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Biomedical subjects

C Harris

Publications and source records attributed to C Harris.

At least 307 records · Page 17Linked to original sources

Lindane embryotoxicity and differential alteration of cysteine and glutathione levels in rat embryos and visceral yolk sacs.

The lindane embryotoxicity and associated changes in cysteine (CYS) and glutathione (GSH) status have been investigated in the early organogenesis-stage rat conceptus utilizing whole embryo culture techniques. Direct exposure of gestational day 10 (GD 10) conceptuses to lindane (50, 100, 200, 300, and 400 microM) in the culture medium resulted in a dose- and time-dependent increase in mortality (88% at 400 microM), frequency, and severity of malformations and in decreased growth parameters. Protein and DNA contents of embryo and visceral yolk sac (VYS), likewise decreased significantly as lindane concentrations increased. Lindane exposures greater than 100 microM produced abnormal axial rotation, pooled blood on lateral cephalic surfaces, cephalic edema, and decreased VYS vasculature. Histologic sections showed a variety of abnormalities, including distended anterior cardinal veins, thinning of the neuroepithelium in forebrain and hindbrain regions, and abnormal branchial arch development. CYS and GSH levels in the VYS were not significantly affected by 100 microM lindane exposure during a 5-h incubation period on GD 10 and GD 11. In contrast, CYS and GSH levels in lindane-exposed embryos remained unchanged while control levels continued to increase with gestational age. At 5 h, treated embryos showed a significant depletion of CYS (GD 10, 22%; GD 11, 35%) and GSH (GD 10, 41%; GD 11, 24%) relative to controls. Selective lindane-induced depletion of embryonic GSH suggests involvement of the glutathione redox cycle in lindane embryotoxicity.

Abnormalities, Drug-Induced↗

Formation of glutathione adducts and 2-aminofluorene from 2-nitrosofluorene in postimplantation rat conceptuses in vitro.

The formation of glutathione (GSH) adducts and 2-aminofluorene (AF), GSH-derived metabolic products from 2-nitrosofluorene (NOF), was examined as a possible mechanism of GSH-mediated protection from NOF embryotoxicity in the gestational day 10 (GD 10) rat conceptus in vitro. When added to whole embryo culture medium, NOF produced dose-dependent decreases in growth parameters and increases in the incidence of axial rotation defects in embryos cultured for 26 h. Culture of GD 10 rat conceptuses in 50 microM NOF for 24 h following 2 h pretreatment with an irreversible inhibitor of glutathione disulfide reductase, 1,3-bis(2-chloroethyl)1-nitrosourea (BCNU, 25 microM) did not result in statistically significant differences in morphology or biochemical parameters compared to NOF alone; viability, however, was decreased relative to controls. Nearly equal amounts of GS-AF(I), a stable S-oxide conjugate of GSH with NOF, AF, a GSH-dependent reaction product of NOF, and the parent NOF were recovered following short-term incubation of conceptuses with NOF (100 microM) in serum-free medium. Stimulation of GSH synthesis with the cysteine prodrug 2-oxothiazolidine-4-carboxylate (OTC, 5 mM) resulted in a significant increase in AF concentrations (205% of control) and a decrease in NOF (50% of control) after 30 min. Sixty-minute exposure to the GSH depletor, diethylmaleate (DEM, 500 microM), resulted in apparent reductions in both GS-AF(I) and AF by 36% and 34%, respectively, though these reductions were not statistically significant. Treatment with 25 microM BCNU for 2 h, followed by exposure to 100 microM NOF in serum-free medium resulted in a significant decrease in AF to 76% of control concomitant with lower GSH levels relative to NOF treatment alone. Exposure of conceptuses to 50 microM NOF in complete medium following pretreatment with BCNU resulted in a reduction of GSH levels in the visceral yolk sac after 3 h and in embryos after 5 h relative to controls. These data demonstrate that the intracellular protective effects of GSH toward NOF embryotoxicity may act through a nonenzymatic mechanism of direct formation of GSH-NOF adducts in the day 10 rat conceptus in vitro, followed by the GSH-mediated conversion to a less toxic metabolite, AF.

