bluuebunny/crossref_metadata_2025 huggingface dataset:
Rifaximin: A Nonabsorbed Antimicrobial in the Therapy of Travelers’ Diarrhea
Authors: DuPont H.L. , Ericsson C.D. , Mathewson J.J. , Palazzini E. , DuPont M.W. , Jiang Z.D. , Mosavi A. , de la Cabada F.J.
Published: April 2003

Background/Aims: Bacterial enteropathogens, the major cause of travelers’ diarrhea, are customarily treated with antibacterial drugs. Rifaximin, a nonabsorbed antimicrobial was examined as treatment for travelers’ diarrhea. Methods: A randomized, prospective, double-blind clinical trial was carried out in 72 US adults in Mexico. Patients with acute diarrhea received one of three doses of rifaximin (200, 400 and 600 mg t.i.d.) or trimethoprim/sulfamethoxazole (TMP/SMX, 160 mg/800 mg b.i.d.) for 5 days. Results were compared with data from 2 placebo-treated historical control populations. Results: The shortest duration of treated diarrhea was seen in the group receiving 200 mg rifaximin t.i.d (NS). Clinical failure to respond to treatment occurred in 6 of 55 (11%) rifaximin-treated subjects versus 5 of 17 (29%) of TMP/SMX-treated subjects (NS). Sixteen of twenty (80%) of the enteropathogens isolated from the rifaximin-treated subjects and 7 of 7 (100%) from the TMP/SMX group were eradicated by treatment (NS). Sixteen of twenty-four (67%) enteropathogens identified were susceptible to TMP and all 24 were inhibited by ≤50 µg/ml of rifaximin. Rifaximin reduced the number of unformed stools passed during the first 24 h of treatment when compared with 2 control placebo groups (3.3 versus 5.1; p = 0.008 and 0.0001) and led to a reduced duration of post-enrollment diarrhea (mean values of 43.1 versus 68.1 and 81.9 h; p = 0.001). Conclusions: Rifaximin shortened the duration of travelers’ diarrhea compared with TMP/SMX and 2 earlier studied placebo-treated groups. A poorly absorbed drug if effective in treating bacterial diarrhea has pharmacologic and safety advantages over the existing drugs.
Colonization with cagA-Positive Helicobacter pylori Strains Inversely Associated with Reflux Esophagitis and Barrett’s Esophagus
Authors: Loffeld R.J.L.F. , Werdmuller B.F.M. , Kuster J.G. , Pérez-Pérez G.I. , Blaser M.J. , Kuipers E.J.
Published: April 2003

Aim: The hypothesis that colonization with cagA+ Helicobacter pylori strains protects against the development of gastroesophageal reflux disease (GERD) and its complications is tested. Methods: Patients with reflux esophagitis and Barrett’s esophagus were studied. Antral biopsy specimens were obtained for detection of H. pylori. A serum sample was obtained for determination of IgG antibodies to H. pylori and to the CagA protein. Results: 736 patients were studied. 118 patients had reflux esophagitis, 36 had Barrett’s esophagus, 108 had hiatal hernia without signs of inflammation (the reflux group), and 20 patients had esophageal or stomach cancer. The remaining 454 patients had no signs of GERD. The 262 patients with reflux disease had a significantly lower prevalence of H. pylori (34.9%) than the 454 controls (54.6%; p < 0.001). Among 310 H. pylori-positive patients from whom serum was available, colonization with cagA+ strains was detected in 59% in the control group versus 35% in the reflux group (p < 0.001). Conclusion: Patients with reflux esophagitis and Barrett’s esophagus have a significantly lower prevalence of H. pylori colonization than controls, in particular of the cagA+ type. These data suggest that colonization with cagA+ H. pylori strains may be protective against the development of GERD
White Matter Changes on CT and MRI: An Overview of Visual Rating Scales
Authors: Scheltens Philip , Erkinjunti Timo , Leys Didier , Wahlund Lars-Olaf , Inzitari Domenico , del Ser Theodoro , Pasquier Florence , Barkhof Frederik , Mäntylä Riita , Bowler John , Wallin Anders , Ghika Joseph , Fazekas Franz , Pantoni Leonardo
Published: April 2003

Since the recognition of white matter changes on CT (leukoaraiosis), rating scales for the location and severity of white matter changes have been developed, mainly for research purposes, to investigate factors such as the relation with cognition, risk factors, and pathology. The main purpose of rating scales is to provide scores that can be used in statistical analyses. The development of the NINDS-AIREN criteria for vascular dementia have introduced a new application for these rating scales in investigating and delineating the amount of white matter changes on CT/MRI sufficient to fulfill the criteria. Furthermore, in Alzheimer’s disease, recognition of white matter changes may serve to delineate homogeneous groups and help to identify patients with different symptomatology. We reviewed the existing rating scales for CT and MRI and judged their properties and reliability. The ideal rating scale does not yet exist, but different rating scales may serve different purposes, for which some recommendations are made.
Quadriceps Atrophy after Knee Traumatisms and Immobilization: Electrophysiological Assessment
Authors: Cruz-Martínez A. , Ramírez A. , Arpa J.
Published: April 2003

Automatic analysis of EMG (T/A analysis) and invasive muscle fiber conduction velocity in situ (MFCV) were performed in 15 patients after traumatic lesions of the knee and immobilization with quadriceps atrophy. T/A analysis showed transient reduced number of turns, consistent with inhibition of quadriceps motoneurons, that recovered within the first 2 weeks after the plaster cast had been removed. MFCV was significantly slowed and showed a gradual improvement, reaching normal values after 6 weeks. These results suggest that decrement in activated motor units may be the cause of the disproportionate weakness of the quadriceps muscle on the first days after immobilization by the plaster cast. The recovery of MFCV was related with functional improvement of strength after the first weeks.
Alterations in Trk A, Trk B and Trk C Receptor Immunoreactivities in Parietal Cortex and Cerebellum in Alzheimer’s Disease
Authors: Savaskan Egemen , Müller-Spahn Franz , Olivieri Gianfranco , Bruttel Sybille , Otten Uwe , Rosenberg Carolyn , Hulette Christine , Hock Christoph
Published: April 2003

The neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 bind to the tyrosine kinase (trk) receptors trk A, trk B and trk C, respectively, with high affinity. We investigated the expression of the trk receptors in the parietal cortex (PC) and cerebellum of patients with Alzheimer’s disease (AD) and age-matched controls. Cortical layers II–VI displayed a distinct cellular immunoreactivity for trk A and C with an emphasis in the pyramidal neurons of layers III and V. Trk B immunoreactivity was primarily located in the deeper cortical layers with a predominance in layer V. There was a decrease in trk A and C immunoreactivity in the PC of AD cases, while trk B density appeared to be unchanged. In addition, cerebellar Purkinje cells revealed a distinct immunoreactivity for trk C both in control and AD cases, suggesting trk C may be important in the maintenance of these cells in the aged brain.
Comparison of Oxidative Phosphorylation in the Anastomosis of the Small and Large Bowel
Authors: Testini M. , Scacco S. , Loiotila L. , Papa F. , Vergari R. , Regina G. , Nicolardi V. , Paccione F.
Published: April 2003

Dehiscence of anastomosis in the large bowel (LB) is more frequent compared with that in the small bowel (SB). The pathophysiological mechanisms underlying the phenomenon are well known. The goal of this study is to demonstrate the different oxidative phosphorylation roles in the response of the anastomosed SB and LB. In 45 male rabbits under general anaesthesia, the ileum and colon were transected always on the same side and an end-to-end anastomosis was constructed using single-layer inverting interrupted 5-0 Ethilon sutures. Tracts containing bowel anastomoses were collected at 3, 12 and 24 h and 3, 7 and 21 days after the operation and compared with non-anastomosed bowel. Respiratory rates with different substrates, enzymatic activities, respiratory complex structures and cytochrome contents were measured in smooth muscle purified mitochondria. Mitochondrial respiration showed significant differences in the LB versus anastomosed SB: respiratory rates were markedly reduced in the LB (residual activity: 25 vs. 95% of the SB). Detailed analysis of other mitochondrial parameters confirmed a better tolerance of the ileum to anastomosis. From these preliminary studies we can consider two different aerobic thresholds for either the large or the small rabbit intestine, the latter being oxygen dependent. This can explain the mitochondrial sufferance of anastomosis in the LB whose prevalent aerobic metabolism can be more easily affected by different noxae if compared with the tendency to glycolytic metabolism of the small intestine.
Attenuation of Renal Ischemia-Reperfusion Injury in Rats by Allopurinol and Prostaglandin E1
Authors: Gupta P.Ch. , Matsushita M. , Oda K. , Nishikimi N. , Sakurai T. , Nimura Y.
Published: April 2003

50 Sprague-Dawley rats were used to study the effect of allopurinol and prostaglandin E1 (PGE1) on renal ischemia-reperfusion injury. They underwent left renal ischemia for 1 h and reperfusion. A right nephrectomy was performed, and 5 groups were made. Group AP received allopurinol 50 mg/kg and PGE1 20 µg/kg; group A, allopurinol; group P, PGE1; group C, control, and group S, sham group. Five animals from each group were used to study renal functions and 5 for renal histology. The serum creatinine values were lower in the treatment groups compared to the controls on days 1–3 and 7 (p < 0.05). The blood urea nitrogen values showed a similar trend. Maximum histological damage was seen in group C, followed by groups A, P and AP, in this order. We conclude that allopurinol and PGE1 attenuate renal ischemia-reperfusion injury in rats.
Effects of Prostaglandin E1 on Hepatic Blood Flow in Conscious Dogs with Chronic Biliary Obstruction
Authors: Machiki Y. , Nimura Y. , Kanda H. , Uematsu T. , Kitagawa Y. , Kamiya S. , Watanabe T.
Published: April 2003

To evaluate the effects of prostaglandin E1 (PGE1) on the hepatic circulation in cholestasis, hepatic arterial blood flow (HAF), portal venous blood flow (PVF), cardiac output, and heart rate during PGE1 infusions were investigated before and 2 weeks after biliary obstruction in conscious dogs by a transit-time ultrasonic flowmeter. In the control period, HAF and PVF increased dose dependently with the infusion of PGE1 from 0.05 to 0.5 µg/kg/min. During the biliary obstruction period, a lower dose of PGE1 increased HAF and PVF. The plasma concentration level of PGE1 during the infusion of PGE1 was significantly higher at each dose in the cholestatic animals. These results suggest that the metabolism of PGE1 is attenuated by cholestasis. Plasma PGE1 concentrations should be useful in deciding the optimal dose of PGE1.
Effect of Omental Angiogenic Lipid Factor on Revascularization of Autotransplanted Spleen in Dogs
Authors: Levy Y. , Miko I. , Hauck M. , Mathesz K. , Furka I. , Orda R.
Published: April 2003

