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J Alexander

Publications and source records attributed to J Alexander.

At least 415 records · Page 23Linked to original sources
PubMed1990

Mechanisms of chromium toxicity in mitochondria.

The oxygen consumption of isolated rat heart mitochondria was potently depressed in presence of 10-50 microM Na2CrO4 when NAD-linked substrates were oxidized. The succinate stimulated respiration and the oxidation of exogeneous NADH in sonicated mitochondria were not affected by chromate at this concentration range. A rapid and persistent drop (40% in 2 min) in the mitochondrial NADH level was observed after chromate addition (30 microM) under conditions which generally should promote regeneration of NADH. Experiments with bis-(2-ethyl-2-hydroxybutyrato)oxochromate(V) and vanadyl induced reduction of Cr(VI) in presence of excess NADH were performed. These experiments indicated that NADH may be directly oxidized by Cr(V) at physiological pH. The activity of 10 different enzymes were measured after lysis of intact mitochondria pretreated with chromate (1-100 microM). Na2CrO4 at a very low level (3-5 microM) was sufficient for 50% inhibition of alpha-ketoglutarate dehydrogenase. Higher concentrations (20-70 microM) was necessary for similar effect on beta-hydroxybutyrate and pyruvate dehydrogenase. The other enzymes tested were unaffected. Thus, the chromate toxicity in mitochondria may be due to NADH depletion as a result of direct oxidation by Cr(V) as well as reduced formation of NADH due to specific enzyme inhibition.

Animals↗
PubMed1990

Elective surgery without transfusion: influence of preoperative hemoglobin level and blood loss on mortality.

To clarify the widespread practice of preoperative transfusion to attain a 10 g/dL level of hemoglobin, the relationship between preoperative hemoglobin level, operative blood loss, and mortality was studied by analyzing the results of 113 operations in 107 consecutive Jehovah's Witness patients who underwent major elective surgery. Ninety-three patients had preoperative hemoglobin values greater than 10 g/dL; 20 had preoperative hemoglobin levels between 6 to 10 g/dL. Mortality for preoperative hemoglobin levels greater than 10 g/dL was 3 of 93 (3.2%); for preoperative hemoglobin levels between 6 to 10 g/dL, mortality was 1 of 20 (5%). Mortality was significantly increased with an estimated blood loss of greater than 500 mL, regardless of the preoperative hemoglobin level (p less than 0.025). More importantly, there was no mortality if estimated blood loss was less than 500 mL, regardless of the preoperative hemoglobin level. From these data, we conclude that: (1) Mortality in elective surgery appears to depend more on estimated blood loss than on preoperative hemoglobin levels; and (2) Elective surgery can be done safely in patients with a preoperative hemoglobin level as low as 6 g/dL if estimated blood loss is kept below 500 mL.

Adolescent↗
PubMed1990

A comparison of oral and rectal absorption of L-dopa esters in rats and mice.

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration. In most cases, oral administration resulted in nondetectable (less than 0.01 micrograms/ml) levels of the esters in plasma. Correspondingly, the plasma levels of L-dopa itself were consistently higher following rectal administration. At very high oral doses (500 mg L-dopa equivalents/kg body weight), systemic plasma levels of the butyl ester could be detected (1.25 micrograms/ml at 10 min), which might indicate saturation of the esterase activity of the small intestine. These studies indicate that the systemic availability of L-dopa from short-chain alkyl esters of L-dopa may be best optimized by rectal administration, which avoids the relatively high esterase activity characteristic of the small intestine.

Administration, Oral↗
PubMed1990

Differential rates of metabolic activation and detoxication of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by different cytochrome P450 enzymes.

