Biomedical subjects

M Gutman

Publications and source records attributed to M Gutman.

At least 91 records · Page 5Linked to original sources

PubMed1993

[Chemofiltration for locally advanced cancer].

In chemofiltration a large dose of a cytotoxic drug is infused into an artery supplying a cancerous area, thus limiting systemic toxicity. The venous return from the area is pumped into a chemofiltration unit at 750 ml/min and the drug is filtered out of the blood, which is then returned to the systemic circulation. Of 22 patients with locally advanced cancer, systemic chemotherapy had failed in 63%. 9 of them underwent chemofiltration of the liver for advanced metastatic cancer of the colon (4 cases), rectum (2), breast (2) and ovaries (1); and 13 underwent chemofiltration of the pelvis for advanced cancer of the rectum (5), malignant melanoma (5), ovaries (1), cervix uteri (1) and vulva (1). The following drugs were used: 5-FU (750 mg/m2/10 min) and mitomycin-C (30 mg/m2/10 min) for colorectal, ovarian and breast carcinomas; melphelan (1 mg/kg/20 min) or cisplatinum (200 mg/m2/30 min) for malignant melanoma or ovarian carcinoma; mitomycin-C or bleomycin (50 mg/m2/10 min) for carcinoma of the cervix or vulva. 1 patient with extensive liver metastases died of respiratory failure 28 days after the procedure. Surgically related complications occurred in 16% and included wound hematoma (2 cases), infection (1) and venous thrombosis (1). Drug-related complications occurred in 50%, and included transient leukopenia (9), mild renal failure (1), hair loss (2) and prolonged paralytic ileus (1). Partial remission was observed in 10/20 patients who had measurable disease. Time to progression was 5.4 months (range: 4 weeks to 20 months). Stabilization of disease occurred in 7/20 (35%), while in 3 the disease progressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗

PubMed1993

Malignant melanoma in different ethnic groups in Israel. Incidence and biologic behavior.

BACKGROUND: The Jewish population of Israel is divided into two ethnic groups: Ashkenazic Jews (AJ) who immigrated from Europe and are fair-skinned, and Sephardic Jews (SJ) who immigrated from the Orient and Africa and who are dark-skinned. The biologic behavior of malignant melanoma (MM) in these two groups has not been investigated. METHODS: Three hundred forty-eight of 380 patients with MM, who could be accurately grouped ethnically, constitute this study group. The gender, site and depth of primary tumor, metastatic involvement and survival analysis, including univariate analysis for level of invasion, were examined. RESULTS: Of 348 patients with MM, 285 were AJ and 63 were SJ. The female:male ratio was 2:1 and 0.9:1, for AJ and SJ, respectively (P < 0.05). Lesion site distribution was similar. The lesions were more invasive in SJ, 53% Clark level 4-5 versus 41% in AJ (P < 0.05). The 5-year survival was worse in SJ relative to AJ--50% versus 71% for female patients and 30% versus 62% for male patients--but did not reach statistical significance (NS). The actuarial 10-year survival showed poorer survival for female SJ: 27% versus 67% in female AJ (P < 0.05) and male SJ; 32% versus 65% in male AJ (P < 0.01). For all stage I MM, the actuarial 10-year survival was in male patients 32% versus 79% (P < 0.05), and in female patients, 27% versus 72% (P < 0.05) in SJ and AJ, respectively. For the more invasive lesions (Clark levels 4 and 5), the actuarial 10-year survival was for male patients 19% versus 75% (P < 0.05) and for female patients, 65% versus 67% (NS) in SJ and AJ, respectively. CONCLUSIONS: The dark-skinned SJ tend to have MM less than the fair-skinned AJ, but once MM occurs in SJ, it appears to have a more virulent nature.

Female↗

PubMed1993

Reaction of bulk protons with a mitochondrial inner membrane preparation: time-resolved measurements and their analysis.

