Biomedical subjects

Mark R Conaway

Publications and source records attributed to Mark R Conaway.

16 recordsLinked to original sources

PubMed2006

Influence of hemoglobin levels on inpatient rehabilitation outcomes after total knee arthroplasty.

This retrospective study examined the influence of hemoglobin (Hb) on the outcomes of 184 acute inpatient rehabilitation patients admitted to a single university-based inpatient rehabilitation facility after primary total knee arthroplasty between 2001 and 2003. Patient function was measured using the Functional Independence Measure (FIM) instrument. Average length of stay was 9.4 days. Total FIM score increased from 81.5 to 110.8. Mean baseline Hb was 10.5 g/dL. Multivariate analyses demonstrated that a higher Hb at baseline was associated with significantly shorter length of stay (P = .004) and greater FIM efficiency (change in total FIM score/length of stay) (P = .04). Hemoglobin is associated with rehabilitation outcomes after total knee arthroplasty; additional research into the influence of blood management strategies on rehabilitation outcomes is warranted.

Aged↗

PubMed2006

Lifestyle intervention in obese patients with type 2 diabetes: impact of the patient's educational background.

OBJECTIVE: To determine whether people with different educational backgrounds respond differently to a lifestyle intervention program for obese patients with type 2 diabetes. RESEARCH METHODS AND PROCEDURES: The study consisted of a 12-month randomized controlled trial of 147 health plan members with type 2 diabetes who were overweight or obese (BMI > or = 27 kg/m(2)). Participants were randomized to lifestyle case management or usual care. Case management (CM) involved group and individual education, support, and referral by registered dietitians. Usual care (UC) participants received educational material. Both groups received ongoing primary care. A post hoc analysis was performed, evaluating the impact of education level on intervention group differences with respect to change in weight and waist circumference. RESULTS: There was a significant education by group interaction for both changes in weight (p = 0.02) and waist circumference (p = 0.01) during the study period. Contrary to expectations, CM participants with less formal education had greater risk reductions compared with more educated participants. Models predicted that, by 12 months, those with less education in the UC group gained 1.71 kg more in weight and 3.67 cm more in waist circumference than those with greater education. However, by 12 months, those in the CM group with less education lost a model-predicted 3.30 kg more in weight and 4.95 cm more in waist circumference than those with more formal education. DISCUSSION: People with varied educational backgrounds may respond differently to a lifestyle intervention for weight management and diabetes control.

Adult↗

PubMed2006

Dobutamine response and myocardial infarct transmurality: functional improvement after coronary artery bypass grafting--initial experience.

The Investigational Review Board approved the protocol, and all patients provided signed informed consent. The protocol was compliant with HIPAA. The purpose of the study was to prospectively test the hypothesis that addition of low-dose dobutamine and quantification of inotropic reserve in segments with 1%-50% infarct transmurality (IT) would improve the predictive value for functional recovery after revascularization in chronic infarction. Fifteen patients with multivessel coronary artery disease and left ventricular systolic dysfunction were enrolled prior to coronary artery bypass grafting (CABG). Late gadolinium-enhanced cardiac magnetic resonance (MR) imaging was used to assess IT. The percentage of wall thickening was measured with cine cardiac MR imaging at rest and during infusion of 10 (microg . kg(-1))/min dobutamine. Repeat cardiac MR imaging was performed 20 weeks +/- 4 (standard error) later. Functional parameters according to segment were compared before and after CABG by using F tests with repeated-measures models. In segments with 1%-50% IT, similar functional recovery was noted in those with 1%-25% or 26%-50% IT. However, in the same segments, those that improved with dobutamine to normal range demonstrated greater improvement in the percentage of wall thickening (22% +/- 4) after revascularization than those that did not (9% +/- 4) (P < .04). In 1%-50% IT, a normal dobutamine response helps differentiate segments with greater functional recovery after CABG.

Adult↗

PubMed2006

Dopamine agonist therapy in low-response children following traumatic brain injury.

