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Biomedical subjects

M Hawkins

Publications and source records attributed to M Hawkins.

At least 55 records · Page 3Linked to original sources
PubMed1997

The tissue concentration of UDP-N-acetylglucosamine modulates the stimulatory effect of insulin on skeletal muscle glucose uptake.

To delineate the biochemical mechanism by which increased availability of GlcN impairs insulin action on skeletal muscle glucose uptake, we replenished the uridine pool during GlcN administration. Co-infusion of uridine with GlcN prevented the GlcN-induced fall in skeletal muscle UDP-glucose levels (24.9 +/- 5. 3 versus 10.1 +/- 2.9 nmol/g; p < 0.01) and further increased the skeletal muscle UDP-GlcNAc levels (198.4 +/- 26.3 versus 96.0 +/- 8. 4 nmol/g; p < 0.01). Greater reductions in the rates of glucose infusion ( approximately 53%), glucose uptake ( approximately 43%), and glycogen synthesis ( approximately 60%) were observed with the addition of uridine. Similarly, the infusion of uridine alone markedly increased the skeletal muscle levels of both UDP-glucose (55.2 +/- 14.2 versus 17.8 +/- 6.1 nmol/g; p < 0.01) and UDP-GlcNAc (86.8 +/- 8.8 versus 35.9 +/- 8.4 nmol/g; p < 0.05) and induced marked insulin resistance. The decrease in insulin action on peripheral glucose uptake was highly correlated with the increase in skeletal muscle UDP-GlcNAc levels. Finally, immunoisolation of GLUT4-containing vesicles revealed that the rate of labeled GlcN incorporation was approximately 100-fold greater following GlcN compared with saline infusions (p < 0.01). We suggest that the marked reduction in insulin action induced by GlcN and uridine is mediated by increased accumulation of muscle UDP-N-acetylhexosamines, perhaps via altered glycosylation of protein(s) in GLUT4-containing vesicles.

Animals↗
PubMed1997

Rapid detection and serotyping of adenovirus by direct immunofluorescence.

Four fluorescent antibody reagents were evaluated for their suitability for the identification of adenovirus isolates by immunofluorescence. The antibodies used in the reagents consist of monoclonal antibodies against adenovirus type 3 (Ad3), Ad4, Ad8, and adenoviruses of subgroup C (Ad1,2,5,6), serotypes known to occur in outbreaks of disease. Most of the monoclonal antibodies employed were reactive against type-specific antigens found on the hexon protein. Reagents employing two noncompeting anti-hexon antibodies were more sensitive than reagents prepared with only one monoclonal antibody, although both types of reagents exhibited a high degree of specificity. Five hundred and seventeen adenovirus isolates (359 of which had previously been typed by other methods) and 46 nonadenovirus isolates were examined with all four type-specific reagents in parallel with an adenovirus group-specific reagent. The results indicate that direct typing of adenovirus isolates is feasible, leading to significant savings in time compared to other typing methods and should contribute to the management of certain adenovirus infections, particularly during outbreaks.

Adenoviridae Infections↗
PubMed1997

Abnormal regulation of HGP by hyperglycemia in mice with a disrupted glucokinase allele.

Glucokinase (GK) catalyzes the phosphorylation of glucose in beta-cells and hepatocytes, and mutations in the GK gene have been implicated in a form of human diabetes. To investigate the relative role of partial deficiencies in the hepatic vs. pancreatic GK activity, we examined insulin secretion, glucose disposal, and hepatic glucose production (HGP) in response to hyperglycemia in transgenic mice 1) with one disrupted GK allele, which manifest decreased GK activity in both liver and beta-cells (GK+/-), and 2) with decreased GK activity selectively in beta-cells (RIP-GKRZ). Liver GK activity was decreased by 35-50% in the GK+/- but not in the RIP-GKRZ compared with wild type (WT) mice. Hyperglycemic clamp studies were performed in conscious mice with or without concomitant pancreatic clamp. In all studies [3-(3)H]glucose was infused to measure the rate of appearance of glucose and HGP during 80 min of euglycemia (Glc approximately 5 mM) followed by 90 min of hyperglycemia (Glc approximately 17 mM). During hyperglycemic clamp studies, steady-state plasma insulin concentration, rate of glucose infusion, and rate of glucose disappearance (Rd) were decreased in both GK+/- and RIP-GKRZ compared with WT mice. However, whereas the basal HGP (at euglycemia) averaged approximately 22 mg x kg(-1) x min(-1) in all groups, during hyperglycemia HGP was suppressed by only 48% in GK+/- compared with approximately 70 and 65% in the WT and RIP-GKRZ mice, respectively. During the pancreatic clamp studies, the ability of hyperglycemia per se to increase Rd was similar in all groups. However, hyperglycemia inhibited HGP by only 12% in GK+/-, vs. 42 and 45%, respectively, in the WT and RIP-GKRZ mice. We conclude that, although impaired glucose-induced insulin secretion is common to both models of decreased pancreatic GK activity, the marked impairment in the ability of hyperglycemia to inhibit HGP is due to the specific decrease in hepatic GK activity.