The laser-induced proton pulse technique [Gutman, M. (1986) Methods Enzymol. 127, 522-538] was applied on suspensions of submitochondrial vesicles, and the exchange of protons between the bulk and the mitochondrial membranes was measured in the time-resolved domain with a submicrosecond resolution. The protons were discharged by photoexcitation of pyranine (8-hydroxypyrene-1,3,6-trisulfonate) by a short laser pulse, and the reprotonation of the pyranine anion was monitored at 457.8 nm. In parallel, the protonation of the membrane was followed at 496.5 nm, looking at the transient absorbance of fluorescein, covalently attached to the M side of the membrane. The analysis of the relaxation dynamics was carried out by a simulation procedure that reconstructs the observed dynamics of the two chromophores. The analysis revealed the presence of the membrane indigenous buffering moieties. The low-pK buffer (pK 4.1) was present in a quantity of 100 +/- 20 nmol/mg of protein, and its kinetics indicate that it appears in multianionic clusters bearing a negative electric charge. The medium-pK buffer (pK 6.9) was present in a larger quantity (200 +/- 20 nmol/mg), and its kinetic parameter indicated clustering into positively charged domains. Both types of indigenous buffer reacted with the proton and pyranine anion in unhindered diffusion-controlled reactions. On the other hand, the exchange of protons between the indigenous buffer moieties was rather slow. No evidence was found for the presence of sites capable of retaining a proton, secluded from the bulk, for a time frame longer than 100 microseconds as required by the models of localized proton gradient.

Anions↗

PubMed1993

Recombinant interferon alpha-2a in combination with dacarbazine in the treatment of metastatic malignant melanoma: analysis of long-term responding patients.

Thirty-four evaluable patients with metastatic malignant melanoma were entered into a phase-II study designed to assess the response rate and analyze the long-term therapeutic efficacy of recombinant interferon (rIFN) alpha-2a and dacarbazine. Patients received 14 days of daily subcutaneous r-IFN alpha-2a (3 x 10(6) IU/day), followed by 9 x 10(6) IU on alternate days, as long as objective response lasted, in combination with i.v. dacarbazine started on day 7 (400 mg/m2) and repeated every 21 days (dacarbazine doses were escalated to 800 mg/m2). In 11 patients, 6 complete (17.6%) and 5 partial (14.7%) responses were seen, with an overall response rate of 32.3% (95% confidence interval: 16%-48%). The median survival time of the responding patients was significantly better than that of patients with progressive disease (P = 0.01) and the median response time of the patients showing complete response was longer than that of the partially responding patients (14 and 7 months respectively, P = 0.06).

Adult↗

PubMed1993

DNA amplification in human gastric carcinomas.

We recently identified a genomic domain at chromosome 10q26 that is highly amplified in the gastric carcinoma cell lines KATO III and SNU-16 and contains the BEK/K-sam gene, which encodes several growth factor receptors. A contiguous segment of 200 kb spanning this gene was amplified in five of 139 (3.6%) primary gastric carcinomas, all of them classified as poorly differentiated tumors. There was no amplification of this genomic region in a variety of other solid tumors. The overall frequency of gene amplification among the gastric carcinomas rose to 19.4% when MYC, ERBB2, and INT2 were included in the analysis, with significant association with advanced tumor stage. Amplification of various genomic regions in solid tumors may be more frequent than previously estimated.

Carcinoma↗

PubMed1993

Gaugement of the inner space of the apomyoglobin's heme binding site by a single free diffusing proton. I. Proton in the cavity.

Time resolved fluorimetry was employed to monitor the geminate recombination between proton and excited pyranine anion locked, together with less than 30 water molecules, inside the heme binding site of Apomyoglobin (sperm whale). The results were analyzed by a numerical reconstruction of the differential rate equation for time-dependent diffusion controlled reaction with radiating boundaries using N. Agmon's procedure (Huppert, Pines, and Agmon, 1990, J. Opt. Soc. Am. B., 7:1541-1550). The analysis of the curve provided the effective dielectric constant of the proton permeable space in the cavity and the diffusion coefficient of the proton. The electrostatic potential within the cavity was investigated by the equations given by Gilson et al. (1985, J. Mol. Biol., 183:503-516). According to this analysis the dielectric constant of the protein surrounding the site is epsilon prot < or = 6.5. The diffusion coefficient of the proton in the heme binding site of Apomyoglobin-pyranine complex is D = 4 x 10(-5) cm2/s. This value is approximately 50% of the diffusion coefficient of proton in water. The lower value indicates enhanced ordering of water in the cavity, a finding which is corroborated by a large negative enthropy of binding delta S0 = -46.6 cal.mole-1 deg-1. The capacity of a small cavity in a protein to retain a proton had been investigated through the mathematical reconstruction of the dynamics. It has been demonstrated that Coulombic attraction, as large as delta psi of energy coupling membrane, is insufficient to delay a free proton for a time frame comparable to the turnover time of protogenic sites.