The objective of this study was to determine whether a dopamine agonist could improve mental status among children in a low-response state following traumatic brain injury. In an 8-week, prospective, double-blind, randomized trial, 10 children and adolescents ages 8 to 21 years (X = 16.7 years) with traumatic brain injury sustained at least 1 month previously and remaining in a low-response state (Rancho Los Amigos Scale level pound 3) received pramipexole or amantadine. Medication dosage was increased over 4 weeks, weaned over 2 weeks, and then discontinued. At baseline and weekly during the study, subjects were evaluated with the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale. Scores improved significantly from baseline to the medication phase on the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale (P < .005). The weekly rate of change was significantly better for all three measures on medication than off medication (P < .05). Rancho Los Amigos Scale levels improved significantly on medication as well (P < .05). There was no difference in efficacy between amantadine and pramipexole. No unexpected or significant side effects were observed with either drug. This clinical trial supports the benefit of two dopamine agonists in the restoration of functional arousal, awareness, and communication. These drugs can be helpful in accelerating eligibility for acute rehabilitation among children and adolescents who have sustained significant brain injuries.

Adolescent↗

PubMed2005

Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling.

The relative contribution of the angiotensin II type 1 and 2 receptors (AT1-R and AT2-R) in postmyocardial infarction (MI) remodeling remains incompletely understood. We studied five groups of C57Bl/6 mice after 1 h of left anterior descending artery occlusion-reperfusion: 1) wild type, untreated (n = 12); 2) wild type, treated with the AT1-R blocker losartan (10-20 mg.kg(-1).day(-1) in drinking water) from day 1 to day 28 post-MI (n = 10); 3) cardiac overexpression of the AT2-R [AT2-transgenic (TG); n = 14]; 4) AT2-TG treated with losartan (n = 13); and 5) AT2-TG and null for the AT1a-R [AT2-TG/AT1 knockout (KO); n = 10]. Cardiac magnetic resonance imaging (CMR) measured ejection fraction and left ventricular end-diastolic and end-systolic volume (EDVI and ESVI) and mass indexed to weight on days 0, 1, 7, and 28 post-MI. Infarct size was measured on day 1 by late gadolinium-enhanced CMR. Regional myocyte hypertrophy and collagen content were measured on day 28 post-MI. Infarct size was similar among groups. Systolic blood pressure was lowest in AT2-TG/AT1KO. By day 28 post-MI, when corrected for baseline differences, EDVI and ESVI were higher and ejection fraction was lower in wild type than other groups. Ejection fraction was highest and EDVI and mass index were lowest in AT2-TG/AT1KO at day 28. The AT2-TG/AT1KO demonstrated less fibrosis in adjacent regions. Regional myocyte hypertrophy was similar in all groups. The AT1-R and AT2-R are intricately intertwined in post-MI remodeling. Pharmacological blockade of AT1-R is equivalent to AT2-R overexpression in attenuating post-MI remodeling. Genetic knockout of the AT1a-R is additive to AT2-R overexpression, due, at least in part, to blood pressure lowering.

Animals↗

PubMed2005

Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial.

CONTEXT: Despite evidence that patients with acute lung injury (ALI) have pulmonary surfactant dysfunction, trials of several surfactant preparations to treat adults with ALI have not been successful. Preliminary studies in children with ALI have shown that instillation of a natural lung surfactant (calfactant) containing high levels of surfactant-specific protein B may be beneficial. OBJECTIVE: To determine if endotracheal instillation of calfactant in infants, children, and adolescents with ALI would shorten the course of respiratory failure. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, blinded trial of calfactant compared with placebo in 153 infants, children, and adolescents with respiratory failure from ALI conducted from July 2000 to July 2003. Twenty-one tertiary care pediatric intensive care units participated. Entry criteria included age 1 week to 21 years, enrollment within 48 hours of endotracheal intubation, radiological evidence of bilateral lung disease, and an oxygenation index higher than 7. Premature infants and children with preexisting lung, cardiac, or central nervous system disease were excluded. INTERVENTION: Treatment with intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart. MAIN OUTCOME MEASURES: Ventilator-free days and mortality; secondary outcome measures were hospital course, adverse events, and failure of conventional mechanical ventilation. RESULTS: The calfactant group experienced an acute mean (SD) decrease in oxygenation index from 20 (12.9) to 13.9 (9.6) after 12 hours compared with the placebo group's decrease from 20.5 (14.7) to 15.1 (9.0) (P = .01). Mortality was significantly greater in the placebo group compared with the calfactant group (27/75 vs 15/77; odds ratio, 2.32; 95% confidence interval, 1.15-4.85), although ventilator-free days were not different. More patients in the placebo group did not respond to conventional mechanical ventilation. There were no differences in long-term complications. CONCLUSIONS: Calfactant acutely improved oxygenation and significantly decreased mortality in infants, children, and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was observed.

