Biomedical subjects

M Gutman

Publications and source records attributed to M Gutman.

At least 19 recordsLinked to original sources

PubMed2005

Intraperitoneal heated chemotherapy affects healing of experimental colonic anastomosis: an animal study.

BACKGROUND: The peritoneal spread of cancer is a well-known entity carrying a dismal prognosis. A new therapeutic approach is the combination of cytoreduction with heated intraperitoneal chemotherapy (HIPC). The risk of an intra-abdominal anastomosis in the presence of such chemotherapy is recognized clinically but the experimental data on the subject are lacking. The aim of this study is to examine the influence of chemotherapy and hyperthermia on the healing of colonic anastomosis. MATERIALS AND METHODS: Colonic anastomosis were performed in four groups of male Wistar rats: (1) control (operation only), (2) HIPC with saline, (3) with mitomycin C (MMC), and (4) with cisplatinum. HIPC was performed using a closed circulation system at 40 degrees C over 20 min. Anastomotic strength was tested on day 4, 7, 10, and 21. RESULTS: The bursting pressure of anastomoses in rats treated by HIPC was significantly lower than in controls. On day 4, it was 54.8 mm Hg, 38 mm Hg, 18 mm Hg, and 14.8 mm Hg in groups 1-4, respectively, while on day 7 it was 170 mm Hg, 188 mm Hg, 83 mm Hg, and 19 mm Hg, respectively (P < 0.01). The difference decreased on day 10 and almost vanished on day 21. HIPC with cisplatinum had the worst effect on anastomotic healing during the early postoperative period. CONCLUSIONS: Cytoreduction and HIPC are gaining popularity. However, the use of heated chemotherapy has a detrimental effect on the strength of colonic anastomosis, especially during the early postoperative period (until day 10). This may cause anastomotic failure and postoperative morbidity. Therefore, careful selection and avoidance of unnecessary anastomoses are mandatory.

Anastomosis, Surgical↗

PubMed2004

Abnormal frequency locking and the function of the cardiac pacemaker.

A heterogeneous reaction-diffusion medium consisting of two adjoining uniform regions is analyzed. The first region is a purely oscillatory one, while the second is bistable (oscillatory/excitable). We show that such a construction allows an abnormal domination of the low natural frequency of the oscillatory regime over the whole medium (abnormal frequency locking). Bifurcations leading to the appearance of the bistable regime are discussed as well as the specific dynamics of the bistable oscillations. The abnormal frequency-locking phenomenon could explain some dynamical properties of the cardiac pacemaker.

Journal Article↗

PubMed2004

Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study.

PURPOSE: The three principal studies dedicated to the natural history of peritoneal carcinomatosis (PC) from colorectal cancer consistently showed median survival ranging between 6 and 8 months. New approaches combining cytoreductive surgery and perioperative intraperitoneal chemotherapy suggest improved survival. PATIENTS AND METHODS: A retrospective multicenter study was performed to evaluate the international experience with this combined treatment and to identify the principal prognostic indicators. All patients had cytoreductive surgery and perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy). PC from appendiceal origin was excluded. RESULTS: The study included 506 patients from 28 institutions operated between May 1987 and December 2002. Their median age was 51 years. The median follow-up was 53 months. The morbidity and mortality rates were 22.9% and 4%, respectively. The overall median survival was 19.2 months. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months, compared with 8.4 months for patients in whom complete cytoreductive surgery was not possible (P <.001). Positive independent prognostic indicators by multivariate analysis were complete cytoreduction, treatment by a second procedure, limited extent of PC, age less than 65 years, and use of adjuvant chemotherapy. The use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis, and poor histologic differentiation were negative independent prognostic indicators. CONCLUSION: The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with PC from colorectal origin with acceptable morbidity and mortality. The complete cytoreductive surgery was the most important prognostic indicator.

Adolescent↗

PubMed2004

Pseudoreflection from interface between two oscillatory media: extended driver.

