Pancreas transplantation with enteroanastomosis to native duodenum poses technical challenges--but offers improved endoscopic access for scheduled biopsies and therapeutic interventions.

To facilitate endoscopic access for rejection surveillance and stenting of the pancreas, we have abandoned the duodenojejunostomy (DJ) in favor of duodenoduodenostomy (DD) in pancreas transplantation (PTx). From September 2012 to September 2013 we performed 40 PTx with DD; 20 solitary-PTx (S-PTx) and 20 simultaneous pancreas and kidney transplantation (SPK). We compared the outcomes with results from 40 PTx-DJ (10 S-PTx and 30 SPK) from the preceding era. The DD-enteroanastomoses were performed successfully. Endoscopic pancreas biopsies (endoscopic ultrasound examination [EUS]) yielded representative material in half of the cases. One exocrine fistula was treated by endoscopic stenting. PTxs-DD were associated with a higher rate of thrombosis compared to PTx-DJ (23% vs. 5%) and reoperations (48% vs. 30%), as well as inferior graft survival (80% vs. 88%). Time on waiting list, HLA A + B mismatches and reoperations were associated with graft loss. Only recipient age remained an independent predictor of patient death in multivariate analysis. PTx-DD showed a higher rate of thrombosis and inferior results, but facilitated a protocol biopsy program by EUS that was feasible and safe. Given that technical difficulties can be solved, the improved endoscopic access might confer long-term benefits, yet this remains to be proven.

Stress and expression of cyclooxygenases (cox1, cox2a, cox2b) and intestinal eicosanoids, in Atlantic salmon, Salmo salar L.

Prostaglandin H synthetases (cyclooxygenases) catalyze the initial reactions leading to prostanoids in animals. They form interesting links between diet and fish physiology as the type and nature of eicosanoids are affected by dietary lipid sources. Their expression is likely to be affected by tissues and environmental conditions leading to altered amount and ratio of eicosanoids. These mechanisms are, however, poorly understood in fish. In the present study, Atlantic salmon Salmo salar L. (1,000 g, 10°C, seawater) were subjected to acute chasing stress. Liver, kidney, spleen, gill, muscle, midgut and hindgut were extracted before and 1 h post-stress and analyzed for mRNA expression of cox1, cox2a and cox2b. Intestinal samples were further sampled over 24 h for both cox expression and analysis of 15 eicosanoids and isoprostanes of the n-3 and n-6 series. Results show a highly variable but consecutively expression of cox1, cox2a and cox2b in most of the tissues analyzed. Low levels were only found for cox2a in liver and cox2b in liver and kidney. The study reveals the general trend that cox1 is about 10 times the level of cox2b, which again is about 10 times the level of cox2a. Cox2b shows the highest level of expression in the gills indicating a possible higher requirement for this protein in gills. Imposing stress to the fish induces a temporal increase in the expression of cox2a in the midgut, while the gene expression of the other genes is not affected in any of the tissues analyzed. There is, however, a general tendency to increased expression of both cox2 genes that merits further studies. Stress had a profound effect on the intestinal eicosanoid content which showed a general decrease in midgut sections after stress that persisted for at least 24 h.

Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis.

BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.

Spinal fluid dynamics during thoracic- and thoracoabdominal aortic surgery.

AIM: The intention was to investigate cerebrospinal fluid pressure (CSFP) and volume of cerebrospinal fluid (CSF) drained during and after thoracic- and thoracoabdominal aneurysm repair. The findings were related to the occurrence of postoperative neurologic deficits. METHODS: Twenty-nine patients (12 with thoracic and 17 with thoracoabdominal aortic aneurysm) were operated without shunting or extracorporeal circulation. For monitoring of CSFP an intrathecal catheter was placed in all patients. The volume of CSF withdrawn intraoperatively, on the day of operation as well as on the 1st and 2nd postoperative day was recorded. RESULTS: Twenty-six patients had no postoperative neurologic sequelae. One patient had postoperative paraplegia while 2 had paraparesis. The three patients with neurologic sequelae had higher CSFP intraoperatively than those without neurologic symptoms (P=0.04). Median CSFP during aortic cross-clamping was 19 mmHg and 10 mmHg and the median volumes of CSF drained on the day of operation 210 and 85 mL in the two groups, respectively. There was a significant positive correlation between CSFP and central venous pressure. CONCLUSIONS: A higher intraoperative CSFP was observed in patients with neurologic sequelae following thoracic- and thoracoabdominal aneurysm repair. Further, there was a tendency of higher volumes of CSF drained in this group of patients. Although, the series is too small to allow firm conclusions, it supports the view that CSFP monitoring and drainage is beneficial during thoracic- and thoracoabdominal aneurysm repair.

