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Biomedical subjects

W Shaw

Publications and source records attributed to W Shaw.

At least 19 recordsLinked to original sources
PubMed2001

The pharmacokinetics of enalapril in children and infants with hypertension.

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First-dose and steady-state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first-dose and steady-state AUCs, the accumulation of enalaprilat in children ranged from 1.13- to 1.45-fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half-life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

Adolescent↗
PubMed2000

Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion.

BACKGROUND: Renal complications of long-term, poorly controlled type 2 diabetes mellitus include glomerulosclerosis and interstitial fibrosis. The onset and progression of these complications are influenced by underlying pathophysiologies such as hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Troglitazone, a thiazolidinedione, has been shown to ameliorate these metabolic defects. However, it was not known whether therapeutic intervention with troglitazone would prevent the onset and progression of glomerulosclerosis. METHODS: Sixty male ZDF/Gmitrade mark rats and 30 age-matched Zucker lean rats were in the study. The ZDF/Gmitrade mark rats were divided into two groups, one in which blood glucose levels were uncontrolled (30 animals) and another (30) in which blood glucose was controlled via dietary administration of troglitazone. Ten animals from each group were sacrificed at one, three, and six months into the study. The kidneys were harvested and processed for immunostaining with BM-CSPG, a marker for mesangial matrix. Images of 200 glomeruli per animal were captured using digital imaging microscopy, and the index of mesangial expansion (total area mesangium/total area of tuft) per glomerular section was measured. RESULTS: The administration of troglitazone ameliorated the metabolic defects associated with type 2 diabetes mellitus. Moreover, the glomeruli from tissue sections of animals given troglitazone showed no mesangial expansion when compared with normoglycemic control animals, whereas the uncontrolled diabetic animals showed significant mesangial expansion at all time intervals. CONCLUSIONS: Therapeutic intervention with the thiazolidinedione troglitazone halts the early onset and progression of mesangial expansion in the ZDF/Gmitrade mark rat, preventing the development of glomerulosclerosis in this animal model of type 2 diabetes mellitus.

Animals↗
PubMed1998

Efficacy and tolerability of losartan in hypertensive patients with renal impairment. Collaborative Group.

We evaluated the blood pressure-lowering activity, tolerability, and safety of losartan in 112 hypertensive (sitting diastolic blood pressure, 90 to 115 mm Hg) patients with chronic renal insufficiency including mild renal insufficiency (30 to 60 mL/min per 1.73 m2; n=51), moderate to severe renal insufficiency (10 to 29 mL/min per 1.73 m2; n=33), or hemodialysis (n=28). After a 3-week placebo period, once-daily losatan was administered for 12 weeks. The daily dose of 50 mg was increased to 100 mg after 4 weeks in patients whose sitting diastolic blood pressure remained > or = 90 mm Hg or was reduced by < 5 mm Hg. A second, non-angiotensin-converting enzyme inhibitor, antihypertensive drug was added after 8 weeks as needed. Twenty-four-hour creatinine clearance was determined and renal clearance studies of inulin and para-aminohippurate were done in a subset of 11 patients. Trough sitting blood pressures were reduced at the end of the first week in all groups. At weeks 4, 8, and 12, the reductions in systolic blood pressure/diastolic blood pressure averaged -11.9/-8.7, -10.8/-9.4, and -14.7/-12.1 mm Hg in patients with mild renal insufficiency; -7.7/-6.3, -13.1/-11.8, and -14.1/-10.6 mm Hg, in moderate to severe renal insufficiency; -17.0/-12.7, -19.1/-14.4, and -22.7/-18.0 mm Hg in hemodialysis. Creatinine clearance, glomerular filtration rate, and effective renal plasma flow were stable. Losartan was withdrawn in only 6 patients because ofa clinical or laboratory adverse experience. Hyperkalemia (> 6 mEq/L) requiring discontinuation of losartan occurred in only one (group 2) patient. We conclude that once-daily losartan, given as monotherapy at doses of 50 or 100 mg or in combination with other antihypertensive drugs, was effective in reducing blood pressure in hypertensive patients with chronic renal disease and that losartan regimens were well tolerated in all groups, including those on hemodialysis.

