Biomedical subjects

M Gottlieb

Publications and source records attributed to M Gottlieb.

At least 19 recordsLinked to original sources

PubMed1992

Blood transfusion and postoperative infection in orthopedic patients.

Adverse effects of the transfusion of homologous blood on tumor recurrence and resistance to bacterial infection have been reported previously, but the findings are inconclusive. A retrospective review of patients undergoing orthopedic surgery was conducted, and the rate of the postoperative infectious complications was compared among those receiving homologous blood, autologous blood, both types, or no transfusion support. An overall postoperative infection rate of 6.1 percent was observed: 6.9 percent among persons receiving homologous blood, 5.0 percent among those receiving autologous blood, 11.9 percent among those receiving both homologous and autologous blood, and 4.9 percent among those not receiving transfusions (p = 0.37). Among patients receiving homologous blood, a subset of 15 patients received homologous whole blood and had an infection rate of 20 percent. Significant predictors of postoperative infection included increasing age, spinal surgery, high admission hematocrit, and greater time in surgery. Of factors relating to transfusion, only the use of homologous whole blood was a significant predictor of postoperative infection, which suggests a detrimental effect of homologous plasma. It can be concluded that, in this group of patients undergoing relatively nontraumatic surgery, several variables that are not related to transfusion, as well as the use of homologous whole blood, were significant predictors of postoperative infection.

Bacterial Infections↗

PubMed1992

Basic epidemiologic and statistical methods in clinical research.

Various study designs and approaches to statistical analysis in clinical research have their own underlying rationales and limitations for interpretation. This information is presented in an intuitive and accessible manner, relying minimally on basic algebra. Epidemiologic concepts of study design and interpretation, bias and confounding, hypothesis testing, and sample size and power are explained. Statistical tests and their appropriate applications are discussed for mean comparisons (t tests and ANOVA), percentages (chi-square), survival analysis, and correlation and regression. Applicable nonparametric tests are also introduced.

Carcinoma, Transitional Cell↗

PubMed1991

Ditiocarb sodium (diethyldithiocarbamate) therapy in patients with symptomatic HIV infection and AIDS. A randomized, double-blind, placebo-controlled, multicenter study.

We randomized 389 symptomatic patients with human immunodeficiency virus (HIV) infection to ditiocarb sodium (400 mg/m2 orally for 24 weeks) or a placebo. Patients were well balanced according to Centers for Disease Control (CDC) group, CD4+ cell number, and duration of disease prior to entry. Ten new acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections occurred in the treated patients and 21 in the controls. Reduction of new opportunistic infections in the ditiocarb group was significant in all patients (relative risk [RR], 0.44) and in patients with AIDS (CDC groups IV-C1 and IV-D) (RR, 0.12). The size of the effect of ditiocarb was maintained when data were reanalyzed after exclusion of a patient who progressed to Pneumocystis carinii pneumonia who was not strictly CDC-defined (RR, 0.46), or when considering as new opportunistic infections three events, which were clinically active at entry, but for which the definitive diagnosis was made during study (RR, 0.49). The administration of ditiocarb did not induce any major adverse clinical or biological reactions. We conclude that, in this study, ditiocarb was safe and reduced the incidence of opportunistic infections in patients with symptomatic HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation.

