime systolic BP of less than 130 mmHg). Initial L/HCTZ induced significantly greater decreases in ABP during each 24 h period after six weeks of therapy. Although reductions in systolic and diastolic ABP were not statistically different at the end of the study, ABP reduction was significantly greater (P0.001) with the L/HCTZ-based regimen. Twice as many patients in the L/HCTZ group achieved the goal ABP with no more than two drugs (30.0% versus 14.7%; P=0.03). Moreover, tolerability was significantly better (P=0.006) in the L/HCTZ group, with a 40.0% incidence of adverse events, versus 65.6% in the stepped-care group.Initiating antihypertensive therapy with the combination of L/HCTZ in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension reaches a target BP faster in a higher proportion of patients, with fewer adverse events and less need for a third drug regimen than the conventional stepped-care approach.

The Canadian Hypertension Education Program reviews the hypertension literature annually and provides detailed recommendations regarding hypertension diagnosis, assessment, prevention, and treatment. This report provides the updated evidence-based recommendations for 2015. This year, 4 new recommendations were added and 2 existing recommendations were modified. A revised algorithm for the diagnosis of hypertension is presented. Two major changes are proposed: (1) measurement using validated electronic (oscillometric) upper arm devices is preferred over auscultation for accurate office blood pressure measurement; (2) if the visit 1 mean blood pressure is increased but < 180/110 mm Hg, out-of-office blood pressure measurements using ambulatory blood pressure monitoring (preferably) or home blood pressure monitoring should be performed before visit 2 to rule out white coat hypertension, for which pharmacologic treatment is not recommended. A standardized ambulatory blood pressure monitoring protocol and an update on automated office blood pressure are also presented. Several other recommendations on accurate measurement of blood pressure and criteria for diagnosis of hypertension have been reorganized. Two other new recommendations refer to smoking cessation: (1) tobacco use status should be updated regularly and advice to quit smoking should be provided; and (2) advice in combination with pharmacotherapy for smoking cessation should be offered to all smokers. The following recommendations were modified: (1) renal artery stenosis should be primarily managed medically; and (2) renal artery angioplasty and stenting could be considered for patients with renal artery stenosis and complicated, uncontrolled hypertension. The rationale for these recommendation changes is discussed.

Each year, the Recommendations Task Force of the Canadian Hypertension Education Program updates its recommendations for the diagnosis and treatment of hypertension in Canada. During the past two years, the task force has made some substantial changes to recommendations in several areas. These

The process of aging can be described as a progressive decline in an organism's function that invariably results in death. This decline results from the activities of intrinsic genetic factors within an organism. The relative contributions of the biological and environmental components to senescence are hard to measure, however different strategies have been devised in Drosophila melanogaster to isolate and identify genetic influences on aging. These strategies include selective breeding, quantitative trait loci (QTL) mapping and single gene mutant analysis. Selective breeding effectively demonstrated a genetic, heritable component to aging while QTL mapping located regions within the Drosophila genome carrying loci that influence the aging process. Within the past decade, single gene mutant analysis has facilitated the identification of specific genes whose activities play a determinative role in Drosophila aging. This review will focus on the application of selective breeding, QTL mapping and single gene mutant analysis used in Drosophila to study aging as well as the results obtained through these strategies to date.

Background The aldosterone-to-renin ratio (ARR) is frequently used to screen primary hyperaldosteronism. This study, part of a clinical trial, was designed to measure the influence of circadian rhythms, antihypertensive drugs, and body posture on plasma renin, on aldosterone, and on their interrelation. Methods In a prospective, randomized, open-label, parallel-designed protocol, 57 essential hypertensives (41 men, 16 women) were randomized to a morning dose of telmisartan (80 mg), ramipril (10 mg), or amlodipine (10 mg) for 8 weeks. At baseline and after 8 weeks of therapy, blood pressure (BP), plasma renin (in nanograms per liter), and plasma aldosterone (in picomoles per liter) concentrations were assessed in the supine position every 4 h for 24 h and after 10 min of standing at 9 am . Results There was no significant association between renin, aldosterone, the ARR and demographic factors, or BP. Circadian variations of plasma renin and aldosterone were clearly present. Aldosterone variations were of greater relative amplitude with earlier-occurring peaks than renin. The ARR exhibited statistically and clinically significant circadian variations with the low and peak values averaging 55.9 ± 32.3 and 161.84 ± 85.4 pmol/L/ng/dL, respectively. Telmisartan, ramipril, and amlodipine significantly decreased the ARR. Telmisartan had the greatest influence on the ARR. Posture had a clinically significant but statistically nonsignificant effect on the ARR. Conclusions Renin, aldosterone, and their interrelation are influenced by circadian rhythms, telmisartan, ramipril, and amlodipine in patients with essential hypertension. Telmisartan has a greater impact on these parameters than ramipril and amlodipine. Measurement of the ARR in treated hypertensive patients should take these influences into account.

