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Biomedical subjects

B Goldberg

Publications and source records attributed to B Goldberg.

At least 91 records · Page 5Linked to original sources
PubMed1994

Clinical and immunologic evaluation of HIV-infected patients treated with dinitrochlorobenzene.

BACKGROUND: Promotion of cell-mediated immunity appears to be an important goal in the control of HIV infection. Topical dinitrochlorobenzene (DNCB) stimulates systemic cell-mediated immunity via the induction of cutaneous delayed-type hypersensitivity. OBJECTIVE: Our goal was to evaluate the clinical and immunologic effects of chronic DNCB application in a group of 24 HIV-infected patients. METHODS: We observed the patients for a mean of 28 months (range, 14 to 44 months). Of the 24 patients, 13 continued weekly DNCB application throughout the study (the compliant group), and 11 discontinued DNCB use after a mean of 10.9 months (the noncompliant group). RESULTS: Two of the 13 compliant patients progressed to AIDS; none of these patients died. In contrast, AIDS developed in 5 of the 11 noncompliant patients and four of these patients died. Analysis of lymphocyte subsets revealed significant increases in natural killer cells and activated/cytotoxic CD8 T-cell subsets in the compliant group. In contrast, these cellular immune-related lymphocyte subsets decreased in the noncompliant subjects. Although CD4 T-cell levels decreased in both groups, there was a significantly greater drop in the noncompliant patients. CD8+CD38+ T cells increased significantly in both groups. CONCLUSION: Chronic DNCB application appears to have a beneficial clinical and immunomodulatory effect in HIV-infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Combination chemotherapy of drug-resistant Trypanosoma brucei rhodesiense infections in mice using DL-alpha-difluoromethylornithine and standard trypanocides.

Combinations of DL-alpha-difluoromethylornithine (DFMO; eflornithine; Ornidyl) with either suramin or melarsen oxide were found to be effective against acute laboratory model infections with Trypanosoma brucei rhodesiense. We used clinical isolates known to be resistant to these drugs when used singly. An infection with a melarsen oxide-refractory isolate was cured by a combination of low-dose DFMO (0.5% in the drinking water) plus low-dose suramin (1 mg/kg of body weight given intraperitoneally). Another strain, moderately resistant to arsenical drugs, was cured with combinations of 4% DFMO with 5 mg of melarsen oxide per kg. Furthermore, a combination of DFMO (2% in the drinking water) and suramin (20 mg/kg) provided a 100% cure rate in a central nervous system model, although the same doses of these drugs used singly were completely ineffective. The synergism of DFMO and suramin against an acute infection was improved when suramin was given at the end of the DFMO administration. No adverse interactions were observed when high doses of DFMO combined with high doses of suramin were administered to uninfected mice. These results suggest that combinations of DFMO and suramin should be examined clinically for activity in arsenical-drug-refractory cases of East African sleeping sickness.

Animals↗
PubMed1994

A few good men.

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Audiology↗
PubMed1994

Influence of biological response modifiers: measurement of tumor blood flow and temperature.

Human recombinant interferon-alpha-2b (IFN) is known to inhibit growth of both normal and tumor cells and to stimulate immune effector cell function. We have previously shown that IFN and other biological response modifiers augment accumulation of radiolabeled antibodies in tumors. This investigation demonstrates that 30 min post i.m. administration of IFN significantly (p < 0.01) enhances tumor perfusion in tumor-bearing mice and persists for a much longer time than in normal tissue, which, in part, may contribute to the enhanced tumor uptake of radiolabeled monoclonal antibodies within 1.5 h of their administration. Histological examinations of tumors obtained from animals receiving IFN 72 h previously did not show changes in inflammatory cells. Our investigation shows that laser Doppler flowmetry and color Doppler imaging can provide an excellent means of measuring tumor perfusion changes in small living animals where radioactive tracers cannot be used.

Animals↗
PubMed1993

Resistance to DL-alpha-difluoromethylornithine by clinical isolates of Trypanosoma brucei rhodesiense. Role of S-adenosylmethionine.

The ornithine decarboxylase (ODC) inhibitor DL-alpha-difluoromethylornithine (DFMO) has emerged as a new treatment for West African sleeping sickness but is less effective against East African sleeping sickness. We examined uncloned clinical isolates of Trypanosoma brucei rhodesiense, agent of the disease in East Africa, which were refractory to DFMO in laboratory infections, for characteristics that would explain their resistance. None of the isolates were from patients treated with DFMO. Two isolates took up [3H]DFMO at 50-70% lower rates than drug-sensitive strains but ODC activities, Ki values for DFMO, spermidine and spermine uptake rates, polyamine content and inhibition of polyamine metabolism by DFMO were statistically (P < 0.05) similar between sensitive and refractory isolates. One cloned strain, continuously passaged in vivo under DFMO pressure and included for comparison, had > 85% lower ODC activity and up to 14-fold higher putrescine uptake rates than sensitive controls. A statistically important trend was the metabolism of S-adenosylmethionine (AdoMet): activities of AdoMet synthetase and AdoMet decarboxylase were 2- to 5-fold and 3- to 40-fold lower in resistant strains, respectively, while intracellular AdoMet pools (AdoMet + decarboxylated AdoMet) that were > 60-fold elevated in sensitive strains during DFMO treatment, increased only 9-fold in refractory isolates. The extreme elevation of the AdoMet pool in sensitive isolates from 0.7 to 44 nmol/mg protein and an intracellular pool concentration of approximately 5 mM may lead to an imbalance in methylation of proteins or other cell constituents as a consequence of DFMO action. These studies indicate that the metabolism of AdoMet is altered significantly in DFMO refractory isolates and suggest that differences in AdoMet metabolism may be responsible for increased tolerance to DFMO.

