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Biomedical subjects

David Gordon

Publications and source records attributed to David Gordon.

At least 19 recordsLinked to original sources
PubMed2026

Subphenogroups of acute heart failure with preserved ejection fraction: comprehensive proteomics and pathway analysis.

BACKGROUND: Heterogeneity of heart failure with preserved ejection fraction (HFpEF) results in significant challenges for treatment development. Identifying and characterising distinct HFpEF phenogroups may aid in tailoring therapeutic strategies for these patients. The objective of this study was to assess proteomic patterns of HFpEF phenogroups identified through a machine-learning-based clustering model, with the aim of uncovering specific biological pathways associated with each phenogroup. METHODS: This study represents a post-hoc analysis of the ongoing Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a multicentre prospective observational study of hospitalised patients with acute decompensated HFpEF. Of the overall cohort (N=1238), this study analysed 198 patients with HFpEF with available proteomics data. These patients were classified into four phenogroups using the machine-learning-based clustering model. The SomaScan assay V.4.1 was used to measure levels of >7000 plasma proteins, and subsequent pathway analysis was conducted to determine the biological differences among the phenogroups. RESULTS: We identified four distinct phenogroups: Phenogroup 1 ('rhythm trouble'), Phenogroup 2 ('ventricular-arterial uncoupling'), Phenogroup 3 ('low output and systemic congestion') and Phenogroup 4 ('systemic failure'). The proteomics revealed distinct protein expression profiles among the phenogroups, with ribonuclease 4, tax1-binding protein 1, regenerating islet-derived protein 3-gamma and alpha-1-antichymotrypsin being the most significant markers to specific identified phenogroups. Pathway analysis suggested differences in immune response, autonomic activation, cellular homeostasis and tissue repair mechanisms across the phenogroups. CONCLUSIONS: Using a comprehensive plasma proteomics approach, our study identified distinct proteomic profiles of HFpEF phenogroups, which in turn suggest specific underlying biological processes. These profiles suggest the involvement of inflammatory activation, tissue injury and regenerative responses, immune modulation and systemic stress signalling as key components of HFpEF pathophysiology. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

Humans↗
PubMed2007

Characterization and predictive discovery of evolutionarily conserved mammalian alternative promoters.

Recent studies suggest that surprisingly many mammalian genes have alternative promoters (APs); however, their biological roles, and the characteristics that distinguish them from single promoters (SPs), remain poorly understood. We constructed a large data set of evolutionarily conserved promoters, and used it to identify sequence features, functional associations, and expression patterns that differ by promoter type. The four promoter categories CpG-rich APs, CpG-poor APs, CpG-rich SPs, and CpG-poor SPs each show characteristic strengths and patterns of sequence conservation, frequencies of putative transcription-related motifs, and tissue and developmental stage expression preferences. APs display substantially higher sequence conservation than SPs and CpG-poor promoters than CpG-rich promoters. Among CpG-poor promoters, APs and SPs show sharply contrasting developmental stage preferences and TATA box frequencies. We developed a discriminator to computationally predict promoter type, verified its accuracy through experimental tests that incorporate a novel method for deconvolving mixed sequence traces, and used it to find several new APs. The discriminator predicts that almost half of all mammalian genes have evolutionarily conserved APs. This high frequency of APs, together with the strong purifying selection maintaining them, implies a crucial role in expanding the expression diversity of the mammalian genome.

Alternative Splicing↗
PubMed2006

Efficacy and safety of a once-daily fixed-dose combination of abacavir/lamivudine compared with abacavir twice daily and lamivudine once daily as separate entities in antiretroviral-experienced HIV-1-infected patients (CAL30001 Study).

