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Biomedical subjects

M Rosenblum

Publications and source records attributed to M Rosenblum.

At least 19 recordsLinked to original sources
PubMed1992

Developmental regulation of annexin II (Lipocortin 2) in human brain and expression in high grade glioma.

In experiments to identify molecules that might be important in the pathogenesis of glioblastoma multiforme, the most common malignant brain tumor, we found that annexin II (Lipocortin 2, p36), a likely second messenger in several different mitogenic pathways, was highly expressed in tumor tissue of glioblastoma multiforme (9 of 9) and highly anaplastic astrocytoma (2 of 6), but not in astrocytomas of lower pathological grade (0 of 6). We also detected high levels of annexin II expression in fetal brain during the period when radial glia proliferate, although annexin II expression was not detected in normal adult brain. These data demonstrate that annexin II expression is developmentally regulated in the human central nervous system and suggest that the early progenitor radial glia share important characteristics with highly malignant glial tumors.

Amino Acid Sequence↗
PubMed1992

Epstein-Barr virus in acquired immune deficiency syndrome (AIDS) and non-AIDS primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) still occurs mainly in patients who are immunosuppressed, but its incidence is rising dramatically among immunocompetent individuals. The Epstein-Barr virus (EBV) has been detected by in situ hybridization in PCNSL tumor tissue from patients who are immunodeficient, but not from patients who are immunocompetent. Using the more sensitive polymerase chain reaction (PCR) technique, the authors analyzed PCNSL tissue from 13 patients with acquired immune deficiency syndrome (AIDS) and 13 patients who were immunocompetent for the presence of EBV genome. METHODS: DNA was extracted from paraffin-embedded biopsy or autopsy specimens. PCR was run using primers for EBV (from the first internal repeat segment of the EBV genome), and identical samples were run simultaneously with primers against actin or the p53 gene as controls to establish the presence of DNA in the sample. Reaction products were also Southern blotted to confirm EBV specificity. RESULTS: EBV was detected in the tumor tissue of 11 of 13 patients (85%) with AIDS and of 7 of 13 patients (54%) who did not have AIDS. There was a history of illness that might suggest or predispose to immune compromise in 5 of 13 patients without AIDS; however, prior illness did not predict EBV-positive tumors. CONCLUSIONS: Although mechanisms remain to be clarified, EBV was present in a high percentage of patients with AIDS-related PCNSL and non-AIDS-related PCNSL:

Acquired Immunodeficiency Syndrome↗
PubMed1992

Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor.

DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

Adult↗
PubMed1992

p53 gene mutations in primary lung tumors are conserved in brain metastases.

The p53 product is frequently mutated in human tumors. Both acquired and inherited mutations have been described. These mutations transform p53 from a growth suppressor gene to a transforming oncogene. We examined tissue from 6 patients with primary lung carcinoma and the corresponding brain metastases for the presence of p53 mutations by immunohistochemistry. We then confirmed and characterized the mutations by single strand conformation analysis and by direct sequence analysis. All 6 patients had primary and metastatic tumor expressing a mutant p53. The mutations were all G-T transversions and mapped to exons 5, 6, 7, and 8. The mutations in the primary tumors were precisely conserved in the brain metastases.

Aged↗
PubMed1992

Cutaneous T-cell lymphoma presenting with diffuse lymphomatous infiltration of the peripheral nerves: response to combination chemotherapy.

A patient with nonepidermotropic cutaneous T-cell lymphoma presented with severe diffuse peripheral neuropathy that was the result of lymphomatous infiltration of the peripheral nervous system. There was no other evidence of systemic disease. The diagnosis was delayed because of the unusual presentation. A peripheral nerve biopsy was instrumental in establishing the etiology of the neuropathy. The patient achieved complete clinical remission with combination chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Increased neopterin levels in brains of patients with human immunodeficiency virus type 1 infection.