The dynamics of a reaction-diffusion medium composed of two uniform self-oscillating regions is considered. We analyze the phenomenon of pseudoreflection of waves at the region's interface. The reflected waves show an unusual change of wavelength, amplitude, and period. In contrast to our previous results, here this behavior can be perceived as an action of a spatially extended higher-frequency "driver." Observed also are the interesting phenomena of the appearance of narrow transient zones near the interface and of diffusion-induced bifurcations. Furthermore, the pseudoreflection is shown to be a possible mechanism of spiral and "target" waves generation. The relevance of the obtained results to the dynamics of the cardiac sinus node is discussed.

Journal Article↗

PubMed2004

Determination of a unique solution to parallel proton transfer reactions using the genetic algorithm.

Kinetic analysis of the dynamics as measured in multiequilibria systems is readily attained by curve-fitting methodologies, a treatment that can accurately retrace the shape of the measured signal. Still, these reconstructions are not related to the detailed mechanism of the process. In this study we subjected multiple proton transfer reactions to rigorous kinetic analysis, which consists of solving a set of coupled-nonlinear differential rate equations. The manual analysis of such systems can be biased by the operator; thus the analysis calls for impartial corroboration. What is more, there is no assurance that such a complex system has a unique solution. In this study, we used the Genetic Algorithm to investigate whether the solution of the system will converge into a single global minimum in the multidimensional parameter space. The experimental system consisted of proton transfer between four proton-binding sites with seven independent adjustable parameters. The results of the search indicate that the solution is unique and all adjustable parameters converge into a single minimum in the multidimensional parameter space, thus corroborating the accuracy of the manual analysis.

Algorithms↗

PubMed2003

Reaction-diffusion dynamics in an oscillatory medium of finite size: pseudoreflection of waves.

Wave propagation in an oscillatory reaction-diffusion, one-dimensional domain of finite size with Dirichlet boundary conditions is analyzed. For sizes below a certain threshold length, the medium cannot sustain wave motion. Above this threshold we find that for a relatively small domain extent, a strong correlation exists between the dynamics of the system and its size. This correlation gradually disappears with increasing domain size. For still larger sizes, we observe an effect of wave pseudo reflection near the boundary. It is shown both numerically and analytically that pseudoreflected waves are periodically generated inside the medium by a fast, self-generated "source" near the boundary.

Journal Article↗

PubMed2003

Mesenteric and portal vein gas: computerized tomography findings and clinical significance.

BACKGROUND: Gas in the mesenteric or portal veins (PVG) is an uncommon entity. It was first described only in patients with mesenteric ischemia and bowel gangrene. Later, several reports described other causes for PVG in which conservative treatment was successful. In the past, the diagnosis was made by vague signs in abdominal plain films. Since the era of computerized tomography (CT) scan the diagnosis became more objective, but nevertheless it is still an elusive entity. Our objective was to relate clinical and CT findings with outcome of patients with PVG, and to determine the indications for surgical treatment. METHODS: Six-year records of patients from one general hospital with CT scan findings of gas in the mesenteric or portal veins were retrospectively studied, together with details of the clinical presentation, hospital course and outcome. RESULTS: Between 1995 and 2000, 12 patients with findings of mesenteric and portal vein gas were identified. In 7 of 12 patients (58%) PVG developed secondary to ischemia of the small or large bowel, with mortality of 86%. Metabolic acidosis was the prominent laboratory finding. Pneumatosis intestinalis was present in all of these patients. Two patients with PVG had inflammatory bowel disease and both recovered with conservative management. Another 2 patients who were treated conservatively died. One patient had severe pancreatitis and died 2 weeks after PVG was diagnosed, from septic complications, while the other patient admitted with septic shock, died of multiorgan failure. In the last patient, PVG was diagnosed in a CT scan performed to investigate fever of unknown origin. She survived with no specific treatment. CONCLUSION: We suggest that patients in whom PVG is found by CT scan should be treated according to their clinical status, and underlying disease. Patients suspected of having an ischemic mesenteric event should be immediately explored.