Adolescent↗

PubMed2005

Efficacy and complications of covered Wallstents in malignant distal biliary obstruction.

BACKGROUND: This study evaluated the efficacy and the complications associated with the use of the covered Wallstent in the setting of unresectable malignant biliary obstruction. METHODS: Between March 2001 and January 2003, all patients with distal malignant biliary obstruction that required drainage were treated with a covered Wallstent. Every 2 months, the patients were evaluated clinically and biochemical tests of liver function were obtained. Data were recorded for the following variables: early complications (within 30 days of stent placement), early and late stent occlusion, duration of stent patency, need for subsequent biliary intervention, and patient survival. RESULTS: A total of 88 covered Wallstents were inserted in 80 patients. Stent patency rates at 3, 6, and 12 months were 90%, 82%, and 78%, respectively. Complications included stent migration (5), stent occlusion (12), episodes of cholecystitis (3), and episodes of post-ERCP pancreatitis (5). Biliary intervention was required in 9 patients subsequent to placement of the initial covered Wallstent. CONCLUSIONS: Deployment of a covered Wallstent is safe and relatively easy. It achieves biliary drainage with an acceptable risk to benefit ratio in the majority of patients with distal malignant biliary obstruction.

Adult↗

PubMed2004

Profiling the evolution of human metastatic bladder cancer.

Pulmonary metastases frequently develop in patients with aggressive bladder cancer, yet investigation of this process at the molecular level suffers from the poor availability of human metastatic tumor tissue and the absence of suitable animal models. To address this, we developed progressively more metastatic human bladder cancer cell lines and an in vivo bladder-cancer lung-metastasis model, and we successfully used these to identify genes of which the expression levels change according to the degree of pulmonary metastatic potential. By initially intravenously injecting the poorly metastatic T24T human urothelial cancer cells into nude mice, and then serially reintroducing and reisolating the human tumor cells from the resultant mouse lung tumors, three derivative human lines with increasingly metastatic phenotypes, designated FL1, FL2, and FL3, were sequentially isolated. To identify the genes associated with the most lung-metastatic phenotype, the RNA complement from the parental and derivative cells was evaluated with oligonucleotide microarrays. In doing so, we found 121 genes to be progressively up-regulated during the transition from T24T to FL3, whereas 43 genes were progressively down-regulated. As expected, many of the genes identified in these groups could, according to the ascribed functions of their protein product, theoretically participate in tissue invasion and metastasis. In addition, the magnitude of gene expression changes observed during the metastatic transition correlated with the in vivo propensity for earlier lung colonization and decreased host survival. To additionally define which genes found in the experimental system were of relevance to human bladder cancer lung metastasis, we evaluated gene expression profiles of 23 primary human bladder tumors of various stages and grades, and then we compared these gene expression profiles to the altered profiles in our model cell lines. Here we found that the expression of epiregulin, urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP)14, and tissue inhibitor of metalloproteinase (TIMP-2) were consistently and progressively up-regulated when viewed as a function of tumor stage in tissues of patients versus the metastatic potential seen in the mouse lung model. The strong correlation of these four markers between the experimental and clinical situations helps validate this system as a useful tool for the study of lung metastasis and defines targets of therapy that may reduce the incidence of this process in patients.

Animals↗

PubMed2004

Designs for single- or multiple-agent phase I trials.