PURPOSE: Invasive Aspergillus infections cause significant morbidity and mortality in marrow transplant patients. In this study, we examined whether administration of intravenous low-dose prophylactic amphotericin B could reduce the incidence and mortality associate with invasive aspergillosis in patients undergoing allogenic marrow transplantation. PATIENTS AND METHODS: The subjects of this analysis were 186 consecutive patients undergoing allogeneic marrow transplantation in an adult bone marrow transplant unit between July 1, 1985, and September 30, 1990, utilizing consistent disease-specific chemoirradiation and graft-versus-host disease protocols. The incidence, morbidity, and case fatality of invasive aspergillosis in the study group receiving amphotericin chemoprophylaxis were compared with that in two historic cohorts managed without prophylactic amphotericin B. Univariate and multivariate statistical analyses were performed to examine whether an apparent protective effect could be attributed to differences in patient and treatment variables among the cohorts and to determine potential toxicities of the chemoprophylaxis regimen. RESULTS: There was a significant reduction in both the incidence (p = 0.003) and mortality (p = 0.03) of invasive aspergillosis in patients receiving amphotericin B chemoprophylaxis as compared with those not receiving chemoprophylaxis. The prophylactic amphotericin B schedule, as employed here, was not associated with increased renal or hepatic toxicity as compared with that in historically managed patients. CONCLUSION: These data suggest that the risks of invasive aspergillosis in allogeneic marrow transplant recipients can be reduced by administration of prophylactic amphotericin B during the pretransplant and peritransplant periods.

Adolescent↗

PubMed1991

Purification and characterization of the 3'-nucleotidase/nuclease from promastigotes of Leishmania donovani.

The surface membrane-associated 3'-nucleotidase/nuclease (3'-N'ase) of Leishmania donovani has been purified from detergent extracted promastigotes by anion and cation exchange, lectin affinity and gel filtration chromatography. SDS-PAGE analysis of the purified enzyme preparation revealed a 43-kDa polypeptide as well as faster migrating bands. These bands co-migrated, following both one- and two-dimensional electrophoretic analyses, with enzyme activity as determined by an in situ 3'-nucleotidase gel activity assay. It is suggested that the lower molecular weight species arise during purification as a result of proteolytic cleavage of the intact 43-kDa enzyme. The 3'-N'ase exhibited a pI of 5.4, as revealed by 2-dimensional gel electrophoresis. The glycoprotein nature of the 3'-N'ase was suggested by its binding to concanavalin A and by its electrophoretic shift following incubation with N-glycanaseR. In nucleotidase and nuclease assays, the 3'-N'ase was most active with 3'-AMP and poly(A), respectively. Both nucleotidase and nuclease activities exhibited broad pH optima with peaks at 8.5 and 7.5, respectively. At pH 8.5 nucleotidase activity was inhibited by EDTA, Zn2+ and thiols, but was insensitive to tartrate, molybdate and fluoride ions, commonly used inhibitors of phosphatases. The properties of the leishmanial 3'-N'ase was similar to the 3'-N'ase purified from purine-starved Crithidia luciliae, a related trypanosomatid protozoan, and to group of nucleases from fungi and germinating plant seedlings.

5'-Nucleotidase↗

PubMed1991

Chronic effects of focused electrohydraulic shock waves on renal function and hypertension.

The chronic effects of focused electrohydraulic shock waves were studied in a minipig model. Fifteen animals underwent a unilateral nephrectomy and compensatory renal hypertrophy was allowed to take place over a minimum of six months. Baseline studies were then carried out consisting of 1) serum creatinine, blood urea nitrogen, and plasma renin levels 2) intra-arterial blood pressure measurement and 3) 3H-inulin clearance. Ten of the animals then underwent 8 shockwave treatments (2500 shocks per treatment), alternately to the upper and lower pole of the kidney, at two weeks intervals. A total of 20,000 shock waves were administered to each minipig over the four month period. The five control pigs underwent sham procedures. The renal function and blood pressure evaluations were then repeated. No significant decrease in renal function was noted in the experimental animals when compared to the controls. In addition, renin mediated hypertension was not observed despite the excessive number of total shock waves delivered to the kidney.

Animals↗

PubMed1991

Phase I study of safety and pharmacokinetics of a human anticytomegalovirus monoclonal antibody in allogeneic bone marrow transplant recipients.

