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Biomedical subjects

John Williams

Publications and source records attributed to John Williams.

At least 37 records · Page 2Linked to original sources
PubMed2005

Cost-effectiveness of improving primary care treatment of late-life depression.

CONTEXT: Depression is a leading cause of functional impairment in elderly individuals and is associated with high medical costs, but there are large gaps in quality of treatment in primary care. OBJECTIVE: To determine the incremental cost-effectiveness of the Improving Mood Promoting Access to Collaborative Treatment (IMPACT) collaborative care management program for late-life depression. DESIGN: Randomized controlled trial with recruitment from July 1999 to August 2001. SETTING: Eighteen primary care clinics from 8 health care organizations in 5 states. PARTICIPANTS: A total of 1801 patients 60 years or older with major depression (17%), dysthymic disorder (30%), or both (53%). INTERVENTION: Patients were randomly assigned to the IMPACT intervention (n = 906) or to usual primary care (n = 895). Intervention patients were provided access to a depression care manager supervised by a psychiatrist and primary care physician. Depression care managers offered education, support of antidepressant medications prescribed in primary care, and problem-solving treatment in primary care (a brief psychotherapy). MAIN OUTCOME MEASURES: Total outpatient costs, depression-free days, and quality-adjusted life-years. RESULTS: Relative to usual care, intervention patients experienced 107 (95% confidence interval [CI], 86 to 128) more depression-free days over 24 months. Total outpatient costs were USD $295 (95% CI, -$525 to $1115) higher during this period. The incremental outpatient cost per depression-free day was USD $2.76 (95% CI, -$4.95 to $10.47) and incremental outpatient costs per quality-adjusted life-year ranged from USD $2519 (95% CI, -$4517 to $9554) to USD $5037 (95% CI, -$9034 to $19 108). Results of a bootstrap analysis suggested a 25% probability that the IMPACT intervention was "dominant" (ie, lower costs and greater effectiveness). CONCLUSIONS: The IMPACT intervention is a high-value investment for older adults; it is associated with high clinical benefits at a low increment in health care costs.

Age Factors↗
PubMed2005

The occurrence and removal of phthalates in a trickle filter STW.

This study investigated the fate of phthalates in a trickle filter sewage treatment works. A wide variety of phthalates were researched of which only two were present in significant amounts. Mean concentrations of di-(2-ethylhexyl) phthalate (DEHP) and diethyl phthalate (DEP) measured throughout the system were 23.6 and 25.0 microg/l in raw sewage, 22.0 and 24.8 microg/l in primary, 14.6 and 0.60 microg/l in trickle filter, 18.6 and 0.10 microg/l in humus tank and 18.5 and 0.40 microg/l in reedbed effluents, respectively. Removal by the trickle filter was constantly high for DEP (94-99%) whereas DEHP was variable (<1-44%). Mean concentrations of DEHP and DEP in raw sludge were 30.2 and 1.60 microg/g dry wt, respectively. A mass balance for DEHP was calculated using data from field studies and estimates of sludge production at the works. The mass balance approach helped to provide information that could be used to improve the design and operation of sewage treatment works.

Filtration↗
PubMed2004

A screening library for peptide activated G-protein coupled receptors. 1. The test set.

One subset of the G-protein coupled receptor (GPCR) superfamily is that which is activated by a peptide carrying an obligatory positively charged residue (GPCR-PA(+)). This subclass is exemplified by receptors for melanocortins, GnRH, galanin, MCH, orexin, and some chemokine receptors variously involved in eating disorders, reproductive disorders, pain, narcolepsy, obesity, and inflammation. Using the methods described in this study, a region of chemical property space enriched in GPCR ligands was identified. This information was used to design and synthesize a "test" library of 2025 single, pure compounds to sample portions of this property space associated with GPCR-PA(+) ligands. The library was evaluated by high-throughput screening against three different receptors, rMCH, hMC4, and hGnRH, and found to be highly enriched in active ligands (4.5-61-fold) compared to a control set of 2024 randomly selected compounds. In addition, the analysis suggested that about 7000 compounds will be necessary to complete the sampling of this GPCR-PA(+) ligand-rich region and to better define its borders.