Rat liver microsomes metabolized the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to the genotoxic metabolite 2-hydroxamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (2-hydroxamino-PhIP) and to the detoxified product 2-amino-4'-hydroxy-1-methyl-6-phenylimidazo[4,5-b]pyridine (4'-hydroxy-PhIP). A 25-fold higher rate of metabolism was measured in microsomes from polychlorinated-biphenyl-treated rats (94 nmol/mg proteins/30 min) in comparison with those from untreated rats. Other effective inducers of PhIP metabolism were beta-naphthoflavone and isosafrole (ISF), whereas phenobarbital was ineffective. About twice as much 2-hydroxamino-PhIP as 4'-hydroxy-PhIP was formed in microsomes irrespective of the inducer the rats had been treated with. The metabolism was dependent on NADPH and was abolished by the cytochrome P450 inhibitor alpha-naphthoflavone. In a reconstituted enzyme system purified rat cytochrome P450 IA2 (P450ISF-G) had the highest N-hydroxylation rate (30 nmol/nmol P450/30 min) closely followed by the rat cytochrome P450 IA1 (P450BNF-B). Less activity was seen with rat P450 IIC11 (P450UT-A) and rabbit P450 IA2 (P450 LM4). Rat P450 IIE1 (P450j), P450 IIB1 (P450PB-B) and rabbit P450 IIB4 (P450 LM-2) and P450 IIE1 (P450 LM3a) were essentially inactive. Rat P450 IA1 (P450BNF-B) produced five times more 4'-hydroxy-PhIP (32 +/- 2 nmol/nmol P450/30 min) than did P450 IA2 (P450ISF-G). Hence, the measured ratio of activation to detoxication for rat P450 IA2 (P450ISF-G) enzyme was 7-fold higher than that of the other active P450 enzymes.

Animals↗
PubMed1990

Hemodynamic dependence of myocardial oxygen consumption indexes.

We tested the afterload and contractile state dependency of three indexes of myocardial oxygen consumption (MVO2): total energy requirement (Et), pressure work index (PWI), and pressure-volume area (PVA). MVO2 was measured in seven isolated canine hearts at four or five different end-diastolic volumes at each of three settings of afterload resistance and with the hearts contracting isovolumically. In several hearts, contractility was also varied by dobutamine infusion. Measured MVO2 (MMVO2) was compared with values predicted (PMVO2) by each index. There was always a high degree of correlation between MMVO2 and PMVO2 for each of the indexes. However, there was a large degree of variability in the coefficients of the MMVO2-PMVO2 relation from one heart to another. We also observed a statistically significant influence of both afterload and contractile state on the predictive power of each of the indexes. Thus each index that we tested had shortcomings in being able to predict MVO2 accurately over a wide range of hemodynamic conditions.

Animals↗
PubMed1990

Profile of hospital governance: a report from the nation's hospitals.

During the 1980s, hospital governing boards struggled to solve a host of new and difficult problems while attempting to meet the needs of their communities. As we enter the last decade of the 20th century, different challenges lie ahead. To meet these challenges, hospital boards must first understand their various responsibilities. The results of this survey will provide a starting point to understand how hospitals are currently dealing with issues such as governing board composition and organization, board/CEO relations, and governing board operations. (Future articles in Trustee will focus on individual aspects of the survey.) In so doing, readers may begin to unlock the key to increased effectiveness.

Data Collection↗
PubMed1990

A case report: clinically benign anti-Cs(a).

Previous reports on the clinical significance of anti- Csa(Cost-Stirling) have presented conflicting data. We report our findings, over an 8-month period, of a patient whose serum contained anti-Csa and anti-Fya. Nineteen donor units of ABO and Rh-matched, Fya-negative red cells, which were crossmatch incompatible, were transfused with no clinical, serological, or biochemical evidence of a hemolytic transfusion reaction.

Journal Article↗
PubMed1990

Noninvasive diagnosis of deep vein thrombosis.

Deep vein thrombosis is a serious medical problem that may lead to pulmonary embolus. The authors discuss the noninvasive diagnosis of deep vein thrombosis using venous occlusion plethysmography and ultrasonic duplex scanning.

Humans↗
PubMed1989

The alpha 1/alpha 2 domains of class I HLA molecules confer resistance to natural killing.

The expression of transfected HLA class I Ag has previously been shown to protect human target cells from NK-mediated conjugation and cytolysis. In this same system, transfected H-2 class I Ag fail to impart resistance to NK. In this study, we have mapped the portion of the HLA class I molecule involved in this protective effect by exploiting this HLA/H-2 dichotomy. Hybrid class I genes were produced by exon-shuffling between the HLA-B7 and H-2Dp genes, and transfected into the class I Ag-deficient B-lymphoblastoid cell line (B-LCL) C1R. Only those transfectants expressing class I Ag containing the alpha 1 and alpha 2 domains of the HLA molecule are protected from NK, suggesting the "protective epitope" is located within these domains. Since a glycosylation difference exists between HLA and H-2 class I Ag within these domains (i.e., at amino acid residue 176), the role of carbohydrate in the class I protective effect was examined. HLA-B7 mutant genes encoding proteins which either lack the normal carbohydrate addition site at amino acid residue 86 (B7M86-) or possess an additional site at residue 176 (B7M176+) were transfected into C1R. Transfectants expressing either mutant HLA-B7 Ag were protected from NK. Thus, carbohydrate is probably not integral to a class I "protective epitope." The potential for allelic variation in the ability of HLA class I Ag to protect C1R target cells from NK was examined in HLA-A2, A3, B7, and Bw58 transfectants. Although no significant variation exists among the HLA-A3, B7, and Bw58 alleles, HLA-A2 appears unable to protect. Comparison of amino acid sequences suggests a restricted number of residues which may be relevant to the protective effect.

