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Biomedical subjects

A Asher

Publications and source records attributed to A Asher.

15 recordsLinked to original sources
PubMed2003

Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma.

PURPOSE: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas Exotoxin (NBI-3001) in patients with recurrent malignant glioma. PATIENTS AND METHODS: A total of 31 patients with histologically verified supratentorial grade 3 and 4 astrocytoma were studied. Of these, twenty-five patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma (AA). Patients were over 18 years of age and had Karnofsky performance scores > or = 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 microg/ml x 40 ml, 9 microg/ml x 40 ml, 15 microg/ml x 40 ml, or 9 microg/ml x 100 ml of NBI-3001 administered intratumorally via stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. RESULTS: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related Grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 microg/ml x 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. CONCLUSIONS: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

Adult↗
PubMed2001

In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a recombinant IL-4 cytotoxin in primary glioblastoma cell cultures.

We have reported that human malignant glioma cell lines express high levels of plasma membrane interleukin-4 receptors (IL-4R). We have also reported that biopsy/surgical samples or primary explant cell cultures from brain tumors express mRNA and protein for the IL-4Ralpha chain, a primary IL-4-binding protein. However, whether IL-4R are expressed in brain tumors in situ has not been resolved. In addition, expression of IL-4R on the cell surface of various normal brain tissues is not known. We examined the expression of IL-4R by using a monoclonal antibody to the IL-4Ralpha chain (also known as IL-4R beta) in surgical/biopsy samples of brain tumor tissues by immunohistochemistry. Our data indicate that 15 of 18 glioblastoma multiforme (GBMs) tumors obtained from two different institutions and 12 other brain tumor samples are moderately to intensely positive for IL-4Ralpha. In contrast, although IL-4Ralpha mRNA was expressed, no IL-4R protein was detectable in two adult and one pediatric brain tissue specimens. In addition, a commercially available human neural tissue grid containing fixed tissues from various areas of brain showed no positive staining for the IL-4Ralpha chain. IL-4Ralpha expression was also demonstrated on astrocytoma grades I, II, and III. Because IL-4 cytotoxin comprised of a circularly permutated IL-4 and a mutated form of Pseudomonas exotoxin [IL4(38-37)-PE38KDEL] is cytotoxic to IL-4R-expressing cells, we tested whether primary GBM explant cell cultures are sensitive to IL-4 cytotoxin. Our data indicate that 13 of 15 GBM cell cultures were 25-74 times more sensitive to IL-4 cytotoxin compared with normal human astrocytes or the NT2 neuronal cell line. These observations indicate that human brain tumors in situ overexpress IL-4R compared with normal brain tissues, thus confirming our previous conclusions that IL-4R in brain tumors may serve as an attractive target for anticancer therapy.

Brain Neoplasms↗
PubMed2000

Effect of loperamide on mucosal guanylyl cyclase activity in rat jejunum following Escherichia coli heat-stable toxin-induced fluid accumulation.

Loperamide has antidiarrhoeal activities against secretagogues with different mechanisms of action. Besides its opioid-like effect on intestinal motility and secretion it might exhibit additional antisecretory properties which may not be completely elucidated yet. Direct effects of loperamide on mucosal guanylyl cyclase have never been observed. We therefore investigated the effect of loperamide on intestinal fluid transport altered by heat-stable Escherichia coli enterotoxin which acts by stimulating mucosal guanylyl cyclase. Net fluid movement was determined during a 1 hr incubation period in ligated jejunal loops of anaesthetised female Wistar rats. Transport rates of net fluid movement were calculated from the loop contents measured gravimetrically at the beginning and the end of the experiments. Addition of heat-stable Escherichia coli enterotoxin to the luminal solution resulted in a net secretion of water which was significantly reversed into net absorption by loperamide. The specific activity of the particulate guanylyl cyclase was determined in mucosal scrapings of the jejunum without and with the addition of heat-stable Escherichia coli enterotoxin and/or loperamide. Additions of loperamide of up to 10 micromol/l did not change guanylyl cyclase activity. We conclude that the effect of loperamide counteracting heat-stable Escherichia coli enterotoxin induced changes of intestinal fluid transport does not involve a direct effect on guanylyl cyclase.

Animals↗
PubMed1993

Long-term trends in organochlorine and mercury residues in some predatory birds in Britain.

Residue levels of organochlorine pesticides (HEOD, DDE), polychlorinated biphenyls (PCBs) and mercury (Hg) in the livers of five predatory bird species were monitored in Britain over a 28-year (1963-1990) period. Of two raptor species, sparrowhawks contained higher levels of most chemicals than did kestrels. Among three fish-eaters, herons and kingfishers contained the highest levels of DDE and HEOD, while herons and great-crested grebes contained the highest levels of PCBs and mercury. Species differences were related partly to diet and habitat. In sparrowhawks and kestrels, residues of HEOD and DDE were higher in eastern, arable districts than elsewhere, especially in the 1960s and 1970s. In the fish-eaters, similar regional differences in residue levels were apparent in herons, especially in the 1970s, but not in the other species, for which samples were smaller. Over the 28 years, most species showed significant downward trends in HEOD, DDE and Hg levels, but only two fish-eaters showed significant declines in PCB levels. The downward trends in DDE and HEOD followed successive restrictions in the use of organochlorine pesticides, and were accompanied by recoveries in the populations and breeding success of affected species. Downward trends in mercury were associated with reductions in both agricultural use and industrial emissions.

