PubMed Health⌕ Search

Biomedical subjects

A M McGrath

Publications and source records attributed to A M McGrath.

12 recordsLinked to original sources
PubMed2001

Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin.

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a key regulator in cholesterol biosynthesis and HMG CoA reductase inhibitors (statins) have become a widely prescribed family of lipid lowering agents. Cholesterol synthesis occurs predominantly in liver which is the target organ of statins. We studied the effects of fluvastatin (Lescol), a member of the statin family, on hepatic protein regulation. Male F344 rats treated with 0.8 mg/kg per day fluvastatin or 24 mg/kg per day fluvastatin for 7 days showed treatment-related changes in 58 liver proteins (P<0.005). Major effects were evident in the cholesterol biosynthesis pathway including the induction of enzymes upstream and downstream of the target enzyme HMG CoA reductase. Treatment also triggered alterations in key enzymes of carbohydrate metabolism and was associated with changes in a heterogeneous set of cellular stress proteins involved in cytoskeletal structure, calcium homeostasis and protease activity. The latter set of protein alterations indicates that hepatotoxicity is associated with high-dose treatment. Based on the results it is suggested that HMG-CoA synthase and isopentenyl-diphosphate delta-isomerase may be explored as alternative drug targets and that the induction levels of these enzymes may serve as a measure of potency of individual statin drugs. It is proposed that efficacy and cellular stress markers discovered in this study may be used in a high throughput screen (HTS) assay format to compare efficiently and accurately the therapeutic windows of different members of the statin family.

Animals↗
PubMed2001

Is home peak expiratory flow monitoring effective for controlling asthma symptoms?

A case in which a home peak expiratory flow (PEF) monitoring device was recommended led us to review the evidence examining this intervention. The clinical question to be answered was: should these devices be consistently recommended to all patients with asthma? A comprehensive search revealed eight randomized controlled trials, one review and one consensus report. Four trials provided all subjects with asthma education and compared patient-specific action plans based on symptoms to those based on PEF readings. Four trials compared usual asthma care to peak flow monitoring (PFM) and varied in both their content and intensity of asthma education. Six out of eight studies showed improvement in some selected markers of asthma morbidity with home PFM-based action plans. Improvements were also observed in patients using a symptom-based action plan. These studies did not demonstrate any obvious advantage of PFM compared with symptom-based monitoring but did suggest that a monitoring plan with predetermined actions based on PEF measurements or symptoms can lead to improved asthma control. Although not specifically studied, PFM may be more appropriate and effective for patients who have difficulty identifying worsening of asthma control through symptom monitoring.

Asthma↗
PubMed2001

Dietary recommendations to prevent and manage chronic pediatric health conditions: adherence, intervention, and future directions.

This review provides a summary of the dietary aspects of pediatric health conditions. Within each condition, dietary recommendations are reviewed, and adherence rates, factors affecting adherence, and known interventions are reported. Findings indicate that knowledge is necessary but not sufficient for dietary change. Interventions specifically targeting diet appear more promising than interventions aimed at global treatment adherence. Behavioral interventions and group treatment modalities also appear promising. Recommendations for future research include a systematic assessment of barriers to dietary adherence across populations, integration of the research on normative development of eating behavior in childhood, and the application of this information to the design and implementation of future treatment.

Behavior Therapy↗
PubMed2000

Proteomics to display lovastatin-induced protein and pathway regulation in rat liver.