The efficacy of losartan (L) in combination with hydrochlorothiazide (HCTZ) has been demonstrated to reduce blood pressure. However, there are limited data on the effects of L/HCTZ combinations versus HCTZ monotherapies in reducing ambulatory systolic blood pressure. The aim of this study was to compare the effects of these treatment approaches in patients with ambulatory systolic hypertension.Patients were randomized to receive L 50 mg (n = 60) or HCTZ 12.5 mg (n = 60) for 6 weeks. Patients were then force-titrated to L 50/HCTZ 12.5 mg and to L 100/HCTZ 25 mg or were sham-titrated to HCTZ 12.5 mg and force-titrated to HCTZ 25 mg, respectively. Clinic and 24-h ambulatory blood pressure (ABP) were measured at baseline and after each 6-week treatment period.We found that L 50 and HCTZ 12.5 induced significant and similar decreases in clinic and ABP. The combinations of L 50/HCTZ 12.5 and L 100/HCTZ 25 provided significantly greater decreases in clinic and ABP than did HCTZ monotherapies. The L 50/HCTZ 12.5 and L 100/HCTZ 25 combinations provided significant additional decreases in systolic/diastolic ABP during daytime (-5.3/-2.0 mm Hg; P.001 and -5.8/-3.4 mm Hg; P.001) and the other periods of the 24-h interval compared with the levels achieved by the previous treatment, indicating a clear dose-response relationship. However, increasing the dose of HCTZ from 12.5 mg to 25 mg was not associated with additional ABP reductions.Combinations of L 50/HCTZ 12.5 and L 100/HCTZ 25 provided greater reductions in clinic and ABP than HCTZ monotherapies, with a clear dose-response relationship with regard to ABP. These results support the use of ABP monitoring when assessing the efficacy of antihypertensive therapies.

The QT interval corrected for heart rate (QTc) is believed to reflect sympathovagal balance. It has also been established that beta-blockers and dihydropyridine-type calcium channel blockers (DHPCCB) influence the autonomic nervous system. This study tested the hypothesis that QTc interval length is a predictor of the blood pressure reduction induced by beta1-selective beta-blockers or DHPCCB. The predictive values of pretreatment heart rate and of the heart rate change with therapy were also evaluated. The authors conducted an historical reanalysis of 5 clinical trials that looked at the antihypertensive effects of beta-blockers (nebivolol) or DHPCCB (amlodipine, felodipine, isradipine, nifedipine). Correlation and quintile analyses were performed to measure the association between QTc interval, heart rate, or heart rate change and therapeutic blood pressure response. Separate analyses were undertaken for beta-blockers and DHPCCB. Seventy-three and 98 hypertensive subjects respectively were included in the beta-blocker and DHPCCB analyses. QTc interval, pretreatment heart rate, and heart rate change with therapy were not associated with therapeutic blood pressure response. In this study, QTc interval length, pretreatment heart rate, and heart rate change with therapy were not good predictors of the blood pressure response to beta1-selective beta-blockers or DHPCCB in hypertensive subjects.

