The relationships among physical activity, sedentary behaviour, obesity and quitting behaviours within a cohort of smokers in California.

BACKGROUND: Smoking, insufficient physical activity (PA), sedentary behaviour (SB) and obesity are leading risk factors for morbidity and premature mortality. Few studies examining the relationship between these behavioural risk factors and quitting behaviours among cohorts of smokers have been published. PURPOSE: The goals of this study are to examine the cross-sectional relationships among behavioural health risk factors (insufficient PA, SB and obesity) and past year quitting behaviours within a sample of smokers. METHODS: The California Smokers Cohort, conducted from 2011 through 2013, is a population-based survey of adult smokers in California. Using follow-up data (n = 1050), participants' self-reported health behaviours and past year quitting behaviours were examined in univariate analyses and multivariate logistic regression analyses controlling for demographic covariates. RESULTS: In univariate analyses examining health behaviours among smokers, all three health behaviours examined (PA, SB and obesity) were related, and significantly more obese smokers with high PA and low SB reported a ≥20% smoking rate reduction than smokers with other combinations of health behaviours (48.8%, Chi-squared = 4.765, P = 0.045). In multivariate models adjusted for sociodemographic characteristics, obese smokers (odds ratio [OR] = 1.450, 95% confidence interval [CI]: 1.088-1.932, P = 0.011) and smokers with higher levels of PA (OR = 1.448, 95% CI: 1.111-1.887, P = 0.006) were more likely to report a past year ≥24-hour quit attempt regardless of SB, and obese smokers (OR = 1.760, 95% CI: 1.095-2.828, P = 0.019) were more likely to report being quit for ≥30 days regardless of PA and SB. CONCLUSIONS: Overall, the results demonstrated that more physically active and obese smokers were more likely to report positive strides towards quitting. These findings support the potential positive effect of addressing multiple health behaviours along with smoking.

New approach to measurement of blood pressure in the office

Automated office blood pressure (AOBP) measurement has important advantages over conventional manual office blood pressure (MOBP) readings. AOBP requires the use of a fully automated sphygmomanometer which takes multiple readings with the patient resting alone. By following these three principles of AOBP, it is possible to obtain office readings which are similar to home BP and to the awake ambulatory BP recorded with 24-h BP monitoring. All three methods of automated BP measurement define hypertension as a BP ≥ 135/85 mm Hg. The correlation between the awake ambulatory BP (a recognized gold standard for predicting future cardiac events in relation to BP status) and AOBP is significantly stronger than it is for routine MOBP. AOBP eliminates office-induced hypertension (white coat hypertension) and correlates with target organ damage significantly stronger than does routine MOBP. After 100years of manual BP measurement with the mercury sphygmomanometer, it is now time to adopt AOBP for use in routine clinical practice in order to achieve a more accurate assessment of a patient’s BP status and future cardiovascular risk (AU)

La medición automática de la presión sanguínea en consulta (MAPSC) presenta importantes ventajas sobre la medición manual de la presión arterial en consulta (MMPAC). La MAPSC requiere el uso de un esfigmomanómetro totalmente automático que registra múltiples lecturas con el paciente en reposo y sin la presencia del clínico. Al seguir estos tres principios de la MAPSC, es posible obtener lecturas en consulta similares a las obtenidas en domicilio y con monitorización ambulatoria de la PA de 24 horas con el paciente despierto. Los tres métodos de medición automática de la PA definen la hipertensión como una presión arterial ≥ 135/85 mmHg La correlación entre la PA ambulatoria con el paciente despierto (un estándar de oro reconocido para la predicción de futuros eventos cardíacos en relación con el estado de la PA) y la MAPSC es mucho mayor que para la MMPAC rutinaria. La MAPSC elimina la hipertensión de bata blanca y se correlaciona con el daño al órgano diana de forma significativamente superior que la MMPAC rutinaria. Después de 100 años de medición manual de la PA con el esfigmomanómetro de mercurio, es hora de adoptar el uso de la MAPSC de forma rutinaria en la práctica clínica a fin de lograr una evaluación más precisa de la PA del paciente y su riesgo cardiovascular futuro (AU)

Leptin signaling in intestinal epithelium mediates resistance to enteric infection by Entamoeba histolytica.