Since the turn of the century, studies have been carried out showing that the omentum contains a factor which enhances revascularization of ischemic tissues. This study was conducted for a period of 3 months and was designed to evaluate the effect of an omental lipid fraction on neovascularization of autotransplanted spleen chips in dogs. Twelve dogs underwent splenectomy and autotransplantation of 5 splenic chips into an omental pouch. In 4 dogs, the splenic chips were immersed in omental angiogenic lipid factor (OAF), while on another 4 dogs, an intramuscular injection of 4 cm3 of OAF was given each day for 7 days postoperatively. A further 4 dogs were not given any of the above treatments (control group). Serial angiographies and histologic examinations demonstrated better neovascularization and regeneration of the transplanted spleen in the dogs from the immersion plus injection group. These data suggest that the omental lipid fraction contains a factor which induces a better regeneration of splenic transplants.
Surgical Trauma Evokes a Rise in the Frequency of Hematopoietic Progenitor Cells and Cytokine Levels in Blood Circulation
Authors: Grzelak I. , Olszewski W.L. , Zaleska M. , Ziolkowska A. , Durlik M. , Lagiewska B. , Muszynski M. , Rowinski W.
Published: April 2003

Alterations in the mononuclear cell populations in the blood circulation are among the most characteristic changes after surgical trauma. They reflect changes in the hematopoietic compartment which develop following surgery. The process of mobilization and differentiation of the hematopoietic population is regulated by cytokines known as growth factors for stem and progenitor cells (SCF, IL-1, IL-3, IL-6, IL-11, TNF, CSFs). Our question was whether operative trauma resulted in the release of the hematopoietic progenitor cells to the blood circulation and an increase in the blood level of cytokines participating in hematopoiesis. The studies were carried out in patients with chronic cholelithiasis, undergoing elective open cholecystectomy under general anesthesia. An increase in the frequency of circulating CD34+ hematopoietic progenitor cells was seen between days 3 and 7 after surgery. Moreover, a significant increase in the percentage of immature cells of myeloid lineage (CD13+, CD14+, CD33+) was seen on the 1st and 3rd postoperative days. This could be the result of an expansion of the total bone marrow cell number after surgery and a subsequent release of these cells into the blood circulation. The changes in blood cell populations were accompanied by an increase in IL-6 on days 1, 3, and 7 following surgery, in IL-6sR on days 10 and 14 and in IL-8 on days 1 and 3. No significant changes in IL-1α, IL-1β, IL-3 and IL-11 were noted. A small rise in GM-CSF was noted in few patients on the 3rd and 7th postoperative days. It is known that IL6 is involved in hematopoiesis, that the IL-6-IL-6sR complex may induce both proliferation and differentiation of hematopoietic progenitor cells and that IL-8 possesses progenitor cell mobilization properties. The appearance of hematopoietic progenitor cells in the blood following surgery may represent a process for the expansion of the immune cell pool after trauma and maintaining of the reserves at a certain level.
Effect of Magnetic Stimulation on the Contractile Activity of the Rectum in the Dog
Authors: Shafik A.
Published: April 2003

Purpose: Magnetic stimulation (MS) produces its effect, according to Faraday’s law, by creating an electric field which can stimulate the neuromuscular tissues. The current study investigates, to our knowledge for the first time, the effect of MS on rectal pressure and evacuation with a view on its possible application in emptying the inertic or neuropathic rectum. Methods: The rectal, rectal neck and vesical pressures as well as the EMG activity of the two rectus abdominis muscles were recorded during sacral MS with a magnetic coil while the rectum was empty and while filled. Stimulation parameters were set at 70% intensity, 20 Hz freqency and 1- to 5-second burst length. Results: Sacral MS of both the filled and empty rectum effected a significant increase in rectal (p < 0.01) and vesical (p < 0.01) pressures and a decrease in rectal neck pressure (p < 0.01). Rectal evacuation of the filled rectum using intermittent stimulation was achieved in all animals. Conclusion: Sacral MS resulted in a rectal evacuation. It is a simple, easy and noninvasive method that might prove applicable in the treatment of inertic constipation and neuropathic rectum.
Quantitative Analysis of Vascular Endothelial Growth Factor in Colon Cancer
Authors: Konno H. , Tanaka T. , Baba M. , Kanai T. , Matsumoto K. , Kamiya K. , Nakamura S. , Baba S.
Published: April 2003

Although some studies have shown that overexpression of vascular endothelial growth factor (VEGF) mRNA or protein is correlated with the progression of human malignancies, it is still unknown whether the VEGF level in tumor tissue correlates with tumor growth or metastasis. The present clinical study enrolled 26 patients with colon cancer and revealed that the VEGF level in tumor tissue was significantly higher than in adjacent normal tissue (220.93 ± 217.64 pg/mg protein in the tumor tissue; n = 26; 38.93 ± 20.26 in the normal tissue; n = 26) and significantly correlated with tumor size, whereas it did not correlate with other clinicopathological variables. The animal study involved orthotopic transplantation of a human colon cancer strain into nude mice and demonstrated that the VEGF level of transplanted tumor tissue (2,318.5 ± 1,340.9 pg/mg protein) was significantly correlated with tumor weight (1,856.4 ± 928.9 mg), but not with the number of the liver metastatic foci. These results indicate that VEGF produced by primary tumors of colon cancers may mainly promote primary tumor growth.
FK506 with Portal Decompression Exerts Beneficial Effects following Extended Hepatectomy in Dogs
Authors: Mitsumoto Y. , Dhar D.Kumar , Yu L. , Soda Y. , Kinugasa S. , Kohno H. , Nagasue N.
Published: April 2003