Postmortem levels of native neopterin (D-erythro-neopterin) were measured in cerebral cortical samples from 44 human immunodeficiency virus type 1-infected and eight uninfected, nonneurological control patients. Cerebral cortical gray and white matter neopterin levels for the controls ranged from 0.5 to 7.2 pmol/mg of protein in contrast to neopterin levels in brains of the virus-infected patients, which frequently were more than threefold and occasionally more than 30-fold higher than mean control levels. Cortical neopterin levels did not correlate with severity of the acquired immunodeficiency syndrome dementia complex, but subcortical levels correlated with the presence of active human immunodeficiency virus type 1 infection, as reflected by pathological evidence of multinucleated giant cell encephalitis. Evidence of opportunistic cytomegalovirus infections in approximately 25% of the human immunodeficiency virus type 1-infected patients was associated with enhanced levels of neopterin in frontal cortex.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Central pain from cerebral abscess: thalamic syndrome in AIDS patients with toxoplasmosis.

We describe two patients with acquired immunodeficiency syndrome (AIDS) who developed classic thalamic syndrome (TS) due to Toxoplasma abscesses in the thalamic region. Treatment with amitriptyline provided substantial relief in both patients. Postmortem examination in one case revealed a lesion in the internal capsule and thalamic reticular nucleus. These observations indicate that (1) TS can result from an isolated lesion in the internal capsule and reticular nucleus of the thalamus, (2) cerebral abscess can cause classic TS, (3) central pain can be added to the many pain syndromes that afflict AIDS patients, and (4) an analgesic response to amitriptyline is possible in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Recombinant human TNF-alpha: preclinical studies and results from early clinical trials.

The application of recombinant DNA technology to the production of tumor necrosis factor has resulted in the availability of large quantities of a highly purified protein product. This product has been evaluated extensively in preclinical studies, which have documented a direct cytostatic and cytotoxic effect on human tumor cells, as well as a variety of immunomodulatory effects on various immune effector cells, including neutrophils, macrophages, and T cells. In addition, a number of anti-infective and metabolic effects have been documented. In addition to its in vitro effects, rTNF has been shown to have antitumor activity in vivo in preclinical studies involving both transplantable murine tumors and human tumor xenografts. Such observations have led to the evaluation of rTNF as a potential antineoplastic agent in humans. Both single- and multiple-dose phase I studies have confirmed that rTNF can be safely administered to patients with advanced malignancies in a dose range associated with anticancer effect without concomitant serious toxicities such as shock and cachexia. The most commonly observed clinical toxicities include constitutional symptoms, such as fever, chills, headache, and fatigue, and toxicities, which can be at least partially controlled with concomitant administration of nonsteroidal anti-inflammatory drugs, such as acetaminophen and meperidine. Hypotension, which occurs at high doses administered by short intravenous infusion, can usually be prevented by prehydration with intravenous fluids or otherwise controlled by the administration. An intense local inflammatory reaction at the injection site as well as thrombocytopenia appear to be the dose-limiting toxicities after subcutaneous and intramuscular administration. Neurologic toxicity is infrequent, except following continuous intravenous infusion, where it may manifest as transient focal neurologic deficits or seizure. Prolonged administration of rTNF at higher doses may be associated with transient, subclinical decreases in diffusing capacity. Patients with underlying cardiopulmonary disease should be excluded from rTNF therapy in future clinical studies until the end-organ toxicities of this agent are better defined. For at least one preparation of rTNF there appears to be no evidence for the formation of antibodies to rTNF in patients who receive multiple administrations of the agent. Pharmacokinetic studies have shown a relatively rapid clearance following intravenous infusion with a half-life of 15 to 30 min and dose-dependent pharmacokinetics. rTNF can be detected in the serum following intramuscular or subcutaneous injection at only relatively high doses, suggesting a decreased bioavailability with the routes of administration. Early phase I studies defined tolerable dose ranges for each route of administration and began to explore immunomodulatory and metabolic effects of rTNF.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone and Bones↗
PubMed1991

Comparison of epidural and patient-controlled intravenous morphine following joint replacement surgery.

