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Biomedical subjects

D Kelley

Publications and source records attributed to D Kelley.

At least 19 recordsLinked to original sources
PubMed2001

Karyometry of secretory cell nuclei in high-grade PIN lesions.

BACKGROUND: The goal of this study was a karyometric characterization of secretory cell nuclei in high-grade prostatic intraepithelial neoplasia (PIN) lesions. Specifically, the hypothesis is tested that distinctly different subgroups of nuclei exist in these lesions. METHODS: High-resolution images of 1,713 nuclei from high-grade PIN lesions were recorded. Karyometric features were computed. Discriminant function scores against normal reference nuclei, and nuclear abnormality values were derived. Data sets were processed by a nonsupervised learning algorithm to establish the presence of subgroups of nuclei with statistically different nuclear chromatin distributions. RESULTS: Three sets of nuclei were formed, facing an intact basal cell layer, a near vanishing basal cell layer, and a gap in the basal cell layer. For each set, a nonsupervised learning algorithm formed three statistically different subgroups of approximately equal sizes. Each subgroup is found in every one of the three sampling locations. The total optical density distribution of nuclei in two subgroups suggests an aneuploid distribution, the third subgroup has a near diploid distribution. CONCLUSIONS: Secretory cell nuclei in high-grade PIN lesions are a heterogeneous population, forming statistically different subgroups. Studies aimed at characterizing the progression of such lesions should consider the inhomogeneous nature of these nuclei.

Algorithms↗
PubMed2001

The acute versus the chronic response to exercise.

PURPOSE: There is strong and consistent evidence that a single exercise session can acutely reduce triglycerides and increase high-density lipoprotein (HDL) cholesterol (HDL-C), reduce blood pressure, and improve insulin sensitivity and glucose homeostasis. Such observations suggest that at least some of the effects on atherosclerotic cardiovascular disease (ASCVD) risk factors attributed to exercise training may be the result of recent exercise. RESULTS: These acute and chronic exercise effects cannot be considered in isolation. Exercise training increases the capacity for exercise, thereby permitting more vigorous and/or more prolonged individual exercise sessions and a more significant acute effect. The intensity, duration, and energy expenditure required to produce these acute exercise effects are not clearly defined. The acute effect of exercise on triglycerides and HDL-C appears to increase with overall energy expenditure possibly because the effect maybe mediated by reductions in intramuscular triglycerides. Prolonged exercise appears necessary for an acute effect of exercise on low-density lipoprotein (LDL) cholesterol (LDL-C) levels. The acute effect of exercise on blood pressure is a low threshold phenomenon and has been observed after energy expenditures requiring only 40% maximal capacity. The acute effect of exercise on glucose metabolism appears to require exercise near 70% maximal, but this issue has not been carefully examined. CONCLUSIONS: Exercise has definite acute effects on blood lipids, blood pressure, and glucose homeostasis. Exercise also has acute effects on other factors related to atherosclerosis such as immunological function, vascular reactivity, and hemostasis. Considerable additional research is required to define the threshold of exercise required to produce these putatively beneficial effects.

Adult↗
PubMed2000

Practice-related functional activation changes in a working memory task.

The effects of practice on the functional anatomy of a visuospatial working memory (VSWM) task were studied using functional Magnetic Resonance Imaging (fMRI). Functional imaging was conducted as subjects completed a moderate (Experiment 1) or extensive (Experiment 2) amount of practice on a delayed-match-to-sample task. While improvement in task performance was seen with practice, the task's dependence upon VSWM did not change. Activations in frontal (inferior, middle, and precentral gyri and superior frontal sulcus), parietal (intra-parietal sulcus, inferior parietal lobule, and precuneus) and cingulate (anterior and posterior) regions were observed as were bilateral insular and occipital activations. With the exception of the posterior cingulate, practice produced activation decreases in these regions, thus providing little evidence for a re-organization of the functional neuroanatomy. Fewer regions passing statistical criteria were observed at the end of practice relative to early in practice. Regions that were lost were mostly posterior (occipital and precuneus) but also included the left middle frontal gyrus, left precentral gyrus, and right insula suggesting that a more precise VSWM functional map can be observed once processes specific to encountering a novel task are removed. Little further activation changes were observed after extensive practice. These results suggest, minimally, that practice effects should be considered so as to avoid incorrectly attributing functional activation to a cognitive process of interest. Further, these data show that the dynamics of functional change can be tracked while a task is being learned and as an important cognitive process becomes more skilled.

Adult↗
PubMed2000

Magnetic resonance imaging in human body composition research. From quantitative to qualitative tissue measurement.