Phase I trials of cytotoxic agents in oncology are usually dose-finding studies that involve a single cytotoxic agent. Many statistical methods have been proposed for these trials, all of which are based on the assumption of a monotonic dose-toxicity curve. For single-agent trials, this is a valid assumption. In many trials, however, investigators are interested in finding the maximally tolerated dose based on escalating multiple cytotoxic agents. When there are multiple agents, monotonicity of the dose-toxicity curve is not clearly defined. In this article we present a design for phase I trials in which the toxicity probabilities follow a partial order, meaning that there are pairs of treatments for which the ordering of the toxicity probabilities is not known at the start of the trial. We compare the new design to existing methods for simple orders and investigate the properties of the design for two partial orders.

Antineoplastic Agents↗

PubMed2004

Factors predictive of malignancy and endoscopic resectability in ampullary neoplasia.

OBJECTIVE: Endoscopic treatment of ampullary lesions has been well described, though it remains uncertain if specific features predict malignancy, and whether identifiable factors are associated with successful endoscopic resection of benign lesions. METHODS: Fifty-six consecutive patients undergoing endoscopic evaluation of ampullary neoplasia between March 2000 and May 2004 were included in the study. Clinical presentation, underlying medical conditions, endoscopic treatment, endoscopic ultrasound (EUS) to define extent of local involvement, pathology results, and outcome were documented. Data elements for analysis included EUS findings, lesion lifting with submucosal injection, age, gender, tumor size, and endoscopic intervention. Analyses were performed to determine the ability to predict malignancy and the ability to extirpate benign lesions. RESULTS: Thirty-one males and 25 females were included; mean age was 62 yr. Final diagnoses included 29 adenomas, 20 adenocarcinomas, 4 adenomyomas, 2 paragangliomas, and 1 neuroendocrine tumor. Thirty of 35 patients with benign lesions had extirpation with a mean of two endoscopic procedures. Complications of endoscopic resection included cholangitis (1), bleeding (2), and pancreatitis (4). The presence of malignancy was associated by multivariate analysis with the inability to obtain a cleavage plane with saline injection. Univariate analysis also identified EUS T stage as a predictor of malignancy. In benign lesions, none of the analyzed variables predicted successful endoscopic resection. CONCLUSION: In ampullary lesions, failure to achieve a cleavage plane with submucosal injection is the strongest predictor of malignancy followed by EUS T stage. Endoscopic treatment of benign ampullary neoplasia is effective; no factor was predictive of successful extirpation.

Adult↗

PubMed2004

Translating lifestyle intervention to practice in obese patients with type 2 diabetes: Improving Control with Activity and Nutrition (ICAN) study.

OBJECTIVE: To assess the efficacy of a lifestyle intervention program that can be readily translated into clinical practice for obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The study consisted of a 12-month randomized controlled trial of 147 health plan members with type 2 diabetes and obesity (BMI >or=27 kg/m(2)). Participants were randomized to lifestyle case management or usual care. Case management entailed individual and group education, support, and referral by registered dietitians; intervention cost was US dollars 350 per person. Individuals treated with usual care received educational material. Both groups received ongoing primary care. Outcomes were difference between groups for change in weight (kilograms), waist circumference (centimeters), HbA(1c), fasting lipid levels, use of prescription medications, and health-related quality of life. RESULTS: Case management resulted in greater weight loss (P < 0.001), reduced waist circumference (P < 0.001), reduced HbA(1c) level (P = 0.02), less use of prescription medications (P = 0.03), and improved health-related quality of life (P < 0.001) compared with usual care. The 12-month group difference in weight loss and waist circumference was 3.0 kg (95% CI -5.4 to -0.6) and -4.2 cm (-6.8 to -1.6). HbA(1c) differences were greatest at 4 months (-0.59%, P = 0.006) but not significant by 12 months (-0.19%, P = 0.45). Participants in the case management group lowered their use of medications, primarily diabetes medications, by 0.8 medications per day more than participants treated with usual care (P = 0.03). In seven of nine quality-of-life domains, the case management group improved compared with usual care (P < 0.05). CONCLUSIONS: Moderate-cost dietitian-led lifestyle case management may improve diverse health indicators among obese patients with type 2 diabetes.