Starting lipid-lowering therapy in the hospital, especially with statins, has become an important component in the management of patients with acute coronary syndromes (ACS). It improves outcomes and increases patient motivation and long-term adherence. In addition, discontinuation of statin therapy in patients with ACS after hospital admission is associated with an increased risk of adverse outcomes. Recent non-ST elevation ACS guidelines recommend beginning statin therapy, along with dietary intervention, in patients whose low-density lipoprotein cholesterol levels exceed 130 mg/dl within 24-96 hours after hospital admission. Various strategies have been developed to aid in the implementation of in-hospital lipid-lowering therapy. Pharmacists can play a valuable role in optimizing drug therapy for dyslipidemia and ensuring long-term adherence.

In the past decade, many publications have dealt with the possible relationship between biological rhythms and the incidence of cardiovascular events. A high proportion of treated hypertensive patients have cardiovascular complications, and chronotherapy, which permits the use of drugs that are maximally effective at different points in the circadian cycle, may be an interesting and valuable approach to decreasing morbidity and mortality in these patients. This article summarizes current knowledge on the new science of chronopharmacology, as demonstrated in several clinical studies that have used conventional agents administered at various points in the circadian cycle as well as new chronotherapeutic agents, such as controlled onset extended release (COER)-verapamil. In addition, emphasis is given to a rigorous evaluation of antihypertensive agents in terms of efficacy and duration of effect to obtain adequate and sustained lowering of blood pressure over the 24-hour period.

Reversal of left ventricular hypertrophy has been shown to improve left ventricular diastolic function in elderly patients with hypertension, but little is known about whether this affects physical performance. Left ventricular mass, cardiac function at rest and during submaximal exercise, and physical performance were assessed in 38 elderly patients with hypertension with left ventricular hypertrophy and normal systolic function before and after 8 and 14 months of therapy with amlodipine or hydrochlorothiazide or both. Blood pressure control was achieved with amlodipine in 18 patients, with hydrochlorothiazide in seven, and with the combination of these drugs in 13. Left ventricular mass index was similarly reduced from approximately 150 to approximately 100 g/m2 at 14 months' in each treatment group. Systolic function was maintained with the three treatment regimens, whereas similar decreases in time to peak filling rate and increases in first-third filling fraction occurred both at rest and during submaximal exercise after 8 months and further after 14 months of therapy. Exercise capacity did not significantly change in the group as a whole, but individual changes in peak oxygen uptake at the end of treatment correlated significantly with the decrease in time to peak filling rate during submaximal exercise (r = -0.49; p < 0.01). It is concluded that long-term blood pressure control with amlodipine or hydrochlorothiazide or both is associated with significant reductions in left ventricular mass and improved diastolic function in elderly patients with hypertension with left ventricular hypertrophy. Despite this reduction in left ventricular mass, left ventricular systolic function and physical performance are well preserved during submaximal exercise.

Mibefradil is a novel calcium antagonist that blocks selectively the T-type calcium channels. In this double-blind forced titration study design we compared the effects of mibefradil 50, 100, and 150 mg and nifedipine GITS 30, 60, and 90 mg monotherapies or combined with lisinopril 20 mg in 71 moderate to severe hypertensives (59 men and 12 women) with confirmed ambulatory hypertension. An incremental dose-response effect was observed both in clinic and ambulatory blood pressure parameters during treatment with mibefradil and nifedipine GITS alone and combined with lisinopril. At maximal dosage, patients treated with mibefradil experienced a greater (P.05) reduction in clinic and ambulatory diastolic blood pressures as well as a greater response rate (86% v 69%). Trough:peak ratios for systolic and diastolic blood pressures were90% at each dose level. Significant decrease in baseline heart rate was observed with mibefradil 150 mg alone or combined with lisinopril, but no patients experienced clinically significant atrioventricular conduction abnormalities. Adverse events related to vasodilation were more prevalent in the nifedipine GITS group. Consequently, the results of the present study demonstrate that the novel calcium channel blocker mibefradil, either alone or in combination with lisinopril, is effective in reducing clinic and 24-h blood pressures while decreasing heart rate and is well tolerated in patients with moderate to severe hypertension.