The present study was designed to elucidate the effectiveness of portal decompression and FK506 (FK) pretreatment in extended hepatectomy in dogs. In the first set of experiment the effect of portal decompression was evaluated in two groups of dogs which underwent extended hepatectomies (80%) with or without (control) a side-to-side portacaval shunt. The presence of the shunt significantly (p < 0.05) improved the 7-day survival of the animals (57.1%) when compared with those of the control group (28.6%) and eventually the portal pressure was significantly lower and mean arterial pressure was significantly higher in the shunt group (p < 0.05). Moreover, the animals with lower portal pressure (≤220 mm of saline) had a significantly improved 7-day survival rate than those with higher portal pressure (p < 0.001). To evaluate the role of FK pretreatment in extended hepatectomy, a more severe model of 90% hepatectomy was used in four different groups: portacaval shunt, shunt and FK pretreatment, FK pretreatment, and hepatectomy only (control). Although the shunt improved the survival rate in the 80% hepatectomy model, neither shunt (8.3%) nor FK pretreatment (0%) independently improved the survival of the animals when the hepatectomy was extended to 90%. FK pretreatment significantly improved the survival (33.3%, p < 0.05) and hepatic functions of the animals only in the presence of a shunt. Also hepatic microcirculation measured with a laser Doppler flowmeter was significantly better in the remnant liver of all treated groups than in the control group (p < 0.01). In conclusion, extended hepatectomy (90%) could be performed in otherwise normal liver after FK pretreatment and a side-to-side portacaval shunt, which improve the regenerative response in a stable hemodynamic animal.
Effects of Selective Nitric Oxide Synthase Inhibition in Hyperdynamic Endotoxemia in Dogs
Authors: Wolfárd A. , Kaszaki J. , Szabó C. , Balogh Z. , Nagy S. , Boros M.
Published: April 2003

Objectives: Our aims were to investigate the systemic hemodynamic effects of constitutive endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) inhibitors in hyperdynamic endotoxemia. Patients and Methods: Group 1 comprised sham-operated controls, while in group 2, 3 and 4, a hyperdynamic circulatory reaction was elicited by a 2-hour infusion of Escherichia coli endotoxin (ETX) in a dose of 5.3 μg/kg. The animals in group 3 were treated with 12.5 mg/kg nonselective NOS inhibitor N-ω-nitro-L-arginine methyl ester (L-NAME), and those in group 4 with 2 mg/kg of the specific iNOS inhibitor S-methyl-isothiourea (SMT). Mean arterial pressure (MAP), cardiac output (CO) and myocardial contractility (MC) were measured, and total peripheral resistance (TPR) was calculated. The eNOS and iNOS activities were determined in myocardial biopsy samples taken after 8 h of endotoxemia. Results: ETX induced significant decreases in TPR and MAP, a transient myocardial depression, and increased the myocardial eNOS and iNOS activities. L-NAME decreased the activities of both isoenzymes, increased MC but induced a fall in CO. SMT inhibited iNOS by 60%, without influencing the eNOS activity, increased MAP and contractility in the early phase of endotoxemia, and induced only a slight decrease in CO. Conclusions: Nonselective NOS inhibition restores the arterial pressure and exerts a positive inotropic effect, but decreases CO. SMT selectively decreases the iNOS activation without disturbing the vasoregulatory function of the eNOS-derived nitric oxide in hyperdynamic endotoxemia in the dog.
Effect of Hyperoxia and Hypoxia on Subcutaneous Tissue Gases and pH
Authors: Mellström Å. , Hartmann M. , Jedlinska Barbara , Jönsson K.
Published: April 2003

The effect of different fractions of inspired oxygen on subcutaneous oxygen tension, carbon dioxide tension and pH in relation to arterial and mixed venous blood gases and pH and hemodynamic variables was evaluated in 13 domestic pigs. Subcutaneous, arterial and mixed venous oxygen tensions were closely correlated (r = 0.94). A minor significant increase in subcutaneous carbon dioxide tension was noted during hyperoxia (p < 0.05). A major increase (33%) was noted during the last step of hypoxia, when arterial and mixed venous carbon dioxide tensions increased only 12 and 17%, respectively. A minor decrease in subcutaneous pH was noted during hyperoxia (p < 0.05) and a major decrease during hypoxia (p < 0.05). Measurements of subcutaneous tissue gases and pH are indicators of oxygen utilization during hyper- and hypoxia.
Delayed Healing of Acetic-Acid-Induced Gastric Ulcer in Portal Hypertensive Rats
Authors: Baatar D. , Kitano S. , Yoshida T. , Bandoh T. , Ninomiya K. , Tsuboi S.
Published: April 2003

The aim of the present study was to determine the effect of portal hypertension on the healing of gastric ulcers in rats. Portal hypertension was induced by staged portal vein ligation. Sham-operated (SO) rats served as controls. Gastric ulcers were induced by application of acetic acid to the serosal surface of the stomach. Healing was assessed by determining the ulcer area on days 3, 7, and 10 after ulcer induction. Epithelial proliferation at the ulcer margin was assessed by evaluating the proliferating cell nuclear antigen labeling index. On days 3 and 7, the proliferating cell nuclear antigen labeling index was lower in portal hypertensive (PHT) rats than in SO rats. On day 10, the ulcer area in PHT rats was nearly twice that in SO rats (4.13 ± 0.29 vs. 2.28 ± 0.22 mm2, p < 0.05). These results suggest that portal hypertension may delay gastric ulcer healing. Furthermore, the inhibition of epithelial proliferation at the ulcer margin may be involved in the delayed healing in portal hypertension.
Hepatorenal Interaction in Glutathione Redox State during Partial Hepatic Ischemia-Reperfusion in Rats
Authors: Saito S. , Honda K. , Kobayashi N.
Published: April 2003

