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Biomedical subjects

D Levy

Publications and source records attributed to D Levy.

At least 37 records · Page 2Linked to original sources
PubMed2003

Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme.

Despite advances in the molecular pathogenesis of glioblastoma multiforme, no reliable prognostic markers have been identified. We analysed telomerase activity and telomere lengths in glioblastoma multiformes from 77 patients. 19 patients (25%) had tumours with the alternative-lengthening-of-telomere (ALT) phenotype. Median survival for patients with this phenotype was 542 days (95% CI 114-970) compared with 247 days (224-270) for glioblastoma multiformes with normal telomeres (p=0.0003). Cox's regression analysis showed that this association is independent of age. In patients with non-ALT tumours, telomerase activity did not affect survival (median 287 [199-375] vs 236 [230-242] days, p=0.275). We conclude that ALT is a prognostic indicator for patients with glioblastoma multiforme.

Adult↗
PubMed2003

Frailty and the biochemical effects of recombinant human growth hormone in women after surgery for hip fracture.

We report a randomised double blind controlled trial investigating the short-term biochemical and adverse clinical responses to recombinant human growth hormone (r-hGH) after surgery for hip fracture. Hip fractures are common, dangerous and expensive, typically affecting frail women with osteoporosis and reduced muscle mass and strength, factors also associated with poor clinical outcomes. Growth hormone therapy increases IGF-I levels, promotes anabolism and increases muscle strength in well older people and selected patient groups and therefore has therapeutic potential to assist recovery of frail patients.Thirty-one women, mean age 86 years, received 14 nightly subcutaneous injections of r-hGH 0.05 mg/kg/day (high dose) or 0.025 mg/kg/day (low dose), or placebo from the 4th post-operative day. There were several serious adverse clinical events but no excess number of adverse events in the r-hGH treatment groups. The r-hGH treatment groups had similar serum IGF-I and IGFBP-3 responses, both significantly different from placebo. The large inter-individual variation of IGF-I responses were inversely correlated with pre-treatment indicators of frailty (body composition and functional abilities).

Aged↗
PubMed2003

Neuro-oncology practice in the UK.

The aim of the study was to determine current U.K. neuro-oncology practice. A questionnaire was sent to all U.K. clinical oncologists who treat primary brain tumours. Results were distributed to these doctors with an invitation to attend a workshop in September 2000 to debate areas of differing practice and to review the existing related evidence. A further workshop was held in May 2002. The questionnaire responses and discussion of controversial areas, including the management of high-grade gliomas, low-grade gliomas, meningiomas, pituitary adenomas and multiple-brain metastases are included in this paper.

Adult↗
PubMed2002

Distinct sensitizing effects of the cAMP-PKA second messenger cascade on rat dural mechanonociceptors.

Activation of the cAMP/protein kinase A (PKA) second messenger cascade has been implicated in the induction of mechanical hyperalgesia by inflammatory mediators. We examined the role of this cascade in mechanical sensitization of nociceptive neurons that innervate the meninges, a process thought to be involved in the pathophysiology of headache syndromes such as migraine. Single unit activity was recorded in the trigeminal ganglion from 40 mechanosensitive dural afferents (conduction velocitity: 0.3-6.6 m s(-1)) and nine mechanically insensitive dural afferents (MIAs) (conduction velocitity: 0.3-2.8 m s(-1)) while stimulating the dura with a servo force-controlled stimulator or von Frey monofilaments, respectively. Local application to the dura of dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP, 100 microM), a stable membrane-permeant cAMP analogue, produced mechanical sensitization in the majority of mechanosensitive units (19/29, 66 %). Two distinct patterns of mechanical sensitization were observed. Thirty-eight per cent of the units exhibited only a decrease in threshold (TH group), while 28 % showed only an increase in suprathreshold responses (STH group). dbcAMP also induced mechanosensitivity in the majority of MIA units (6/9, 67 %). dbcAMP-induced sensitization was blocked by the PKA inhibitors, Rp-cAMP (1 mM) and H-89 (100 microM). A mixture of inflammatory mediators induced both components of sensitization in the majority of mechanosensitive units tested. However, in each unit, PKA inhibitors blocked only one of the two effects (either TH or STH). Units that were classified as TH or STH also differed in their baseline stimulus-response slopes, thresholds and conduction velocities. These findings implicate the cAMP-PKA cascade in sensitization of dural mechanonociceptors and suggest that this cascade may produce sensitization through at least two different mechanisms operating in separate neuronal populations.