Adolescent↗
PubMed1997

Health-related quality of life in older patients with schizophrenia and other psychoses: relationships among psychosocial and psychiatric factors.

OBJECTIVE: Few multivariate studies relating psychosocial factors to symptoms of psychosis among older patients exist. We assessed environmental stressors, satisfaction with emotional support, coping responses and psychiatric symptoms, and sought to relate these factors to quality of well-being among older patients with schizophrenia and other psychoses. METHOD: Subjects were 70 psychosis patients with a mean age of 58. Predictors included measures of stressors (number of negative life events), satisfaction with emotional support, coping responses, positive and negative symptoms, depressive symptoms, social adjustment and a general quality of well-being (QWB) score. RESULTS: A conceptual model was tested and modified using path analytic techniques. Preliminary analyses suggested that psychosocial environment (life events, coping and emotional support) was primarily a product of psychiatric symptoms. Therefore, psychiatric symptoms preceded psychosocial environment variables in the proposed model. Further results suggested that depression mediated all of the effects of psychotic symptoms on social maladjustment, but not all of their effects on well-being. CONCLUSIONS: In older patients with schizophrenia and other psychoses, health-related quality of well-being is influenced by symptoms of psychoses, psychosocial factors and social maladjustment.

Adaptation, Psychological↗
PubMed1997

Aging and caloric restriction affect mitochondrial respiration and lipid membrane status: an electron paramagnetic resonance investigation.

Previous studies have indicated that reactive oxygen species (ROS) are likely involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). ROS, generated by succinate-stimulated mitochondria, have been reported to be spin trapped and detected by electron paramagnetic resonance (EPR). Our aim in the current study was to study the impact of aging on the effect of increased metabolic stimuli on mitochondrial respiration in terms of oxy-radical generation and possible lipid peroxidative changes in brain neocortical membranes. A mixed population of brain synaptosomes and mitochondria from brown norway male rats of differing ages being fed either ad lib (AL) or a caloric-restricted diet (DR) was prepared and labeled with 5-nitroxyl stearate (5-NS), a membrane lipid-specific spin label. The changes in anisotropic motion of the intercalated 5-NS spin probe also allows one to evaluate the status of the membrane fluidity in the lipid microenvironment via the order parameter. Upon succinate stimulation of mitochondria, the ROS generated resulted in a decrease in the EPR signal amplitude of the 5-NS reporter molecule indicative of the flux of oxy-radicals produced and possible peroxidation-induced changes in the synaptosomal lipid membrane. The line width remained constant, indicating that the overall intensity was reduced. The results showed a significant overall age effect in the ability to generate oxygen-derived radicals following metabolic stimulation (p < .0001). Stimulation of state 4 mitochondrial respiration with 20 mM succinate resulted in greater oxy-radical production in 25-month-old animals as compared to younger animals, suggesting increased mitochondrial leakage with age. Free radical stress induced by metabolic stimulation also causes a concomitant increase in membrane fluidity (p < .0001). There was also a significant age effect (p < .0007) on the order parameter of the mixed population of membranes. Although caloric restriction attenuated the membrane rigidization caused by aging, it was found to play a role in limiting the oxy-radical production following metabolic stimulation of mitochondria. The overall effect of age on membrane spin-label intensities EPR signal upon succinate stimulation suggests that progressive mitochondrial dysfunction may be a key factor in the aging process and in development of age-associated diseases.

Aging↗
PubMed1997

In vitro and in vivo gene delivery mediated by a synthetic polycationic amino polymer.