Adult↗

PubMed2001

Proton-collecting properties of bovine heart cytochrome C oxidase: kinetic and electrostatic analysis.

Proton-transfer reactions on the surface of bovine heart cytochrome c oxidase were investigated by combining a laser-induced proton-pulse technique with molecular modeling. The experimental approach simultaneously monitors the state of pyranine protonation in the bulk phase and that of a fluorescein indicator specifically attached to the native Cys(III-115) residue of subunit III of cytochrome oxidase. The reversible dynamics of the acid-base equilibration between the surface and the bulk phase were measured with submicrosecond time resolution and analyzed by numerical integration of coupled nonlinear differential rate equations. Kinetic analysis shows that carboxylates on the surface of the protein act as a proton-collecting antenna, which is able to rapidly transfer protons to nearby histidines that function as a local proton reservoir. These properties enable cytochrome oxidase to carry out its redox-linked proton translocation. Molecular modeling of the fluorescein-binding site indicates that, in addition to the covalent bond, the dye is anchored through a hydrogen bond to the hydroxyl moiety of Tyr(VII-50). The protonation of the dye is mediated through three residues that shuttle protons between the bulk and the dye. A correlation between the measured kinetic properties of the bound fluorescein and the different configurations of the dye allows us to predict the identity of the proton-binding sites in the fluorescein-binding domain.

Animals↗

PubMed2001

Probing of the substrate binding domain of lactose permease by a proton pulse.

The lactose permease of Escherichia coli coupled proton transfer across the bacterial inner membrane with the uptake of beta-galactosides. In the present study we have used the cysteine-less C148 mutant that was selectively labeled by fluorescein maleimide on the C148 residue, which is an active component of the substrate transporting cavity. Measurements of the protonation dynamics of the bound pH indicator in the time resolved domain allowed us to probe the binding site by a free diffusing proton. The measured signal was reconstructed by numeric integration of differential rate equations that comply with the detailed balance principle and account for all proton transfer reactions taking place in the reaction mixture. This analysis yields the rate constants and pK values of all residues participating in the fast proton transfer reaction between the bulk and the protein's surface, revealing the exposed residues that react with free protons in a diffusion controlled reaction and how they transfer protons among themselves. The magnitudes of these rate constants were finally evaluated by comparison with the rate predicted by the Debye-Smoluchowski equation. The analysis of the kinetic and pK values indicated that the protein-fluorescein adduct assumes two conformation states. One is dominant above pH 7.4, while the other exists only below 7.1. In the high pH range, the enzyme assumes a constrained configuration and the rate constant of the reaction of a free diffusing proton with the bound dye is 10 times slower than a diffusion controlled reaction. In this state, the carboxylate moiety of residue E126 is in close proximity to the dye and exchanges a proton with it at a very fast rate. Below pH 7.1, the substrate binding domain is in a relaxed configuration and freely accessed by bulk protons, and the rate of proton exchange between the dye and E126 is 100,000 times slower. The relevance of these observations to the catalytic cycle is discussed.

Binding Sites↗

PubMed2001

Inwards propagating waves in a limit cycle medium.

The existence of a novel inwards propagating wave motion is demonstrated in a limit-cycle medium both for the FitzHugh-Nagumo and for modified Chernyak-Starobin-Cohen reaction-diffusion systems. The waves (pulses) are seen to be moving "backwards," that is, towards the point where the triggering pulse was initiated, instead of the regular propagation away from the origin. The feasibility of the phenomenon and some of its features are analyzed.

Journal Article↗

PubMed2001

Dynamics of the proton transfer reaction on the cytoplasmic surface of bacteriorhodopsin.