This study examined the safety and pharmacokinetic profile of a potentially therapeutic and fully human anti-CMV monoclonal antibody (SDZ MSL-109) in a phase I dose escalation trial in patients receiving allogeneic bone marrow transplants. Fifteen adult marrow transplant patients, twelve with chronic myelogenous leukemia and three with acute nonlymphocytic leukemia, in cohorts of five patients each, were administered monoclonal antibody intravenously at doses of 50, 250, and 500 micrograms/kg at approximately three-week intervals for six months. Administration of the monoclonal antibody was associated with minimal side effects and no dose-related toxicity. Antibody elimination curves in all dose groups were consistent with a two-compartment model with an alpha half-life at the low, middle, and high dose groups of 1.03, 0.82, and 0.79 days, and a beta half life of 13.9, 14.0, and 16.5 days, respectively. The volume of distribution decreased with repetitive dosing to approximate the plasma volume in each patient and the pharmacokinetic profile was comparable to that of human IgG. There was no host antiidiotypic or antiallotypic antibody formation, indicating that MSL-109 was not immunogenic. Further studies are warranted to assess the potential efficacy of human monoclonal anti-CMV disease in marrow transplant recipients and other patients with immunodeficiency disorders.

Adult↗

PubMed1991

Allogeneic bone marrow transplantation for relapsed and refractory lymphoma using genotypically HLA-identical and alternative donors.

Twenty-two patients, ages 16.6 to 43.9 years (median age, 30 years), with relapsed or refractory lymphoma were treated by allogeneic bone marrow transplantation after high-dose chemotherapy with or without total body irradiation (TBI). Seven patients had Hodgkin's disease, four had low-grade histology non-Hodgkin's lymphoma (NHL), seven had intermediate-grade NHL, and four had high-grade NHL. Of the 22 patients, 17 received T-cell (CD-3)-depleted marrow after intensive pretransplant chemoradiotherapy, and five received T-cell-replete grafts after chemotherapy-based preparative regimens. Five patients were transplanted from donors other than genotypically HLA-identical siblings: four from partially HLA-matched relatives, and one from a phenotypically HLA-identical unrelated donor. Acute graft-versus-host disease (GVHD) was less than or equal to grade II in all patients, and chronic GVHD was limited or absent in all but one patient. Of the 21 assessable patients, 17 (80.9%) achieved complete remissions. Death due to transplant-associated complications occurred in five patients, and five patients have relapsed. Thirteen patients are alive, and 12 are continuously relapse-free at a median follow-up of longer than 28 months (range, greater than 10 to greater than 58 months) from transplant. The cumulative probability of treatment failure from relapse or progression of lymphoma was 29% (95% confidence interval [CI], 12% to 51%), while the actuarial lymphoma-free (ie, event-free) survival plateau is 54.6% (95% CI, 34% to 76%). For young patients with advanced malignant lymphoma, allogeneic bone marrow transplantation appears superior to salvage chemotherapy for achievement of long-term, lymphoma-free survival and may be preferable to autologous bone marrow transplantation for selected patients.

Actuarial Analysis↗

PubMed1991

The influence of mechanical injury on the metabolic activity of transplanted cerebral cortex.

The authors studied the metabolic activity of rat embryonic cerebral cortex grafts (ED 15-16) implanted into rat brains immediately (TR0) and 14 days (TR14) after cavity formation. Over a period of two months, the ATP, lactate and glucose concentration in TR0 transplants remained at the same level as observed in the intact cortex, whereas in TR14 transplants the ATP and glucose concentration fell significantly and the lactate concentration rose. The DNA concentration rose in both types of transplants, but the increase was more pronounced in TR0 grafts. Choline acetyltransferase activity (a neuron marker) fell significantly in both cases, but the decrease was greater in TR14 transplants. The results indicate that grafts implanted into the brain immediately after cavities had been formed have better metabolic activity and are capable of longer survival than grafts implanted 14 days after cavitation.

Acetylcholine↗

PubMed1990

Risk factors for postvitrectomy fibrin formation.