A synthetic polyamino polymer with a glucose backbone was used for gene transfer in vitro and in vivo. Gene transfer in vitro to various human carcinoma cell lines was achieved with an efficiency superior to a commercially available cationic liposome preparation. The polymer was resistant to inhibition by serum, which allowed for efficient gene transfer in vivo. Direct Intracranial tumor injection using this reagent resulted in reporter gene expression levels comparable to those achieved by a recombinant adenoviral vector. Thus, this compound represents a new class of agent that may have broad utility for gene transfer and gene therapy applications.

Animals↗
PubMed1996

The water adsorption characteristics of charged phospholipids.

The hydration isotherms of the negatively charged phospholipids, egg phosphatidic acid, bovine heart cardiolipin and two phosphatidylserines as well as one positively charged phospholipid, 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine, have been obtained gravimetrically. The presence of an electrical charge on these phospholipids does not, in itself, determine whether the water binding to the phospholipids is 'strong' or 'weak'. Interestingly, hysteresis effects were present for certain charged phospholipids suggesting some rearrangement of the lipid molecular organization upon hydration and dehydration, perhaps due to the presence of the ionizable moiety. The hydration isotherms of the charged phospholipids have been analyzed by BET theory, although, of the charged lipids studied, all may not be amenable to the application of BET theory. The hydration isotherms and the resulting parameters obtained from the BET analysis are compared to those found previously for zwitterionic phospholipids, especially egg phosphatidylcholine. The water adsorption characteristics of phospholipids are found to depend mainly on the total head-group structure including the presence of hydrophobic groups as well as electrical charge on the head group.

Adsorption↗
PubMed1996

Cost and outcome of osteocutaneous free-tissue transfer versus pedicled soft-tissue reconstruction for composite mandibular defects.

Thirty-nine patients underwent reconstruction of composite mandibular defects following resection for squamous cell carcinoma. Thirty-four underwent immediate reconstruction, while 5 were reconstructed secondarily. Twenty-one received soft-tissue reconstruction only with a pectoralis major myocutaneous flap, 14 underwent osteocutaneous free-tissue transfer, and 4 received a reconstruction plate with free-tissue transfer for soft-tissue coverage. The mandibular defects in the pectoralis major myocutaneous flap group tended to be posterolateral, while free-tissue transfer defects were more severe, usually involving the anterior mandible. Length of surgery and duration of intensive care unit care were significantly longer for free-tissue transfer patients, while flap complications were more common in the pectoralis major myocutaneous flap patients. Facial appearance scores were higher for the free-tissue transfer group by both patient and physician assessment. Social function, speech, and oral function did not differ significantly. Patients reconstructed secondarily with free-tissue transfer reported significant improvement in appearance, oral continence, and social function, with little change in speech intelligibility, deglutition, or diet tolerance. The cost of the main hospitalization was significantly higher in the free-tissue transfer group than in the pectoralis major myocutaneous flap group, although when the costs of subsequent hospitalizations are included, the difference in total cost narrows. Despite more adverse defects, free-tissue transfer provided more predictable aesthetic results and expeditious return to normal social function than did pectoralis major myocutaneous flap reconstruction. The fiscal impact of these complex reconstructions is, however, significant. Cost-containment issues are presented and recommendations are made.

Aged↗
PubMed1996

Efficiency of plasmid delivery and expression after lipid-mediated gene transfer to human cells in vitro.

Cationic liposome-mediated gene transfer has become increasingly important in the development of experimental therapies for human diseases, such as melanoma, human immunodeficiency virus infection, cystic fibrosis and alpha-1 antitrypsin deficiency. However, very little is known about the mechanisms by which lipid-mediated gene transfer occurs. We studied the kinetics of plasmid delivery and expression by using this technique. Plasmid entry in the cystic fibrosis respiratory epithelial cell line 2CFSME0-1 as well as in two other cell lines (HeP 2g and HeLa) occurred in 95 to 100% of cells within 1 hr of the initiation of lipid-mediated gene transfer. In hepatic and respiratory cells, transcription of a construct containing the cystic fibrosis transmembrane conductance regulator was observed in more than 80% of the cell population; similarly high levels of plasmid utilization were obtained in studies of HLA-B7 expression in human melanoma cells. Studies directly relevant to current human trials of lipid-mediated gene transfer indicate that plasmid entry, transcription and translation are often surprisingly efficient, and may occur in nearly 100% of human cells in culture when sensitive methods for detection are used. Furthermore, conventional X-gal immunohistochemistry markedly underestimates transfection efficiency during transient gene expression. These studies point to a new mechanistic understanding of the features that limit expression by using cationic liposomes.