The authors conducted a randomized, prospective study comparing epidural morphine with patient-controlled intravenous (iv) morphine in 30 patients recovering from total hip or total knee arthroplasty. Six, 18, and 24 hr postoperatively, patients used a 10 cm visual-analogue scale to indicate both their current degree of discomfort and the maximum discomfort they had experienced since the previous evaluation. Pain at the time of evaluation did not differ between patients receiving epidural (2.6 +/- 0.4 cm, mean +/- SEM) and patient-controlled iv morphine (3.4 +/- 0.3 cm). However, patients who received epidural morphine recalled less pain during the period preceding evaluation (4.2 +/- 0.5 cm) than did those receiving patient-controlled analgesia (5.5 +/- 0.4 cm, P less than 0.05). Patients receiving epidural morphine were more likely to require treatment for pruritus (4 of 15) than patients who received patient-controlled iv morphine (none of 15, P less than 0.05). Minimum respiratory rates were lower in patients receiving epidural morphine (15.0 +/- 0.3) than in those receiving patient-controlled analgesia (16.5 +/- 0.4, P less than 0.05), but no patients required treatment for respiratory depression. The authors conclude that epidural morphine may provide more consistent analgesia following joint replacement surgery than patient-controlled morphine; however, there is a higher incidence of side-effects with the epidural technique.

Adult↗
PubMed1991

Amplification of JC virus DNA from brain and cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy.

We have established an assay to detect JC viral DNA in brain tissue and CSF of patients with progressive multifocal leukoencephalopathy (PML) and amplified a 106-base pair segment of the gene encoding JC viral large T antigen by polymerase chain reaction (PCR) from the brains of eight patients with PML and from one of six CSF samples. Brain and CSF of patients without PML did not yield JC virus-specific DNA amplification products. Southern analysis documented that the sequences of the 106-base pair PCR product and JC viral DNA are identical. This assay can be used in the diagnosis of PML and to investigate the biology of JC virus.

Base Sequence↗
PubMed1991

Ibuprofen provides longer lasting analgesia than fentanyl after laparoscopic surgery.

The authors compared the analgesic efficacy of one dose of oral ibuprofen with that of intravenously administered fentanyl for relief of pain after outpatient laparoscopic surgery. Thirty healthy female patients received either 800 mg of oral ibuprofen preoperatively or 75 micrograms of intravenous fentanyl intraoperatively plus respective intravenous or oral placebos in a randomized, double-blind manner. Patients recorded their degree of pain and nausea in the recovery room, in the same-day surgery stepdown unit, during the ride home, and upon arrival at home. The postanesthesia care nurse recorded the amount of fentanyl and droperidol needed to treat pain and nausea in the recovery room. Patients who received ibuprofen were more comfortable in the stepdown unit (P less than 0.05) and after arrival home (P less than 0.05) than those in the fentanyl group. Additionally, patients who received ibuprofen had lower nausea scores in the step-down unit (P less than 0.05); this may have been related to the lower total fentanyl dose in these patients. The authors conclude that ibuprofen may be a useful alternative to fentanyl for providing postoperative analgesia for outpatient surgery.

Administration, Oral↗
PubMed1991

Evidence for molecular subtypes of HIV-associated lymphoma: division into peripheral monoclonal, polyclonal and central nervous system lymphoma.