Animals↗
PubMed2004

Critical appraisal of the mouse model of myocardial infarction.

In order to critically evaluate the utility of a mouse model of myocardial infarction (MI) for therapeutic studies, we investigated survival, haemodynamic measurements and histopathology in mice with an occluding suture placed at one of three distinct sites along the left anterior descending coronary artery. The suture was placed at the atrioventricular juncture (High), or at two sites more distally towards the base (Middle and Low). In the High group, only 33% of animals survived 7 days after MI (P < 0.05 compared to all other groups). Only the Middle group had significantly reduced haemodynamics compared to sham-operated animals (maximum left ventricular pressure: 55.9 +/- 3.5 versus 80.8 +/- 5.1 mmHg, maximum change in pressure over time : 2003 +/- 172 versus 4402 +/- 491, P < 0.01). Histological examination showed morphological changes in all MI groups. The Middle group had larger lesions than the Low group (P < 0.05). Lesions in the anterior and lateral walls correlated, albeit weakly, with cardiac function. Power calculations indicated that, despite a certain amount of intragroup variation, the Middle Suture model may be useful for therapeutic studies to assess the effects of treatment on cardiac function and overall lesion size.

Animals↗
PubMed2004

Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.

Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie disease gene, is a secreted protein of unknown biochemical function. One form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. We show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and ear, and they indicate that ligands unrelated to Wnts can act through Fz receptors.

Animals↗
PubMed2004

Proximal and distal sequences control UV cone pigment gene expression in transgenic zebrafish.

The molecular basis of cone photoreceptor-specific gene expression is largely unknown. In this study, we define cis-acting DNA sequences that control the cell type-specific expression of the zebrafish UV cone pigment gene by transient expression of green fluorescent protein transgenes following their injection into zebrafish embryos. These experiments show that 4.8 kb of 5'-flanking sequences from the zebrafish UV pigment gene direct expression specifically to UV cones and that this activity requires both distal and proximal sequences. In addition, we demonstrate that a proximal region located between -215 and -110 bp (with respect to the initiator methionine codon) can function in the context of a zebrafish rhodopsin promotor to convert its specificity from rod-only expression to rod and UV cone expression. These experiments demonstrate the power of transient transgenesis in zebrafish to efficiently define cis-acting regulatory sequences in an intact vertebrate.

5' Untranslated Regions↗
PubMed2004

Model for end stage liver disease score predicts mortality across a broad spectrum of liver disease.

BACKGROUND/AIMS: The utility of the model for end stage liver disease (MELD) score in non-transplant patients, particularly in those with less severe chronic liver disease remains uncertain. We studied and compared the predictive abilities of the MELD score and the Child-Turcotte-Pugh (CTP) score for intermediate (1-year) and long-term (5-year) mortality. METHODS: One thousand six hundred and eleven patients with chronic liver disease were studied. Observed and predicted survival curves were plotted to evaluate the predictive ability of the MELD score for survival. Receiver operating characteristic (ROC) curves was used to compare the MELD and CTP score. A multivariable model was constructed to examine predictors of mortality. RESULTS: The MELD score was a good predictor of 1-year mortality in chronic liver disease (c-statistics for all subgroups >/=0.75) and of 3- and 6-month mortality in alcoholic hepatitis (c-statistic >/=0.83). The CTP score had similar predictive abilities as the MELD. Hepatic encephalopathy was a strong independent predictor of death (Hazard ratio-2.8, P<0.0001). CONCLUSIONS: The MELD score is a valid prognostic score for intermediate term mortality in a heterogeneous population with chronic liver disease although the CTP score is equivalent in predicting survival. Inclusion of hepatic encephalopathy adds additional prognostic value to the MELD score.

Female↗
PubMed2004

A double-blind placebo-controlled pilot study of risperidone for decreasing cue-elicited craving in recently withdrawn cocaine dependent patients.