Animals↗
PubMed1993

Trichomonas vaginalis: characterization of ornithine decarboxylase.

Ornithine decarboxylase (ODC), the lead enzyme in polyamine biosynthesis, was partially purified from Trichomonas vaginalis and its kinetic properties were studied. The enzyme appears to be of special significance in this anaerobic parasite, since the arginine dihydrolase pathway generates ATP as well as putrescine from arginine. ODC from T. vaginalis had a broad substrate specificity, decarboxylating ornithine (100%), lysine (1.0%) and arginine (0.1%). The enzyme had a pH optimum of 6.5, a temperature optimum of 37 degrees C and was pyridoxal 5'-phosphate-dependent. Attempts to separate ornithine- from lysine-decarboxylating activity by thermal-stability and pH-optima curves were not successful. Although Km values for ornithine and lysine were 109 and 91 microM respectively, and the Vmax values for these substrates were 1282 and 13 nmol/min per mg of protein respectively, the most important intracellular substrate is ornithine, since intracellular ornithine levels are 3.5 times those of lysine and extracellular putrescine levels are 7.5 times those of cadaverine. Ornithine was also an effective inhibitor of lysine-decarboxylating activity (Ki 150 microM), whereas lysine was relatively ineffective as inhibitor of ornithine-decarboxylating activity (Ki 14.5 mM). Crude ODC activity was localized (86%) in the 43,000 g supernatant and 3303-fold purification was obtained by (NH4)2SO4 salting and DEAE-Sephacel, agarose-gel and hydroxyapatite chromatography steps. The enzyme bound difluoro[3H]methylornithine ([3H]DFMO) with a ratio of drug bound to activity of 2500 fmol/unit, where 1 unit corresponds to 1 nmol of CO2 released from ornithine/min. The enzyme had a native M(r) of 210000 (gel filtration), with a subunit M(r) of 55,000 (by SDS/PAGE), suggesting that the trichomonad enzyme is a tetramer. From the subunit M(r) and binding ratio of DFMO, there is about 137 ng of ODC per mg of T. vaginalis protein (0.013%). The significant amount of ODC protein present supports the view that putrescine synthesis in T. vaginalis plays an important role in the metabolism of the parasite.

Animals↗
PubMed1993

S-adenosylmethionine synthetase in bloodstream Trypanosoma brucei.

S-adenosylmethionine synthetase was studied from bloodstream forms of Trypanosoma brucei brucei, the agent of African sleeping sickness. Two isoforms of the enzyme were evident from Eadie Hofstee and Hanes-Woolf plots of varying ATP or methionine concentrations. In the range 10-250 microM the Km for methionine was 20 microM, and this changed to 200 microM for the range 0.5-5.0 mM. In the range 10-250 microM the Km for ATP was 53 microM, and this changed to 1.75 mM for the range 0.5-5.0 mM. The trypanosome enzyme had a molecular weight of 145 kDa determined by agarose gel filtration. Methionine analogs including selenomethionine, L-2-amino-4-methoxy-cis but-3-enoic acid and ethionine acted as competitive inhibitors of methionine and as weak substrates when tested in the absence of methionine with [14C]ATP. The enzyme was not inducible in procyclic trypomastigotes in vitro, and the enzyme half-life was > 6 h. T. b. brucei AdoMet synthetase was inhibited by AdoMet (Ki 240 microM). The relative insensitivity of the trypanosome enzyme to control by product inhibition indicates it is markedly different from mammalian isoforms of the enzyme which are highly sensitive to AdoMet. Since trypanosomes treated with the ornithine decarboxylase antagonist DL-alpha-difluoromethylornithine accumulate AdoMet and dcAdoMet (final concentration approximately 5 mM), this enzyme may be the critical drug target linking inhibition of polyamine synthesis to disruption of AdoMet metabolism.

Amines↗
PubMed1993

Effect of glucose and confluency on phosphorus metabolites of perfused human prostatic adenocarcinoma cells as determined by 31P MRS.