Animals↗

Abnormal supranuclear eye movements in the child: a practical guide to examination and interpretation.

Abnormal eye movements in the infant or voting child can be congenital or acquired. They may be a result of abnormal early visual development or a sign of underlying neurologic or neuromuscular disease. It is important to be able to detect these abnormalities and to distinguish them from normal but immature eye movements. The spectrum of disease in children differs from that in adults. Serious, potentially fatal but treatable disorders can be acquired in infancy, and abnormal eye movements in a sometimes apparently well child should never be labeled as congenital or benign without careful investigation. Eye movement analysis can indicate the presence of an underlying condition and help the clinician to classify different neurologic diseases. It is important to carefully examine the ocular motor system in any children at risk of neurologic disease. This review provides a practical guide to the examination and interpretation of eye movements in the child and includes recent literature on eye movement disorders of childhood. We describe supranuclear abnormalities of the ocular motor system in the order in which we would normally examine it: saccades, pursuit, convergence, vestibulo-ocular reflex, and optokinetic nystagmus. Nystagmus, internuclear ophthalmoplegia, cranial nerve abnormalities, and "miswiring" phenomena (such as Duane's syndrome and synergistic divergence) are not discussed.

Child↗

Pyridine nucleotide flux and glutathione oxidation in the cultured rat conceptus.

It is proposed that protection of the developing embryo from chemical and environmental insults that produces oxidative stress requires a proper glutathione (GSH) and pyridine nucleotide status in both the embryo and extra-embryonic membranes. Modulation of pyridine nucleotide flux [NAD(H) and NAD(P)H] in the visceral yolk sac (VYS) by the thiol oxidants diamide and tert-butyl hydroperoxide (tBH) was studied in real time using microfiberoptic sensors in GD 10 rat conceptuses. Consecutive 5-min exposures to 125- and 250-microM diamide resulted in a fluorescence decrease of 14 and 32 Arbitrary Fluorescence Units (AFU). An additional consecutive exposure to 500-microM diamide caused an attenuated decrease followed by a rebound increase of 22 AFU. Consecutive 5-min exposures to tBH at 250 and 500 microM produced fluorescence decreases similar to that of 500 microM diamide, but the decreases were attenuated at 1000 microM. However, there was variability in the rebound increase. A 5-min exposure to tBH (500 microM) alone caused a fluorescence decrease of 14 AFU followed by a rebound increase of 8 AFU. The rate of fluorescence decrease was attenuated by 50% with pretreatment with the glutathione reductase (GSSG-Rd) inhibitor, BCNU (1,3, bis(2 chloroethyl)-1-nitrosourea), indicating that the decrease in surface fluorescence was probably attributable to a decrease in NADPH. Decreases in fluorescence, observed from the surface of the VYS, correlated with decreases in GSH/GSSG ratios in the embryos and the VYS. After exposure to tBH, GSH levels in conceptuses decreased at the end of 5 and 15 min, with a corresponding increase in oxidized glutathione (GSSG) at the end of 3, 5, and 15 min. Our results demonstrate that the increased production of GSSG on exposure to thiol oxidants correlates with a decrease in the reduced pyridine nucleotide, implying the presence of an active GSSG-Rd pathway in the conceptus during organogenesis, and implicating an important role of the pyridine nucleotides in the restoration of GSH homeostasis in the developing rat conceptus during organogenesis.

Animals↗

Differential alteration by thalidomide of the glutathione content of rat vs. rabbit conceptuses in vitro.