BACKGROUND: A one-tablet, once-daily abacavir/lamivudine fixed-dose combination (FDC) has been recently approved to treat HIV-1 infection. METHODS: A randomized, open-label, parallel-group, multicenter study to compare the efficacy and safety of the FDC group to the separate entities (SE) group, in combination with tenofovir and a new protease inhibitor or nonnucleoside reverse transcription inhibitor in antiretroviral-experienced adults experiencing virologic failure (VF). Eligible subjects had viral loads >1000 copies/mL with < or =3 nucleoside reverse transcription inhibitor-associated mutations. The primary efficacy end point was time-average changed from baseline (average area under the curve minus baseline) in plasma HIV-1 RNA over 48 weeks. RESULTS: A total of 186 subjects were enrolled. The average area under the curve minus baseline was -1.65 and -1.83 log10 copies/mL in the FDC and SE groups, respectively (intention to treat; 95% confidence interval: -0.13, 0.38). Patients in the FDC (50%) and SE groups (47%) achieved viral loads <50 copies/mL based on the time to loss of virologic response algorithm. VF was low and similar in both groups (FDC, 16%; SE, 18%). Tolerability was similar between the 2 groups. CONCLUSIONS: The FDC group had noninferior efficacy over 48 weeks to the SE group in treatment-experienced subjects with VF.

Adult↗
PubMed2006

Alpha-galactosidase A deficiency leads to increased tissue fibrin deposition and thrombosis in mice homozygous for the factor V Leiden mutation.

BACKGROUND: Factor V Leiden (FVL) is a common genetic risk factor for vascular thrombosis in humans. Fabry disease, an X-linked lysosomal storage disorder attributable to alpha-galactosidase A (GLA) deficiency, is associated with premature vascular events that may be thrombotic in nature. METHODS: To examine a potential interaction between FvL and Gla deficiency in vivo, we analyzed tissue fibrin deposition in mice carrying combined mutations in FvL and Gla. Gla deficiency markedly increased tissue fibrin deposition in mice carrying the FvL mutation (0.33+/-0.03%; n=7) compared with FvL mutation (0.14+/-0.02%; n=10; P<0.0005). CONCLUSIONS: These observations demonstrate a synergistic interaction between Gla deficiency and FvL toward tissue fibrin deposition in mice. Concomitant mutations in these genes may increase the penetrance of vascular thrombotic events in humans.

Animals↗
PubMed2006

Surgical management of traumatic parenchymal lesions.

INDICATIONS: Patients with parenchymal mass lesions and signs of progressive neurological deterioration referable to the lesion, medically refractory intracranial hypertension, or signs of mass effect on computed tomographic (CT) scan should be treated operatively. Patients with Glasgow Coma Scale (GCS) scores of 6 to 8 with frontal or temporal contusions greater than 20 cm3 in volume with midline shift of at least 5 mm and/or cisternal compression on CT scan, and patients with any lesion greater than 50 cm3 in volume should be treated operatively. Patients with parenchymal mass lesions who do not show evidence for neurological compromise, have controlled intracranial pressure (ICP), and no significant signs of mass effect on CT scan may be managed nonoperatively with intensive monitoring and serial imaging. TIMING AND METHODS: Craniotomy with evacuation of mass lesion is recommended for those patients with focal lesions and the surgical indications listed above, under Indications. Bifrontal decompressive craniectomy within 48 hours of injury is a treatment option for patients with diffuse, medically refractory posttraumatic cerebral edema and resultant intracranial hypertension. Decompressive procedures, including subtemporal decompression, temporal lobectomy, and hemispheric decompressive craniectomy, are treatment options for patients with refractory intracranial hypertension and diffuse parenchymal injury with clinical and radiographic evidence for impending transtentorial herniation.

Craniocerebral Trauma↗
PubMed2006

Surgical management of posterior fossa mass lesions.

INDICATIONS: Patients with mass effect on computed tomographic (CT) scan or with neurological dysfunction or deterioration referable to the lesion should undergo operative intervention. Mass effect on CT scan is defined as distortion, dislocation, or obliteration of the fourth ventricle; compression or loss of visualization of the basal cisterns, or the presence of obstructive hydrocephalus. Patients with lesions and no significant mass effect on CT scan and without signs of neurological dysfunction may be managed by close observation and serial imaging. TIMING: In patients with indications for surgical intervention, evacuation should be performed as soon as possible because these patients can deteriorate rapidly, thus, worsening their prognosis. METHODS: Suboccipital craniectomy is the predominant method reported for evacuation of posterior fossa mass lesions, and is therefore recommended.