Body Mass Index↗

PubMed2003

Transient, ligand-dependent arrest of the androgen receptor in subnuclear foci alters phosphorylation and coactivator interactions.

Here we report that mutations within the DNA-binding domain of AR, shown previously to inhibit nuclear export to the cytoplasm, cause an androgen-dependent defect in intranuclear trafficking of AR. Mutation of two conserved phenylalanines within the DNA recognition helix (F582, 583A) results in androgen-dependent arrest of AR in multiple subnuclear foci. A point mutation in one of the conserved phenylalanines (DeltaF582, F582Y) is known to cause androgen insensitivity syndrome (AIS). Both AIS mutants (DeltaF582, F582Y) and the export mutant (F582, 583A) displayed androgen-dependent arrest in foci, and all three mutants promoted androgen-dependent accumulation of the histone acetyl transferase CREB binding protein (CBP) in the foci. The foci correspond to a subnuclear compartment that is highly enriched for the steroid receptor coactivator glucocorticoid receptor-interacting protein (GRIP)-1. Agonist-bound wild-type AR induces the redistribution of GRIP-1 from foci to the nucleoplasm. This likely reflects a direct interaction between these proteins because mutation of a conserved residue within the major coactivator binding site on AR (K720A) inhibits AR-dependent dissociation of GRIP-1 from foci. GRIP-1 also remains foci-associated in the presence of agonist-bound F582, 583A, DeltaF582, or F582Y forms of AR. Two-dimensional phospho-peptide mapping and analysis with a phospho-specific antibody revealed that mutant forms of AR that arrest in the subnuclear foci are hypophosphorylated at Ser81, a site that normally undergoes androgen-dependent phosphorylation. Our working model is that the subnuclear foci are sites where AR undergoes ligand-dependent engagement with GRIP-1 and CBP, a recruitment step that occurs before Ser81 phosphorylation and association with promoters of target genes.

Androgen-Insensitivity Syndrome↗

PubMed2003

Gene profiling and promoter reporter assays: novel tools for comparing the biological effects of botanical extracts on human prostate cancer cells and understanding their mechanisms of action.

The use of botanical mixtures is commonplace in patients with prostate cancer, yet the majority of these products have not been rigorously tested in clinical trials. Here we use PC-SPES, a combination of eight herbs that has been shown to be effective in clinical trials in patients with prostate cancer, as a model system to demonstrate 'proof of principle' as to how gene expression profiling coupled with promoter assays can evaluate the effect of herbal cocktails on human prostate cancer. In addition, we demonstrate how such approaches may be used for standardization of herbal extract activity by comparing the gene profile of PC-SPES with that of PC-CARE, a product with a similar herbal composition. Since prior studies have shown that PC-SPES contains estrogenic organic compounds, and such compounds are known to affect prostate cancer, an important issue is whether these are the primary drivers of the gene profile. Our data suggest that gene expression profiles of LNCaP human prostate cancer cells in response to PC-SPES are different from those found when diethylstilbestrol (DES), a synthetic estrogen, is used, suggesting that the estrogenic moieties within PC-SPES do not drive this expression signature. In contrast, the expression profile of PC-CARE was almost identical to that of DES, highlighting that mixtures containing similar herbal compositions do not necessarily result in similar biological activities. Interestingly, these three agents cause similar in vitro morphological changes and growth effects on LNCaP. To validate the expression profiling data, we evaluated the protein expression and promoter activity of prostate-specific antigen (PSA), a gene induced by PC-SPES but repressed by DES. In order to gain a mechanistic understanding of how PC-SPES and DES affect PSA expression differently, LNCaP cells were transiently transfected with wild-type and mutagenized PSA promoter, ARE concatemers and appropriate controls. We provide evidence that androgen response elements (ARE) II and III within the promoter region are responsible for the suppressive effects of DES and stimulatory effects of PC-SPES. In addition, we show that the effects on PSA transcription are ARE specific in the case of DES while PC-SPES affects this promoter nonspecifically. In conclusion, expression profiling coupled with mechanistic target validation yield valuable clues as to the mode of action of complex botanical mixtures and provides a new way to compare objectively mixtures with similar components either for effect or quality assurance prior to their use in clinical trials.