The cytoplasmic surface of bacteriorhodopsin is characterized by a group of carboxylates that function as a proton attractive domain [Checover, S., Nachliel, E., Dencher, N. A., and Gutman, M. (1997) Biochemistry 36, 13919-13928]. To identify these carboxylates, we selectively mutated them into cysteine residues and monitored the effects of the dynamics of proton transfer between the bulk and the surface of the protein. The measurements were carried out without attachment of a pH-sensor to the cysteine residue, thus avoiding any structural perturbation and change in the surface charge caused by the attachment of a reporter group, and the protein was in its BR state. The purple membranes were suspended in an unbuffered solution of pyranine (8-hydroxypyrene-1,3,6-trisulfonate) and exposed to a train of 1000 laser pulses (2.1 mJ/pulse, lambda = 355 nm, at 10 Hz). The excitation of the dye ejected the hydroxyl's proton, and a few nanoseconds later, a pair of free protons and ground-state pyranine anion was formed. The experimental observation was the dynamics of the relaxation of the system to the prepulse state. The observed signals were reconstructed by a numeric method that replicates the chemical reactions proceeding in the perturbed space. The detailed reconstruction of the measured signal assigned the various proton-binding sites with rate constants for proton binding and proton exchange and the pK values. Comparison of the results obtained by the various mutants indicates that the dominant proton-binding cluster of the wild-type protein consists of D104, E161, and E234. The replacement of D104 or E161 with cysteine lowered the proton binding capacity of the cluster to approximately 60% of that of the native protein. The replacement of E234 with cysteine disrupted the structure of the cluster, causing the two remaining carboxylates to function as isolated residues that do not interact with each other. The possibility of proton transfer between monomers is discussed.

Anions↗

PubMed2001

Multiple primary malignancies in association with soft tissue sarcomas.

BACKGROUND: Modern cancer treatment has increased the survival of patients with various malignancies substantially. One of the late sequelae of successful treatment is the development of a second malignant tumor. However, in many cases of second primary tumors, exposure to chemotherapy or radiation therapy is not evident, and it should be postulated that the putative mechanism for the development of the second tumor is different. In the current series, the association between soft tissue sarcoma (STS) in adults and the development of other primary malignancies was studied. METHODS: A retrospective search of the data files of 610 patients with STS or bone sarcomas who were treated at the study institution between January 1995 and December 1999 was performed. All files regarding patients with STS who developed a second malignant tumor were retrieved for analysis. RESULTS: Of 375 patients with STS, 28 (7.5%) developed other malignant neoplasms either before or after the diagnosis of STS. STS as the first tumor occurred in 14 patients (ages 16-72 years). Only three patients were treated with chemotherapy for their sarcoma. Radiation therapy was administered to five patients as an adjuvant to surgery for the first tumor. The second tumor types mainly included STS and renal cell carcinoma. The time interval between the diagnosis of the STS and the second malignancy was 0 (for synchronous tumors) to 21 years. Three patients developed a third primary tumor within 3 years after the diagnosis of the second tumor. The median overall survival was > 78 months. Fourteen patients (ages 35-87 years) had a first primary tumor other than STS (mainly breast carcinoma and genitourinary malignancies). The second tumors (mainly STS) appeared within 0 (for synchronous tumors) to 27 years. The median overall survival for the 14 patients in this group from the time of diagnosis of the first tumor was > 102 months. CONCLUSIONS: The phenomenon of two or three primary neoplasms developing in patients in whom one of the tumors was STS occurs at a rate of 7.5%, a significantly higher rate than that reported for the occurrence of STS among the general cancer population (1%). The majority of cases occur incidentally. The clinical implication includes the need to search for an occult second primary tumor in patients with STS as an integral part of their follow-up. This is especially true in patients with primary malignant fibrous histiocytoma who demonstrate a risk for developing a renal cell carcinoma.

Adolescent↗

PubMed2001

Time-resolved study of the inner space of lactose permease.