Animals↗
PubMed2002

Genome scan for quantity of hand osteoarthritis: the Framingham Study.

OBJECTIVE: To search for markers linked to quantity of radiographic hand osteoarthritis (OA) in the Framingham Heart Study. METHODS: The sample included 684 original cohort members and 793 offspring in 296 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence (K/L) score, osteophytes, and joint space narrowing (0-3 scale). Four quantitative phenotypes were computed from these measurements: sum of K/L scores across hand joints, sum of osteophyte scores, sum of joint space narrowing scores, and proportion of affected joints. Prior to linkage analysis, these phenotypes were adjusted for age using a linear regression analysis from which standardized residuals were computed. The regression analysis was performed separately for each sex and each generation. The variance component model (SOLAR) was then applied to the normalized scores of the residuals. RESULTS: The average age was 62 years for the original cohort and 54 years for the offspring. Fifty percent of the original cohort and 30% of their offspring had at least 1 affected joint (K/L score >or=2). Heritability ranged from 28% (proportion of joints affected with OA) to 34% (sum of K/L scores). Eight chromosomal regions indicated suggestive linkage (multipoint logarithm of odds [LOD] score >1.5) for at least 1 phenotype; LOD scores were highest for joint space narrowing, with a multipoint LOD score = 2.96 on chromosome 1p at D1S1665. Chromosomes 7, 9, 13, and 19 indicated consistent LOD score elevation for multiple OA phenotypes. CONCLUSION: There are several chromosomes that may harbor OA susceptibility genes. Further investigation of these regions using larger studies and finer maps will be important to confirm linkage.

Adult↗
PubMed2002

Risk factors in HIV-associated diarrhoeal disease: the role of drinking water, medication and immune status.

In a cross-sectional survey of 226 HIV-infected men, we examined the occurrence of diarrhoea and its relationship to drinking water consumption patterns, risk behaviours, immune status and medication use. Diarrhoea was reported by 47% of the respondents. Neither drinking boiled nor filtered water was significantly associated with diarrhoea (OR = 0.5 [0.2, 1.6], 1.2 [0.6, 2.5] respectively), whereas those that drank bottled water were at risk for diarrhoea (OR = 3.0 [1.1, 7.8]). Overall, 47% always or often used at least one water treatment. Of the 37% who were very concerned about drinking water, 62% had diarrhoea, 70% always or often used at least one water treatment. An increase in CD4 count was protective only for those with a low risk of diarrhoea associated with medication (OR = 0.6 [0.5, 0.9]). A 30% attributable risk to diarrhoea was estimated for those with high medication risk compared to those with low medication risk. The significant association between concern with drinking water and diarrhoea as well as between concern with drinking water and water treatment suggests awareness that drinking water is a potential transmission pathway for diarrhoeal disease. At the same time we found that a significant portion of diarrhoea was associated with other sources not related to drinking water such as medication usage.

Adult↗
PubMed2001

Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study.