Amino Acid Sequence↗
PubMed1989

The induction of protective immunity to Leishmania major in the BALB/c mouse by interleukin 4 treatment.

The ability of interleukin 4 (IL4), administered subcutaneously around the cutaneous lesion in the form of hydrophilic gels, to affect the development of established Leishmania major infections in the BALB/c mouse was studied. IL4 had a therapeutic effect on L. major lesion growth compared with control mice, causing not only resolution of the parasite lesions over a period of 10 weeks but also rendering animals resistant to reinfection. Adoptive transfer of splenic T cells, obtained from IL4-treated animals, conferred significant resistance to L. major infection in naive BALB/c mice compared with controls. These results demonstrate that IL4 is capable of not only reversing the usual (i.e. non-curing) course of L. major infection in the BALB/c mouse, but also of promoting the generation of protective immunity. The nature of the gel used to deliver the cytokine was found to be important since the therapeutic activity of IL4 in poloxamer gel was not observed when a hydroxypropylmethyl cellulose (hypromellose) gel was used as the IL4 vehicle.

Animals↗
PubMed1989

Differential transport requirements of HLA and H-2 class I glycoproteins.

Transport of human and mouse major histocompatibility complex class I glycoproteins has been examined in a transport deficient B-lymphoblastoid cell line X T-lymphoblastoid cell line (B-LCL X T-LCL) hybrid, 174 X CEM.T2 (T2). This cell line expresses no detectable endogenous HLA-B5 and reduced levels of HLA-A2 on its surface although these molecules are synthesized. In order to study this defect further, either HLA-Bw58 or HLA-B7 genomic clones were transfected into T2. Metabolic labeling and immune precipitation demonstrated biosynthesis of the Bw58 or B7 glycoprotein. However, like the endogenous HLA-B5 molecule, neither HLA-Bw58 nor HLA-B7 was expressed at the cell surface. The cloned genes were properly expressed on the surface of C1R, a control B-LCL. To determine if mouse class I alleles had the same transport requirements as the human class I glycoproteins, either mouse H-2Dp or H-2Kb class I genes were introduced into T2. Surprisingly, the H-2 class I glycoproteins were transported to the cell surface normally. These data suggest a fundamental difference between human and mouse histocompatibility antigens in their requirements for intracellular transport.

Animals↗
PubMed1989

T-cell populations in liver and renal transplant recipients with infectious esophagitis.

Individuals undergoing hepatic and renal transplants are susceptible to infections of the gastrointestinal tract, particularly the esophagus. The most common responsible agents are Candida and herpes simplex virus (HSV) with cytomegalovirus (CMV), Aspergillus, and other agents being regarded as unusual pathogens even in this unique population. Altered T-cell populations have been associated with CMV colitis in healthy homosexuals and in individuals with the acquired immunodeficiency syndrome (AIDS). Similarly, individuals with Epstein-Barr virus infections have altered T-cell populations. Whether these infections alter T-cell populations in infected individuals or the abnormalities in T-cell subpopulations occur first and enhance the likelihood of an infection in susceptible populations is as yet unknown. In this study peripheral blood T-cell populations in individuals before (19 patients) and after (47 patients) liver transplantation and after receiving a renal allograft (21 patients) were compared. Those individual having any symptoms related to esophageal disease underwent upper gastrointestinal endoscopy combined with mucosal biopsies, brushings, and cultures and were subdivided into those with and without infectious esophagitis. CMV esophagitis was found to be associated with an arithmetically decreased T-cell helper/suppressor (H/S) ratio principally due to an increase in the suppressor cell number. Such a reduction in the TH/S ratio and in the number of circulating suppressor cells was not found in esophagitis due to either HSV or Candida and was unrelated to the serum cyclosporine level or prednisone dosage prescribed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Characterisation of metabolites of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline formed after incubation with isolated rat liver cells.