Leptin is an adipocytokine that links nutrition to immunity. Previous observation that a genetic polymorphism in the leptin receptor affected susceptibility to Entamoeba histolytica infection led to the hypothesis that leptin signaling has a protective role during intestinal amebic infection. In this study we show that mice lacking the functional leptin receptor developed devastating mucosal destruction after E. histolytica infection. Bone marrow chimera experiments demonstrated that leptin receptor expressed on hematopoietic cells was not sufficient to confer resistance. Similarly, peripheral knockout of the leptin receptor rendered animals susceptible, indicating that central expression of the leptin receptor was not sufficient to confer protection. The site of leptin action was localized to the gut via an intestinal epithelium-specific deletion of the leptin receptor, which rendered mice susceptible to infection and mucosal destruction by the parasite. Mutation of tyrosine 985 or 1138 in the intracellular domain of the leptin receptor, which mediates signaling through the SH2-containing tyrosine phosphatase/extracellular signal-regulated kinase (SHP2/ERK) and signal transducer and activator of transcription 3 (STAT3) pathways, respectively, demonstrated that both were important for mucosal protection. We conclude that leptin-mediated resistance to amebiasis is via its actions on intestinal epithelium rather than hematopoietic cells or the brain, and requires leptin receptor signaling through both the STAT3 and SHP2/ERK pathways.

Blood pressure variability and prevalence of hypertension using automated readings from multiple visits to a pharmacy-based community-wide programme.

Blood pressure (BP) measurements taken outside the routine office context may be a useful adjunct strategy to monitor BP. Community-based BP data can also provide estimates of the prevalence of elevated BP. We compared multiple readings taken on different days in pharmacies using an automated BpTRU device during a cardiovascular health programme targeting community-dwelling older adults. Mean systolic (S) and diastolic (D) BP values were compared over time using repeated measures analysis of variance for all participants with at least three separate sets of readings (n=317). BP variability was then examined among four subgroups based on report of antihypertensive medication or no treatment, and normal or elevated SBP at the initial visit (< or >or=140, or 130 if diabetes reported). Prevalence of elevated BP was compared across visits. Overall, mean SBP decreased between visits 1 and 2 (140.4 vs 137.1 mm Hg; P<0.001). Among participants with normal SBP at the initial visit, SBP did not vary significantly, whether or not antihypertensive treatment was reported. Those with initially elevated SBP experienced a significant decrease between visits 1 and 2, also regardless of treatment status. Prevalence of elevated BP decreased from visits 1 to 2 (55.8 vs 48.9%; P=0.026) and from visits 1 to 3 (55.8 vs 42.9%; P<0.001). Analyses of BP data from a community-based programme using an accurate device showed that initial readings may inflate the population estimate of elevated BP. Findings suggest that more than one set of BP readings measured on different occasions are needed, particularly if the first set is elevated.

LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action.

The adipose tissue-derived hormone, leptin, acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. In order to understand leptin action we have explored the physiological function of LRb signalling pathways, defining important roles for signal transducer and activator of transcription-3 (STAT3) in positive signalling and for LRbTyr(985)-mediated feedback inhibition in leptin signal attenuation. As the cells on which leptin acts are not homogeneous, but rather represent a broadly distributed network of neurones with divergent projections and functions, it is also crucial to consider how each of these populations responds to LRb signals to contribute to leptin action. While well-known LRb-expressing neurones within the arcuate nucleus of the hypothalamus mediate crucial effects on satiety and energy expenditure, other populations of LRb-expressing neurones in the ventral tegmental area and elsewhere likely control the mesolimbic dopamine system. Additional populations of LRb-expressing neurones likely contribute to other aspects of neuroendocrine regulation. It will be important to define the molecular mechanisms by which leptin acts to regulate neurophysiology in each of these LRb-expressing neural populations in order to understand the totality of leptin action.

Leptin receptor signaling and the regulation of mammalian physiology.

The adipocyte-derived hormone, leptin, signals the status of body energy stores to the central nervous system to regulate appetite and energy expenditure. A specific long-form leptin receptor (LepRb), a type I cytokine receptor, mediates leptin action on LepRb-expressing neurons in the brain. Leptin binding to LepRb activates the associated Janus kinase-2 (Jak2) tyrosine kinase to promote the phosphorylation of Jak2 and three residues on LepRb; each of these sites mediates a distinct aspect of downstream LepRb signaling, with differing physiologic functions. Tyr(1138) --> STAT3 signaling suppresses feeding, but is not required for a number of other leptin actions. Tyr(985) binds SH2-containing tyrosine phosphatase-2 and suppressor of cytokine signaling-3 and primarily mediates the attenuation of LepRb signaling in vivo. The role for Tyr(1077), the major regulator of signal transducer and activator of transcription-5 (STAT5) during leptin signaling, in the physiologic response to leptin remains unclear, although the obese phenotype of animals deleted for STAT5 in the brain suggests the potential importance of this signaling pathway. Leptin also modulates a number of other signaling pathways in the brain, including PI 3-kinase, mammalian target of rapamycin and AMP-dependent protein kinase; the pathways by which leptin controls these signals remain unclear, however, and may involve some indirect mechanisms. Important issues regarding leptin action and LepRb signaling in the future include not only the more thorough analysis of intracellular signaling pathways, but the neural substrate by which leptin acts, as most major populations of LepRb neurons remain poorly studied.