Animals↗

PubMed1993

Gaugement of the inner space of the apomyoglobin's heme binding site by a single free diffusing proton. II. Interaction with a bulk proton.

The reaction mechanism and the dynamic aspects of protonation of a defined moiety located inside an aqueous cavity in a protein were monitored by time resolved spectroscopy using the pyranine apomyoglobin complex as a model (Shimoni, Tsfadia, Nachliel, and Gutman, 1993, Biophys. J. 64:472-479). The reaction was synchronized by a short laser pulse and the reprotonation of the ground state pyranine anion (phi O-) was monitored, in the microsecond time scale, by its transient absorption at 457 nm. The observed signal was reconstructed by a numeric solution of nonlinear, coupled differential equations which account for the direct reaction of phi O- with bulk proton and by proton transfer from the nearby amino acids: His 64, Asp 44, Asp 60, and Glu 59. A unique combination of rate constant was obtained which quantitates the contribution of each pathway to the overall relaxation process. In the first phase of the dynamics phi O- abstracts a proton from the nearby protonated histidine. The bulk proton interacts preferentially with the cluster of three carboxylates and immediately shuttled to the deprotonated histidine. The high proximity of the reactive groups and the strong electrostatic forces operating inside the heme binding cavity render the rate of proton transfer in the site ultrafast.

Animals↗

PubMed1993

The role of the radionuclide renal study in the management of renal colic.

If renal colic is suspected in the patient presenting with acute flank or lower abdominal pain it must be established whether or not the affected kidney is obstructed and whether there is functional impairment that may require urological intervention. The radionuclide renal study developed in this hospital and used routinely for over 10 years can reveal obstruction when the results of commonly used tests are negative. It also provides information on renal function, morphology and blood flow. It is a cost-effective, safe and reliable procedure for the initial investigation of patients presenting with suspected renal colic.

Adult↗

PubMed1993

Fecal peritonitis--the effect on anastomotic healing.

The present study evaluates colonic anastomosis healing in the presence of fecal peritonitis in rats. After induction of fecal peritonitis, the animals were treated by surgery alone or with the addition of systemic supportive treatment. It is shown that survival in the latter group was significantly better, while burst strength of anastomoses in surviving animals in both groups was identical. The results suggest that the outcome of fecal peritonitis depends mainly on fluid resuscitation and antimicrobial therapy, but not on primary repair.

Anastomosis, Surgical↗

PubMed1993

Major histocompatibility complex class IV restriction fragment length polymorphism markers in replicated meat-type chicken lines divergently selected for high or low early immune response.

Information on MHC may improve the efficiency of selection for immunological traits via the application of marker assisted selection or by selecting directly for a specific restriction fragment length polymorphism (RFLP) band or MHC haplotype. An experimental procedure is presented here for identifying MHC genes that are related to early immune response. A Class IV cDNA clone was used to probe Southern blots of erythrocyte genomic DNA from chickens. Chickens were taken from the second (S2) and third (S3) generations of replicated lines divergently selected for high antibody response (HC1, HC2) or low antibody response (LC1, LC2) to Escherichia coli vaccination at 10 days of age. These selection criteria have been found to be associated with other immunological parameters. The hypothesis that these selected lines differ in their MHC loci was evaluated by comparing the frequencies of MHC RFLP markers (single RFLP bands) and haplotypes (patterns of RFLP bands). The significant differences between LC and HC in the frequency of many MHC RFLP bands and of five MHC haplotypes indicate that early antibody production is influenced by MHC genes. The reliability of the association between the selection and frequency differences was tested and proven in most cases by analysis of the replicated lines. These differences in RFLP markers represent a change in allelic frequencies in MHC genes, probably due to selection. The results imply a connection between the Class IV genes and early antibody production, and they show the potential of prospective breeding not only by immunological phenotype but also by genotype (i.e., using RFLP markers of the MHC).

Animals↗

PubMed1993

Metastases-induced acute pancreatitis: a rare presentation of cancer.