A series of perfused cell 31P MRS studies were conducted using a well established human prostate adenocarcinoma cell line (DU 145) at different phases of growth, and exposed to varying glucose concentrations during growth. The spectral characteristics of perfused DU 145 cells were compared with the same cells grown in nude mice (xenografts). Perfused DU 145 cells had lower levels of inorganic phosphate and phosphocreative relative to in vivo nude mice xenografts. 31P MR spectra obtained from perfused cells at different phases of growth and exposed to varying glucose concentrations during grown suggest that increases in diphosphodiester levels are associated with high glucose concentrations and confluency. Perfused DU 145 cells grown in 5.5 mM glucose and harvested at log phase of growth best reflected the phosphorus MR spectra of the same cell line grown in nude mice.

Adenocarcinoma↗
PubMed1993

The future of long-term and permanent contraceptive methods. Developments in technology.

The Association for Voluntary Surgical Contraception (AVSC) does not expect dramatic advances in female sterilization during the decade. Minilaparotomy and laparoscopy will endure as the standard surgical approaches, but programs will continue to shift toward the use of local anesthesia for these procedures because of greater safety and lower costs. No-scalpel vasectomy demonstrated by AVSC to be popular, effective, and safe holds greater potential for expanding the vast, and largely ignored, male market. The injection methods of vasectomy now being tested in China and elsewhere may make male sterilization even more acceptable. Markets for IUDs, implants, and injectables will continue to expand as more clients seek safe and effective long term contraception, and as national family planning programs (particularly in Asia) realize the ethical and programmatic importance of offering choices. Norplant is expensive and requires a skilled network of providers to both insert and remove the implants. For these reasons, AVSC expects Norplant to remain a niche method, mostly for urban clients who are not interested in sterilization or who are ill-suited for IUDs or injectables. Injectables, already popular in many parts of the world, will become increasingly available and used now that the US food and Drug Administration has approved Depo-Provera. New types of injectables, currently being developed, will be brought to market. The potential for IUDs is vast, particularly the low-cost, highly-effective Copper T 380A, which is expected to be approved as a 10-year method. However, poor quality service delivery and the high prevalence of sexually transmitted diseases could limit the potential of this method.

Contraception↗
PubMed1993

Acute myocardial infarction complicating prothrombin complex concentrate therapy in an 8-year-old boy with hemophilia A and factor VIII inhibitor.

PURPOSE: An 8-year-old boy with mild hemophilia A and inhibitors developed an acute myocardial infarction during treatment with prothrombin complex concentrates. CONCLUSIONS: This rare complication warrants restriction of dosage and length of treatment with these products to the recommended guidelines. It also appears that noninvasive cardiac monitoring of these patients is beneficial.

Blood Coagulation Factors↗
PubMed1993

Rehabilitation in the outpatient setting.

A working familiarity with rehabilitation techniques is absent from most primary care settings. Primary care clinicians can benefit greatly from better knowledge of the principles of geriatric rehabilitation. Physiatrists and geriatricians can have a greater impact if future research also explores the practical barriers to providing rehabilitation services outside institutional settings. An active, collaborative search for new models of care is needed. If more elderly citizens are to benefit from effective rehabilitation services, established geriatric rehabilitation programs must learn how to select from the many patients referred for evaluation those who will most benefit from outpatient rehabilitation services. Impending national health care reform creates a window of opportunity to establish rational systems to deliver health services designed for our aging population.

Aged↗
PubMed1992

Inhibition of Trichomonas vaginalis ornithine decarboxylase by amino acid analogs.

Ornithine decarboxylase (ODC) from Trichomonas vaginalis was inhibited irreversibly by several substrate analogs. Of these, DL-alpha-monofluoromethyldehydroornithine (MFMDO) and DL-alpha-monofluoromethylornithine (MFMO) were the most potent. The enzyme was unaffected by putrescine analogs suggesting that differences exist between the regulation of the trichomonad enzyme and that in other eukaryotes. In culture the ornithine analogs strongly inhibited putrescine synthesis and increased the generation time after 24 hr of exposure. In a semi-defined growth medium MFMDO methyl and ethyl esters increased the generation time from 4.5 hr to 9.0 and 8.2 hr, respectively. In standard undefined growth medium the trichomonad ODC was fully induced only after 15 hr (late log) and had an extended half-life of greater than 8 hr.

Amino Acids↗
PubMed1992

Origin of AIDS.

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Acquired Immunodeficiency Syndrome↗
PubMed1992

Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor.

The compound 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL73811), a potent inhibitor of S-adenosylmethionine decarboxylase, was effective in mice against six of eight clinical isolates of Trypanosoma brucei rhodesiense, the causative agent of East African sleeping sickness. In combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl), MDL73811 acted synergistically to cure seven of eight infections. MDL73811 was effective when given singly at 50 to 100 mg/kg of body weight per day for 7 days (osmotic pumps). In combination with subcurative DFMO levels (0.25 to 1.0% in drinking water for 7 days), the curative MDL73811 dose could be lowered to 25 or 50 mg/kg, depending on the isolate. Oral administration of the MDL73811-DFMO combination was also effective in an acute infection and in a long-term central nervous system model of Trypansoma brucei brucei infection. These data indicate that MDL73811 may be effective therapeutically in drug-refractory and late-stage East African trypanosomiasis.

Adenosylmethionine Decarboxylase↗