The impact of one or two missed doses on the duration of action of combined perindopril and indapamide.

To evaluate the persistence of the antihypertensive effect of perindopril 4 mg+indapamide 1.25 mg once daily for up to 72 h using the 'missed-dose' technique. Hypertensive patients were initially treated with perindopril 2 mg+indapamide 0.625 mg once daily. After 4 weeks, the 135 of 216 patients who still had a diastolic BP> or =85 mm Hg went on to receive perindopril 4 mg+indapamide 1.25 mg daily for a further 8 weeks. During either week 9 or 11, placebo was substituted for perindopril 4 mg+indapamide 1.25 mg on either one or two consecutive days to simulate BP changes, which might occur after one or two missed doses. A 24-h ambulatory BP recording was performed at baseline, after 9 or 11 weeks of perindopril+indapamide therapy and during the simulated missed doses, 24- 48 and 48-72 h after the administration of perindopril 4 mg+indapamide 1.25 mg. Significant (P<0.001) reductions in mean (+/-s.d.) 24-h ambulatory BP (mm Hg) during the first 24 h after perindopril 4 mg+indapamide 1.25 mg therapy versus baseline were noted for patients later randomized to the one missed dose (-15.9+/-10.5/-9.4+/-7.6) or two missed dose (-17.4+/-8.7/-10.3+/-5.1) sub-groups. A significant reduction in BP (P<0.001 versus baseline) was still present on the days when placebo was substituted for perindopril 4 mg+indapamide 1.25 mg with decreases in mean 24-h ambulatory BP from 24 to 48 h and 48 to 72 h after dosing being -11.9+/-10.1/-6.9+/-6.2 and -10.6+/-9.9/-5.8+/-5.7, respectively. Use of the 'missed-dose' technique has demonstrated a prolonged antihypertensive effect for perindopril 4 mg+indapamide 1.25 mg for up to 72 h, supporting the use of this combination as therapy for hypertension.

Leptin receptor action and mechanisms of leptin resistance.

The adipose tissue-derived hormone leptin regulates energy balance and neuroendocrine function. Resistance to the appetite-suppressing effects of leptin is associated with common forms of obesity. Here, we review the mechanisms by which leptin activates intracellular signals and the roles that these signals play in leptin action in vivo. Furthermore, we discuss potential mechanisms of leptin resistance, specifically focusing on data regarding the neuroanatomical locus of leptin resistance and potential mechanisms by which expression of the suppressor of cytokine signaling-3 may impair leptin action.

Effects of motivational interviewing on smoking cessation in adolescents with psychiatric disorders.

OBJECTIVE: To test the hypothesis that among adolescent smokers hospitalised for psychiatric and substance use disorders, motivational interviewing (MI) would lead to more and longer quit attempts, reduced smoking, and more abstinence from smoking over a 12 month follow up. DESIGN: Randomised control trial of MI versus brief advice (BA) for smoking cessation, with pre- and post-intervention assessment of self efficacy and intentions to change, and smoking outcome variables assessed at one, three, six, nine, and 12 month follow ups. SETTING: A private, university affiliated psychiatric hospital in Providence, Rhode Island, USA. PATIENTS OR OTHER PARTICIPANTS: Consecutive sample (n = 191) of 13-17 year olds, admitted for psychiatric hospitalisation, who smoked at least one cigarette per week for the past four weeks, had access to a telephone, and did not meet DSM-IV criteria for current psychotic disorder. INTERVENTIONS: MI versus BA. MI consisted of two, 45 minute individual sessions, while BA consisted of 5-10 minutes of advice and information on how to quit smoking. Eligible participants in both conditions were offered an eight week regimen of transdermal nicotine patch upon hospital discharge. MAIN OUTCOME MEASURES: Point prevalence abstinence, quit attempts, changes in smoking rate and longest quit attempt. Proximal outcomes included intent to change smoking behaviour (upon hospital discharge), and self efficacy for smoking cessation. RESULTS: MI did not lead to better smoking outcomes compared to BA. MI was more effective than BA for increasing self efficacy regarding ability to quit smoking. A significant interaction of treatment with baseline intention to quit smoking was also found. MI was more effective than BA for adolescents with little or no intention to change their smoking, but was actually less effective for adolescents with pre-existing intention to cut down or quit smoking. However, the effects on these variables were relatively modest and only moderately related to outcome. Adolescents with comorbid substance use disorders smoked more during follow up while those with anxiety disorders smoked less and were more likely to be abstinent. CONCLUSIONS: The positive effect of MI on self efficacy for quitting and the increase in intention to change in those with initially low levels of intentions suggest the benefits of such an intervention. However, the effects on these variables were relatively modest and only moderately related to outcome. The lack of overall effect of MI on smoking cessation outcomes suggests the need to further enhance and intensify this type of treatment approach for adolescent smokers with psychiatric comorbidity.