Recent studies and authorities have advocated the use of low-dose thiazide diuretics as first-line treatment agents in elderly hypertensives. However, these recommendations were based solely on blood pressure (BP) measured in the clinic. The objective of the present 32-week double-blind study was to compare the effects of hydrochlorothiazide (HCTZ) and amlodipine (AML) in elderly patients with confirmed ambulatory hypertension. After a 4-week placebo washout period, 42 (25 men, 17 women) patients (mean age, 69 years) with clinic sitting diastolic BP of 95 to 114 mm Hg and daytime ambulatory diastolic BP of > or = 90 mm Hg were randomized double-blind to receive AML 5 to 10 mg (n = 21) or HCTZ 12.5 to 25 mg (n = 21) once daily. After 8 weeks of monotherapy, patients in whom clinic diastolic BP remained > or = 90 mm Hg were given combination therapy with the other agent. Amlodipine monotherapy induced significant reductions in clinic, mean 24-h, daytime and sleep systolic/diastolic BPs whereas only clinic BP decreased significantly in patients treated with HCTZ monotherapy. Moreover, 19/21 versus 8/21 patients on AML and HCTZ monotherapies achieved adequate BP control. At the end of the 32-week treatment period, combination therapy in the HCTZ group resulted in statistically significant reductions in clinic as well as in 24-h, daytime and sleep ambulatory BPs that were similar to those observed in the AML monotherapy group. In conclusion, the administration of AML monotherapy induced significant reductions in both clinic and ambulatory BPs in elderly patients whereas only clinic BP was significantly decreased by HCTZ monotherapy. Moreover, the addition of AML to HCTZ in patients inadequately controlled by monotherapy has permitted statistically significant decrements in clinic as well as in ambulatory BP. Consequently, the results of the present study suggest that the use of HCTZ in doses of up to 25 mg daily is inadequate for ambulatory BP control in the elderly despite official recommendations.

Alkylation of isobutane with ethylene was investigated over a γ-Al2O3-Cl catalyst at temperatures below 380 K. Ethylene was fully converted over a period of 5–20 h, then conversion steadily decreased. The only products were alkanes, mainly C6 and C8. The composition of the alkylate varied with the isobutane/ethylene ratio and with time-on-stream. Among the C6, 2,3-dimethylbutane became predominant (>95%) after a few hours. The composition of octanes appeared less selective. The kinetic distributions of isomers are interpreted by a new mechanism based on cyclopropane-carbonium ions. Upon catalyst ageing, alkane isomerization decays faster than alkylation, oligomerization being least affected.

A comparative prospective study of 120 adult diabetics (60 insulin dependent, 60 non-insulin dependent) and 120 non-diabetic adults as controls showed significantly higher incidence of Dupuytren's disease, limited joint motion, carpal tunnel syndrome, and flexor tenosynovitis in the diabetic population. Of the diabetic patients one third had a mild non-progressive form of Dupuytren's disease, which commonly involved the long and ring rays. Limited joint motion was noted in a third of diabetics, and carpal tunnel syndrome was observed in 15-25%, and flexor tenosynovitis in about a fifth. Limited joint motion co-existed with Dupuytren's disease in 57% of insulin-dependent diabetics. Diabetic polyneuropathy was found in two thirds of insulin-dependent diabetics and in one third of non-insulin dependent diabetics. All these hand changes were more marked in insulin-dependent diabetics and they showed a positive correlation with increasing age of the patient, duration of the diabetes, and the presence of a microangiopathy.

Inhibitors of the vascular endothelial growth factor (vegf-is) signalling pathway have fundamentally changed the treatment of metastatic renal cell carcinoma (mrcc). Hypertension is one of the most common side effects of vegf-is and has been reported with almost every vegf-i used for treatment to date. The exact mechanism of vegf-i&ndash, induced hypertension appears complex and multifactorial, and it remains to be fully explained. No randomized clinical trials are available to guide the management of hypertension during vegf-i treatment in mrcc patients. The guiding principles suggested here summarize the consensus of opinions on the diagnosis and management of vegf-i&ndash, induced hypertension during treatment of mrcc obtained from an expert working group composed of 4 Canadian medical oncologists and 5 Canadian hypertension specialists. The Canadian Hypertension Education Program guidelines, available literature, and expert opinion were used to develop the guiding principles.