Cancer as the etiology of acute pancreatitis is considered rare. Presented are three patients in whom acute pancreatitis was the first manifestation of malignancy due to primary or metastatic cancer within the pancreas. In one case, metastatic large cell bronchogenic carcinoma was found in the pancreas and in two patients non-Hodgkin's lymphoma confined to the pancreas induced the acute pancreatitis. One of the patients did not survive a severe acute pancreatitis, one died 8 months later due to metastatic lung carcinoma, and the third has been disease-free for the past 18 months following chemotherapy. Several reports described acute pancreatitis secondary to metastasis in the pancreas, mostly small cell lung carcinoma. It seems that the immediate survival of such patients depends on the severity of the pancreatitis. If this is overcome, specific chemotherapy could be beneficial.

Acute Disease↗

PubMed1992

The effect of delta mu H+ on the interaction of rotenone with complex I of submitochondrial particles.

The inhibition by rotenone of the forward (NADH-oxidase) and reverse (delta mu H(+)-dependent succinate-NAD+ reductase activities of submitochondrial vesicles was measured. The inhibition of NADH-oxidase, measured in the presence of uncoupler, followed a monophasic inhibition curve with Ki < or = 2 nM. The reverse electron flow was only partially (40%) inhibited at these rotenone concentrations. The rest of the activity was less sensitive to the inhibitor (Ki approximately 30 nM). The lower affinity for the inhibitor of the reverse electron flow is a consequence of enhanced rate of rotenone dissociation caused by the high delta mu H+ value required for this reaction. The analysis of the results indicates that the AS-SMP preparation consists of two subpopulations: one with a relatively low degree of coupling, which exhibits high sensitivity to rotenone and the other which is highly coupled with lower affinity to the inhibitor.

Mitochondria↗

PubMed1992

Quantitation of physical-chemical properties of the aqueous phase inside the phoE ionic channel.

The anion-specific channel of the phoE porine is a miniature body of water surrounded by peptide walls. The physical and chemical properties of the water in such a microscopic space were measured by monitoring the dynamics of a well-studied reaction--the protolytic dissociation of a strong acid. To attain this purpose, we allowed pyranine (8-hydroxypyrene-1,3,6-trisulfonate) to bind to the anion-specific channel. The dye is bound, with a 1:1 stoichiometry, with a delta G = -9.5 kcal/mol. Photoexcitation of the dye, to its first electronic singlet state (phi OH*), renders it very acidic and the hydroxyl proton dissociates to H+ and excited anion (phi O*-). We employed single photon-counting time-resolved fluorimetry, to monitor the reversible dissociation of pyranine as it proceeds within the channel and reconstructed the observed signal by a numerical integration of the differential diffusion equation pertinent for a proton within the channel. The most characteristic feature of the water-filled channel, is the intensified electrostatic interactions attained by the low dielectric constant of the diffusion space, epsilon eff = 24. For this reason, the electric field of a few positive charges is sufficient to ensure that an anion entering the channel will be effectively sucked in. The interaction of the water molecules with the peptide structure forming the channel affects the physical properties of the water. Their capacity to conduct proton, quantitated by the protons diffusion coefficient (4.5.10(-5) cm2/s), is reduced by 50% with respect to that of bulk water. The activity of the water in the channel is reduced to alpha H2O = 0.966. These observation are in accord with our previous studies of water in small defined cavities in proteins.

Algorithms↗

PubMed1992

Interaction of ubiquinone and vitamin K3 with mitochondrial succinate-ubiquinone oxidoreductase.

Two new methods have been devised for measuring fumarate reduction by beef heart succinate-ubiquinone oxidoreductase with quinols as electron donors. In one assay the quinone is maintained in the reduced state by coupling fumarate reduction with the DT-diaphorase reaction, in the other assay by the presence of excess dithionite. The advantages of these methods are discussed, along with preliminary characterization of the quinol-protein interaction.

Animals↗

PubMed1992

DNA sequences amplified in cancer cells: an interface between tumor biology and human genome analysis.