Thalidomide has been shown to cause limb reduction defects in rabbits with much greater potency than in rats, possibly due to inherent biochemical differences between the two species. Whole embryo culture was used to make direct comparisons between thalidomide-sensitive New Zealand White rabbits and thalidomide-resistant Sprague-Dawley rats, focusing on the possible roles of glutathione (GSH) and cysteine in mechanisms of thalidomide teratogenicity. Conceptuses were treated by adding thalidomide (0, 5, 15, and 30 microM) directly to the culture media containing conceptuses of similar gestational stages. Embryos and visceral yolk sacs (VYS) were measured for changes in GSH and cysteine content using HPLC after 24 h of exposure in vitro. Thalidomide-induced (15 and 30 microM) depletion of VYS GSH occurred only in the rabbit, where GSH concentrations (pmol/microg protein) fell significantly to about 50% of control. Rat VYS did not show a significant GSH depletion at any thalidomide concentration tested. Comparison between species showed that the control rabbit VYS contained 35% less GSH than the control rat VYS. Control rat embryos and control rabbit embryos contained similar concentrations of GSH, but thalidomide treatment preferentially depleted GSH in the rabbit at lower thalidomide concentrations (5 micro/M). Cysteine concentrations were not significantly altered from control in the embryo or VYS of either species when treated with thalidomide. However, although control cysteine concentrations did not differ significantly between rat and rabbit VYS, control cysteine levels in rabbit embryos were 65% lower than those in control rat embryos. Rabbit conceptuses displayed lower species-specific GSH and cysteine levels and a greater propensity for thalidomide-induced GSH depletion than in rat conceptuses, consistent with the greater sensitivity of the rabbit to thalidomide teratogenicity. These thalidomide-induced and inherent species differences implicate a possible role for GSH and redox status in the mechanisms of thalidomide teratogenicity.

Animals↗

Cost-benefit analysis of extended antifungal prophylaxis in ventricular assist devices.

This report defines the cost and benefit of extended antifungal prophylaxis in ventricular assist device (VAD) patients (pts). Extended antifungal prophylaxis is defined as prophylaxis with fluconazole or nystatin that is given until pts are extubated and off antibiotics. These data are compared with that obtained from earlier VAD patients who only received anti-fungal drugs for documented fungal colonization or infection. Thirty-six patients had HeartMate (n = 15) or Thoratec (n = 21) VADs between 1989 and 1997. Cultures positive for fungus (n = 52 cultures) were obtained from 16 of 36 patients (44% of patients). Forty-three fungal cultures were in the preprophylaxis and nine in the postprophylaxis era. There was one death attributable to fungal sepsis in the preprophylaxis era and none in the postprophylaxis era. The total cost of antifungal drugs in the preprophylaxis era was $3,840 over 1,498 patient days (PD) (mean $2.56 per PD), versus $70,670 over 1,525 PD in the postprophylaxis era (mean $46.34 per PD). Extended antifungal prophylaxis was not cost effective in VAD patients at this institution. However, short-term perioperative antifungal prophylaxis was not addressed by this study. We are now using short-term antifungal prophylaxis with fluconazole and nystatin in VAD patients because of the potential for serious morbidity and mortality that is associated with fungal device infections. A future analysis will determine the usefulness of this change in strategy.

Antifungal Agents↗

Application of autologous fibrin glue in burn wounds.

Biological adhesive fixation of skin grafts has been performed successfully on patients with facial burns and burns at difficult sites by using autologous human fibrin adhesive, which eliminates the danger of multidonor pool preparations. There are several distinct advantages to the use of fibrin glue: There is no danger of multidonor pool preparations. Wounds do not require any sutures or pressure dressings in the immediate postoperative period. Grafts demonstrate excellent take with minimal postoperative care. The patients can maintain normal ambulation. Fibrin glue seems to be an important factor in the application of skin grafts to burned areas in these two groups of patients.

Burns↗

Identical cytogenetic clones and clonal evolution in pediatric monozygotic twins with acute myeloid leukemia: presymptomatic disease detection by interphase fluorescence in situ hybridization and review of the literature.