The pathogenesis of the HIV-associated lymphomas is not well understood. In order to begin characterizing this class of lymphoma, we initiated a molecular genetic study of DNA extracted from 31 diagnostic biopsy specimens from patients diagnosed with AIDS-associated non-Hodgkin's lymphoma. Analysis of 25 peripheral lymphomas showed that 14 were monoclonal B-cell processes, while 11 appeared to be of polyclonal origin. Five of the 14 monoclonal lymphomas were found to have rearrangements of the c-myc gene. Epstein-Barr virus (EBV) genomes were found in seven out of 14 monoclonal samples, but only two out of nine polyclonal samples. The six primary central nervous system (CNS) lymphoma samples were more homogeneous than the peripheral samples and all were monoclonal, positive for EBV and lacked detectable c-myc gene rearrangements. This study allows us to subdivide the HIV-associated lymphomas into three major molecular subtypes: (1) monoclonal B-cell process frequently associated with c-myc rearrangement or detectable EBV genomes, (2) polyclonal B-cell process typically without evidence of EBV, and (3) monoclonal primary CNS process associated with EBV genomes and lacking detectable c-myc rearrangement.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Blockade of morphine analgesia by both pertussis and cholera toxins in the periaqueductal gray and locus coeruleus.

Rats demonstrating analgesia following microinjection of morphine into the periaqueductal gray (PAG) or locus coeruleus (LC) were injected with either pertussis toxin, cholera toxin or saline into the same brain region. Both pertussis and cholera toxin blocked the analgesic effect of morphine at both injection sites for up to 7 days after toxin treatment. These results indicate that morphine analgesia is a complex response involving systems dependent upon Gs as well as Gi or Go proteins.

Analgesia↗
PubMed1990

Low dose rate radiotherapy for transplantable gliosarcoma in the rat brain.

Interstitial brachytherapy with low energy radionuclides is becoming widely used in conjunction with external beam radiotherapy in the treatment of primary malignant gliomas of the brain. Few radiobiological studies have been carried out with low dose rate brachytherapy for brain tumors. Since we have recently developed a non-invasive low dose rate radiotherapy model for the treatment of transplantable 9L gliosarcoma growing in the rat brain, we carried out a series of radiobiological studies to determine the dose rate effect on the tumor and normal brain tissue. Using TCD50 (the radiation dose to control 50% tumor control) as the endpoints, we obtained the results indicating that the tumor control rate was highly dependent on the dose rate and the total dose delivered to the tumor. The TCD50 of dose rates ranging from 100 cGy/min, 120 cGy/hr, and 40 cGy/hr were 25 Gy, 80 Gy, and 100 Gy, respectively. The normal tissue effects were most pronounced with high dose rate irradiation (100 cGy/min). The LD50 for high dose rate irradiation to the whole brain was 29 Gy. In contrast, the majority of animals treated with low dose rate radio-therapy behaved quite normal up to a year follow-up. The late histopathological changes of the irradiated brain usually consisted of vascular and white matter necrosis, although the extent of such changes showed a considerable individual variation within the long-term survivors.

Animals↗
PubMed1990

Pharmacokinetics of the recombinant fusion protein DAB486IL-2 in animal models.

The kinetics of the in vitro cytotoxicity of DAB486IL-2, a genetically engineered fusion protein containing a portion of diphtheria toxin and human interleukin-2, were examined in the C91/PL cell line, which constitutively expresses IL-2 receptors. Maximal inhibition of protein synthesis was observed by 4-6 h after DAB486IL-2 addition at a concentration of 300 ng/ml. The tissue distribution, urinary excretion, and plasma pharmacokinetics of DAB486IL-2 in the rat and its plasma pharmacokinetics in the monkey were also examined. In rats the primary site of distribution of [35S]-DAB486IL-2 outside the vasculature appears to be the liver, followed by the kidney, spleen, and lung. Persistence of radioactive material in the liver and urinary excretion of metabolic degradation products suggest that labeled protein is metabolized by hepatic tissue. Following i.v. bolus administration of DAB486IL-2, the initial serum half-life for both the rat and the monkey was approximately 5 min. The overall clearance rate of drug for the two species differed, with DAB486IL-2 being cleared from circulation 2-3 times more rapidly in the monkey. Presence of high levels of neutralizing antibodies to diphtheria toxin in the rat significantly influenced the clearance of bioactive DAB486IL-2. However, the question as to whether the presence of in vitro biological activity for the molecule is masked by the presence of antibodies cannot be clearly answered.

Animals↗