Reactive oxygen species (ROS) modulate aging and aging-related diseases. Dietary composition is critical in modulating lifespan. However, how ROS modulate dietary effects on lifespan remains poorly understood. Superoxide dismutase 1 (SOD1) is a major cytosolic enzyme responsible for scavenging superoxides. Here we investigated the role of SOD1 in lifespan modulation by diet in Drosophila. We found that a high sugar-low protein (HS-LP) diet or low-calorie diet with low-sugar content, representing protein restriction, increased lifespan but not resistance to acute oxidative stress in wild-type flies, relative to a standard base diet. A low sugar-high protein diet had an opposite effect. Our genetic analysis indicated that SOD1 overexpression or dfoxo deletion did not alter lifespan patterns of flies responding to diets. However, sod1 reduction blunted lifespan extension by the HS-LP diet but not the low-calorie diet. HS-LP and low-calorie diets both reduced target of rapamycin (TOR) signaling and only the HS-LP diet increased oxidative damage. sod1 knockdown did not affect phosphorylation of S6 kinase, suggesting that SOD1 acts in parallel with or downstream of TOR signaling. Surprisingly, rapamycin decreased lifespan in sod1 mutant but not wild-type males fed the standard, HS-LP, and low-calorie diets, whereas antioxidant N-acetylcysteine only increased lifespan in sod1 mutant males fed the HS-LP diet, when compared to diet-matched controls. Our findings suggest that SOD1 is required for lifespan extension by protein restriction only when dietary sugar is high and support the context-dependent role of ROS in aging and caution the use of rapamycin and antioxidants in aging interventions.

Alkylation of isobutane by ethylene produces mainly hexanes, but a variety of other compounds, alkanes or alkenes, may be formed by secondary reactions such as successive alkylations, isomerization, and ethylene polymerization. The equilibrium distribution of products is evaluated in the temperature range 280--680 K and at various initial compositions and pressures. Isomer groups are treated using Alberty's formulation. Calculations show that alkenes are thermodynamically unstable under usual reaction conditions. The equilibrium amounts of alkanes are such that C[sub 6] [much gt] C[sub 8] [much gt] C[sub 10] and heavy alkanes also appear unstable. The selective formation of particular isomers (dimethylbutanes, trimethylpentanes) is also integrated in the equilibrium equations. The calculated compositions (C[sub 6]:C[sub 8]:C[sub 10]) are compared with experimental data.

This placebo-controlled multifactorial design trial assessed the antihypertensive efficacy of nebivolol, a novel cardioselective beta 1-blocker with vasodilating properties, and hydrochlorothiazide monotherapy and in combination. After a 4-week placebo period, 240 white patients with a mean daytime ambulatory blood pressure of > or = 90 mm Hg were randomized to receive either placebo, nebivolol (1, 5, or 10 mg), hydrochlorothiazide (12.5 or 25 mg), or one of the six possible combinations of nebivolol and hydrochlorothiazide for 12 weeks. A dose-related reduction in clinic and ambulatory blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination. Nebivolol, 5- and 10-mg doses, showed a larger effect than hydrochlorothiazide doses on clinic blood pressure and over the 24-h interval. Moreover, the combination doses had substantial antihypertensive effects that were sustained over the entire 24-h profile with a greater effect observed with the higher dose combinations. The reduction in ambulatory blood pressure was further substantiated by the reduction of blood pressure loads (% of BP > 140/90 mm Hg awake and > 120/80 mm Hg asleep) to as low as 11.5% with 10 mg of nebivolol combined with 25 mg of hydrochlorothiazide. Nebivolol and hydrochlorothiazide were well tolerated. We provided evidence that nebivolol, given as monotherapy or in combination with low dose of hydrochlorothiazide, is effective in reducing clinic and 24-h ambulatory blood pressure in patients with ambulatory hypertension. The results provided further evidence for the use of ambulatory blood pressure monitoring and factorial designs when investigating new antihypertensive agents.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patient's cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.