Incremental improvements in our knowledge of human body composition are abetted by advances in research technology. Indeed, magnetic resonance imaging (MRI) represents a technological advance that has profoundly influenced body composition research. Routine applications of MRI include the measurement of whole-body and regional adipose tissue distribution, quantification of lean tissue and its principal constituent skeletal muscle, and the measurement of visceral adipose tissue. MRI is now the method of choice for calibration of field methods designed to measure body fat and skeletal muscle in vivo. Common to these applications is the measurement of tissue quantity. More recently proton (1H) and sodium (23Na) MRI protocols have been developed that measure the quality (lipid and sodium concentration) of skeletal muscle tissue. These unique applications of MRI represent a major advance in the study of altered muscle composition in vivo, with numerous applications in both applied and clinical medicine. In this review we provide a brief overview of routine applications of MRI in body composition research, followed by a focus on more recent applications of MRI that employ fast-imaging sequences for qualitative measurement of human skeletal muscle.

Adipose Tissue↗
PubMed2000

Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli.

OBJECTIVE: Cocaine-related cues have been hypothesized to perpetuate drug abuse by inducing a craving response that prompts drug-seeking behavior. However, the mechanisms, underlying neuroanatomy, and specificity of this neuroanatomy are not yet fully understood. METHOD: To address these issues, experienced cocaine users (N=17) and comparison subjects (N=14) underwent functional magnetic resonance imaging while viewing three separate films that portrayed 1 ) individuals smoking crack cocaine, 2) outdoor nature scenes, and 3) explicit sexual content. Candidate craving sites were identified as those that showed significant activation in the cocaine users when viewing the cocaine film. These sites were then required to show significantly greater activation when contrasted with comparison subjects viewing the cocaine film (population specificity) and cocaine users viewing the nature film (content specificity). RESULTS: Brain regions that satisfied these criteria were largely left lateralized and included the frontal lobe (medial and middle frontal gyri, bilateral inferior frontal gyrus), parietal lobe (bilateral inferior parietal lobule), insula, and limbic lobe (anterior and posterior cingulate gyrus). Of the 13 regions identified as putative craving sites, just three (anterior cingulate, right inferior parietal lobule, and the caudate/lateral dorsal nucleus) showed significantly greater activation during the cocaine film than during the sex film in the cocaine users, which suggests that cocaine cues activated similar neuroanatomical substrates as naturally evocative stimuli in the cocaine users. Finally, contrary to the effects of the cocaine film, cocaine users showed a smaller response than the comparison subjects to the sex film. CONCLUSIONS: These data suggest that cocaine craving is not associated with a dedicated and unique neuroanatomical circuitry; instead, unique to the cocaine user is the ability of learned, drug-related cues to produce brain activation comparable to that seen with nondrug evocative stimuli in healthy comparison subjects.

Adult↗
PubMed1998

Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Troglitazone is a new insulin-sensitizing agent used to treat type 2 diabetes mellitus. The mechanism by which troglitazone exerts its effect on systemic glucose metabolism is unknown. OBJECTIVE: To determine the effects of 6 months of troglitazone monotherapy on glucose metabolism in patients with type 2 diabetes mellitus. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Six general clinical research centers at university hospitals. PATIENTS: 93 patients (mean age, 52 years) with type 2 diabetes mellitus (mean fasting plasma glucose level, 11.2 mmol/L) who were being treated with diet alone or who had discontinued oral antidiabetic medication therapy. INTERVENTION: Patients were randomly assigned to one of five treatment groups (100, 200, 400, or 600 mg of troglitazone daily or placebo) and had metabolic assessment before and after 6 months of treatment. MEASUREMENTS: Plasma glucose and insulin profiles during a meal tolerance test; basal hepatic glucose production and insulin-stimulated glucose disposal rate during a hyperinsulinemic-euglycemic clamp procedure. RESULTS: Troglitazone at 400 and 600 mg/d decreased both fasting (P < 0.001) and postprandial (P = 0.016) plasma glucose levels by approximately 20%. All four troglitazone dosages also decreased fasting (P = 0.012) and postprandial (P < 0.001) triglyceride levels; 600 mg of the drug per day decreased fasting free fatty acid levels (P = 0.018). Plasma insulin levels decreased in the 200-, 400-, and 600-mg/d groups (P < 0.001), and C-peptide levels decreased in all five study groups (P < 0.001). Basal hepatic glucose production was suppressed in the 600-mg/d group compared with the placebo group (P = 0.02). Troglitazone at 400 and 600 mg/d increased glucose disposal rate by approximately 45% above pretreatment levels (P = 0.003). Stepwise regression analysis showed that troglitazone therapy was the strongest predictor of a decrease in fasting (P < 0.001) or postprandial (P = 0.01) glucose levels. Fasting C-peptide level was the next strongest predictor (higher C-peptide level equaled greater glucose-lowering effect). CONCLUSION: Troglitazone monotherapy decreased fasting and postprandial glucose levels in patients with type 2 diabetes, primarily by augmenting insulin-mediated glucose disposal.