PURPOSE: Observation of identical acquired genetic changes in infant monozygotic (MZG) twins with acute leukemia has provided strong evidence for in utero twin-twin transfusion as the cause of concordance. Documentation of similar phenomenon in older MZG twins offers insight into the latency period for leukemia and may provide the opportunity for presymptomatic disease detection in one twin. DESIGN: The literature describing leukemia in MZG twins is reviewed and the results of classical and molecular cytogenetic studies of one pair of MZG twins at 3 and 4 years with acute nonlymphocytic leukemia-FAB type M1 are reported. RESULTS: The twins studied had cytogenetically identical neoplastic clones with identical clonal evolution. Retrospective fluorescence in situ hybridization studies demonstrated the presence of the abnormal clone in the asymptomatic twin at the time of bone marrow transplant of the first twin. CONCLUSIONS: These observations support in utero twin-twin transfer as the origin of leukemic clones in pediatric and infant leukemia, demonstrate that clonal evolution of a leukemic clone may occur years before onset of overt disease, and indicate that knowledge of acquired genetic change(s) in one twin may provide markers to assess disease in the asymptomatic twin.

Child, Preschool↗

Renal effects of COX-2-selective inhibitors.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat a variety of inflammatory diseases, these agents may cause deleterious effects on kidney function, especially with respect to solute homeostasis and maintenance of renal perfusion and glomerular filtration. NSAIDs act by reducing prostaglandin biosynthesis through inhibition of cyclooxygenase (COX) which exists as two isoforms (COX-1 and COX-2). NSAID-induced gastrointestinal toxicity is generally believed to occur through blockade of COX-1 activity, whereas the anti-inflammatory effects of NSAIDs are thought to occur primarily through inhibition of the inducible isoform, COX-2. However, the situation in the kidney may be somewhat different. Recent studies have demonstrated that COX-2 is constitutively expressed in renal tissues of all species; this isoform may, therefore, be intimately involved in prostaglandin-dependent renal homeostatic processes. Drugs that selectively inhibit COX-2 might, therefore, be expected to produce effects on renal function similar to nonselective NSAIDs which inhibit both COX-1 and COX-2. This assertion is borne out by recent clinical studies showing that the COX-2 inhibitors rofecoxib and celecoxib procedure qualitative changes in urinary prostaglandin excretion, glomerular filtration rate, sodium retention, and their consequences similar to nonselective NSAIDs. It, therefore, seems unlikely that these COX-2 inhibitors (and perhaps their successors) will offer renal safety benefits over nonselective NSAID therapies, and, at this juncture, it is reasonable to assume that all NSAIDs, including COX-2-selective inhibitors, share a similar risk for adverse renal effects.

Animals↗

Correlation of the ratio of CD4+/CD8+ cells in lymph node fine needle aspiration biopsies with HIV clinical status. A preliminary study.

OBJECTIVE: To test the hypothesis that lymph node (LN) fine needle aspiration biopsy (FNAB) may provide reliable measures of human immunodeficiency virus (HIV) disease status. STUDY DESIGN: HIV+ participants in this study had persistent generalized lymphadenopathy without clinical evidence of lymphoma or nodal infections due to organisms other than HIV. Seven males and five females ranging in age from 23 to 55 and at HIV Centers for Disease Control (CDC) stages A2-C3 were enrolled in this study. From each participant, LN and blood samples were submitted for cytologic examination and flow cytometric analysis of lymphocyte subsets. Flow cytometry measures included T, B, CD4+, CD8+ and natural killer (NK) cells. The percentages of T, B and NK cells in LN and blood samples were different and reflected the expected distribution of these cell types in the respective tissues. RESULTS: The percentages of CD4+ and CD8+ cells in blood and LN were different, but this variation was not statistically significant. In contrast, the ratio of CD4+/CD8+ cells in LN and blood was different and statistically significant (P < .001) for patients in CDC categories A2-B2 but not different for categories B3-C3. More important, there was a significant (r = .76) correlation between the ratio of CD4+/CD8+ cells in LN with CDC stage. CONCLUSION: FNAB, in combination with flow cytometry, may prove to be an important tool in HIV clinical staging. However, further assessment, including clinical follow-up and participation of additional patients, is necessary and currently under way.