Alleles↗
PubMed1997

Induction of hepatic glucose-6-phosphatase gene expression by lipid infusion.

The distal enzymatic step in the process of glucose output is catalyzed by the glucose-6-phosphatase (Glc-6-Pase) complex. The recently cloned catalytic unit of this complex has been shown to be regulated by insulin, dexamethasone, cAMP, and glucose. Using a combination of intralipid and/or nicotinic acid infusions and a pancreatic clamp technique, we maintained plasma free fatty acids (FFAs) at three different levels (0.26 +/- 0.07, 0.56 +/- 0.09, and 1.59 +/- 0.12 mmol/l) in the presence of well-controlled hormonal and metabolic conditions. An increase in the plasma FFA concentration within the physiological range caused a rapid, greater than threefold increase in the mRNA and protein levels of the catalytic subunit of Glc-6-Pase in the liver. These data indicate that the in vivo gene expression of Glc-6-Pase in the liver is regulated by circulating lipids independent of insulin and thus that prolonged hyperlipidemia may contribute to the increased production of glucose via increased expression of this protein.

Animals↗
PubMed1997

The impact of nonacademic variables on performance at two medical schools.

Recent research shows that nonacademic variables must be taken into account when analyzing the indicators of medical student success. However, most previous studies have been limited to a single institution or population. This study investigated the relationship between nonacademic variables and performance at two very different medical schools. The Noncognitive Questionnaire was administered to 104 students at School A (predominantly white and historically oriented toward women) and 102 at School B (predominantly black). Correlation and multiple regression analyses were conducted to determine the relationship among nonacademic variables, undergraduate academic variables (Medical College Admission Test, undergraduate grade point average, and college quality), basic science grades, and US Medical Licensure Exam Step I (USMLE 1) scores. At School A, leadership/decisiveness, expected difficulty, and motivation predicted higher USMLE I scores and higher basic science grades each semester. At School B, expected difficulty was correlated with higher first semester grades only. For School A women, initiative/commitment was positively associated with both higher grades and higher USMLE scores. For black students of School B, expected difficulty was positively associated with higher grades. Identifying school-specific nonacademic variables of performance is critical to developing improved student support services.

Achievement↗
PubMed1997

Children's exposure to traffic and risk of pedestrian injury in an urban setting.

Pedestrian injuries to children represent a major urban health problem in the United States. Thousands of children each year are struck by moving motor vehicles; such collisions result in numerous hospitalizations and deaths. At particular risk are young school-age children between the ages of 5 and 9 years. Using a survey methodology, we collected data regarding the method by which children in an urban setting travel to and from school, in addition to the number of streets they cross in a typical school day. This information was compared with data from police records on street intersection locations of pedestrian collisions. There is a wide variation in the number of streets children cross in 1 day, calculated as the number of streets crossed in the entire day, not only those crossed to and from school. Children whose parents own a car and home cross an average of 3.7 streets per day, whereas children whose parents do not own both a car and home cross an average of 5.4 streets per day; this difference is highly significant (P < 0.0001). The largest differences in traffic exposure are between families reporting car- and-home ownership (x = 3.70 streets) versus those who do not own both a car and home (x = 5.39 streets) (Mann-Whitney = -5.5, P < 0.0001). There is a significant correlation between the proportion of children driven home from school and the rate of pedestrian injury in different regions of Baltimore. In areas where children are driven home, rates of pedestrian injury are significantly lower, whereas in areas where children walk home, rates of pedestrian injury are high (r = -0.79, P < 0.01). This study underscores the importance of adapting the child's environment to prevent injury. Interventions that alter the nature of the hazard are indicated. Changing the environment may ultimately prove more useful than attempting to change children's behavior.