Adult↗
PubMed1998

Synergistic effects of 13-cis retinoic acid and arachidonic acid cascade inhibitors on growth of head and neck squamous cell carcinoma in vitro.

Products of arachidonic acid metabolism can influence normal and malignant cell growth. In vivo, inhibitors of arachidonic acid metabolism have been associated with inhibition of tumor growth, including head and neck squamous cell carcinoma (HNSCC). This has not been evaluated extensively in vitro in an HNSCC model. Therefore we investigated the effects of several arachidonic acid cascade inhibitors (AACIs) (indomethacin, curcumin, phenidone, nordihydroguaiaretic acid, 5,8,11,14-eicosatetraynoic acid, and 13-cisretinoic acid) on the growth of two HNSCC cell lines (MDA 886Ln and 1483). We found that AACIs caused dose-dependent growth inhibition of both cell lines. In an effort to inhibit HNSCC cell growth at lower concentrations of these drugs, we evaluated the effects of a variety of AACIs in combination with 13-cis retinoic acid. We observed synergistic growth inhibition when the drugs were used in all combinations, with the exception of indomethacin. These results suggest that AACIs may have some utility in the direct treatment of HNSCC, and a strategy combining 13-cis retinoic acid with other AACIs may prove to be even more effective.

Arachidonic Acid↗
PubMed1998

Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study.

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

Adult↗
PubMed1997

Radar detection of the nucleus and coma of comet hyakutake

Radar observations of comet Hyakutake (C/1996 B2) made at the Goldstone Deep Space Communications Complex in California have detected echoes from the nucleus and from large grains in the inner coma. The nucleus of this bright comet was estimated to be only 2 to 3 kilometers in diameter. Models of the coma echo indicate backscatter from porous, centimeter-size grains ejected anisotropically at velocities of tens of meters per second. The radar observations suggest that a comet's activity may be a poor indicator of its size and provide evidence that large grains constitute an important component of the mass loss from a typical active comet.

Journal Article↗
PubMed1995

Androgen biosynthesis and secretion in developing Xenopus laevis.

In the frog, Xenopus laevis, castration or anti-androgen treatment during late tadpole or early juvenile stages blocks masculinization of vocal neuroeffectors in males while exogenous androgen or a testicular transplant masculinizes vocal neuroeffectors in females. To elucidate the relation between androgen secretion and the process of masculinization, we measured androgens by radioimmunoassay in adults, juveniles, and tadpoles. In adult females, values for both testosterone (T) and dihydrotestosterone (DHT) were essentially identical during the winter and the summer while in males, summer values for both androgens were 7 to 8x winter values. For DHT, circulating values in males significantly exceeded those in females in both winter and summer while for T, values differed significantly only in summer. Sex differences in circulating androgen arise at late juvenile stages (PM4 and PM5); T values are higher in males than in females and higher, for both sexes, in winter than in summer. During early juvenile stages (PM1-PM3), there were no seasonal or sex differences in circulating androgens. While androgens were detected in liver during late tadpole stages (stage 56-66), no sex differences were apparent. Androgens can be detected in tadpole tissues, as early as tadpole stage 47. delta 5-3 beta-Hydroxysteroid dehydrogenase (HSD) histochemistry indicates that tadpole gonads and interrenals (and, to a much lesser extent, kidneys) are the only tissues capable of steroid biosynthesis. Interrenal HSD activity was present throughout tadpole development; in gonads, activity began before sexual differentiation. Thin-layer chromatographic separation of steroid metabolites following in vitro incubation with radioactive precursors indicated that the interrenals were more active than the gonads in tadpoles but not in juveniles. Thus, interrenals and gonads of developing X. laevis can synthesize delta 4 steroids (which include androgens) and, from early tadpole stages, are capable of metabolizing pregnenolone and testosterone, early and late compounds in the steroid synthetic pathway, respectively. The absence of dramatic sex differences in T or DHT levels during late tadpole and early juvenile stages suggests that while necessary, androgen secretion is not sufficient for masculinization of vocal neuroeffectors.

Aging↗
PubMed1994

Tumor necrosis factor-alpha plays a central role in interleukin-2-induced pulmonary vascular leak and lymphocyte accumulation.