Acquired Immunodeficiency Syndrome↗

Improving outpatient diabetes management through a collaboration of six competing, capitated Medicare managed care plans.

This report addresses diabetes care in the managed care setting and improvement in care brought about by collaboration between 6 Medicare managed care plans (MCPs) and a Peer Review Organization (PRO). The objective was to improve the quality of care of outpatient diabetes patients provided by primary care physicians through the mutual collaboration of 6 Medicare managed care plans and a Medicare Peer Review Organization. The design involved pre-post intervention trial based on 2 random samples, a baseline sample drawn in 1995 and a remeasurement sample drawn in 1996. Medical records of patients in both samples were reviewed by the PRO to determine provision of 14 quality indicator services over a 1-year period. The setting was 6 Arizona Medicare managed care plans comprising approximately 40% of the Arizona Medicare population. Two random samples were drawn from type 2 diabetes patients continuously enrolled in the same managed care plan for at least 1 year. The intervention was comparative feedback of baseline data by the PRO, enabling each plan to compare itself to any other plan on any or all indicators. Each plan developed and implemented its own intervention in response to the 1995 baseline results. The main outcome measures were mean HbA1c, the proportion of HbA1c values below 8%, and positive change in provision of 14 quality indicator services. At postintervention remeasurement, mean HbA1c values fell from 8.9 +/- 2.2 to 7.9% +/- 2.1, and the proportion of patients with HbA1c values below 8.0% rose from 40% to 61.6%. The proportion of the 14 indicator services provided to patients rose from 35% to 55%. The mean number of physician office visits fell 13% and the number of services provided per visit doubled. We conclude that improving the process of care improves glycemic control. Better outpatient diabetes management in competing, capitated managed care plans is an attainable goal when mediated through a neutral third party such as a PRO.

Ambulatory Care↗

Four-week supplementation with a natural dietary compound produces favorable changes in body composition.

The purpose of this study was to determine whether a natural dietary supplement produced favorable changes in body composition during a 4-week diet- and-exercise program. The active compound contains a patented combination of chromium picolinate, inulin, capsicum, L-phenylalanine, and other lipotropic nutrients. A double-blind, weight-loss intervention design was used. Participants were randomly assigned to either a diet/exercise/supplement group (n = 56) or a diet/exercise/placebo group (n = 67). Caloric intake was reduced to 1500 kcal/d and participants walked for 45 minutes, 5 days a week, to attain between 60% and 80% of predicted maximal heart rate. Analysis of covariance (ANCOVA) showed significant differences (P < .05) between groups in percent body fat, fat mass, and fat-free mass; no significant differences were found (P > .05) in body weight, body mass index, or energy intake. Independent t tests showed no significant differences (P > .05) in diet composition between groups. Results indicate that the addition of a natural dietary supplement during a 4-week diet-and-exercise weight-loss program accelerates the rate of body fat loss and helps maintain fat-free mass (lean tissue), thereby producing favorable changes in body composition.

Adipose Tissue↗

Solitary midbrain toxoplasmosis and olivary hypertrophy in a patient with acquired immunodeficiency syndrome.

Toxoplasmosis, one of the most common central nervous system lesions in patients with the acquired immunodeficiency syndrome (AIDS), has not been reported as a solitary lesion in the brainstem. This report describes a patient with AIDS that presented with third cranial nerve palsy and contralateral cerebellar signs, who at autopsy had a necrotic midbrain lesion due to toxoplasma. Inferior olivary hypertrophy, due to interruption of olivary afferent fibers by the lesion, in addition to subacute encephalitis and vacuolar myelopathy were other CNS findings.

Acquired Immunodeficiency Syndrome↗