Journal Article↗
PubMed1991

A modeling framework for AIDS/HIV nonacute care services.

This paper describes the conceptual structure underlying the microcomputer-based modeling system developed by Mathematica Policy Research, Inc. The modeling system was developed to assist communities in planning nonacute care services for symptomatic human immunodeficiency virus (HIV)-infected persons. The modeling system is based on the assumptions that (1) the characteristics of the HIV epidemic and the availability of nonacute care service vary across communities and (2) combinations of nonacute care services can be appropriately substituted for one another and for hospital-based nonacute care to meet the varying medical and social needs of symptomatic HIV-infected persons.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Role of reactive oxygen metabolites in early cardiopulmonary changes of acute hemorrhagic pancreatitis.

The role of reactive oxygen metabolites in extrapancreatic organ dysfunction associated with acute hemorrhagic pancreatitis was studied in dogs. Experimental pancreatitis was induced by the intraductal infusion of activated trypsin and taurocholate. Cardiac output, pulmonary and systemic blood pressure, pulmonary wedge pressure, central venous pressure, heart rate, blood gases and serum amylase were measured. Cardiac index, pulmonary and systemic vascular resistance, and the right and left stroke work were calculated. Systemic arterial and venous blood pressure and cardiac index gradually declined over 6 hr, while pulmonary mean blood pressure and pulmonary vascular resistance increased. Pretreatment of pancreatitis with catalase and superoxide dismutase prevented the rise in mean pulmonary blood pressure, moderated the rise in pulmonary vascular resistance, and decreased the rate and extent of the fall in cardiac index. These data suggest that reactive oxygen metabolites may play some role in the extraabdominal organ manifestations of acute pancreatitis.

Acute Disease↗
PubMed1989

A modified retention suture technique with external and internal "booties" to close difficult abdominal wounds.

In a patient with acute hemorrhagic pancreatitis complicated by pancreatic abscess, closure of the abdominal wall 7 days following marsupialization was difficult owing to the marked distension and edema of the bowel wall, especially the transverse colon. A simple technique using retention sutures with internal and external rubber "booties" above and below the fascia was used to prevent injury to the edematous bowel. The rubber catheters, or "booties," were removed at the bedside, thus making it a simple procedure in a difficult situation.

Abdominal Muscles↗
PubMed1988

Antitumor effect of recombinant tumor necrosis factor-alpha against murine sarcomas at visceral sites: tumor size influences the response to therapy.

We examined the antitumor efficacy of rTNF-alpha administration on established tumor at two visceral sites, lungs and liver. Treatment of B6 mice harboring multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) 10-day pulmonary macrometastases from the MCA-106 sarcoma, with dosages of rTNF-alpha (5-10 micrograms, single dose i.v.) that caused hemorrhagic necrosis and regression of a 6 mm MCA-106 s.c. tumor, had no impact on the number (or size) of lung nodules. Similarly, rTNF-alpha failed to show an antitumor effect in B6 mice with advanced day 8 or 10 multiple (greater than 100 foci of less than or equal to 0.5 mm diameter) hepatic metastases at single i.v. doses up to 20 micrograms, as measured by either enumeration of residual liver nodules or survival. B6 mice injected s.c. with MCA-106 sarcoma and treated with rTNF-alpha as a single i.v. dose on day 0, 3, 5, or 7 experienced marked tumor regression only after the day 7 rTNF-alpha injection, when the tumor had achieved a size of 5-6 mm in diameter. Since tumor size appeared important for rTNF-alpha susceptibility in vivo, we next induced a single hepatic tumor of the MCA-106 sarcoma by the direct injection of cells into the left lobe of the liver and treated these mice at day 10 when the nodule had achieved a size of 5-6 mm in diameter. Increasing doses of rTNF-alpha (up to 8 micrograms) given as a single i.v. injection resulted in increasingly greater reductions in hepatic tumor as well as significant survival benefit of the treated mice. Sites of regressing hepatic tumor exhibited central necrosis accompanied by polymorphonuclear leukocytes and lymphocytes. Collectively, these results show that rTNF-alpha administration can mediate a significant antitumor effect on visceral tumor and suggest that tumor size is an important factor in rTNF-alpha susceptibility not only for tumors growing at s.c. sites but also for those established at visceral sites.

Animals↗
PubMed1987

Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo.