The hepatic glutathione metabolism during partial hepatic ischemia-reperfusion was studied in a rat model with special reference to the hepatorenal glutathione metabolism system. Bile samples, and in- and outflow blood and tissue samples of the rat liver, kidney and small intestine were collected during 60 min of 70% partial liver ischemia and reperfusion. Both reduced and oxidized glutathione levels were determined by HPLC. The tissue ratio of reduced to oxidized glutathione (GSH/GSSG ratio) decreased significantly in the ischemic hepatic lobe at 60 min after reperfusion. The GSH/GSSG ratio in bile from the ischemic hepatic lobes decreased significantly after 60 min of ischemia and gradually recovered after reperfusion. The net release of GSH from the nonischemic hepatic lobe increased at 60 min after reperfusion, since the calculated net release of GSH from the whole liver increased significantly whereas there was no change in the net release from the ischemic hepatic lobe. The tissue GSH level in the kidney increased significantly at 180 min after reperfusion. The calculated net uptake of GSH into the kidney, and the net release of total cysteine from the kidney, tended to decrease at the end of 60 min of ischemia, to increase at 60 min after reperfusion and then decrease at 180 min after reperfusion. We found that the hepatorenal glutathione metabolism was changed by partial hepatic ischemia-reperfusion. These changes might reflect a hepatorenal interaction to maintain the glutathione redox state of the vital organs.
Contribution of Proliferating Leukocytes to Phenotypic Change in Smooth Muscle Cells during the Development of Coronary Arteriosclerosis in Transplanted Hearts
Authors: Shirasawa B. , Hamano K. , Ueda M. , Ito H. , Kobayashi T. , Fujimura Y. , Kojima A. , Esato K.
Published: April 2003

Background: It is well known that coronary arteriosclerosis after heart transplantation is concentric and rich in smooth muscle cells (SMCs); however, the role played by rejection in the intimal thickening caused by SMCs in coronary arteriosclerosis remains unclear. In this study, we examined the process of intimal hyperplasia caused by SMCs and evaluated the relationship between the differentiation state of SMCs and local inflammation caused by rejection. Methods: Lewis rat hearts were heterotopically transplanted into F344 rats (allotransplantation group) or other Lewis rats (isotransplantation group). Cyclosporin A (5 mg/kg/day) was injected intramuscularly for 20 days after transplantation in both groups. The transplanted hearts were examined immunohistochemically using several monoclonal antibodies; namely, HHF-35, CGA7, vimentin, α-actin, HIS36, R73 and proliferating cell nuclear antigen (PCNA). To evaluate the degree of local immunological response caused by rejection, the anti-PCNA antibody was used. To reveal the subtypes of proliferating cells in the thickened intima, HIS36 and R73 antibodies were used. Results: In the allotransplantation group, SMCs in the media began to undergo a phenotypic change toward a poorly differentiated state 30 days after transplantation. Intimal hyperplasia was observed 60 days after transplantation, the thickened intima being composed mainly of dedifferentiated SMCs with abundant PCNA+, most of which were macrophages and T cells. The state of differentiation of SMCs in the thickened intima 90 days after transplantation varied from a dedifferentiated to a highly differentiated state. These changes were strongly correlated with the expression of PCNA. Conclusion: The expression of PCNA was strongly correlated with the differentiation state of SMCs. Thus, local inflammation caused by rejection may play an important role in the initiation of phenotypic change in SMCs.
Effect of Fluid Resuscitation with and without Endothelin A Receptor Blockade on Hemoconcentration and Organ Function in Experimental Pancreatitis
Authors: Forgács B. , Eibl G. , Faulhaber J. , Kahrau S. , Buhr H. , Foitzik T.
Published: April 2003

Background: Intravascular fluid loss contributes to pancreatitis-associated multiple organ dysfunction and is thus a major target for therapy in this life-threatening disease. Aim: To evaluate intravascular fluid loss and extravascular fluid sequestration together with cardiorespiratory and renal function in a well-established rat model of severe acute pancreatitis (AP) and to investigate the effect of fluid resuscitation with and without endothelin receptor A blockade on these parameters. Method: Induction of AP in rats by a standardized bile salt infusion into the pancreatic duct and intravenous cerulein hyperstimulation. Six hours after AP induction, animals were randomized into 4 groups to receive (1) no therapy; (2) 4 ml/kg/h Ringer’s lactate (RL) i.v.; (3) 8 ml/kg/h RL i.v., or (4) 4 ml/kg/h RL plus an endothelin receptor antagonist. Target parameters measured before and after AP induction and during the 24-hour observation period included: mean arterial blood pressure, heart rate, hematocrit, arterial blood gases, urine production, ascites and pleural effusions. Results: After 6 h, all animals presented with severe hemoconcentration (hematocrit >57%) and oliguria (<0.5 ml/6 h). Cardiorespiratory parameters were within the normal range. Up to 12 h after AP induction, animals without therapy had an increased hematocrit and oliguria and developed metabolic acidosis. Animals receiving fluid resuscitation had a significant drop in hematocrit and maintained compensated blood gas values. A significant increase in urine production was only observed in animals given 8 mg/kg/h RL. Between 12 and 24 h, urine production significantly increased with fluid resuscitation and respiratory parameters stabilized except for animals treated with 8 ml/kg/h RL which developed arterial hypoxia and hypercapnia. Conclusions: Intravascular fluid loss and extravascular fluid sequestration together with decreased urine production characterize the early phase of this model of severe AP. Massive fluid resuscitation necessary for increasing urine output may lead to respiratory distress. Reduction of intravascular fluid loss by endothelin receptor blockade is associated with improved renal and respiratory function.
Overexpression of Vascular Endothelial Growth Factor Is Responsible for the Hematogenous Recurrence of Early-Stage Gastric Carcinoma
Authors: Konno H. , Baba M. , Tanaka T. , Kamiya K. , Ota M. , Oba K. , Shoji A. , Kaneko T. , Nakamura S.
Published: April 2003