Challenges in the development, licensure, and use of combination vaccines.

Before substantial public health benefits associated with use of combination vaccines can be realized, a variety of challenges must be addressed. In February 2000, the National Vaccine Program Office convened the International Symposium on Combination Vaccines to explore solutions for barriers to development, licensure, and use of safe and effective combination vaccines. The symposium focused on the following questions: (1) What immunologic standards should be used to evaluate new combination vaccines? (2) How should correlates of protection be developed, and how should the data they provide be interpreted? (3) What sample size is adequate for prelicensure safety trials of combination vaccines? (4) Should standards for evaluation of combination vaccines containing licensed components be different from standards for evaluation of combinations containing unlicensed components? (5) How can the "great expectations" of postlicensure surveillance be realized? Available data relevant to these issues were presented, providing a foundation for furthering the science of combination vaccines.

Ambulatory blood pressure monitoring in clinical practice.

Ambulatory blood pressure (ABP) monitoring has become increasingly more available in routine clinical practice in Canada. The ABP is more reliable and more reproducible than office readings, and is a better predictor of target organ damage. Normal values for ABP have been established using both cross-sectional and longitudinal outcome data. Abnormal mean 24 h and awake ABP values should exceed 135/85 mmHg and 140/90 mmHg, respectively. ABP recordings are useful in making a diagnosis of hypertension by identifying people with high office but normal ABP values. ABP monitoring can also be performed in patients already receiving antihypertensive therapy to determine the extent of any white coat effect that may be increasing office readings. The interpretation of the ABP should take into account cardiac risk factors, any target organ damage that may be present or coexisting conditions such as diabetes mellitus.

Differential activation of protein kinase B and p70(S6)K by glucose and insulin-like growth factor 1 in pancreatic beta-cells (INS-1).

It has been shown that IGF-1-induced pancreatic beta-cell proliferation is glucose-dependent; however, the mechanisms responsible for this glucose dependence are not known. Adenoviral mediated expression of constitutively active phosphatidylinositol 3-kinase (PI3K) in the pancreatic beta-cells, INS-1, suggested that PI3K was not necessary for glucose-induced beta-cell proliferation but was required for IGF-1-induced mitogenesis. Examination of the signaling components downstream of PI3K, 3-phosphoinositide-dependent kinase 1, protein kinase B (PKB), glycogen synthase kinase-3, and p70-kDa-S6-kinase (p70(S6K)), suggested that a major part of glucose-dependent beta-cell proliferation requires activation of mammalian target of rapamycin/p70(S6K), independent of phosphoinositide-dependent kinase 1/PKB activation. Adenoviral expression of the kinase-dead form of PKB in INS-1 cells decreased IGF-1-induced beta-cell proliferation. However, a surprisingly similar decrease was also observed in adenoviral wild type and constitutively active PKB-infected cells. Upon analysis of extracellular signal-regulated protein kinase 1 and 2 (ERK1/ERK2), an increase in ERK1/ERK2 phosphorylation activation by glucose and IGF-1 was observed in kinase-dead PKB-infected cells, but this phosphorylation activation was inhibited in the constitutively active PKB-infected cells. Hence, there is a requirement for the activation of both ERK1/ERK2 and mammalian target of rapamycin/p70(S6K) signal transduction pathways for a full commitment to glucose-induced pancreatic beta-cell mitogenesis. However, for IGF-1-induced activation, these pathways must be carefully balanced, because chronic activation of one (PI3K/PKB) can lead to dampening of the other (ERK1/2), reducing the mitogenic response.

Free fatty acid-induced inhibition of glucose and insulin-like growth factor I-induced deoxyribonucleic acid synthesis in the pancreatic beta-cell line INS-1.