Lovastatin is a lipid lowering agent that acts by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key regulatory enzyme in cholesterol biosynthesis. In this study the pattern of gene network regulation induced in hepatic proteins as a response to lovastatin treatment was analyzed by proteomics. In livers of male F344 rats treated with 1.6 mg/kg/day lovastatin or 150 mg/kg/day lovastatin for seven days, 36 proteins were found to be significantly altered (p<0.001) in relation to treatment. The changed proteins were classified according to their cellular function and participation in biochemical pathways. The following observations were made: (i) inhibition of HMG-CoA reductase provoked a regulatory response in the cholesterol synthesis pathway including the induction of cytosolic HMG-CoA synthase and of isopentenyl-diphosphate delta-isomerase, (ii) manipulation of the lipid metabolism triggered alterations in key enzymes of the carbohydrate metabolism, and (iii) lovastatin treatment was associated with signs of toxicity as reflected by changes in a heterogeneous set of cellular stress proteins involved in functions such as cytoskeletal structure, calcium homeostasis, protease inhibition, cell signaling or apoptosis. These results present new insights into liver gene network regulations induced by lovastatin and illustrate a yet unexplored application of proteomics to discover new targets by analysis of existing drugs and the pathways that they regulate.

Amino Acids↗
PubMed1999

A review of the diagnostic methods reported in the Journal of Autism and Developmental Disorders.

This review summarizes subject selection and diagnostic procedures documented in the Journal of Autism and Developmental Disorders. One hundred forty-two empirical articles published between February 1993 and April 1997 were examined. Reviewers independently evaluated articles using a coding instrument developed by the authors. Results indicated that a majority of researchers reported the use of one or more standard diagnostic criteria in classifying their subjects. However, numerous studies did not report the methods by which the diagnostic criteria were quantified or applied. Additionally, there was a lack of clear specification of inclusion and exclusion criteria for comorbid disorders. Improving the documentation of diagnostic practices in research on autism will benefit researchers and practitioners.

Autistic Disorder↗
PubMed1998

Filtration of diaspirin crosslinked hemoglobin into lung and soft tissue lymph.

Diaspirin crosslinked hemoglobin (DCHb) is a new blood substitute manufactured from human blood. To evaluate its microvascular filtration properties, we infused DCLHb into unanesthetized sheep (10%, 20 ml/kg) and measured the flow and composition of lung and soft tissue lymph. For comparison, we also infused human serum albumin (HSA; 10%, 20 ml/kg). DCLHb raised systemic and pulmonary arterial pressures from baseline values of 83 +/- 7 and 13 +/- 2 mm Hg, respectively, to peak values of 113 +/- 9 and 26 +/- 3 mm Hg (p < 0.05 versus baseline). These increases were significantly greater than those associated with HSA, which raised systemic and pulmonary arterial pressures from baseline values of 86 +/- 4 and 13 +/- 2 mm Hg, respectively, to peak values of 97 +/- 3 and 21 +/- 7 mm Hg (p <= 0.05 versus baseline and versus DCLHb). These differences reflect the known pressor properties of DCLHb. Accordingly, DCLHb raised lung and soft tissue lymph flows to peak values of 12.2 +/- 3.8 and 1.6 +/- 0.7 ml/30 min, respectively, while HSA raised lung and soft tissue lymph flows to peak values of 7.5 +/- 4.8 and 4.6 +/- 1.9 ml/30 min, respectively (p <= 0.05 versus DCLHb). The half-times of DCLHb equilibration from plasma into lung and soft tissue lymph of 1. 0 +/- 0.3 and 2.1 +/- 1.1 h, respectively, were significantly faster than HSA equilibration half-times of 3.1 +/- 0.2 and 3.8 +/- 0.9 h. Filtration differences between DCLHb and HSA appear to be due to the pressor properties DCLHb.

Animals↗
PubMed1997

Resuscitation from hemorrhagic shock with diaspirin cross-linked hemoglobin, blood, or hetastarch.