Brain↗
PubMed2006

Surgical management of depressed cranial fractures.

INDICATIONS: Patients with open (compound) cranial fractures depressed greater than the thickness of the cranium should undergo operative intervention to prevent infection. Patients with open (compound) depressed cranial fractures may be treated nonoperatively if there is no clinical or radiographic evidence of dural penetration, significant intracranial hematoma, depression greater than 1 cm, frontal sinus involvement, gross cosmetic deformity, wound infection, pneumocephalus, or gross wound contamination. Nonoperative management of closed (simple) depressed cranial fractures is a treatment option. TIMING: Early operation is recommended to reduce the incidence of infection. METHODS: Elevation and debridement is recommended as the surgical method of choice. Primary bone fragment replacement is a surgical option in the absence of wound infection at the time of surgery. All management strategies for open (compound) depressed fractures should include antibiotics.

Disease Management↗
PubMed2006

Surgical management of acute epidural hematomas.

INDICATIONS FOR SURGERY: An epidural hematoma (EDH) greater than 30 cm3 should be surgically evacuated regardless of the patient's Glasgow Coma Scale (GCS) score. An EDH less than 30 cm3 and with less than a 15-mm thickness and with less than a 5-mm midline shift (MLS) in patients with a GCS score greater than 8 without focal deficit can be managed nonoperatively with serial computed tomographic (CT) scanning and close neurological observation in a neurosurgical center. TIMING: It is strongly recommended that patients with an acute EDH in coma (GCS score < 9) with anisocoria undergo surgical evacuation as soon as possible. METHODS: There are insufficient data to support one surgical treatment method. However, craniotomy provides a more complete evacuation of the hematoma.

Disease Management↗
PubMed2006

Surgical management of acute subdural hematomas.

INDICATIONS FOR SURGERY: An acute subdural hematoma (SDH) with a thickness greater than 10 mm or a midline shift greater than 5 mm on computed tomographic (CT) scan should be surgically evacuated, regardless of the patient's Glasgow Coma Scale (GCS) score. All patients with acute SDH in coma (GCS score less than 9) should undergo intracranial pressure (ICP) monitoring. A comatose patient (GCS score less than 9) with an SDH less than 10-mm thick and a midline shift less than 5 mm should undergo surgical evacuation of the lesion if the GCS score decreased between the time of injury and hospital admission by 2 or more points on the GCS and/or the patient presents with asymmetric or fixed and dilated pupils and/or the ICP exceeds 20 mm Hg. TIMING: In patients with acute SDH and indications for surgery, surgical evacuation should be performed as soon as possible. METHODS: If surgical evacuation of an acute SDH in a comatose patient (GCS < 9) is indicated, it should be performed using a craniotomy with or without bone flap removal and duraplasty.

Disease Management↗
PubMed2005

Role of socioeconomic markers and state prohibition policy in predicting alcohol consumption among men and women in India: a multilevel statistical analysis.

OBJECTIVE: To investigate the independent contribution of individual socioeconomic markers and state prohibition policy on alcohol consumption among men and women in India. METHODS: The study used a multilevel cross-sectional analysis of alcohol consumption from the 1998-1999 Indian national family health survey of 301 984 adult individuals in 92 447 households in 3215 villages in 440 districts in 26 states, stratified by sex. FINDINGS: Men with no education were more likely to consume alcohol that those with a post graduate education (OR, 2.28; 95% CI, 2.08-2.50). Unlike men, women showed a U-shaped association between education and alcohol consumption. Men and women living in households at the lowest standard-of-living quintile were more likely to consume alcohol (OR, 1.92; 95% CI, 1.81-2.03, and OR, 2.72, 95% CI, 2.18-3.39), respectively, than those classified as living in the top quintile. Members of scheduled tribes and castes and other backward classes were more likely to consume alcohol than members of other caste groups. There was no difference in alcohol consumption between men from states that were not under prohibition (OR, 1.36; 95% CI 0.69-2.03) and those that were. By contrast, states not under prohibition has higher alcohol use by women (OR, 3.04, 95% CI, 1.59-4.48) than those under partial or complete prohibition. CONCLUSION: Caste, education and standard of living independently influence alcohol use in India. Prohibition policies appear to have little effect on alcohol use by men, but may reduce the proportion of women who consume alcohol. The socioeconomic patterning of health behaviours is likely to feed substantially into inequalities in health outcomes. Further investigation is required to understand how social and cultural factors in more localized contexts (e.g. districts) influence alcohol consumption.