We prospectively studied 194 patients undergoing vitrectomy between July 1988 and April 1989 to determine the incidence of postvitrectomy intraocular fibrin formation and the association of a variety of preoperative and intraoperative variables with the formation of severe postvitrectomy fibrin. Overall, 62 (32%) patients developed postvitrectomy fibrin; 25 (13%) had mild fibrin formation, 13 (6.5%) had moderate fibrin formation, and 24 (12.4%) had severe fibrin formation. By logistic multivariate analysis, preoperative factors that were independently predictive of severe fibrin formation included severe flare (P = .004), the presence of a previously placed scleral buckle (P = .001), and poor preoperative visual acuity (P = .007). Anterior epiretinal membrane dissection was the only intraoperative factor that was independently associated with an increased fibrin risk (P = .0003). A risk score derived from the multivariate analysis effectively categorized patients according to their likelihood of developing severe postvitrectomy fibrin. Results of this study may be useful in designing prophylactic interventions to decrease postvitrectomy fibrin formation.

Adult↗

PubMed1990

An inducible 3'-nucleotidase/nuclease from the trypanosomatid Crithidia luciliae. Purification and characterization.

Several species of protozoan parasites of the family Trypanosomatidae have a surface membrane-associated enzyme which is capable of hydrolyzing extracellular 3'-nucleotides and nucleic acids, thereby aiding in the acquisition of nutritionally required purines and Pi from their hosts. In Crithidia luciliae, this 3'-nucleotidase/nuclease previously has been shown to be highly regulated as purine and/or Pi starvation of this trypanosomatid leads to as much as a 1000-fold increase in enzyme activity. We have purified the enzyme to apparent homogeneity from detergent extracts of purine-starved C. luciliae by heparin-agarose chromatography followed by Mono Q and Mono S fast protein liquid chromatography. The enzyme had an apparent molecular weight of 43,000 and a pI of approximately 5.8. The enzyme displayed broad pH optima, with peaks at 8.0, for both nucleotidase and nuclease activities. The pH optima shifted to lower values when the activity was assayed in the presence of sulfhydryl reagents. The enzyme was most active with 3'-AMP and poly(A) in nucleotidase and nuclease assays, respectively. As a nuclease the enzyme hydrolyzed RNA at a faster rate than single-stranded DNA with no detectable hydrolysis of double-stranded DNA. The loss of enzyme activity which occurred upon storage at acid pH was prevented by the inclusion of Zn2+ in storage buffers. The physicochemical and kinetic properties of this trypanosomatid enzyme suggest that it is similar to the class I nucleases found in fungi and in germinating seedlings of higher plants.

Animals↗

PubMed1990

Crithidia luciliae: starvation for purines and/or phosphate leads to the enhanced surface expression of a protein responsible for 3'-nucleotidase/nuclease activity.

It has been shown previously that starvation of the trypanosomatid protozoan Crithidia luciliae for purines and/or inorganic phosphate results in increased levels of a surface membrane-associated 3'-nucleotidase/nuclease (3'-N'ase) activity which hydrolyzes both 3'-ribonucleotides and nucleic acids, thereby permitting the organisms to transport these essential nutrients across their cell membranes. A polypeptide with the requisite catalytic properties has been identified by an in situ gel activity assay following sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In current studies, differential synthesis of the protein responsible for the 3'-N'ase activity was not demonstrable by comparisons of SDS-PAGE patterns of nutrient-replete or purine-starved parasites metabolically labeled with either [35S]methionine, [3H]leucine, or [3H]tyrosine. However, surface labeling of nutrient-replete and purine-starved cells revealed the enhanced expression of an 125I surface-labeled 43-kDa protein which comigrated with the 3'-N'ase activity in one- and two-dimensional electrophoretic systems. The amount of this surface-labeled peptide correlated with the level of 3'-N'ase activity as measured by test tube assay. Refeeding adenosine to purine-starved cells led to the loss of both the enzyme activity and the surface iodinatable 43-kDa band as a result of renewed cell division. Starvation of these organisms for phosphate also led to the enhanced expression of the 43-kDa radioiodinatable band. The results indicated that the 3'-N'ase protein, itself, is differentially expressed at the cell surface under conditions which lead to increased enzyme activity.