BACKGROUND: An oxygen-transporting hemoglobin solution should be more effective than a nonhemoglobin solution for resuscitation from hemorrhagic shock. A way to evaluate this effectiveness is to determine whether a hemoglobin solution can reverse the base deficit accumulated during hemorrhage at a faster rate than a nonhemoglobin solution. Using this criterion, we compared the resuscitative powers of autologous blood, hetastarch (Het), and diaspirin cross-linked hemoglobin (DCLHb). METHODS: Fifteen sedated, spontaneously breathing sheep (37.5 +/- 10.2 kg) were bled until base deficits fell to -5 to -10 mEq/L, and plasma lactate concentrations rose to 6 to 9 mg/L. The animals were resuscitated with autologous blood (n = 5), Het (n = 5), or DCLHb (n = 5) (3.5-4.0 mL/kg every 15 minutes) until base deficits returned to prehemorrhage baseline. RESULTS: Exsanguination to target base deficits required removal of an average of 41.4 +/- 5.5 mL blood/kg (estimated total blood volume, 80 mL/kg). Resuscitation required 18 +/- 3, 38 +/- 2 (different from blood), and 35 +/- 1 (different from blood) mL/kg of autologous blood, Het and DCLHb, respectively, over periods of 78 +/- 8, 163 +/- 10 (different from blood), and 129 +/- 9 minutes (different from blood and different from Het (p < or = 0.05)). Based on regression analysis, autologous blood, Het, and DCLHb corrected the base deficit at rates of, respectively, 0.074 (different from Het (p < or = 0.05)), 0.016, and 0.056 (different from Het (P < or = 0.05)) mEq/L/min. CONCLUSIONS: Based on the rate of base deficit correction and the volume of solution required, autologous blood was the most effective resuscitation solution. However, DCLHb was more effective than Het. DCLHb may be an attractive alternative to blood for resuscitation from hemorrhagic shock.

Animals↗
PubMed1997

Lung lymph oncotic pressure may not modulate pulmonary vascular filtration in sheep.

We tested the hypothesis that plasma oncotic pressure alone, not the plasma-to-lymph oncotic pressure difference, modulates pulmonary transvascular fluid filtration. To do this we measured lung lymph flow after raising left atrial pressure (by inflating a balloon) in sheep that were receiving a continuous (32 h) infusion of dextran 40. For comparison, we also raised left atrial pressure elevation, plasma oncotic pressures in dextran and control sheep, respectively, were 39.5 +/- 4.5 and 17.7 +/- 2.2 mm Hg; plasma-to-lymph oncotic pressure gradients, respectively, were 4.4 +/- 0.6 and 4.4 +/- 0.6 mm Hg. Left atrial pressure elevation during dextran infusion increased lung lymph flow by a factor of 2.4 +/- 0.4, compared with a factor of 4.2 +/- 2.3 in control sheep. Thus, left atrial pressure elevation increased lymph flow less in dextran-treated animals than in control animals, even though the plasma-to-lymph oncotic pressure gradients were equal. This suggests that plasma oncotic pressure alone may be a more important determinant of pulmonary transvascular fluid filtration than the plasma-to-lymph oncotic pressure difference.

Animals↗
PubMed1997

Molecular distribution of hetastarch in plasma and lung lymph of unanesthetized sheep.

We used high performance size exclusion chromatography (HPSEC) to measure concentrations and molecular masses of hetastarch (Het) in plasma and lung lymph of unanesthetized sheep. Our goal was to assess the osmotic effectiveness of Het in the pulmonary circulation as judged by its exclusion from lung lymph. Sheep (n = 5) received 35 ml/kg of Het (6%) over 90 min. At the end of the infusion, Het concentrations in plasma reached a peak value of 2.9 +/- 0.1% (mean +/- SD). Lymph concentrations reached a peak value of 1.3 +/- 0.3% at 4.5 h. Het molecular masses in plasma averaged 650 +/- 36 kD at 90 min, but ranged from 31 to 2,942 +/- 187 kD. Masses in lung lymph averaged 373 +/- 71 kD, and ranged from 19 +/- 2 to 1,693 +/- 514 kD (p < or = 0.05 vs. plasma). Het contributed 6.7 +/- 1.5 mm Hg to the plasma macromolecular osmotic pressure, and 3.7 +/- 1.8 mm Hg to the lymph osmotic pressure. Despite the fact that Het has the largest molecular mass of any of the current macromolecular plasma volume expanders, we found that it filtered readily into lymph, raising the lymph osmotic pressure. These findings suggest that the rationale for the osmotic performance of such solutions may need to be reconsidered.