BACKGROUND: Patients with optimum (<120/80 mm Hg), normal (120-129/80-84 mm Hg), and high normal (130-139/85-89 mm Hg) blood pressure (BP) may progress to hypertension (>140/90 mm Hg) over time. We aimed to establish the best frequency of BP screening by assessing the rates and determinants of progression to hypertension. METHODS: We assessed repeated BP measurements in individuals without hypertension (BP<140/90 mm Hg) from the Framingham Study (4200 men, 5645 women; mean age 52 years) who attended clinic examinations during 1978-94. The incidence of hypertension (or use of antihypertensive treatment) and its determinants were studied. FINDINGS: A stepwise increase in hypertension incidence occurred across the three non-hypertensive BP categories; 5.3% (95% CI 4.4-6.3%) of participants with optimum BP, 17.6% (15.2-20.3%) with normal, and 37.3% (33.3-41.5%) with high normal BP aged below age 65 years progressed to hypertension over 4 years. Corresponding 4-year rates of progression for patients 65 years and older were 16.0% (12.0-20.9), 25.5% (20.4-31.4), and 49.5% (42.6-56.4), respectively. Obesity and weight gain also contributed to progression; a 5% weight gain on follow-up was associated with 20-30% increased odds of hypertension. INTERPRETATION: High normal BP and normal BP frequently progress to hypertension over a period of 4 years, especially in older adults. These findings support recommendations for monitoring individuals with high normal BP once a year, and monitoring those with normal BP every 2 years, and they emphasise the importance of weight control as a measure for primary prevention of hypertension.

Adult↗
PubMed2001

Impact of high-normal blood pressure on the risk of cardiovascular disease.

BACKGROUND: Information is limited regarding the absolute and relative risk of cardiovascular disease in persons with high-normal blood pressure (systolic pressure of 130 to 139 mm Hg, diastolic pressure of 85 to 89 mm Hg, or both). METHODS: We investigated the association between blood-pressure category at base line and the incidence of cardiovascular disease on follow-up among 6859 participants in the Framingham Heart Study who were initially free of hypertension and cardiovascular disease. RESULTS: A stepwise increase in cardiovascular event rates was noted in persons with higher baseline blood-pressure categories. The 10-year cumulative incidence of cardiovascular disease in subjects 35 to 64 years of age who had high-normal blood pressure was 4 percent (95 percent confidence interval, 2 to 5 percent) for women and 8 percent (95 percent confidence interval, 6 to 10 percent) for men; in older subjects (those 65 to 90 years old), the incidence was 18 percent (95 percent confidence interval, 12 to 23 percent) for women and 25 percent (95 percent confidence interval, 17 to 34 percent) for men. As compared with optimal blood pressure, high-normal blood pressure was associated with a risk-factor-adjusted hazard ratio for cardiovascular disease of 2.5 (95 percent confidence interval, 1.6 to 4.1) in women and 1.6 (95 percent confidence interval, 1.1 to 2.2) in men. CONCLUSIONS: High-normal blood pressure is associated with an increased risk of cardiovascular disease. Our findings emphasize the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease.

Adult↗
PubMed2001

Heritability of longitudinal change in lung function. The Framingham study.

There have been multiple reports of heritability of lung function in cross-sectional analysis, but no prior reports of heritability of rate of change in lung function. We examined heritability of rate of change of lung function in families participating in the Framingham Heart Study. Spirometric measures from two time points were used to calculate annualized rate of change in FEV(1), FVC, and FEV(1)/FVC ratio, adjusting for the effects of age, height, and weight using multiple linear regression models. Standardized residuals from these models were used as phenotypic variables in variance components analysis to assess effects of smoking and heritable factors on rate of change in lung function. Heritable factors explained a modest proportion of the population variance, with heritability estimates for change in FEV(1), FVC, and ratio of 0.05, 0.18, and 0.13, respectively. Restricting the analysis to subjects concordant for smoking status during the interval over which lung function was measured, the heritability estimates increased to 0.18, 0.39, and 0.14, respectively, among interim smokers. These data suggest that in middle-aged and older persons in the general population, genetic factors contribute modestly to the overall population variance in rate of lung function decline, and further suggest the importance of gene-environment interactions.

Adult↗
PubMed2001

Alcohol consumption and hemostatic factors: analysis of the Framingham Offspring cohort.