Vascular endothelial growth factor (VEGF) is crucial for angiogenesis in various malignant tumors. However, it is still unclear whether VEGF is responsible for hematogenous metastasis after the curative resection of gastric carcinoma. In the present study, we evaluated the relevance of VEGF expression to the hematogenous recurrence of stage 1 or 2 primary gastric adenocarcinoma. Among 530 patients, 11 (2.1%) had hematogenous recurrence. Clinicopathological variables were compared between these 11 patients (group R) and 88 patients without intramucosal carcinoma who survived for more than 5 years (group S). Microvessel density (MVD) was assessed immunohistochemically along with VEGF protein expression in all patients from group R and 21 randomly selected patients from group S. There were significant differences in age, tumor size and VEGF expression in tumor tissue between the groups. Positive staining for VEGF protein was observed in all patients of group R, of whom 6 had strongly positive staining. On the other hand, 11 out of 21 patients in group S had positive staining and it was weak in all cases. Both the positive and strongly positive rate were significantly higher in group R than those in group S. There was no significant difference in MVD between the 2 groups (17.7 ± 11.09/field in group R vs. 14.8 ± 10.27/field in group S) and no significant correlation between VEGF expression, MVD and venous invasion, though a weak correlation between the intensity of VEGF staining and MVD was observed (negative staining 12.1 ± 10.51; weakly positive 16.67 ± 10.41; strongly positive 19.7 ± 9.97). Our results suggest that overexpression of VEGF, and not MVD or venous invasion, plays an important role in the hematogenous recurrence of curatively resected gastric carcinoma.
Wound Healing in Denervated Rat Groin Skin Flap
Authors: Ranne J. , Kalimo H. , Pyykkö K. , Scheinin M. , Aaltonen V. , Niinikoski J. , Laato M.
Published: April 2003

The purpose of the present study was to investigate the effect of denervation on dermal wound healing in rat groin skin flaps for 1–10 weeks. The structural differences between wounds in normal and in denervated skin were investigated histologically using Herovici’s staining. Pro α1(I) collagen mRNA levels were studied using Northern hybridization. Denervation and reinnervation of the skin flaps was demonstrated with quantitative noradrenaline determination and immunohistochemically using neurofilament and S-100 antibodies. Denervation of the skin did not seem to have any apparent effects on wound healing as assessed by light microscopy. There were no significant differences in pro α1(I) collagen mRNA levels either. The thin muscle layer underlying the skin was the only element that clearly responded to the denervation.
Permanent Access to the Portal Vein in Rats: An Experimental Model
Authors: Gervaz P. , Scholl Beatrix , Gillet M.
Published: April 2003

A safe and reproducible method for placement of indwelling catheters into the portal venous system is a prerequisite for improved delivery of anticancer drugs to experimental liver metastases. Due to the lack of tumor models in large animals and the difficulty in establishing permanent access to the portal vein in rodents, this type of model has rarely been described in the laboratory setting. We propose a simple, minimally invasive method for repeated portal vein injections in rats. A vascular access device was used, which remained patent for periods of up to 3 months. Placement and support of the catheter tip in the portal vein was performed with a technique designed to avoid portal thrombosis and infections. Permanent portal vein access in a rodent model of liver metastases will be invaluable for the development of novel therapeutic strategies.
Measurement of Hepatic Tissue Hypoxia Using Near Infrared Spectroscopy: Comparison with Hepatic Vein Oxygen Partial Pressure
Authors: El-Desoky A.E.H. , Jiao L.R. , Havlik R. , Habib N. , Davidson B.R. , Seifalian A.M.
Published: April 2003

Hepatic hypoxia occurs during liver surgery and transplantation. The critical level associated with irreversible hepatocellular damage is unknown. Measurement of hepatic tissue oxygenation and hepatic vein oxygen partial pressure (HVPO2) reflects oxygen supply and consumption. Near infrared spectroscopy (NIRS) can be used to monitor hepatic oxyhaemoglobin (HbO2), deoxyhaemoglobin (Hb) and cytochrome oxidase (Cyt Ox) oxidation. This study compared regional hepatic tissue oxygenation (HbO2, Hb and Cyt Ox) using NIRS with HVPO2. The use of tissue oxygenation measured by NIRS and HVPO2 as indicators of hepatic tissue hypoxia was also investigated. Large Landrace pigs (n = 5) underwent laparotomy and liver exposure. Systemic and hepatic haemodynamics were monitored continuously. NIRS probes were placed on the liver to record continuously HbO2, Hb and Cyt Ox. Graded hypoxaemia was achieved by stepwise reduction of the fraction of inspired oxygen (FiO2) from 30% (baseline) to 4%. A significant decrease in hepatic arterial blood flow and total hepatic blood flow was seen with severe hypoxaemia while there was no significant change to portal vein blood flow. Oxygen partial pressures in the hepatic artery, portal vein and hepatic vein decreased progressively with all grades of hypoxaemia. There was an immediate reduction of hepatic HbO2 and simultaneous increase in hepatic Hb with all grades of hypoxaemia. Hepatic Cyt Ox was reduced significantly only with FiO2 ≤10%. A significant correlation (p < 0.001) was found between the changes in hepatic oxygenation parameters measured by NIRS and HVPO2. HVPO2 measurement did not predict the reduction in intracellular tissue oxygenation demonstrated by NIRS with a decrease of Cyt Ox oxidation. In conclusion there was a good correlation between the tissue oxygenation parameters measured by NIRS and HVPO2. However, the reduction of intracellular oxygenation found with severe hypoxaemia was demonstrated only by NIRS.
Influence of Positive End-Expiratory Pressure Ventilation on Peripheral Tissue Perfusion Evaluated by Measurements of Tissue Gases and pH
Authors: Jedlińska Barbara , Mellström Å. , Jönsson K. , Hartmann M.
Published: April 2003