The metabolism of 14C-labelled 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) was studied in suspensions of hepatocytes isolated from PCB-pretreated rats. The metabolites found after incubation of IQ/MeIQ (0.1 mM) with PCB-pretreated hepatocytes for 3 h were separated into three principal groups: ethyl acetate-extractable metabolites (2-4%), water soluble metabolites (94-98%) and covalently bound metabolites (0.4-0.5%). The water soluble metabolites were separated by HPLC. The metabolites were evaluated by beta-glucuronidase lability, sulphate incorporation and compared with glucuronides formed by microsomes. Mass spectroscopy and proton NMR were also run. The major metabolites formed were a N2-sulphamate, an O-sulphate in position 5 for IQ and 5 for MeIQ and an O-glucuronide in the same position. The MeIQ N2-sulphamate was much less abundant than the IQ N2-sulphamate. When compared with hepatocytes from uninduced rats, it was found that primarily the formation of ring-hydroxylated conjugates increased after PCB-pretreatment. The major ethyl acetate-extractable metabolites were the N2-acetyl derivatives and an unidentified metabolite. A small peak representing the 5-hydroxy-IQ or 5-hydroxy-MeIQ could also be seen in the HPLC chromatogram of the ethyl acetate extractable metabolites. All major water soluble products described in hepatocytes were also found in urine and bile of uninduced rats exposed to IQ/MeIQ in vivo.

Animals↗
PubMed1989

Reduction of hexavalent chromium in a reconstituted system of cytochrome P-450 and cytochrome b5.

The reduction of hexavalent chromium (Cr(VI] by the monooxygenase components was studied. Both a reconstituted system of cytochrome P-450 (P-450) and cytochrome b5 (b5) with NADPH was capable of reducing Na2CrO4 (30 microM) provided anaerobic atmosphere. The rates were 1.29 nmol Cr.min-1 nmol P-450(-1) and 0.73 nmol Cr.min-1 nmol b5(-1). Using NADH instead of NADPH gave very low reducing activities, confirming the enzymic nature of the P-450 dependent Cr(VI) reductase reaction. Oxygen, 22% (air) and 0.1% gave 89% and 69% inhibition of Cr(VI) reducing activity, respectively. Carbon monoxide (100%) caused an inhibition of about 37% and 44% for P-450 and b5, respectively. Externally added flavin mononucleotide (FMN) (3 microM) or Fe-ADP (10 microM) to the complete system stimulated the enzymatic reaction about 2-fold and 3-fold, respectively.

Animals↗
PubMed1989

Microsomal metabolism of hexavalent chromium. Inhibitory effect of oxygen and involvement of cytochrome P-450.

The reduction of hexavalent chromium (Cr(VI] by rat liver microsomes was studied. With 15-120 microM Na2CrO4 microsomes (0.5 mg protein/ml) effectively reduced Cr(VI) in the presence of NADPH provided anaerobic conditions. Phenobarbital (PB) and Aroclor 1254 (PCB) pretreatment increased microsomal Cr(VI) reduction while CoCl2 reduced the rate. The rates with 30 microM Na2CrO4 were: 6.4 +/- 0.1, 7.8 +/- 0.7, 13.4 +/- 0.5, 2.95 +/- 0.09 nmol Cr.mg prot.-1 min-1 for control, PB, PCB and cobalt pretreated microsomes respectively. Kinetic studies gave a Michaeli-Menten like first-order kinetics with increases both in Km and Vmax values after pretreatment with PB or PCB. CO partly inhibited the microsomal Cr(VI) reduction. The CO-sensitive reduction rate was directly correlated to the cyt. P-450 content of the different microsomal preparations. Substituting NADH for NADPH gave approximately 27% lower activity with 30 microM Na2CrO4. This activity was neither inducible by cyt. P-450 inducers nor influenced by CO. Oxygen 1.0% and 0.10% gave approximately 100% and 30% inhibition of Cr(VI) reduction (30 microM Na2CrO4) respectively, and an uncompetitive like inhibitory pattern was found. No redox cycling of Cr(VI) was seen. 51Cr binding to the microsomes was approximately 10% after complete reduction of 30 microM Na2CrO4. Externally added FMN, Fe3+-ADP and nitrobenzen stimulated microsomal Cr(VI) reduction. A 60% higher reduction rate of Cr(VI) by isolated hepatocytes was found during anaerobic in comparison with aerobic conditions.

Animals↗