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Biomedical subjects

M G Myers

Publications and source records attributed to M G Myers.

At least 19 recordsLinked to original sources
PubMed2006

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.

Antihypertensive Agents↗
PubMed2005

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.

Animals↗
PubMed2003

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.

Adolescent↗
PubMed2001

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.

Clinical Trials as Topic↗
PubMed2001

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.

Adenoviridae↗
PubMed2001

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.

Antihypertensive Agents↗
PubMed2001

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.

Adaptor Proteins, Signal Transducing↗
PubMed2001

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.

Blood Pressure Monitoring, Ambulatory↗
PubMed2001

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.

Adrenal Gland Neoplasms↗
PubMed2000

SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985.

During leptin signaling, each of the phosphorylated tyrosine residues on the long form of the leptin receptor (LRb) mediates distinct signals. Phosphorylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and transcriptional activation, while phosphorylated Tyr(985) binds the tyrosine phosphatase SHP-2 and reportedly mediates both activation of ERK kinases and inhibition of LRb-mediated STAT3 activation. We show here that although mutation of Tyr(985) does not alter STAT3 signaling by erythropoietin receptor-LRb (ELR) chimeras in transfected 293 cells at short times of stimulation, this mutation enhances STAT3 signaling at longer times of stimulation (>6 h). These data suggest that Tyr(985) may mediate feedback inhibition of LRb signaling by an LRb-induced LRb inhibitor, such as SOCS3. Indeed, SOCS3 binds specifically to phosphorylated Tyr(985) of LRb, and SOCS3 fails to inhibit transcription by ELR following mutation of Tyr(985), suggesting that SOCS3 inhibits LRb signaling by binding to phosphorylated Tyr(985). Additionally, overexpression of SOCS3, but not SHP-2, impairs ELR signaling, and the overexpression of SHP-2 blunts SOCS3-mediated inhibition of ELR signaling. Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr(985) of LRb mediates feedback inhibition of LRb signaling by binding to LRb-induced SOCS3.

Carrier Proteins↗
PubMed2000

Divergent roles of SHP-2 in ERK activation by leptin receptors.

The protein tyrosine phosphatase SHP-2 has been proposed to serve as a regulator of leptin signaling, but its specific roles are not fully examined. To directly investigate the role of SHP-2, we employed dominant negative strategies in transfected cells. We show that a catalytically inactive mutant of SHP-2 blocks leptin-stimulated ERK phosphorylation by the long leptin receptor, ObRb. SHP-2, lacking two C-terminal tyrosine residues, partially inhibits ERK phosphorylation. We find similar effects of the SHP-2 mutants after examining stimulation of an ERK-dependent egr-1 promoter-construct by leptin. We also demonstrate ERK phosphorylation and egr-1 mRNA expression in the hypothalamus by leptin. Analysis of signaling by ObRb lacking intracellular tyrosine residues or by the short leptin receptor, ObRa, enabled us to conclude that two pathways are critical for ERK activation. One pathway does not require the intracellular domain of ObRb, whereas the other pathway requires tyrosine residue 985 of ObRb. The phosphatase activity of SHP-2 is required for both pathways, whereas activation of ERK via Tyr-985 of ObRb also requires tyrosine phosphorylation of SHP-2. SHP-2 is thus a positive regulator of ERK by leptin receptors, and both the adaptor function and the phosphatase activity of SHP-2 are critical for this regulation.

Animals↗
PubMed2000

IRS-2 pathways integrate female reproduction and energy homeostasis.

Severe dietary restriction, catabolic states and even short-term caloric deprivation impair fertility in mammals. Likewise, obesity is associated with infertile conditions such as polycystic ovary syndrome. The reproductive status of lower organisms such as Caenorhabditis elegans is also modulated by availability of nutrients. Thus, fertility requires the integration of reproductive and metabolic signals. Here we show that deletion of insulin receptor substrate-2 (IRS-2), a component of the insulin/insulin-like growth factor-1 signalling cascade, causes female infertility. Mice lacking IRS-2 have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin and sex steroids are low in these animals. Pituitaries are decreased in size and contain reduced numbers of gonadotrophs. Females lacking IRS-2 have increased food intake and obesity, despite elevated levels of leptin. Our findings indicate that insulin, together with leptin and other neuropeptides, may modulate hypothalamic control of appetite and reproductive endocrinology. Coupled with findings on the role of insulin-signalling pathways in the regulation of fertility, metabolism and longevity in C. elegans and Drosophila, we have identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis.

Animals↗
PubMed2000

Activation of downstream signals by the long form of the leptin receptor.

The adipocyte-derived hormone leptin signals the status of body energy stores by activating the long form of the leptin receptor (LRb). Activation of LRb results in the activation of the associated Jak2 tyrosine kinase and the transmission of downstream phosphotyrosine-dependent signals. We have investigated the signaling function of mutant LRb intracellular domains under the control of the extracellular erythropoietin (Epo) receptor. By using this system, we confirm that two tyrosine residues in the intracellular domain of murine LRb become phosphorylated to mediate LRb signaling; Tyr(985) controls the tyrosine phosphorylation of SHP-2, and Tyr(1138) controls STAT3 activation. We furthermore investigated the mechanisms by which LRb controls downstream ERK activation and c-fos and SOCS3 message accumulation. Tyr(985)-mediated recruitment of SHP-2 does not alter tyrosine phosphorylation of Jak2 or STAT3 but results in GRB-2 binding to tyrosine-phosphorylated SHP-2 and is required for the majority of ERK activation during LRb signaling. Tyr(985) and ERK activation similarly mediate c-fos mRNA accumulation. In contrast, SOCS3 mRNA accumulation requires Tyr(1138)-mediated STAT3 activation. Thus, the two LRb tyrosine residues that are phosphorylated during receptor activation mediate distinct signaling pathways as follows: SHP-2 binding to Tyr(985) positively regulates the ERK --> c-fos pathway, and STAT3 binding to Tyr(1138) mediates the inhibitory SOCS3 pathway.

Adaptor Proteins, Signal Transducing↗