The anti-tumor activity of recombinant human tumor necrosis factor (rHTNF) was examined against four newly induced murine sarcomas (MCA-101, -102, -105, and -106) and a murine adenocarcinoma (MCA-38) transplanted s.c. into C57BL/6 mice. The serum half-life after a single i.v. injection of rHTNF was determined to be 30 +/- 2 min. Tumor-bearing mice were more susceptible to the toxic side effects of rHTNF than were normal mice. Forty-eight percent (41/86) of tumor bearing animals that received 10 micrograms rHTNF died within 48 hr after treatment compared with no deaths in 28 normal animals receiving this dose. Treatment of mice bearing either the MCA-101, -102, -105, or -106 sarcoma or the MCA-38 adenocarcinoma with rHTNF resulted in a marked necrosis of the central portion of each tumor within 24 hr. Animals bearing the weakly immunogenic tumors MCA-105, -106, and -38 experienced a reduction in average tumor area of 47% +/- 5, 46% +/- 6, and 37% +/- 11, respectively, by 3 to 4 days after treatment with rHTNF compared with pre-treatment values (p less than 0.001); increases of 79% +/- 11, 74% +/- 10, and 41% +/- 6 were seen in excipient-treated control animals over the same period. In contrast, animals bearing the non-immunogenic tumors MCA-101 and -102 experienced little if any decrease in tumor area at the doses of rHTNF used. rHTNF failed to mediate cures in animals bearing MCA-38, -101, or -102. In contrast, 67 and 28% of animals bearing MCA-105 and -106, respectively, which received 6 to 10 micrograms rHTNF were cured. Likewise, animals bearing MCA-105 and -106 sarcomas treated with 6 to 10 micrograms rHTNF had significantly increased survival compared with excipient-treated control animals. In contrast, no significant difference in mean survival was observed between excipient and rHTNF treated animals bearing MCA-38, -101, or -102. Histologically, the necrotic response of immunogenic MCA-106 and non-immunogenic MCA-102 tumors to systemically administered rHTNF was very similar. These two tumors differed morphologically, however, by the greater degree of chronic inflammation that was present at the periphery of the MCA-106 tumor in comparison with the MCA-102. By 72 hr after rHTNF administration, the sites of regressed MCA-106 tumors were replaced by a heterogeneous population of inflammatory cells and tumor cell "ghosts".(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1987

Disseminated intravascular coagulation as a result of supraceliac clamping: implications for thoracoabdominal aneurysm repair.

Massive coagulopathy and bleeding continues to play a major role in the operative mortality and perioperative multi-system failure of patients requiring elective thoracoabdominal aneurysm repair. It was the purpose of this study to determine the coagulation defect that occurs with supraceliac aortic clamping and the effects of increasing aortic cross-clamp time (AXCT) on the coagulation system and its recovery. Through a standard thoracoabdominal incision, 16 mongrel dogs had their aortas cross-clamped simultaneously just above the diaphragm and at the aortic bifurcation. Animals were divided into four groups of four animals each; sham operation, 30 minute AXCT, 60 minute AXCT, and 90 minute AXCT. Central venous blood was sampled prior to aortic cross clamping (AXC), during AXC and 1 hour, 2 hours, 5 hours, 7 hours, 12 hours, and 24 hours after the clamp was removed. All samples were assayed for platelets, fibrinogen, fibrin split products, prothrombin time (PT) and partial thromboplastin time (PTT). Platelets and fibrinogen decreased as PT and PTT increased with increasing AXCT consistent with disseminated intravascular coagulation (DIC) (P less than .001). Fibrin split products were positive in the 90 minute AXCT group only. The drop in platelets was greater for increasing AXCT and continued to fall in the 30, 60 and 90 minute AXCT groups at 24 hours (p less than .001). Fibrinogen dropped to the lowest levels between two and twelve hours after AXC and returned to normal at twenty-four hours in the 60 and 90 minute AXCT groups (p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Ascorbic acid and catecholamine secretion from cultured chromaffin cells.

Ascorbic acid was found to be secreted from cultured bovine adrenal chromaffin cells coincidentally with catecholamines using a variety of secretagogues, including veratridine, nicotine, acetylcholine, and potassium chloride. Secretion of ascorbic acid was measured by preloading the cells for 3 h with (R)-[14C]ascorbic acid and then quantitating release of the label. The newly transported ascorbic acid constituted nearly 90% of total cellular ascorbic acid. Although chromaffin granules are known to contain endogenous ascorbic acid, only 16% of the total labeled ascorbic acid taken up by cultured cells was localized to the chromaffin granule fraction. Under the same isolation conditions, 95% of the endogenous catecholamines was found in the granule fraction. The secretion of both (R)-[14C] ascorbic acid and catecholamines was calcium dependent. However, only catecholamine secretion was effectively inhibited by the presence in the medium of isethionate, an impermeant ion that inhibits catecholamine secretion from isolated chromaffin granules. Analysis of the ratios of cellular and granular (R)-[14C] ascorbate as well as secreted (R)-[14C]ascorbate and catecholamines revealed that the secreted (R)-[14C]ascorbic acid did not come exclusively from the chromaffin granule fraction but also from a nonsedimenting cytoplasmic compartment. Indeed, for all four agonists, the amounts of (R)-[14C]ascorbic acid secreted were more than 1.5 times greater than could be accounted for by chromaffin granule ascorbate alone. We took these data to indicate that, while ascorbic acid and catecholamines were secreted concomitantly, the sources of the secreted substances were not necessarily identical.

Acetylcholine↗