Animals↗

PubMed1990

Leishmania donovani: regulated changes in the level of expression of the surface 3'-nucleotidase/nuclease.

Leishmania donovani promastigotes have previously been shown to possess a surface membrane bound 3'-nucleotidase/nuclease (3'-N'ase) capable of hydrolyzing both nucleic acids and 3'-ribonucleotides. The specific activity of the 3'-N'ase was increased following transfer of the parasites to fresh, nutrient-replete media or to media lacking purines and/or inorganic phosphate (Pi). In nutrient-replete media, the enzyme activity was transiently elevated during the lag and early logarithmic phases of the growth curve; enzyme activity fell as the cells continued into late log and stationary phases. Purine- and Pi-starved cells exhibited significantly greater levels of 3'-N'ase activity than nutrient-replete cells. These levels remained elevated as long as the organisms were maintained in the deficient media. Nutrient-replete and purine-starved 125I surface-labeled parasites displayed differences in electrophoretic patterns. Upon purine starvation, incorporation of radiolabel was increased in proteins which migrated with apparent molecular weights of 70, 43, and 40 kDa. Comigration, in both one- and two-dimensional systems, of 3'-N'ase activity with the radiolabeled 43-kDa band demonstrated that this band was the catalytically active protein. Peptide mapping of the 70-, 43-, and 40-kDa proteins failed to demonstrate similarities in peptide sequence consistent with either a degradation or a precursor/product relationship. Treatment of the 43- and 40-kDa peptides with N-Glycanase indicated that they were differentially glycosylated. The cumulative results of these studies indicated that L. donovani can respond to altered culture conditions by the differential expression of surface proteins. In particular, the differential expression of the protein responsible for 3'-N'ase activity is consistent with the role of this enzyme in purine acquisition.

Animals↗

PubMed1990

Alterations in Leishmania donovani 3'-nucleotidase/nuclease activity banding pattern in polyacrylamide gels.

1. In the absence of protease inhibitors, partial purification of the 3'-nucleotidase/nuclease (3'-N'ase) from detergent extracts of Leishmania donovani leads to the appearance of bands, at 42,000 and 38,000 Da, of enzyme activity which, in SDS-PAGE, migrate faster than 43,000 Da, the apparent weight of the intact polypeptide. 2. The generation of these faster migrating species is a consequence of detergent extraction and is prevented by the addition of the protease inhibitors PMSF and leupeptin, suggesting that degradation by an endogenous protease is responsible. 3. Treatment of leishmanial membranes with exogenous proteases yields activity at 38,000 Da which is membrane-associated. Protease treatment has no effect on living cells. 4. The observed changes in enzyme migration are discussed in terms of enzyme stability and regulation. 5. The advantages and limitations of the in situ gel activity assay are considered.

Animals↗

PubMed1989

Muscle glycogen depletion patterns during draught work in Standardbred horses.

Muscle fibre recruitment was investigated during draught loaded exercise by studying glycogen depletion patterns from histochemical stains of muscle biopsies from the gluteus and semitendinosus muscles. Three Standardbred trotters performed several intervals of draught loaded exercise on a treadmill with 34 kp at a trot (7 m/sec) and with 34 and 80 kp, respectively at a walk (2m/sec). Exercise was continued until the horses were unwilling to continue. Glycogen depletion was seen in all three fibre types when trotting with 34 kp for 5 or 10 mins. When an equal weight resistance was pulled at a walk, glycogen depletion was first seen in type I fibres only, then followed by a small percentage of type IIA fibres after at least 1 h. When 80 kp was pulled at a walk both type I and IIA fibres showed glycogen depletion, and after at least 30 mins exercise a small percentage of type IIB fibres was also depleted. These results indicate that the muscle fibres are depleted, in order, from type I through IIA to IIB as the intensity or duration of draught work increases.