Measurements of subcutaneous oxygen tension (PscO2), subcutaneous carbon dioxide tension (PscCO2) and subcutaneous pH (pHsc) were used for evaluation of peripheral oxygenation in pigs subjected to oleic acid-induced lung injury during ventilation with increasing levels of positive end-expiratory pressure (PEEP). Lung injury resulted in a decrease of arterial oxygen tension (PaO2) from 93 to 37 mm Hg (p < 0.01) with maintained cardiac output. PscO2 decreased from 45 to 17 mm Hg (p < 0.01) and pHsc from 7.47 to 7.39 (p < 0.05), and PscCO2 increased from 46 to 59 mm Hg (p < 0.05). Increase of PEEP level between 5 and 20 cm H2O resulted in a continuous increase of PaO2 from 45 to 145 mm Hg and a decrease of cardiac output from 4.1 to 2.0 liters/min (p < 0.01). PscO2 increased up to a PEEP level of 15 cm H2O, reaching 26 mm Hg. Further increase of PEEP level up to 20 cm H2O resulted in an increase of PscCO2 from 65 to 71 mm Hg (p < 0.05) and a decrease of pHsc from 7.31 to 7.29 (p < 0.05). In conclusion: measurements of tissue gases and pH can be used to evaluate optimum peripheral tissue oxygenation during titration of PEEP level. Whether these measurements can be used as the only indicator to guide therapy in an individual case remains to be studied.
Prolongation of Cardiac Allograft Survival by Selective Injection of Donor Liver Leukocytes in Non-Immunosuppressed Rats
Authors: Sfeir R. , Gambiez L. , Labalette Myriam , Brami F. , Lecomte Martine , Dessaint J.P. , Pruvot F.R.
Published: April 2003

Liver grafts are spontaneously accepted in several animal combinations and are able to induce acceptance of another organ originating from the same donor, which would be rejected when transplanted alone. However, the exact mechanism of this unique tolerance induction capability remains unclear. The aim of our study was to investigate the ability of nonparenchymal liver cells to induce tolerance when they were separated from their parenchymal environment. In the murine combination we used (BN → LEW), heart transplants were constantly tolerated after combined liver plus heart grafting, but rejected when transplanted alone. Nonparenchymal liver cells were isolated from BN rat livers by enzymatic digestion and injected, at different times, to LEW rats, which were recipients of BN heart transplants. The average number of mononuclear cells obtained after isolation was 20 × 106/5 g of rat liver. Immediate trypan-blue exclusion test showed more than 95% of viable cells. Phenotypic studies showed a predominant (47%) lymphocyte population, 7% were monocytes and 46% were cellular debris. Among the lymphocyte population, the majority of cells were bearing the NKR-P1 receptor and about 30% CD3 receptors. Inoculation of nonparenchymal liver cells 7 and 30 days prior to heart transplantation significantly prolonged graft survival compared to controls (14.6 and 12.7 vs. 8.1 days; p = 0.0008 and 0.0059, respectively), whereas simultaneous injection (day 0) had no effect. Injection of donor splenocytes or nonparenchymal liver cells from a third party, at any time, had no effect on rejection. These results provide some more evidence about the specific role of liver lymphocytes in allogenic unresponsiveness. They also suggest that the hepatic parenchymal environment is necessary for the optimal development of this phenomenon.
Low Myometrial Glycogen Content Compared with Rectus Muscle in Term Pregnant Women before Labor
Authors: Steingrímsdóttir Thóra , Ronquist Gunnar , Ulmsten Ulf , Waldenström Anders
Published: April 2003

Glycogen, glucose, some nucleosides and purine base derivatives were determined in biopsies from 10 term pregnant women undergoing elective cesarean sections before labor. The concentrations were compared in the biopsies which were cut from isthmus and fundus of the uterus and m. rectus abdominis. M. rectus biopsies had 1.5 and 2 times higher concentration of glycogen than the isthmic and fundal uterine biopsies, respectively. The glucose concentration in the striated muscle was on the other hand only half that in the myometrium. The uterus displayed regional differences in concentrations of glycogen (higher in isthmus). A relatively low glycogen content in term pregnant uterine smooth muscle compared with striated muscle signifies the restricted energy demands of pregnant myometrium.
Long-Term Follow-Up and Prognostic Factors in Ewing’s Sarcoma
Authors: Aparicio Jorge , Munárriz Blanca , Pastor Miguel , Vera Francisco J. , Castel Victoria , Aparisi Francisco , Montalar Joaquín , Badal M. Dolores , Gómez-Codina José , Herranz Constantino
Published: April 2003

The records of 116 patients from a single center (1970–1993) with newly diagnosed Ewing’s sarcoma or primitive neuroectodermal tumor were reviewed retrospectively. The aim of this study was to ascertain the impact of pretreatment variables on disease-free survival. Median age was 14 years (range 1–34). Twenty patients presented with metastatic disease. Treatment consisted of systemic multiagent chemotherapy plus local irradiation (39%), wide resection (22%), or both (35%). Median potential follow-up was 10.7 years (range 2–26). Three patients developed second malignancies (1 breast carcinoma, 2 acute myeloid leukemias). Median time to relapse was 24 months (range 3–143). The actuarial disease-free survival was 37.4% at 5 years, 33.3% at 10 years and 27.8% at 15 years. Neoadjuvant chemotherapy and a therapy-induced tumor necrosis ≥90% were associated with a better outcome. Patients undergoing surgical resection had a superior disease-free survival than those treated without surgery (45 vs. 18% at 10 years, p = 0.0009). Multiple regression analysis showed that raised serum lactate dehydrogenase levels (p < 0.001), hypoalbuminemia ( p = 0.001) and distant metastases at diagnosis (p = 0.03) were independent adverse prognostic factors. In conclusion, one third of patients with Ewing’s sarcoma become long-term survivors with combined modality treatment. Late relapses and second neoplasms are of concern. Prognostic factors should be considered in the selection of therapy, and the value of serum albumin warrants confirmatory studies.
Prognostic Significance of 67-kDa Laminin Receptor Expression in Advanced Gastric Cancer
Authors: de Manzoni Giovanni , Guglielmi Alfredo , Verlato Giuseppe , Tomezzoli Anna , Pelosi Giuseppe , Schiavon Ivana , Cordiano Claudio
Published: April 2003