Animals↗
PubMed1996

Pulmonary vascular filtration of starch-based macromolecules: effects on lung fluid balance.

BACKGROUND: Pulmonary edema is a complication of critical care fluid management that may be restricted by the use of oncotically effective resuscitation fluids. Potentially beneficial oncotic properties of starch-based plasma volume expanders such as hetastarch (Het), pentafraction (Pen), and Dextran-70 (Dex) may be compromised by their broad range of molecular masses, some of which are small enough to filter from the circulation. Leakage of these molecules into the pulmonary interstitium may limit their oncotic effectiveness and enhance fluid filtration. We measured the filtration of these three resuscitation solutions into lung lymph to evaluate their oncotic contribution to pulmonary edema formation. MATERIALS AND METHODS: Unanesthetized euvolemic adult sheep, prepared with chronic lung lymph fistulae, underwent plasma volume expansion with Het (n = 6), Pen (n = 6), or Dex (n = 6 ) (6%, 35 ml/kg/90 min). Oncotic effectiveness was determined by measuring plasma and lymph oncotic pressures and the oncotic pressures contributed by each starch. Pulmonary hydrostatic pressures and lung lymph flows (Q(L)) were also measured. Results are expressed as means +/- SEM. Comparisons were made by two-factor analysis of variance. RESULTS: Dex contributed 9.0 +/- 0.9 mmHg to the plasma oncotic pressure, significantly more than Het and Pen (5.3 +/- 0.6, 6.5 +/- 0.6 mmHg, respectively). However, Dex filtration also contributed 6.1 +/- 0.5 mmHg to the lymph oncotic pressure, compared to 3.1 +/- 0.3 and 4.7 +/- 0.5 mmHg for Het and Pen, respectively (P < or = 0.05). Dex, Het, and Pen raised Q(L) over baseline by 7.7 +/- 1.5, 4.3 +/- 1.0, and 3.2 +/- 0.7 ml/30 min, respectively (P < or = 0.05). Dex increased Q(L) significantly more than Het or Pen. CONCLUSIONS: Pen and Het demonstrated greater oncotic effectiveness because of restricted plasma-to-lymph macromolecular filtration and limited transvascular fluid flux. By comparison, Dex filtered rapidly and increased transvascular fluid filtration. Pen appears to possess filtration properties that optimize critical care fluid management compared to currently available colloid solutions such as Het and Dex.

Animals↗
PubMed1996

Does plasma protein depletion increase lung liquid conductance?

Lung liquid conductance (Kf) is calculated as the quotient of lung lymph flow divided by net filtration pressure (Pnf), where Pnf is the balance of osmotic and hydrostatic pressures in the lung microcirculation. In protein depletion, lymph flow rises with little change in Pnf, suggesting that calculated Kf also rises. However, several previous reports have concluded that protein depletion causes little change in Kf, leaving open the question of how lung lymph flow can rise in protein depletion with little change in Pnf. To address this, we measured Kf in sheep following two kinds of protein depletion: batch plasmapheresis (BP; n = 5) and thoracic duct drainage (TD; n = 5). Both methods lowered plasma protein concentrations by 30%, and raised lung lymph flows by 55%. Lung microvascular hydrostatic pressures and plasma-to-lymph osmotic pressure gradients both changed by 1 to 2 mm Hg. With BP, calculated Kf rose from 0.26 +/- 0.09 at baseline to 0.50 +/- 0.20 on Day 1, and to 0.39 +/- 0.27 ml/mm Hg/30 min on Day 2 (p < or = 0.05). With TD, calculated Kf rose from 0.28 +/- 0.13 at baseline to 0.43 +/- 0.19 on Day 1, and to 0.43 +/- 0.19 ml/mm Hg/30 min on Day 2 (p < or = 0.05). Calculated Kf rose because filtration increased even though the hydrostatic and osmotic driving forces responsible for filtration changed little. This is puzzling because it suggests that lymph flow rose with little or no change in the forces affecting filtration. Our findings contradict several previous reports that concluded that protein depletion produces little or no change in calculated Kf.

Animals↗