Pyranine (8-hydroxy pyrene-1,3,6-trisulfonate) is a commonly used photoacid that discharges a proton when excited to its first electronic singlet state. Follow-up of its dissociation kinetics reveals the physicochemical properties of its most immediate environment. At vanishing ionic strength the dye adsorbs to the Escherichia coli lactose permease with stoichiometry of 1:1 and an association constant of 2.5 x 10(5) M(-1). The reversal of the binding at high ionic strength and the lower pK value of the bound dye imply that positive charge(s) stabilize the dye in its site. The fluorescence decay curve of the bound dye was measured by time-correlated single photon counting and the measured transient was subjected to kinetic analysis based on the geminate recombination model. The analysis indicated that the binding domain is a cleft (between 9 and 17 A deep) characterized by low activity of water (a((water)) = 0.71), reduced diffusivity of protons, and enhanced electrostatic potential. The binding of pyranine and a substrate are not mutually exclusive; however, when the substrate is added, the dye-binding environment is better solvated. These properties, if attributed to the substrate-conducting pathway, may explain some of the forces operating on the substrate in the cavity. The reduced activities of the water strips the substrate from some of its solvation water molecules and replace them by direct interaction with the protein. In parallel, the lower dielectric constant enhances the binding of the proton to the protein, thus keeping a tight seal that prevents protons from diffusing.

Arylsulfonates↗

PubMed2001

Hydronephrosis associated with colorectal carcinoma: treatment and outcome.

AIM: Obstruction of the upper urinary tract, hydronephrosis, is not uncommon in the context of primary or recurrent colorectal cancer (CRC). Its presence poses a therapeutic dilemma. This study focuses on the significance of hydronephrosis as a prognostic marker for CRC by analysing the resectability and survival rates of patients affected. PATIENTS AND METHODS: Retrospective data of 52 patients with hydronephrosis were analysed. Ten had primary CRC at different sites and 42 developed hydronephrosis 1-84 months following resection of a primary CRC. Twenty eight had unilateral and 24 bilateral hydronephrosis. RESULTS: In 10 patients with primary CRC and in 38 of those with a history of CRC, hydronephrosis was secondary to malignant obstruction. In four it was related to iatrogenic injury to the urinary tract. Complete surgical resection was possible in five patients (10%) with malignant obstruction. The remaining 90% underwent palliative or no surgical treatment due to diffuse metastasis or extensive local disease. No difference in survival was found between these two groups (6 vs 8 months) nor when comparing CEA levels, Duke's staging, or unilateral vs bilateral hydronephrosis. Patients with benign obstruction were treated by a ureteric stent, leading to resolution of hydronephrosis. All four are alive. CONCLUSIONS: Malignant hydronephrosis, secondary to primary or recurrent CRC, represents local manifestation of a disseminated disease with almost no probability of long-term survival and cure. It would seem that patients with such disease do not benefit from aggressive operations.

Adult↗

PubMed2001

Is forequarter amputation justified for palliation of intractable cancer symptoms?

BACKGROUND: Limb-sparing surgery has replaced the radical surgical approach for treating limb sarcomas in most cases. Amputation has been advocated as a palliative procedure for symptomatic locally advanced disease that has already failed to respond to radiation therapy, chemotherapy and limited surgery. METHODS: Twelve patients with advanced malignant tumors involving the shoulder girdle or the proximal humerus underwent forequarter amputation (FQA) for palliative purposes. The tumor-related local problems were severe pain, limb dysfunction, tumor fungation, bleeding (requiring emergency FQA in one case) and infection. The preoperative Karnofsky performance status (KPS) in our series ranged from 30 to 70%. RESULTS: No perioperative mortality was observed. The morbidity was well tolerated by the patients. The KPS improved in most of the patients, and was assessed as 90-100% in 9 of the 12 patients. Overall, quality of life was reported to be at least moderately improved by 2 out of 3 patients. Survival was measured in months (3-24 months), but ultimately had no meaning since the procedure was palliative. Lung metastases were the dominant cause of death in our patients. CONCLUSIONS: The results of FQA in our series point to its feasibility and the gain in quality of life and performance status in severely ill patients with advanced malignancies. Local symptoms and signs were controlled, and quality of life was restored.

Adolescent↗

PubMed2000

Theoretical calculations of the permeability of monensin-cation complexes in model bio-membranes.