Alcohol Drinking↗
PubMed2005

Characterization of agonist-induced motilin receptor trafficking and its implications for tachyphylaxis.

The motilin receptor (MR) is a member of the seven-transmembrane receptor family and is expressed throughout the gastrointestinal tract of humans and other species. Motilin, the natural MR peptide ligand, has profound stimulatory effects on gastrointestinal contractility, indicating a therapeutic potential for MR modulators. However, long-term clinical use of certain MR agonists is limited by tachyphylaxis, a reduced responsiveness to repeated compound exposure. This study was meant to characterize the ligand-induced endocytosis of MR and to test whether receptor trafficking contributes to tachyphylaxis. A cell-based assay was developed by fusing a green fluorescent protein (GFP) moiety to the motilin receptor, and high-content biology instrumentation was used to quantify time and dose dependence of MR-GFP endocytosis. Maximal internalization of MR-GFP was induced after 45 min of constant exposure to 80 nM motilin. This process was disrupted by nocodazole, suggesting an essential role for microtubules. Internalized MR-GFP vesicles disappeared within 15 to 45 min of motilin withdrawal but did not overlap with the lysosomal compartment, indicating that MR-GFP escaped degradation and was recycled back to the plasma membrane. It is noteworthy that the kinetics of MR-GFP redistribution varied substantially when stimulated with motilin, erythromycin, 6,9-hemiacetal 8,9-anhydro-4''-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B (ABT-229), or N-[(1S)-1-[[[(1S)-1-(aminocarbonyl)-3-phenylpropyl]amino]carbonyl]-3-phenylpropyl]-2'-(1,3-benzodioxol-5-ylmethyl)tetrahydro-1',3'-dioxo-spiro[piperidine-4,5'(6'H)-[1H][1,2,4]triazolo[1,2-a]pyridazine]-8'-carboxamide (BMS-591348) at equipotent doses for Ca(2+)-mobilization. Retardation of the intracellular MR-GFP sorting cycle seemed to correlate with the tachyphylaxis-inducing properties of each compound, but not its EC(50). These results indicate that MR internalization, desensitization, and resensitization are ligand-dependent and that appropriate screening strategies may enable the development of small molecule agonists with ideal combinations of these distinct properties.

Base Sequence↗
PubMed2005

Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial.

CONTEXT: Basic research and observational evidence as well as results from trials of colon polyp recurrence suggest a role for aspirin in the chemoprevention of cancer. OBJECTIVE: To examine the effect of aspirin on the risk of cancer among healthy women. DESIGN, SETTING, AND PARTICIPANTS: In the Women's Health Study, a randomized 2 x 2 factorial trial of aspirin and vitamin E conducted between September 1992 and March 2004, 39 876 US women aged at least 45 years and initially without previous history of cancer, cardiovascular disease, or other major chronic illness were randomly assigned to receive either aspirin or aspirin placebo and followed up for an average of 10.1 years. INTERVENTION: A dose of 100 mg of aspirin (n=19 934) or aspirin placebo (n=19 942) administered every other day. MAIN OUTCOME MEASURES: Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma skin cancer. Incidence of breast, colorectal, and lung cancer were secondary end points. RESULTS: No effect of aspirin was observed on total cancer (n = 2865; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1230; RR, 0.98; 95% CI, 0.87-1.09; P = .68), colorectal cancer (n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83), or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI, 0.59-1.03; P = .08). There was also no reduction in cancer mortality either overall (n = 583; RR, 0.95; 95% CI, 0.81-1.11; P = .51) or by site, except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found. CONCLUSIONS: Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.

Aspirin↗
PubMed2005

Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.