The ability of cancer cells to attach to laminin has been correlated with their metastatic potential and highly metastatic cancer cells seem to express on their surface significantly more laminin receptors than do their much less metastatic or benign counterparts. The expression of 67-kDa laminin receptors (LR) was investigated in a group of 75 patients who underwent gastrectomy for advanced gastric cancer, with special reference to the possible role in the tumor progression and in the overall survival. The tumor LR expression was immunohistochemically determined in paraffin-embedded sections using the MLuC5 monoclonal antibody which recognizes the 67-kDa LR and the avidin-biotin immunoperoxidase method. Of the 75 cases analyzed, 43 cases (57.3%) displayed a positive reaction. The cumulative 5-year survival rate was 72.6% (95% CI 52.5–85.3) for patients without expression of LR and 46.6% (29.8–61.8) for those with positive LR expression. A significant association between LR expression and depth of tumor invasion (0.022) was found. By univariate analysis the presence of laminin receptors seemed to be associated with a higher risk of death [RR 1.72 (95% CI 0.71–4.20], but this effect disappeared after controlling for depth of tumor invasion. In conclusion, these results suggest that tumor expression of laminin receptors could be correlated with tumor aggressiveness. However, the prognostic significance of laminin receptor expression is already provided by the depth of tumor invasion.
Predicting the Hematopoietic Response to Recombinant Human Erythropoietin (Epoetin Alfa) in the Treatment of the Anemia of Cancer
Authors: Adamson John W. , Ludwig Heinz
Published: April 2003

Recombinant human erythropoietin (Epoetin alfa) is effective in increasing hemoglobin concentration and hematocrit, and in significantly reducing transfusion requirements in the majority of patients with either the anemia of chronic renal failure or chemotherapy-induced anemia of cancer. Identification of factors that could enable the clinician to predict individual patient hematological responses to Epoetin alfa therapy would be of great value. Changes in levels of serum transferrin receptor protein, hemoglobin, ferritin and reticulocyte count, following a short course of Epoetin alfa therapy, were useful markers for predicting later hematopoietic responses to Epoetin alfa. In addition, recent data suggest that low baseline erythropoietin levels, in association with increases of either >0.5 g/dl in hemoglobin or ≥25% in circulating levels of transferrin receptor protein after 2 weeks of Epoetin alfa therapy, are highly predictive of a response (≥2 g/dl increase in hemoglobin) to Epoetin alfa. Progress has clearly been made in the development of predictive models that can identify those patients most likely to respond to Epoetin alfa by monitoring several specific hematological parameters at baseline and early in therapy. Future studies will focus on nonhematological measures of response, such as transfusion requirement and quality of life benefit.
Phase II Study of Combined Administration of 5-Fluorouracil, Epirubicin and Mitomycin-C by Hepatic Artery Infusion in Patients with Liver Metastases of Gastric Cancer
Authors: Kumada Takashi , Arai Yasuaki , Itoh Kazuki , Takayasu Yukio , Nakamura Kenji , Ariyoshi Yutaka , Tajima Kazuo
Published: April 2003

This multicenter phase II study evaluated the efficacy of the FEM regimen (5-fluorouracil 333 mg/m2 each week, epirubicin 30 mg/m2 once every 4 weeks and mitomycin-C 2.7 mg/m2 once every 2 weeks) administered by hepatic artery infusion (HAI) for unresectable hepatic metastases of gastric cancer. The response rates were 55.6% (complete response: 3, partial response: 32, no change: 21, progressive disease: 7/63) and the mean 50% survival was 10.5 months. Most responders died due to the progression of extrahepatic lesions. HAI of the FEM regimen induced a high response rate in patients with hepatic metastases of gastric cancer, and the prognosis-determining factor was the existence of extrahepatic lesions in many patients.
Secretion of Extracellular Matrix (Fibronectin), Growth Factor (Transforming Growth Factor β) and Protease (Cathepsin D) by Hepatoma Cells
Authors: Ito Hiroshi , Miyazaki Masaru , Nishimura Fusanori , Nakajima Nobuyuki
Published: April 2003

We investigated facilitation of invasion by growth factors and chemotactic factors in tumor cell lines, particularly hepatocellular carcinoma. Hepatoma cells (PLC/PRF/5 and Hep G2) showed strong chemotaxis toward their respective conditioned media while metastatic pancreatic cancer cells (SU.86.86) and colon cancer cells (LS 174T) did not migrate toward their respective conditioned media. Based on immunoblotting, PLC/PRF/5 cells secrete fibronectin (an extracellular matrix constituent), transforming growth factor-β (TGFβ; a growth factor), and cathepsin D (a protease). Fibronectin induced a migratory response in PLC/PRF/5 cells, and anti-fibronectin antibody abolished the migratory response of these cells to their conditioned medium. Anti-integrin-β1 antibody also impeded migration of these cells toward conditioned medium. Polyclonal anti-TGFβ antibody and protease inhibitors (α2-macroglobulin and leupeptin) added to culture media-modulated secretion of fibronectin by PLC/PRF/5 cells. Although exogenous TGFβ suppressed SU.86.86 cells, it enhanced PLC/PRF/5 cell adhesion to substrate, increasing viable cell numbers. These actions indicate that hepatocellular carcinoma may possess a forceful autocrine mechanism enabling cells to survive and proliferate under cirrhotic conditions.