Accidents, Traffic↗
PubMed1996

Breathlessness and exercise capacity in heart failure: the role of bronchial obstruction and responsiveness.

The cause of the breathlessness and reduced exercise capacity that occur in patients with chronic heart failure remains obscure. We examined the hypothesis that airway obstruction and bronchial hyper-responsiveness, which are recognised features of chronic heart failure, might contribute to the breathlessness and reduced exercise capacity in this condition. We studied 37 patients (7 female) with chronic heart failure, of mean age 61 years. Each patient underwent: (i) lung function testing with spirometry and expiratory flow volume loops. (ii) Measurement of bronchial responsiveness to methacholine. (iii) Symptom-limited treadmill exercise capacity using both incremental and fixed workload protocols, with measurement of Borg scores for breathlessness. Lung function was not significantly related to either exercise time, or Borg symptom scores in either exercise protocol. Bronchial hyper-responsiveness to methacholine was demonstrated in 12 patients. Exercise time did not correlate with the degree of bronchial hyper-responsiveness in these 12 patients. Group mean exercise time and Borg scores were not significantly different in these 12 patients when compared to the 25 patients in whom bronchial hyper-responsiveness was not found. We conclude that airway obstruction and bronchial hyper-responsiveness are not likely to be important determinants of reduced exercise capacity and breathlessness in chronic heart failure.

Airway Obstruction↗
PubMed1996

Immunomodulation following chemotherapy.

In the last decade, immunomodulation has emerged as a mode of therapy capable of mediating the regression of cancer in some patients. This article reviews our experience with immunomodulation following transplant and non-transplant chemotherapy. We used interferon and cyclosporine A following conventional chemotherapy in a non-transplant setting for a B16 melanoma in a murine model. This combination generated cells with MHC-unrestricted cytotoxicity. We have also used immunotherapy in the transplant setting with IL-2 activated PBSC in patients with breast cancer. Of the 28 patients treated, 20 developed GVHD and the average time to reconstitution was 12 days (comparable to a control group). This article also raises the possibility of extending immunomodulation to breast cancer patients in the nontransplant setting to induce an antitumor immune response following cytoreductive chemotherapy.

Animals↗
PubMed1996

Generation and analysis of 280,000 human expressed sequence tags.

We report the generation of 319,311 single-pass sequencing reactions (known as expressed sequence tags, or ESTs) obtained from the 5' and 3' ends of 194,031 human cDNA clones. Our goal has been to obtain tag sequences from many different genes and to deposit these in the publicly accessible Data Base for Expressed Sequence Tags. Highly efficient automatic screening of the data allows deposition of the annotated sequences without delay. Sequences have been generated from 26 oligo(dT) primed directionally cloned libraries, of which 18 were normalized. The libraries were constructed using mRNA isolated from 17 different tissues representing three developmental states. Comparisons of a subset of our data with nonredundant human mRNA and protein data bases show that the ESTs represent many known sequences and contain many that are novel. Analysis of protein families using Hidden Markov Models confirms this observation and supports the contention that although normalization reduces significantly the relative abundance of redundant cDNA clones, it does not result in the complete removal of members of gene families.

Adult↗
PubMed1996

Glucosamine-induced inhibition of liver glucokinase impairs the ability of hyperglycemia to suppress endogenous glucose production.