Monensin is one of the best-characterized ionophores; it functions in the electroneutral exchange of cations between the extracellular and cytoplasmic sides of cell membranes. The X-ray crystal structures of monensin in free acid form and in complex with Na(+), K(+) and Ag(+) are known and we have recently measured the diffusion rates of monensin in free acid form (Mo-H) and in complex with Na(+) (Mo-Na) and with K(+) (Mo-K) using laser pulse techniques. The results have shown that Mo-H diffuses across the membrane one order of magnitude faster than Mo-Na and two orders of magnitude faster than Mo-K. Here, we report calculations of the translocation free energy of these complexes across the membrane along the most favorable path, i.e. the lowest free energy path. The calculations show that the most favorable orientation of monensin is with its hydrophobic furanyl and pyranyl moieties in the hydrocarbon region of the membrane and the carboxyl group and the cation at the water-membrane interface. Further, the calculations show that Mo-H is likely to be inserted deeper than Mo-Na into the bilayer, and that the free energy barrier for transfer of Mo-H across the membrane is approximately 1 kcal/mol lower than for Mo-Na, in good agreement with our measurements. Our results show that the Mo-K complex is unlikely to diffuse across lipid bilayers in its X-ray crystal structure, in contrast to the Mo-H and Mo-Na complexes. Apparently, when diffusing across the membrane, the Mo-K complex assumes a different conformation and/or thinning defects in the bilayer lower significantly the free energy barrier for the process. The suitability of the model for treating the membrane association of small molecules is discussed in view of the successes and failures observed for the monensin system.

Cations, Monovalent↗

PubMed2000

Biophysical aspects of intra-protein proton transfer.

The passage of proton trough proteins is common to all membranal energy conserving enzymes. While the routes differ among the various proteins, the mechanism of proton propagation is based on the same chemical-physical principles. The proton progresses through a sequence of dissociation association steps where the protein and water molecules function as a solvent that lowers the energy penalty associated with the generation of ions in the protein. The propagation of the proton in the protein is a random walk, between the temporary proton binding sites that make the conducting path, that is biased by the intra-protein electrostatic potential. Kinetic measurements of proton transfer reactions, in the sub-ns up to micros time frame, allow to monitor the dynamics of the partial reactions of an overall proton transfer through a protein.

Arylsulfonates↗

PubMed2000

Metastases to the retroperitoneum in patients with extremity soft tissue sarcoma: an unusual metastatic pattern.

BACKGROUND: Extremity soft tissue sarcoma (STS) metastasizes preferentially to the lungs via the hematogenous route. Metastases in extrapulmonary sites such as bone, brain, and subcutaneous tissues are observed less frequently. To the authors' knowledge, limb STS primarily metastasizing to the retroperitoneum has not been described to date. The current study reviews the clinical course, management, and patient prognosis in such a pattern of metastasis. METHODS: Records of patients with retroperitoneal metastases originating from an extremity STS between 1994-1998 were reviewed. Patient demographics, primary tumor site, other tumor sites, local recurrence, distant metastasis, treatment, and survival were analyzed. RESULTS: Ten patients were included in the study. All had primary STS of different histologic types and high histologic grade confined to a lower limb. The retroperitoneal metastases were diagnosed between 6-120 months (mean, 45 months) after diagnosis of the primary sarcoma. At that time, one patient had evidence of local recurrence of the primary tumor site, two patients had lung metastases, and one patient had diffuse bone metastases. Eight patients were eligible for surgery. In six of these patients the metastases were excised completely. The median follow up was 12 months. Of the six patients who underwent complete resection, 3 were alive at last follow-up with no evidence of disease after 12 months, 14 months, and 24 months, respectively. Two patients with recurrent retroperitoneal disease and one patient with retroperitoneal and lung metastases died despite systemic chemotherapy. CONCLUSIONS: Extremity STS can metastasize hematogenously to the retroperitoneum, a fact that mandates a high index of suspicion and abdominal imaging studies during the follow-up of such patients. Retroperitoneal metastases necessitate aggressive surgical resection to enable prolongation of survival.

Adult↗