This is a summary of the theme, key new recommendations, and supporting science of the 2011 Canadian Hypertension Education Program (CHEP). In 2011, the ACCORD trial challenged current blood pressure treatment targets for people with diabetes. After consideration of multiple factors relating to the ACCORD trial design and its reporting, the current treatment target of130/80 mm Hg was not changed. A meta-analysis implicated angiotensin receptor blockers in causing cancer; however, weaknesses in the meta-analysis and ongoing close scrutiny of the issue by the U.S. Food and Drug Administration precluded any changes in current CHEP recommendations. New expert opinion-based recommendations were added to assist the management of hypertension in the setting of acute stroke. To promote healthier blood pressure in Canadians, CHEP emphasizes the need for all Canadians-in particular, health care professionals and their organizations-to more actively work with different levels of government to implement healthy public policies. These should build community capacity to promote healthy behaviours with the goal of the prevention of hypertension and its consequences. To aid a substantive knowledge translation gap, health care professionals and people with hypertension can now receive regular CHEP updates by signing up at the Web sites htnupdate.ca and www.myBPsite.ca.

A double-blind, crossover study was carried out to compare the antihypertensive efficacy of the long-acting ACE inhibitor trandolapril 1 mg administered once daily and 0.5 mg twice daily in 31 patients with mild to moderate essential hypertension. After randomization, patients entered a single-blind placebo period of 4 weeks. After a double-blind treatment of 4 weeks with either of the dosage regimens, patients were then crossed over to the alternate regimen for the last 4 weeks of the study. Conventional BP and heart rate were measured on each visit and ambulatory BP monitoring was done at baseline and at the end of each treatment phase. Conventional as well as 24-hour and awake ambulatory systolic and diastolic BPs were significantly (P0.001) and almost identically decreased by both once- and twice-daily formulations. Moreover, the clinical response rates (reduction in seated diastolic BPor = 10% or diastolic BPor = 90 mm Hg) were similar with both treatment regimens (42% vs. 45% with the once- and twice-daily formulations, respectively). However, trandolapril twice daily exerted a significantly (P = 0.03) greater antihypertensive effect on systolic BP during sleep as compared with the once-daily formulation. Due to the fact that the minimal effective dose was used in this trial, further studies with higher doses should demonstrate effective 24-hour control of BP as described with other long-acting ACE inhibitors. In addition, our results suggest that ambulatory BP measurements should be done in dose-response studies.

The effects of long-term treatment with captopril and conventional therapy on albuminuria and metabolic parameters were compared in 74 hypertensive type II diabetics with normal serum creatinine. Patients were treated double-blind with either captopril monotherapy or combined with hydrochlorothiazide or therapy with metoprolol, hydrochlorothiazide, or both for 36 months. The treatment was titrated to achieve goal diastolic blood pressure of < or = 85 mm Hg. The reductions in blood pressures during treatment were similar in patients with (n = 21) and without (n = 53) microalbuminuria treated with either captopril or conventional therapy. No significant changes in albuminuria occurred in normoalbuminuric patients with either therapy. Although albuminuria fell in nearly all patients with microalbuminuria treated with captopril, it rose in eight of 12 patients on conventional therapy, with macroalbuminuria developing in two of them. Renal function was preserved by both types of treatment in both patient groups. Long-term treatment with either conventional therapy or captopril did not alter metabolic variables. We conclude that captopril alone or in combination decreases albuminuria and prevents the development of macroalbuminuria in hypertensive type II diabetics with persistent microalbuminuria. The renoprotective effect of this agent, however, remains to be demonstrated with longer term data on renal function. Aggressive antihypertensive treatment with either captopril or conventional therapy appears to be effective in preventing the onset of microalbuminuria in most normoalbuminuric patients. In contrast, with previous short-term studies, the use of converting enzyme inhibitors or conventional therapy did not cause adverse metabolic effects.