Cocaine use causes an initial increase in dopamine and serotonin neurotransmission that is largely responsible for the pleasurable and reinforcing effects of the drug. Dysregulation of these neurotransmitters during withdrawal plays an important role in craving. Recent research has focused on the use of dopamine and serotonin antagonists early in recovery to reduce cocaine craving in both schizophrenic and non-schizophrenic cocaine dependent patients. This 2-week, double blind, placebo-controlled study compared risperidone vs. placebo in reducing cue-elicited cocaine craving. Thirty-four subjects with cocaine dependence were randomized to either risperidone or a placebo and underwent a weekly cue-exposure procedure. Although both groups had a reduction in craving over time, there were no significant differences among those treated with risperidone (n=19) compared to those taking a placebo (n=16) on the four craving dimensions. The results do not support the hypothesis that risperidone reduces cocaine craving among non-schizophrenic cocaine-dependent individuals.

Adult↗
PubMed2004

The prevalence of alcohol-induced liver disease and hepatitis C and their interaction in a tertiary care setting.

BACKGROUND & AIMS: We examined the prevalence and clinical characteristics of alcohol-induced liver disease (ALD) in patients referred to a tertiary care center and examined the interaction between ALD and hepatitis C virus (HCV) in a longitudinal survival model. METHODS: A total of 1611 patients with chronic liver disease referred to a tertiary care center between 1994 and 2001 were analyzed. The survival of ALD, HCV, and the combination of the 2 (ALD + HCV) was compared in cirrhotic and precirrhotic patients by using Kaplan-Meier estimates. A Cox proportional hazards model was used to examine the independent effects of predictors on survival. RESULTS: ALD comprised 31% of the cohort, ALD + HCV comprised 14%, HCV comprised 22%, and the rest comprised 33%. The survival of precirrhotic patients with HCV was significantly better than the survival of those with ALD (hazard ratio, 0.27; P = 0.0006) over long-term and 1-year (hazard ratio, 0.24; P = 0.016) follow-up periods. There was no difference in survival between patients with ALD and ALD + HCV ( P = 0.62). In patients with cirrhosis, survival did not differ by cause; decompensated liver disease (hazard ratio, 1.67; P = 0.004) and continued alcohol abuse (hazard ratio, 2.19; P = 0.002) predicted worse survival in this group. CONCLUSIONS: ALD with HCV remains a prevalent cause of chronic liver disease in patients referred to a U.S. tertiary care center. In patients with ALD, the addition of HCV does not change survival, suggesting alcoholism is the driving force for mortality in patients coming to clinical attention. In patients with cirrhosis, ongoing excessive alcohol use and complications of end-stage liver disease drive mortality, irrespective of the underlying cause of chronic liver disease.

Age Factors↗
PubMed2004

CYP1A2 in a smoking and a non-smoking population; correlation of urinary and salivary phenotypic ratios.

The use of caffeine as a probe for CYP1A2 phenotyping has been extensively investigated over the last 25 years. Numerous metabolic ratios have been employed and various biological fluids analysed for caffeine and its metabolites. These investigations have used non-smoking, smoking and numerous disease populations to investigate the role of CYP1A2 in possible disease aetiology and for induction and inhibition studies in vivo using dietary, environmental and pharmaceutical compounds. This investigation found that the 17X/137X CYP1A2 metabolic ratio in a 5 h saliva sample and 0-5 h urine collection was not normally distributed in both a non-smoking and a smoking population. The urinary and salivary CYP1A2 metabolic ratio was log normally distributed in the non-smoking population but the smoking population showed a bi- (or tri-)modal distribution on log transformation of both the urinary and salivary CYP1A2 metabolic ratios. The CYP1A2 metabolic ratios were significantly higher in the smoking population compared to the non-smoking population when both the urinary and salivary CYP1A2 metabolic ratios were analysed. These results indicate that urinary flow rate was not a factor in the variation in CYP1A2 phenotype in the non-smoking and smoking populations studied here. The increased CYP1A2 activity in the smoking population was probably due to induction of the CYP1A2 gene via the Ah receptor causing an increase in the concentration of CYP1A2 protein.

Adolescent↗
PubMed2003

Neural correlates of the emergence of consciousness of thirst.