Although the kinetic characteristics of hepatic glucokinase (GK) suggest its potential role as the hepatic "glucose sensor," its impact on the regulation of in vivo hepatic glucose production (HGP) is still controversial. Since decreased GK activity has been linked to experimental and human diabetes, we examined whether a moderate and transient inhibition of GK activity diminishes the ability of hyperglycemia to suppress HGP. We first determined the concentration of the competitive inhibitor, glucosamine (GlcN), which decreases hepatic GK activity by approximately 60% in vitro. GlcN was then infused into conscious rats to achieve a similar inhibition of the in vivo GK activity (plasma GlcN levels = approximately 2 mmol/l; rats infused with saline served as control, n = 20). To maintain equal plasma insulin and glucagon concentrations throughout the studies, somatostatin and insulin (basal replacement) were infused for 4 h. [3-(3H)]-glucose and [U-(14C)]-lactate were infused to measure HGP, gluconeogenesis, and glucose cycling (GC) during 2 h of euglycemia (glucose approximately 8 mmol/l) followed by 2 h of hyperglycemia (glucose approximately 18 mmol/l). Our results support the notion that hepatic GK activity is indeed decreased by GlcN in vivo. In fact, in response to hyperglycemia the "direct" pathway of hepatic glucose-6-phosphate (G-6-P) formation was approximately 40% lower with GlcN compared with saline infusion (37 +/- 3 vs. 63 +/- 3%; P < 0.001). Furthermore, while hyperglycemia stimulated GC by approximately 2.5-fold during saline infusion (from 3.0 +/- 0.6 to 7.7 +/- 1.4 mg.kg-1.min-1, P < 0.001, euglycemia vs. hyperglycemia), this increase was blunted in the presence of GlcN (4.6 +/- 0.6 mg.kg-1.min-1, P = NS). Finally, in the presence of GlcN, the hepatic concentration of G-6-P was decreased by approximately 40% compared with saline (234 +/- 38 and 390 +/- 24 nmol/g, P < 0.01). During the euglycemic studies, HGP was similar (12.6 +/- 0.6 and 11.3 +/- 0.2 mg .kg-1.min-1 with GlcN or saline infusion, respectively). However, while hyperglycemia per se suppressed HGP by approximately 65%, HGP was inhibited by approximately 38% and it was approximately twofold higher than in the saline-infused rats (7.8 +/- 0.8 and 4.0 +/- 0.3 mg.kg-1.min-1, P < 0.01) in the presence of GlcN-induced inhibition of hepatic GK. This increase in HGP was largely accounted for by the decreased inhibition of hepatic net glycogenolysis by hyperglycemia (3.3 +/- 0.8 and 1.1 +/- 0.3 mg.kg-1.min-1 with GlcN or saline infusion, respectively, P < 0.01). We conclude that intact GK activity is required for the normal suppression of HGP by hyperglycemia and its impairment may contribute to increased HGP in experimental and human diabetes.

Animals↗
PubMed1996

Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal.

Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (Rd), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 microg x kg(-1) x min(-1)) and insulin (3 and 18 mU mg x kg(-1) x min(-1)) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to approximately 2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80-150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU x kg(-1) x min(-1), plasma insulin approximately 50 microU/ml), GlcN infusion caused comparable decreases in Rd (15.7 +/- 1.0 [5-7 h] vs. 21.7 +/- 2.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.01) and glycogen synthesis (5.4 +/- 0.5 [5-7 h] vs. 10.4 +/- 1.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). Furthermore, GlcN markedly decreased Rd by 7.8 +/- 1.2 mg x kg(-1) x min(-1) (18.7 +/- 0.7 [5-7 h] vs. 26.5 +/- 1.3 [0-2 h] mg x kg(-1) x min(-1); P < 0.001 vs. control) during IGF-1 (5 microg x kg(-1) x min(-1)) clamp studies. This decline was associated with a 26% decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 +/- 45 vs. 386 +/- 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 +/- 0.5 [5-7 h] vs. 13.9 +/- 0.9 [0-2 h] mg x kg(-1) x min(-1); P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in Rd) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU x kg(-1) x min(-1)) were infused for 7 h during euglycemic clamps, and IGF-1 (15 microg x kg(-1) x min(-1)) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on Rd (39.4 +/- 3.2 [4-5 h] vs. 49.8 +/- 3.6 [1-2 h] mg x kg(-1) x min(-1); P < 0.05), which the addition of IGF-1 failed to improve (35.9 +/- 2.3 [6-7 h] vs. 39.4 +/- 3.2 [4-5 h] mg x kg(-1) x min(-1); P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.