There is growing evidence that amplification of specific genes is associated with tumor progression. While several proto-oncogenes are known to be activated by amplification, it is clear that not all the genes involved in DNA amplification in human tumors have been discovered. Our approach to the identification of such genes is based on the 'reverse genetics' methodology. Anonymous amplified DNA fragments are cloned by virtue of their amplification in a given tumor. These sequences are mapped in the normal genome and hence define a new genetic locus. The amplified domain is isolated by long-range cloning and analyzed along three lines of investigation: new genes are sought that can explain the biological significance of the amplification; the structure of the domain is studied in normal cells and in the amplification unit in the cancer cell; attempts are made to identify molecular probes of diagnostic value within the amplified domain. This application of genome technology to cancer biology is demonstrated in our study of a new genomic domain at chromosome 10q26 which is amplified specifically in human gastric carcinomas.

Blotting, Southern↗

PubMed1992

Immunological parameters in meat-type chicken lines divergently selected by antibody response to Escherichia coli vaccination.

Our group has established two lines of meat-type chickens divergently selected for early (HC line) and late (LC line) antibody responsiveness at 10 days of age to immunization with inactivated pathogenic Escherichia coli bacteria. The question addressed in the study presented here is whether this selection has changed other immunological responses, increasing the overall 'early' immunocompetence. Broilers of the third and fourth generations (S3 and S4) of the selected lines (HC and LC) and a control, unselected line (CT) were vaccinated at 10 days of age with E. coli vaccine, Newcastle virus vaccine (NDV), sheep erythrocytes (SRBC) or bovine serum albumin (BSA). Line-HC chicks exhibited higher antibody titers to E. coli, NDV and SRBC than CT or LC chicks. At 20 days of age HC chicks demonstrated a higher total protein and a higher beta- and gamma-globulin levels in their serum. At 21 days of age, HC chicks cleared carbon particles faster than LC chicks. Peripheral blood lymphocytes (PBL) from HC chicks vaccinated with E. coli vaccine, proliferated in vitro more actively in the presence of the stimulating antigen than the PBL of LC chicks. Peripheral blood lymphocytes (PBL) obtained from HC-line chicks exhibited a higher proliferative response to concanavalin A (Con A)-, phytohemagglutinin (PHA)- or pokeweed mitogen (PWM)-stimulation than LC PBL. These results demonstrate that the selection for high or low antibody response to E. coli at a young age resulted also in a significant change in the response of other parameters of the immune system. The high response to E. coli was found to be associated with a high antibody response to other antigens (NDV and SRBC), increased phagocytic activity and increased proliferative response to antigen or mitogens. The selection most probably affected early immunocompetence.

Aging↗

PubMed1992

Replicated divergent selection of broiler chickens for high or low early antibody response to Escherichia coli vaccination.

Four sublines of broiler chickens were selected from a base population for three generations for high or low antibody response to vaccination with Escherichia coli at 10 days of age. Two sublines were selected for a high response (HC) and two for a low response (LC). Realized heritability estimates over three generations of selection for each pair of replicated lines averaged .23 in HC lines and .32 in LC lines. No correlated response in the important production trait, body weight at marketing age, was observed. The ability to survive pathogenic E. coli challenge with or without prevaccination showed no differences between the lines in the unvaccinated chicks, although following vaccination there was higher mortality and morbidity in the LC lines. These data suggest that the use of antibody response in young chicks to E. coli vaccine may be a useful genetic indication of more general disease resistance.

Animals↗

PubMed1992

Malignant melanoma of the mucous membranes.

Primary malignant melanoma occurring in mucous membranes is uncommon. Of 410 patients with malignant melanoma, 14 (3.4%) had their primary tumour located in mucosal membranes. Five of the tumours were in the mucosal lining of the head and neck, five in the gastrointestinal tract mucosa and four in the female genitalia. Eight of the tumours were ulcerated, necrotic and deeply invasive. The most common histological subtype was acral lentiginous melanoma. Surgical resection of the primary tumour was performed in 10 patients. In the other four, surgery was not feasible, and they were treated by irradiation and immunotherapy. Six patients underwent regional lymph node dissection. In four of them, regional metastases were found. Chemotherapy was given to seven patients for widespread metastases. Nine patients (64%) died of metastatic melanoma within 2 years. The remaining five patients are alive after 3 to 8 years. It appears that mucosal membrane melanoma is a distinct variant of the disease due to both its aggressive biological behaviour and its relative inaccessibility for surgical removal, and may therefore be classified separately.

Adult↗