Administration of interleukin-2 (IL-2) leads to pulmonary vascular leak. This form of pulmonary edema has previously been postulated to be due to the in vivo induction of tumor necrosis factor-alpha (TNF-alpha). To determine whether TNF-alpha plays a role in IL-2-induced pulmonary vascular leak, we performed in situ hybridization of lung sections and reverse transcriptase-polymerase chain reaction of bronchoalveolar lavage macrophages from IL-2-challenged mice. The results confirm an in situ upregulation of TNF-alpha mRNA expression in the lungs associated with vascular leak. In addition, a significant increase in TNF-alpha protein production was found in the lung following IL-2 administration, as measured by TNF-alpha-specific ELISA of lung supernatants (P = 0.028). Intravenous administration of a soluble TNF receptor significantly diminished IL-2-induced pulmonary vascular leak (P = 0.006). These findings confirm a central role for TNF-alpha in mediating the pulmonary vascular leak associated with IL-2 toxicity.

Animals↗
PubMed1994

Impaired postprandial glucose utilization in non-insulin-dependent diabetes mellitus.

The importance of impaired glucose utilization in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) is controversial. Three methods were used to assess glucose utilization following ingestion of a mixed meal in 18 NIDDM and 12 nondiabetic subjects. Dual glucose isotopes were used to determine first-pass splanchnic glucose uptake, suppression of endogenous glucose production, and systemic glucose utilization. Leg balance was used to evaluate skeletal muscle glucose metabolism, and systemic and limb indirect calorimetry were used to assess glucose and lipid oxidation. NIDDM subjects had marked postprandial hyperglycemia as compared with nondiabetics (15.35 +/- 0.72 v 5.83 +/- 0.28 mmol, P < .001), accompanied by lower postprandial insulin (179 +/- 25 v 253 +/- 46 pmol, P < .01) and elevated plasma free fatty acids ([FFA] 569 +/- 34 v 314 +/- 20 mumol/L, P < .001). Cumulative postprandial glucose appearance was nearly twofold greater in NIDDM (82.2 +/- 4.7 v 48.7 +/- 4.9 g.5h, P < .001) due to increased endogenous glucose production (56.4 +/- 4.8 v 24.5 +/- 1.9 g, P < .001), whereas first-pass splanchnic uptake of ingested glucose was normal in NIDDM. Cumulative postprandial glucose utilization in NIDDM, after correction for urinary glucose, was unchanged from postabsorptive rates, a pattern also found for postprandial glucose oxidation. Cumulative leg glucose uptake was somewhat less in NIDDM subjects (123 +/- 18 v 173 +/- 14 mumol/100 mL leg tissue.5 h, P = .06), whereas lactate and alanine net release across the leg were nevertheless twofold greater in NIDDM (P = .04) and accounted for nearly half of the leg glucose metabolism in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

An androgen receptor mRNA isoform associated with hormone-induced cell proliferation.

The larynx of male Xenopus laevis undergoes an androgen-driven developmental transformation that enables the adult to produce his complex mate attraction song. During the early postmetamorphic period, androgen directs proliferation and differentiation of laryngeal muscle and cartilage. To explore the cellular and molecular basis of androgen control, we have cloned an androgen receptor cDNA from juvenile larynx. Here we identify two androgen receptor mRNA isoforms, alpha and beta, differing within the A/B, or hypervariable, domain. Northern blot analyses reveal that the beta isoform is transiently expressed during early juvenile stages, whereas the alpha transcript is expressed throughout postmetamorphic life. Using in situ hybridization and [3H]thymidine autoradiography, we examined the expression of androgen receptor mRNA isoforms during androgen-evoked cell proliferation and differentiation. The alpha and beta transcripts are coexpressed in proliferating tissues of the juvenile larynx; in postmitotic differentiated tissues, only the alpha transcript is expressed. Because androgen receptor beta mRNA is specifically expressed during hormone-evoked cell proliferation, we propose that this developmentally regulated mRNA isoform is required for the masculine program of cell addition within the developing vocal organ.

Aging↗
PubMed1993

Interleukin-2-responsive wound-infiltrating lymphocytes in surgical adjuvant cancer immunotherapy.

Wound-infiltrating lymphocytes (WIL) were assessed in murine models of localized sarcoma and carcinoma to evaluate the role of interleukin-2 (IL-2)-responsive lymphocytes in adjuvant immunotherapy. Following tumor resection, IL-2 or diluent was injected at the surgical site for 6 days. Surgical site tissues were harvested and digested in a triple enzyme mixture, and single cell suspensions were prepared. Thy 1.2+ lymphocytes were isolated by incubating cells with monoclonal anti-Thy 1.2 antibody-coated magnetic beads. Lymphocyte-bead complexes were extracted with a magnet and cultured in medium containing IL-2 (100 units/ml) for 1-3 weeks. Perioperative IL-2 immunotherapy led to a three- to four-fold increase in WIL yield. WIL from IL-2-treated mice also demonstrated enhanced cytolysis of the autologous tumor and bound to activated endothelial cells with greater avidity than did the controls. We conclude that perioperative IL-2 therapy augments the yield, as well as the cytolytic and adhesive properties, of wound-infiltrating lymphocytes.

Animals↗