Animals↗
PubMed1995

African-American and white patients admitted to the intensive care unit: is there a difference in therapy and outcome?

OBJECTIVE: To evaluate variations in patient characteristics, hospital mortality, intensive care unit (ICU) length of stay, and treatment among African-American and white patients admitted to the ICU. DESIGN: Prospective, inception cohort study. SETTING: Forty-two ICUs at 40 U.S. hospitals, including 26 hospitals that were randomly selected and 14 volunteer institutions, primarily large university or tertiary care centers. PATIENTS: A consecutive sample of 17,440 ICU admissions. MEASUREMENTS AND MAIN RESULTS: Selected demographic, physiologic, and treatment information for an average of 415 admissions at each ICU, and payor information at 36 of 40 hospitals. Outcomes were compared using the ratio of observed to risk-adjusted predicted hospital mortality rate, ICU length of stay, and resource use during ICU day 1 and the first seven ICU days. Compared with 14,006 white patients admitted to the ICU, 2,450 African-American patient admissions were significantly (p < .0001) younger, had a higher mean severity of disease, and a greater proportion of nonoperative and emergency department admissions. African-Americans had fewer life-threatening Acute Physiology and Chronic Health Evaluation III (APACHE III) comorbidities, but a higher prevalence of severe compromise in activities of daily living, diabetes mellitus, chronic renal disease, and intravenous drug abuse. There was no significant racial difference in risk-adjusted hospital mortality rate. For African-Americans, adjusted ICU length of stay was significantly (p < .0003) shorter, and the first 7 days of resource use was significantly (p < .0004) lower, but the differences were small (3% to 4%). CONCLUSIONS: After adjusting for variations in patient characteristics at ICU admission, race has no significant effect on hospital survival. The small but statistically significant differences in adjusted ICU length of stay and resource use could indicate undertreatment for African-Americans or overtreatment for whites.

APACHE↗
PubMed1995

Whole systems shared governance: a model for the integrated health system.

The healthcare system is under renovation and renewal. In the process, roles and structures are shifting to support a subscriber-based continuum of care. Alliances and partnerships are emerging as the models of integration for the future. But how do we structure to support these emerging integrated partnerships? As the nurse executive expands the role and assumes increasing responsibility for creating new frameworks for care, a structure that sustains the point-of-care innovations and interdisciplinary relationships must be built. Whole systems models of organization, such as shared governance, are expanding as demand grows for a sustainable structure for horizontal and partnered systems of healthcare delivery. The executive will have to apply these newer frameworks to the delivery of care to provide adequate support for the clinically integrated environment.

California↗
PubMed1995

Respiratory muscle strength in chronic heart failure.

BACKGROUND: Several studies have suggested that the respiratory muscles are weak in patients with heart failure, but the aetiology and clinical relevance of this weakness are unclear. In order to see if respiratory muscle weakness in this context is part of a more generalised myopathic process, respiratory and limb muscle strength were compared in patients with heart failure. The relation between respiratory muscle strength, breathlessness on exercise, and exercise capacity was also examined. METHODS: Twenty patients (three women) with New York Heart Association (NYHA) class II-IV heart failure of mean age 63 years were studied. Respiratory muscle strength was assessed using maximum inspiratory and expiratory mouth pressures (MIP and MEP) and transdiaphragmatic pressure during sniffs (sniff PDI). These parameters were compared with cardiac output (indirect Fick) and with limb muscle strength as assessed by grip strength. The patients also performed two exercise tests during which they rated their breathlessness on a Borg scale. RESULTS: Mean (SD) cardiac index was 2.2 (0.4) l/min/m2. MIP and MEP were 66 (27) and 99 (29) cm H2O respectively. Sniff PDI was 103 (21) cm H2O and was positively correlated with grip strength and cardiac output (Spearman rank correlation coefficients 0.527 and 0.451, respectively). None of the indices of respiratory muscle strength were related to exercise time or breathlessness during exercise. CONCLUSIONS: The respiratory muscles are weak in patients with heart failure. This weakness reflects a more generalised myopathic process, possibly related to reduced cardiac output. However, respiratory muscle weakness does not appear to be an important factor in the aetiology of breathlessness on exercise.

Aged↗