BACKGROUND: Moderate alcohol consumers have lower rates of cardiovascular disease than abstainers. One proposed mechanism is a beneficial effect on hemostatic parameters, but previous studies have provided conflicting results. METHODS AND RESULTS: We measured levels of fibrinogen, plasma viscosity, von Willebrand factor, factor VII, plasminogen activator inhibitor antigen-1, and tissue plasminogen activator antigen in a cross-sectional analysis of 3223 adults free of cardiovascular disease enrolled in the Framingham Offspring Study. We assessed their alcohol consumption with a standardized questionnaire. Light-to-moderate alcohol consumption was associated with lower levels of fibrinogen, plasma viscosity, von Willebrand factor, and factor VII. This association was most pronounced for consumers of 3 to 7 drinks weekly for viscosity and 7 to 21 drinks weekly for the other hemostatic measures. Alcohol intake of 7 to 21 drinks weekly or more was associated with impaired fibrinolytic potential, reflected by higher levels of plasminogen activator inhibitor antigen-1 and tissue plasminogen activator antigen. Wine drinkers had lower plasminogen activator inhibitor antigen-1 levels than other drinkers, particularly at 3 to 21 drinks weekly, but beverage type did not otherwise consistently affect the results. CONCLUSIONS: Light-to-moderate alcohol consumption is associated with lower levels of coagulatory factors, but higher intake is associated with impaired fibrinolytic potential. These findings are consistent with the hypothesis that a balance between hemostatic and fibrinolytic activity may contribute to the complex relation of alcohol use with coronary heart disease.

Alcohol Drinking↗
PubMed2001

Echocardiographic features of the right heart in sleep-disordered breathing: the Framingham Heart Study.

The effect of sleep-disordered breathing (SDB) on right heart structure and function is controversial. Studies of patients referred for evaluation of possible sleep apnea have yielded conflicting results, and the impact of SDB on the right heart has not been investigated in the general population. We examined the echocardiographic features of subjects with SDB at the Framingham Heart Study site of the Sleep Heart Health Study. Of 1,001 polysomnography subjects, 90 with SDB defined as a respiratory disturbance index (RDI) score > 90th percentile (mean RDI = 42) were compared with 90 low-RDI subjects (mean RDI = 5) matched for age, sex, and body mass index. Right heart measurements, made without knowledge of clinical status, were compared between groups. The majority of the subjects were male (74%). After multivariable adjustment, right ventricle (RV) wall thickness was significantly greater (p = 0.005) in subjects with SDB (0.78 +/- 0.02 cm) than in the low-RDI subjects (0.68 +/- 0.02 cm). Right atrial dimensions, RV dimensions, and RV systolic function were not found to be significantly different between subjects with SDB and the low-RDI subjects. We conclude that in this community-based study of SDB and right heart echocardiographic features, RV wall thickness was increased in subjects with SDB. Whether the RV hypertrophy observed in persons with SDB is associated with increased morbidity and mortality remains unknown.

Adult↗
PubMed2001

Two-dimensional crystallization of membrane proteins: the lipid layer strategy.

Due to the difficulty to crystallize membrane proteins, there is a considerable interest to intensify research topics aimed at developing new methods of crystallization. In this context, the lipid layer crystallization at the air/water interface, used so far for soluble proteins, has been recently adapted successfully to produce two-dimensional (2D) crystals of membrane proteins, amenable to structural analysis by electron crystallography. Besides to represent a new alternative strategy, this approach gains the advantage to decrease significantly the amount of material needed in incubation trials, thus opening the field of crystallization to those membrane proteins difficult to surexpress and/or purify. The systematic studies that have been performed on different classes of membrane proteins are reviewed and the physico-chemical processes that lead to the production of 2D crystals are addressed. The different drawbacks, advantages and perspectives of this new strategy for providing structural information on membrane proteins are discussed.

Air↗
PubMed2001

A novel grass pollen allergen mimotope identified by phage display peptide library inhibits allergen-human IgE antibody interaction.