Adenocarcinoma↗

PubMed2003

Adaptive hypersensitivity following long-term estrogen deprivation: involvement of multiple signal pathways.

Long-term estrogen deprivation causes hypersensitivity of MCF-7 cells to the mitogenic effect of estradiol (E2) which is associated with activation of mitogen-activated protein kinase (MAPK). However, several lines of evidence indicate that MAPK activation is not the exclusive mechanism for E2 hypersensitivity and multiple signal pathways might be involved. The current study explores the possible role of the PI3 kinase (PI3K) pathway in development of E2 hypersensitivity. Basal PI3K activity in long-term estrogen deprived MCF-7 cells (LTED) was elevated as evidenced by increased phosphorylation of three downstream effectors, Akt, p70 S6 kinase, and eukaryotic initiation factor-4E binding protein (4E-BP1), which was blocked by the specific inhibitor of PI3K, LY294002. Dual blockade of both MAPK and PI3K completely reversed E2 hypersensitivity of LTED cells. Enhancement in aromatase activity is another phenomenon accompanied with E2 hypersensitivity. In aromatase over-expressing MCF-7 cells, aromatase activity was reduced by inhibitors of MAPK and PI3K suggesting the involvement of protein phosphorylation in the regulation of aromatase activity. Our data suggest that in addition to the MAP kinase pathway, activation of the PI3 kinase pathway is involved in E2 hypersensitivity, which develops during adaptation of MCF-7 cells to the low estrogen environment.

Adaptation, Physiological↗

PubMed2002

RhoGDI2 is an invasion and metastasis suppressor gene in human cancer.

To discover novel metastasis suppressor genes that are clinically relevant in common human cancers, we used isogenic human bladder cancer cell lines and used DNA microarray technology to identify genes whose expression diminishes as a function of invasive and metastatic competence. We then evaluated the expression profile of such genes in 105 pathologically characterized tumors from seven common organ sites, and we identified one gene, RhoGDI2, whose expression was diminished as a function of primary tumor stage and grade. When RhoGDI2 was transferred back into cells with metastatic ability that lacked its expression, it suppressed experimental lung metastasis but did not affect in vitro growth, colony formation, or in vivo tumorigenicity. In addition, RhoGDI2 reconstitution in these cells blocked invasion in an organotypic assay and led to a reduction of in vitro motility. These results indicate that RhoGDI2 is a metastasis suppressor gene, a marker of aggressive human cancer, and a promising target for therapy.

Adenocarcinoma↗

PubMedDate not supplied

Brain imaging as a predictor of early functional outcome following traumatic brain injury in children, adolescents, and young adults.

OBJECTIVES: A depth of lesion (DOL) model using brain imaging has been proposed to aid in medical decision-making and planning for rehabilitation resource needs. The purpose of this study was to determine the early prognostic value of a DOL classification system for children and young adults following severe traumatic brain injury. METHODS AND OUTCOME MEASURES: CT/MRI brain imaging studies on 92 patients, aged 3 to 21, admitted to the Kluge Children's Rehabilitation Center, University of Virginia, were evaluated to determine DOL. Images were classified according to 5 DOL levels (cortical to brainstem). Functional outcomes in mobility, self-care, and cognition, as rated on the WeeFIM instrument, were compared by DOL levels. RESULTS: Admission WeeFIM scores were significantly different for the DOL levels with the highest score for frontal and/or temporal lesions and the lowest for lesions including the brainstem or cerebellum (P<.001). However, the deeper the lesion, the greater the functional gains (P=.05), resulting in discharge WeeFIM scores that were not significantly different across DOL levels. Patients with deeper lesions tended to have longer lengths of stay in rehabilitation but were able to "catch up" with patients who had more superficial lesions. CONCLUSIONS: While relatively simple and convenient, the DOL classification system is limited in its usefulness as an early prognostic tool. It may not be possible to predict outcome in the early acute phase in the intensive care unit on the basis of standard brain imaging alone. Patients with deeper lesions may enter rehabilitation at a more impaired level but can make remarkable progress, though it may take longer than for less severely injured individuals.

Adolescent↗