Cell Line↗
PubMed1995

Salvage of traumatic below-knee amputation stumps utilizing the filet of foot free flap: critical evaluation of six cases.

Over a 12-year period between 1979 and 1991, 27 patients were operated on at the New York University Medical Center for salvage of below-knee amputation stumps utilizing free flaps. Six different donor sites were used. In 6 patients, the amputated foot was the donor site for a free flap to cover the tibial stump. There were 3 males and 3 females in this group. Five of the patients underwent immediate filet of foot reconstructions, while 1 patient had a reconstruction performed 69 days after injury, electively, when it was determined that below-knee amputation was the best option. All foot flaps survived and ultimately provided the major soft-tissue coverage for the below-knee amputation stump. The length of hospitalization ranged from 24 to 118 days. The time required from foot filet procedure to ambulation was 2, 4, 6, 7, 9, and 12 months in the 6 patients. Five of the 6 patients have resumed work or school after their injury. Foot flaps were based on the posterior tibial artery, anterior tibial artery, or both vessels. Nerve anastomosis of the posterior tibial nerve was performed in 5 patients. In 1 patient it was possible to maintain the continuity of the posterior tibial nerve. Five of the 6 patients were tested over a year after the flap, and all have good cold, pressure, and vibration sensation. Two of the 5 patients have heat sensation, and all 5 patients have at least protective pressure sensation. All the patients ambulate well with a below-knee prosthesis.

Adolescent↗
PubMed1995

In vitro slow release profile of endothelial cell growth factor immobilized within calcium alginate microbeads.

Although a variety of angiogenic growth factors have been isolated, its appropriate in vivo delivery remains problematic due to nonspecific, uncontrolled delivery by conventional methods. We have investigated calcium alginate microbeads as a vehicle for the controlled slow-release of endothelial cell growth factor (ECGF). Three different microbead compositions, dependent on ECGF amount and alginate percentage were studied. Microbeads were incubated in a 1.5% calcium chloride solution and release of ECGF into solution was measured spectrophotometrically at specific timepoints. Our results show release rate and amount released after the first 2 hours are dependent on initial quick delivery of ECGF in the first 2 hours after which a sustained controlled release occurred for 4-5 days. Beyond this point, release at a slower rate was noted for at least approximately 2 weeks. Calcium alginate microbeads demonstrated a controlled and predictable rate of release and that the amount of ECGF delivered can be varied by varying the initial concentration of ECGF in the microbeads. Based on these observations we conclude that calcium alginate microbeads are a convenient and practical vehicle for sustained ECGF delivery.

Alginates↗
PubMed1995

Increased urinary excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features.

A marked increase in analogs of Krebs cycle metabolites was found in the urine of two brothers with autistic features. These metabolites included citramalic, tartaric (3-OH-malic), and 3-oxoglutaric acids and compounds tentatively identified as a citric acid analog and partially identified as a phenylcarboxylic acid by the fragmentation pattern of the trimethylsilyl (TMS) derivatives of the compounds and mass shifts of the same compounds derivatized with perdeuterated N,O-bis(trimethylsilyl)trifluoroacetamide. The molecular mass of the TMS derivative of the tentatively identified citric acid analog was 596 Da, based on a finding of a significant M - 15 ion at m/z 581. The citric acid analog was excreted in quantities as high as 137 mmol/mol creatinine, based on the response factor of citric acid as a surrogate calibrator. A carbohydrate with a retention time and mass spectrum identical to arabinose was also found in high concentrations in the urine of these brothers.