Animals↗

PubMed1989

Effects of a draft-loaded interval-training program on skeletal muscle in the horse.

Five Standardbred trotters were trained on a treadmill 3 times/wk for 12 wk by intervals of draft-loaded exercise. The draft load was 34 kp and the velocity approximately 7 m/s. Muscle biopsies were taken from the gluteus medius and longissimus muscles before training and after 2, 4, 8, and 12 wk of training and from the brachiocephalicus muscle before and after training. Both the percentage and the area of type IIa fibers increased and the percentage of type IIb fibers decreased in the gluteus medius muscle during the first 2 wk of training, and then no further significant difference was noted. The percentage of type I fibers increased in the brachiocephalicus muscle, and the area of type IIb fibers increased in the longissimus muscle. The citrate synthase activity increased in the gluteus muscle only, and the increase was seen during the first 2 wk. No significant differences were seen in 3-hydroxy-acyl-CoA dehydrogenase and lactate dehydrogenase activities in the muscles during the entire training period. Less glycogen was utilized in the gluteus muscle and less blood lactate accumulated when the horses performed an unloaded submaximal exercise test after compared with before training. It can be concluded that rapid changes are induced in the gluteus medius muscle when horses are trained pulling a light-draft resistance at a submaximal trotting speed.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed1989

Blood and muscle metabolic responses to draught work of varying intensity and duration in horses.

Three standardbred trotters performed treadmill exercise at a velocity of 2 m s-1 with a draught load of both 34 kiloponds (kp) (test 1) and 80 kp (test 2), and also at 7 m s-1 with 34 kp (test 3). The heart rate increased to average values of 111 (+/- 5), 157 (+/- 10) and 197 (+/- 7) beats min-1 in tests 1, 2, and 3, respectively. Plasma free fatty acids increased only during tests 1 and 2. Blood lactate and muscle glucose-6-phosphate and lactate concentrations were low after tests 1 and 2, but high after test 3, where also muscle glycogen utilisation was greatest. Muscle creatine phosphate and adenosine triphosphate concentrations decreased after test 3 only. The study indicates that oxidative metabolism is most important for energy supply in muscles when exercise is performed with draught loads of both 34 and 80 kp at a low velocity. Glycogenolysis with lactate accumulation and phosphagen breakdown becomes much more important when, with a draught load of 34 kp, the velocity of exercise increases.

Adenosine Triphosphate↗

PubMed1988

Crithidia luciliae: factors affecting the expression of 3'-nucleotidase/nuclease activity.

Crithidia luciliae, a trypanosomatid protozoan readily grown in axenic cultures, was shown to possess low levels of a surface membrane-bound ectoenzyme capable of hydrolyzing both 3'-ribonucleotides and nucleic acids. The specific activities of this 3'-nucleotidase/nuclease, with both mononucleotide and nucleic acid substrates, were greatly enhanced when the protozoa were deprived of purines, an essential nutrient. The catalytic activities were exhibited by a polypeptide which migrated in sodium dodecyl sulfate-polyacrylamide gel electrophoresis with an Mr of 47,000. Starvation of these cells for inorganic phosphate (Pi), in media with or without purines, also led to an increase in the specific activity of the ectoenzyme compared to that of Pi- and purine-replete cells. In contrast, the level of enzyme activity was not increased when the protozoa were starved, under purine-replete conditions, for either arginine or hemin, two other essential nutrients. Cells starved simultaneously for either of the latter two nutrients and for purines also did not show increased levels of the 3'-nucleotidase/nuclease. The activation of the enzyme was also prevented by sodium arsenite, cycloheximide, actinomycin D, and tunicamycin indicating that the activation presumably required metabolic energy as well as new transcription, translation, and protein modification. The results demonstrate that the control of 3'-nucleotidase/nuclease expression is a regulated, adaptive response to growth-limiting levels of essential nutrients.

Adenosine↗