CONTEXT: Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons, who self-select for high intakes of vitamin E through diet or supplements, have decreased risks of cardiovascular disease and cancer. Randomized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons. OBJECTIVE: To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women. DESIGN, SETTING, AND PARTICIPANTS: In the Women's Health Study conducted between 1992 and 2004, 39 876 apparently healthy US women aged at least 45 years were randomly assigned to receive vitamin E or placebo and aspirin or placebo, using a 2 x 2 factorial design, and were followed up for an average of 10.1 years. INTERVENTION: Administration of 600 IU of natural-source vitamin E on alternate days. MAIN OUTCOME MEASURES: Primary outcomes were a composite end point of first major cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and total invasive cancer. RESULTS: During follow-up, there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction (relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on the incidences of myocardial infarction (RR, 1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic stroke. For cardiovascular death, there was a significant 24% reduction (RR, 0.76; 95% CI, 0.59-0.98; P = .03). There was no significant effect on the incidences of total cancer (1437 cases in the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI, 0.77-1.31; P = .99). Cancer deaths also did not differ significantly between groups. There was no significant effect of vitamin E on total mortality (636 in the vitamin E group and 615 in the placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53). CONCLUSIONS: The data from this large trial indicated that 600 IU of natural-source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, and decreased cardiovascular mortality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women.

Aged↗
PubMed2005

Poverty, child undernutrition and morbidity: new evidence from India.

Undernutrition continues to be a primary cause of ill-health and premature mortality among children in developing countries. This paper examines how the prevalence of undernutrition in children is measured and argues that the standard indices of stunting, wasting and underweight may each be underestimating the scale of the problem. This has important implications for policy-makers, planners and organizations seeking to meet international development targets. Using anthropometric data on 24 396 children in India, we constructed an alternative composite index of anthropometric failure (CIAF) and compared it with conventional indices. The CIAF examines the relationship between distinct subgroups of anthropometric failure, poverty and morbidity, showing that children with multiple anthropometric failures are at a greater risk of morbidity and are more likely to come from poorer households. While recognizing that stunting, wasting and underweight reflect distinct biological processes of clear importance, the CIAF is the only measure that provides a single, aggregated figure of the number of undernourished children in a population.

Anthropometry↗
PubMed2005

A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.

BACKGROUND: Randomized trials have shown that low-dose aspirin decreases the risk of a first myocardial infarction in men, with little effect on the risk of ischemic stroke. There are few similar data in women. METHODS: We randomly assigned 39,876 initially healthy women 45 years of age or older to receive 100 mg of aspirin on alternate days or placebo and then monitored them for 10 years for a first major cardiovascular event (i.e., nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). RESULTS: During follow-up, 477 major cardiovascular events were confirmed in the aspirin group, as compared with 522 in the placebo group, for a nonsignificant reduction in risk with aspirin of 9 percent (relative risk, 0.91; 95 percent confidence interval, 0.80 to 1.03; P=0.13). With regard to individual end points, there was a 17 percent reduction in the risk of stroke in the aspirin group, as compared with the placebo group (relative risk, 0.83; 95 percent confidence interval, 0.69 to 0.99; P=0.04), owing to a 24 percent reduction in the risk of ischemic stroke (relative risk, 0.76; 95 percent confidence interval, 0.63 to 0.93; P=0.009) and a nonsignificant increase in the risk of hemorrhagic stroke (relative risk, 1.24; 95 percent confidence interval, 0.82 to 1.87; P=0.31). As compared with placebo, aspirin had no significant effect on the risk of fatal or nonfatal myocardial infarction (relative risk, 1.02; 95 percent confidence interval, 0.84 to 1.25; P=0.83) or death from cardiovascular causes (relative risk, 0.95; 95 percent confidence interval, 0.74 to 1.22; P=0.68). Gastrointestinal bleeding requiring transfusion was more frequent in the aspirin group than in the placebo group (relative risk, 1.40; 95 percent confidence interval, 1.07 to 1.83; P=0.02). Subgroup analyses showed that aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and myocardial infarction among women 65 years of age or older. CONCLUSIONS: In this large, primary-prevention trial among women, aspirin lowered the risk of stroke without affecting the risk of myocardial infarction or death from cardiovascular causes, leading to a nonsignificant finding with respect to the primary end point.

Age Factors↗