Arabinose↗
PubMed1994

Achieving mandibular continuity with vascular bone flaps: a comparison of primary and secondary reconstruction.

This retrospective study was performed to compare the functional and aesthetic results achieved in two distinct groups of patients undergoing composite reconstruction of complex head and neck defects using vascularized bone flaps. Fourteen consecutive patients undergoing reconstruction over a 30-month period (January 1988 through June 1991), nine primary and five secondary, were analyzed. The two groups were similar with respect to age, physical status, tumor type and stage, exposure to radiation, and previous history of cigarette smoking and alcohol consumption. The bone defect was similar between the two groups, but the soft tissue deficit was greater in the group of patients reconstructed secondarily. Surgery time and blood loss tended to be less in the patients reconstructed secondarily, but length of hospitalization was similar. Flap survival was 100%, although the complication rate approached 60%. Restoration of mandibular continuity and orofacial soft tissue defects with vascularized composite free flaps had a favorable impact on function and aesthetics in the group of patients reconstructed primarily. In those reconstructed secondarily the benefit was primarily cosmetic. Continued emphasis on primary reconstruction of the composite defect with composite free tissue transfers is advised.

Aged↗
PubMed1994

Electron paramagnetic resonance investigations of free radical-induced alterations in neocortical synaptosomal membrane protein infrastructure.

Evidence is presented that free radical stress can directly induce physico-chemical alterations in rodent neocortical synaptosomal membrane proteins. Synaptosomes were prepared from gerbil cortical brain tissue and incubated with 3 mM ascorbate and various concentrations of exogenous Fe2+ for 30-240 min at 37 degrees C. Synaptosomes were then lysed and covalently labeled with the protein thiol-selective spin label MAL-6 (2,2,6,6-tetramethyl-4-maleimidopiperdin-1-oxyl) and subjected to electron paramagnetic resonance (EPR) spectrometry. In separate experiments, synaptosomal membranes were labeled with the thiol-specific spin label MTS ((1-oxyl-2,2,5,5-tetramethyl-pyrroline-3-methyl)-methanethiosulfonate), or the lipid-specific spin probe 5-NS (5-nitroxide stearate). Free radical stress induced by iron/ascorbate treatment has a rigidizing effect on the protein infrastructure of these membranes, as appraised by EPR analysis of membrane protein-bound spin label, but no change was detected in the lipid component of the membrane. These results are discussed with reference to potential oxidative mechanisms in aging and neurological disorders.

Animals↗
PubMed1993

Various methods of breast reconstruction after mastectomy: an economic comparison.

This study is an economic comparison of various methods of breast reconstruction after mastectomy. The hospital bills of 287 patients undergoing breast reconstruction at three institutions from June of 1988 to March of 1991 were analyzed. The procedures examined included mastectomy, implant and tissue-expander reconstruction, and TRAM and latissimus pedicle flaps, as well as free TRAM and free gluteal flaps. These procedures were subdivided into those which were performed at the time of mastectomy and those performed at a later admission. In addition, auxiliary procedures (i.e., revision, nipple reconstruction, tissue-expander exchange, and contralateral mastopexy/reduction) also were examined. Where appropriate, these procedures were subdivided into those performed under general or local anesthesia and by inpatient or outpatient status. Data from the three institutions were converted to N.Y.U. Medical Center costs for standardization. A table is presented that summarizes the costs of each individual procedure with all the pertinent variations. In addition, a unique and novel method of analyzing the data was developed. This paper describes a menu system whereby other data regarding morbidity, mortality, and revision rates may be superimposed. With this information, the final cost of reconstruction can be extrapolated and the various methods of reconstruction can be compared. This method can be applied to almost any complex series of multiple procedures. The most salient points elucidated by this study are as follows: The savings generated by performing immediate reconstruction varies between $5092 (p < 0.05) for free gluteal flaps and $10,616 (p < 0.05) for pedicled TRAM flaps.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1992

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.

Adult↗