Pancreatic beta-cell mitogenesis is increased by insulin-like growth factor I (IGF-I) in a glucose-dependent manner. In this study it was found that alternative beta-cell nutrient fuels to glucose, pyruvate, and glutamine/leucine independently induced and provided a platform for IGF-I to induce INS-1 cell DNA synthesis in the absence of serum. In contrast, long chain FFA (>/=C(12)) inhibited 15 mM glucose-induced [(3)H]thymidine incorporation (+/-10 nM IGF-I) by 95% or more within 24 h above 0.2 mM FFA complexed to 1% BSA (K(0.5) for palmitate/1% BSA = 65-85 microM for 24 h; t(0.5) for 0.2 mM palmitate/1% BSA = approximately 6 h). FFA-mediated inhibition of glucose/IGF-I-induced ss-cell DNA synthesis was reversible, and FFA oxidation did not appear to be required, nor did FFA interfere with glucose metabolism in INS-1 cells. An examination of mitogenic signal transduction pathways in INS-1 cells revealed that glucose/IGF-I induction of early signaling elements in SH2-containing protein (Shc)- and insulin receptor substrate-1/2-mediated pathways leading to downstream mitogen-activated protein kinase and phosphoinositol 3'-kinase activation, were unaffected by FFA. However, glucose-/IGF-I-induced activation of protein kinase B (PKB) was significantly inhibited, and protein kinase Czeta was chronically activated by FFA. It is possible that FFA-mediated inhibition of ss-cell mitogenesis contributes to the reduction of beta-cell mass and the subsequent failure to compensate for peripheral insulin resistance in vivo that is key to the pathogenesis of obesity-linked diabetes.

Assessment of antihypertensive activity in the regulatory setting.

Before a new antihypertensive drug receives regulatory approval, it must demonstrate a significant blood pressure-lowering effect over its entire dosing interval. The Food and Drug Administration recognizes several different methods for demonstrating antihypertensive activity, the gold standard continuing to be the office/casual blood pressure at the end of the dosing interval (trough). There should be at least two studies demonstrating a significant antihypertensive effect, at least one of which should include a placebo. Data obtained using ambulatory blood pressure monitoring are used for showing the time-course of the antihypertensive effect, particular attention being given to possible marked differences between the drug's maximum (peak) effect and its activity during the trough. In Europe, the Committee for Proprietary Medicinal Products also considers the office/casual blood pressure at trough to be a primary measure of outcome, responder rates using office/casual readings also being noted. The Committee recommends that data be obtained using ambulatory blood pressure monitoring in order to demonstrate a drug's antihypertensive activity. In addition, it specifically requests that a trough : peak ratio be calculated, whereas the Food and Drug Administration does not require this information.

The 2000 Canadian recommendations for the management of hypertension: part two--diagnosis and assessment of people with high blood pressure.

OBJECTIVE: To provide updated, evidence-based recommendations for the diagnosis and assessment of high blood pressure in adults. OPTIONS: For people with high blood pressure, the assignment of a diagnosis of hypertension depends on the appropriate measurement of blood pressure, the level of the blood pressure elevation, the duration of follow-up and the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases. For people diagnosed with hypertension, defining the overall risk of adverse cardiovascular outcomes requires laboratory testing, a search for target organ damage and an assessment of the modifiable causes of hypertension. Out-of-clinic blood pressure assessment and echocardiography are options for selected patients. OUTCOMES: People at increased risk of adverse cardiovascular outcomes and were identified and quantified. EVIDENCE: Medline searches were conducted from the period of the last revision of the Canadian recommendations for the management of hypertension (May 1998 to October 2000). Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other studies. All relevant articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. VALUES: A high value was placed on the identification of people at increased risk of cardiovascular morbidity and mortality. BENEFITS, HARMS AND COSTS: The identification of people at higher risk of cardiovascular disease will permit counselling for lifestyle manoeuvres and the introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. In certain settings, and for specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and/or mortality. RECOMMENDATIONS: The present document contains detailed recommendations pertaining to aspects of the diagnosis and assessment of patients with hypertension, including the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, routine and optional laboratory testing, assessment for renovascular hypertension, home and ambulatory blood pressure monitoring, and the role of echocardiography in hypertension. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Only the recommendations achieving high levels of consensus are reported here. These guidelines will be updated annually. ENDORSEMENT: These recommendations are endorsed by the Canadian Hypertension Society, The Canadian Coalition for High Blood Pressure Prevention and Control, The College of Family Physicians of Canada, The Heart and Stroke Foundation of Canada, The Adult Disease Division and Bureau of Cardio-Respiratory Diseases and Diabetes at the Centre for Chronic Disease Prevention and Control of Health Canada.