Thirst was induced by rapid i.v. infusion of hypertonic saline (0.51 M at 13.4 ml/min). Ten humans were neuroimaged by positron-emission tomography (PET) and four by functional MRI (fMRI). PET images were made 25 min after beginning infusion, when the sensation of thirst began to enter the stream of consciousness. The fMRI images were made when the maximum rate of increase of thirst occurred. The PET results showed regional cerebral blood flow changes similar to those delineated when thirst was maximal. These loci involved the phylogenetically ancient areas of the brain. fMRI showed activation in the anterior wall of the third ventricle, an area that is key in the genesis of thirst but is not an area revealed by PET imaging. Thus, this region plays as major a role in thirst for humans as for animals. Strong activations in the brain with fMRI included the anterior cingulate, parahippocampal gyrus, inferior and middle frontal gyri, insula, and cerebellum. When the subjects drank water to satiation, thirst declined immediately to baseline. A precipitate decline in intensity of activation signal occurred in the anterior cingulate area (Brodmann area 32) putatively related to consciousness of thirst. The intensity of activation in the anterior wall of the third ventricle was essentially unchanged, which is consistent with the fact that a significant time (15-20 min) would be needed before plasma Na concentration changed as a result of water absorption from the gut.

Adult↗
PubMed2003

Prospective study of the airways and pulmonary parenchyma of patients at risk for a second lung cancer.

PURPOSE: We conducted our study to compare the number of preneoplastic lesions in the airways and nodules in the pulmonary parenchyma of patients with resected non-small cell lung cancer with the patients whose treatment included chest radiotherapy. EXPERIMENTAL DESIGN: Patients were eligible if they had successfully resected stage I and II non-small cell lung cancer or advanced stage non-small cell or small cell lung cancer treated with chest radiotherapy with or without chemotherapy and were free of cancer for >2 years. Patients underwent a history and physical examination, white light and fluorescence bronchoscopy, and computerized tomography of the chest. The airway epithelium was examined for preneoplastic histological changes, and the pulmonary parenchyma was examined for the presence of nodules. RESULTS: Twenty-nine patients at risk for lung cancer were studied between 1997 and 1999. Two patients treated with chest radiotherapy had an area of moderate dysplasia (n=1) and carcinoma in situ (n=1), whereas one patient treated with surgical resection alone had an area of mild dysplasia. Six other patients had metaplasia detected in their airway epithelium. Ten of the 13 patients treated with chest radiotherapy had pulmonary nodules compared with 5 of the 13 patients treated with surgical resection alone. CONCLUSIONS: Mild dysplasia, moderate dysplasia, severe dysplasia, and carcinoma in situ are unusual in patients with resected lung cancer who have stopped smoking for an extended period of time. Patients with lung cancer treated with chest irradiation may be at higher risk for preneoplastic lesions and pulmonary nodules than patients treated with surgical resection alone, but additional patients will need to be studied.

Adult↗
PubMed2003

A strabismus susceptibility locus on chromosome 7p.

Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes.

Chromosome Mapping↗
PubMed2003

Interactions of perfluorocarbon liquids and silicone oil as characterized by mass spectrometry.

BACKGROUND: Perfluorocarbon liquids (PFCL) are used extensively in complex vitreoretinal surgery, sometimes before the placement of silicone oil (SiO). We suspected that PFCL and SiO interact physically when in opposition, potentially making their removal more difficult. The nature of some of these interactions was explored using a mass spectrometric approach in in-vitro and in-vivo samples. METHODS: We incubated silicone oil (1,000 or 5,000 centistokes viscosity) and PFCL [perfluoro-n-octane (PFO) or perfluorotributylamine] together in vitro for 6 months and performed electron impact ionization mass spectrometry (EIMS) on the PFCL to characterize interactions between the liquid phases. Packaged samples of PFCL served as controls. We also examined in vivo samples of PFO which had been retained in human eyes for several months prior to surgical removal. RESULTS: Perfluorocarbon liquids packaged for surgical use all contain SiO in trace amounts, possibly as a manifestation of the processes used in their manufacture. Furthermore, all PFCLs incubated with SiO showed much more prominent contamination with SiO molecular fragments. PFCL was found in the SiO phase of eyes in which both liquids were present for extended periods of time. The EIMS analysis of in vivo samples suggested that proteins coat PFCL droplets, forming micelle-like structures. CONCLUSION: Medical-grade PFCLs contain small amounts of SiO, and PFCLs dissolve small amounts of oil into solution over time. Interactions between retained vitreous substitutes may have clinical relevance.

Drug Interactions↗