1. Forty patients with moderate to severe hypertension and daytime ambulatory diastolic blood pressure > or = 90 mm Hg were randomized double-blind to once-daily treatment with either quinapril up to 20 mg (n = 20) or atenolol up to 100 mg (n = 20) as single drugs or in combination with hydrochlorothiazide 25 mg over a period of 12 weeks. 2. Conventional and ambulatory blood pressure, heart rate, side effects and metabolic changes were compared at the end of the run-in period on placebo, after 4 weeks on monotherapy and at the end of the 12-week period of active treatment. 3. Quinapril and atenolol reduced conventional blood pressure equally with substantial additional effect seen on combination therapy. The two regimens induced a significant decrease in ambulatory BP. However, the atenolol treated ambulatory hypertensive group experienced significantly greater decreases in diastolic blood pressure during 24 h, awake and sleep periods than did the quinapril group. 4. Adverse reactions were mild with both drugs except for severe Raynaud phenomenon in one patient in the atenolol group. Triglyceride levels were significantly increased with atenolol alone and in combination with hydrochlorothiazide. 5. Thus, within the limits of the dose ranges tested, quinapril and atenolol as single drugs or in combination with hydrochlorothiazide reduce significantly conventional and ambulatory blood pressure in moderate to severe hypertensives, but atenolol is more effective in reducing ambulatory diastolic blood pressure.

Bei Patienten mit leichter bis mittelschwerer essentieller Hypertonie wurde die 24stundige antihypertensive Wirksamkeit von 2,5 und 5 mg Cilazapril durch ambulantes Blutdruck-Monitoring mit Plazebo ve

The present article is a summary of the theme, the key recommendations for management of hypertension and the supporting clinical evidence of the 2010 Canadian Hypertension Education Program (CHEP). In 2010, CHEP emphasizes the need for health care professionals to stay informed about hypertension through automated updates at www.htnupdate.ca. A new interactive Internet-based lecture series will be available in 2010 and a program to train community hypertension leaders will be expanded. Patients can also sign up to receive regular updates in a pilot program at www.myBPsite.ca. In 2010, the new recommendations include consideration for using automated office blood pressure monitors, new targets for dietary sodium for the prevention and treatment of hypertension that are aligned with the national adequate intake values, and recommendations for considering treatment of selected hypertensive patients at high risk with calcium channel blocker/angiotensin-converting enzyme inhibitor combinations and the use of angiotensin receptor blockers.

Dietary restriction (DR), the reduction of nutrient intake without causing malnutrition, is one environmental intervention that has been shown to extend the life span of a variety of organisms. Drosophila melanogaster is ideally suited for experiments into the biological effects of DR and aging due to its short life span and thorough characterization at the molecular and genetic level. Furthermore, the simple sugar/yeast diet (corresponding to carbohydrate and protein sources respectively) for Drosophila can be easily manipulated and is therefore amenable to experiments designed to determine the relative importance of the different food components (or caloric content) to life span. Although which aspect of nutrition is most important to fly longevity has not yet been determined, DR experiments have shown that many behaviors and functions, including cognition, olfaction and female fecundity, are influenced by the fly’s nutritional status. Genetic studies have identified numerous signaling pathways, including the insulin-like signaling, target of rapamycin and sirtuin pathways, as potential mediators between DR and life span. Most of these pathways are evolutionarily conserved. Therefore, results from DR studies in Drosophila should help with the development of therapeutic interventions to slow the aging process in higher organisms, including humans.