The aim of this study was to investigate the molecular basis of human IgE-allergen interaction by screening a phage-displayed peptide library with an allergen-specific human IgE-mimicking monoclonal antibody (mAb). A mAb that reacted with major grass pollen allergens was successfully identified and shown to inhibit human IgE-allergen interaction. Biopanning of a phage-displayed random peptide library with this mAb yielded a 12 amino acid long mimotope. A synthetic peptide based on this 12-mer mimotope inhibited mAb and human IgE binding to grass pollen extracts. Our results indicate that such synthetic peptide mimotopes of allergens have potential as novel therapeutic agents.

Allergens↗
PubMed2001

Genetic factors contribute to the variance in frequency domain measures of heart rate variability.

Power spectral analysis of heart rate variability (HRV) provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HRV only partially explain its variability in the population. The purpose of this study was to estimate the contribution of genetic factors to the variance in HRV measures and assess the heritability of HRV. Subjects who underwent Holter recordings at a routine examination were eligible, excluding subjects with congestive heart failure, coronary artery disease, diabetes mellitus and those taking cardioactive medications. We analyzed the low-frequency power (LF), high-frequency power (HF), LF/HF ratio, very low-frequency power (VLF) and total power (TP). Heritability analysis was done by studying correlations between siblings (n = 682, in 291 sibships, 517 pairs) and between spouse pairs (n = 206 pairs). Adjustments were made for sex, age, systolic and diastolic blood pressure, heart rate, coffee and alcohol intake. SAS procedure MIXED was used to estimate and test significance of correlation within sibling pairs and within spouse pairs. Results from separate models were combined to estimate the components of variance of each phenotype, i.e. variance attributable to measured covariates, additive genetic effects (heritability) and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21-0.26) compared to spouses (0.01-0.19). The measured covariates in general accounted for 13-40% of the total phenotypic variance, whereas genes accounted for 13-23% of the variation among HRV measures. Genetic factors contribute towards a substantial proportion of the variance in heart rate and HRV. Recognition of the genetic determinants of HRV may provide additional insight into the pathophysiology of the autonomic nervous system and offer clues toward its modulation.

Adult↗
PubMed2001

Platelet glycoprotein IIIa Pl(a) polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study.

BACKGROUND: Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl(A) genotype in modulating platelet aggregability. Methods and Results-- Glycoprotein IIIa Pl(A) genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the Pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl(A2)-positive genotype (P>0.90). CONCLUSION: Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding Pl(A) genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.

Adenosine Diphosphate↗
PubMed2001

Genetic and environmental contributions to platelet aggregation: the Framingham heart study.

BACKGROUND: Platelet aggregation plays an important role in arterial thrombosis in coronary heart disease, stroke, and peripheral arterial disease. However, the contribution of genetic versus environmental influences on interindividual variation in platelet aggregability is poorly characterized. METHODS AND RESULTS: We studied the heritability of platelet aggregation responses in 2413 participants in the Framingham Heart Study. The threshold concentrations of epinephrine and ADP required to produce biphasic platelet aggregation and collagen lag time were determined. Mixed-model linear regression was used to calculate correlation coefficients within sibships and within spouse pairs. Variance and covariance component methods were used to estimate the proportion of platelet aggregation attributable to measured covariates versus additive genetic effects. After accounting for environmental covariates, the adjusted sibling correlations for epinephrine, ADP, and collagen lag time were 0.24, 0.22, and 0.31, respectively (P=0.0001 for each). In contrast, adjusted correlations for spouse-pairs were -0.01, 0.05, and -0.02, respectively (all P>0.30). The estimated heritabilities were 0.48, 0.44, and 0.62, respectively. Measured covariates accounted for only 4% to 7% of the overall variance in platelet aggregation, and heritable factors accounted for 20% to 30%. The platelet glycoprotein IIIa Pl(A2) polymorphism and the fibrinogen Hind III beta-148 polymorphism contributed <1% to the overall variance. CONCLUSIONS: In our large, population-based sample, heritable factors play a major role in determining platelet aggregation, and measured covariates play a lesser role. Future studies are warranted to identify the key genetic variants that regulate platelet function and to lay the groundwork for rational pharmacogenetic approaches.

Adenosine Diphosphate↗