This double-blind, parallel-group study compared the effects of nebivolol, a novel cardioselective beta-blocker, with those of nifedipine sustained-release on 24-hour ambulatory blood pressure and plasma lipoprotein levels. After a washout period of 8 weeks, 51 patients with mild to moderate essential hypertension were randomized to double-blind treatment with either nebivolol 5 mg once a day (n = 26) or nifedipine sustained-release 20 mg bid (n = 25) over a period of 12 weeks. Both treatments produced similar and significant (P = .0001) reduction in office blood pressure as well as in 24-hour, work, awake, and sleep ambulatory blood pressure. The clinical response (diastolic blood pressure less than 90 mmHg or decreased by greater than or equal to 10 mmHg) rate was 69% for nebivolol and 59% for nifedipine, respectively. Moreover, the nebivolol and nifedipine treatment-induced decreases in mean 24-hour ambulatory blood pressure were similar to the decreases in clinic blood pressure. Furthermore, the percentages of "blood pressure loads" (awake greater than 140/90 mmHg and asleep greater than 120/80 mmHg) were lowered significantly (P = .0001), from 60% to 29% with nebivolol and from 60% to 39% with nifedipine. Mean ambulatory heart rate was reduced (P = .0001) from 79 +/- 7 to 68 +/- 7 beats/minute during nebivolol therapy and from 80 +/- 9 to 79 +/- 7 (not significant) with nifedipine. Total plasma cholesterol and low-density lipoprotein levels decreased significantly (P less than .05) by 5 and 8%, respectively, after nebivolol treatment, and each decreased by 3% after nifedipine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The antihypertensive efficacy of sustained-release nicardipine compared to placebo as third-line therapy has been assessed by ambulatory blood pressure monitoring in severly hypertensive patients with clinically unsatisfactory blood pressure control on 50 mg hydrochlorothiazide o.d. and 75 mg captopril b.d. Forty-two patients, 31 m and 11 f, with supine diastolic blood pressure 95–115 mm Hg after a 4 week run-in period on open hydrochlorothiazide and captopril, were randomly allocated to sustained-release nicardipine 45–60 mg/d or placebo. At a visit to the clinic blood pressure and heart rate were measured 12 h after the evening dose by a trained observer unaware of the treatment. Twenty-four hour ambulatory monitoring was performed at the end of baseline and after 8 weeks of blinded medication. There was no significant change in BD at the visit or on ambulatory monitoring in the placebo treated patients. In contrast, nicardipine produced a significant reduction in both blood pressures without affecting heart rate. Nicardipine also decreased the mean 24-h blood pressure by 14/10 mm Hg in patients whose clinical hypertension had been confirmed by ambulatory blood pressure monitoring but by only 3/2 mm Hg in ambulant patients who were normotensive on two-drug therapy. One patient experienced an episode of severe symptomatic hypotension while on nicardipine. Otherwise, the numbers and percentages of patients from each group reporting adverse experiences were similar. It is concluded that nicardipine appears to be an effective antihypertensive agent when used as third line therapy with diuretics and angiotensin converting enzyme inhibitors in patients with severe hypertension. In addition, since 40% of such patients already on two drug therapy were found to have a normal ambulatory blood pressure, the results reinforce the value of ambulatory monitoring in distinguishing hypertensives in whom more aggressive treatment may not by justified.

Goal blood pressure levels are only being achieved in approximately a third of hypertensive patients, which suggests that there is a need for new and/or improved approaches to the treatment of hypertension. The majority of patients with hypertension require combination therapy to control their blood pressure. The use of a combination of drugs with complementary mechanisms of action may provide greater efficacy and tolerability compared with monotherapy, and may allow more rapid achievement of target blood pressure. Moreover, the use of single-pill combinations has the potential to increase adherence and persistence, and reduce costs. The single-pill combination of valsartan plus hydrochlorothiazide was recently approved by the US FDA for first-line use in hypertensive patients who are likely to need multiple drugs to achieve their blood pressure goals. The focus of this article is on those randomized, double-blind trials in which this combination was administered as first-line therapy in patients with essential hypertension.

Oocytes accumulate mRNAs and proteins that direct early embryonic development. Although subsequent development requires the timely degradation of these maternal products, little is known of the underlying mechanisms. The stem-loop-binding protein (SLBP), which regulates the stability and translation of mRNAs encoding histones and is synthesized during S-phase and degraded during G2 in somatic cells, accumulates during oogenesis. Maternal SLBP is required for mouse embryos to develop beyond the 2-cell stage, but must be degraded to allow the cell-cycle-regulated expression of somatic cells to be established. We report that the quantity of maternal SLBP changes little following fertilization until 44–52 h post-hCG, corresponding to mid-/late G2 of the 2-cell stage, when it decreases by 75%. Efficient degradation requires two pathways. The first requires activity of cyclin-dependent kinases (cdk) and embryonic transcription, preferentially targets nuclear SLBP, and likely corresponds to the pathway that degrades SLBP at G2 in somatic cells. The second does not require cdk activity or transcription and becomes active at 44–52 h post-hCG independently of cell-cycle progression to mid-/late G2, but is not solely regulated by the time elapsed since hCG injection. Thus, the co-ordinated activity of two separately regulated pathways eliminates maternally encoded SLBP from early mouse embryos.