Cancer of the uterine cervix in Norway by histologic type, 1970-84.

A total of 6,202 patients with cancer of the uterine cervix was reported to the Cancer Registry in Norway from 1970 to 1984. Squamous cell carcinoma was reported in 86.1% of all cases, adenocarcinoma in 9.5%, and undifferentiated cancer in 3.6%; the heterogeneous group of "other malignant neoplasms" was 0.8% of all cases, most of which were sarcomas. During the 15-year period the average annual age-adjusted incidence rates for both squamous cell carcinoma and undifferentiated cancer decreased by 30 and 79%, respectively, whereas adenocarcinoma increased by 38%. The increase of adenocarcinoma was mostly confined to females 20-34 years of age. The decrease in incidence rates of undifferentiated cancer was observed in all age groups, whereas the fall in incidence rates for squamous cell carcinoma was demonstrated in females above 35 years of age only. Of all patients with squamous cell carcinoma, 55% were diagnosed in clinical stage I. Females with adenocarcinoma and undifferentiated cancer were diagnosed in stage I in 60 and 38% of the cases, respectively. The 5- and 10-year relative survival rates were highest for patients with squamous cell carcinoma at all stages, whereas a significantly less favorable prognosis was found for females with adenocarcinoma and undifferentiated cancer of the uterine cervix.

Analysis of A-kinase anchoring protein (AKAP) interaction with protein kinase A (PKA) regulatory subunits: PKA isoform specificity in AKAP binding.

Compartmentalization of cAMP-dependent protein kinase (PKA) is in part mediated by specialized protein motifs in the dimerization domain of the regulatory (R)-subunits of PKA that participate in protein-protein interactions with an amphipathic helix region in A-kinase anchoring proteins (AKAPs). In order to develop a molecular understanding of the subcellular distribution and specific functions of PKA isozymes mediated by association with AKAPs, it is of importance to determine the apparent binding constants of the R-subunit-AKAP interactions. Here, we present a novel approach using surface plasmon resonance (SPR) to examine directly the association and dissociation of AKAPs with all four R-subunit isoforms immobilized on a modified cAMP surface with a high level of accuracy. We show that both AKAP79 and S-AKAP84/D-AKAP1 bind RIIalpha very well (apparent K(D) values of 0.5 and 2 nM, respectively). Both proteins also bind RIIbeta quite well, but with three- to fourfold lower affinities than those observed versus RIIalpha. However, only S-AKAP84/D-AKAP1 interacts with RIalpha at a nanomolar affinity (apparent K(D) of 185 nM). In comparison, AKAP95 binds RIIalpha (apparent K(D) of 5.9 nM) with a tenfold higher affinity than RIIbeta and has no detectable binding to RIalpha. Surface competition assays with increasing concentrations of a competitor peptide covering amino acid residues 493 to 515 of the thyroid anchoring protein Ht31, demonstrated that Ht31, but not a proline-substituted peptide, Ht31-P, competed binding of RIIalpha and RIIbeta to all the AKAPs examined (EC(50)-values from 6 to 360 nM). Furthermore, RIalpha interaction with S-AKAP84/D-AKAP1 was competed (EC(50) 355 nM) with the same peptide. Here we report for the first time an approach to determine apparent rate- and equilibria binding constants for the interaction of all PKA isoforms with any AKAP as well as a novel approach for characterizing peptide competitors that disrupt PKA-AKAP anchoring.

Lifestyle-related risk factors and chemoprevention for colorectal neoplasia: experience from the large-scale NORCCAP screening trial.

The objective of this study was to evaluate the potential beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) and/or acetylsalicylic acid (ASA) and hormone replacement therapy (HRT) on colorectal neoplasia, and to compare their effects with those of lifestyle-related risk factors in 12 960 individuals who underwent flexible sigmoidoscopy screening examination. The association between these factors and colonic neoplasia was assessed by logistic regression analysis. NSAIDs and/or ASA intake were associated with decreased risk of distal low grade adenoma (DLGA) (adjusted odds ratio (OR) 0.80, P trend=0.02) in men. The duration of HRT was inversely related to the risk of DLGA (OR 0.89, P trend=0.08). Current smoking increased the risk of DLGA and distal advanced neoplasia (DAN) in both men (OR 2.50, P<0.01) and women (OR 2.30, P<0.01). There was a significant positive trend for increasing risk of DLGA (OR 1.16, P<0.01) and DAN (OR 1.20, P=0.02) with increasing use of alcohol among men, but not among women. Prescription of NSAIDs and/or ASA for chronic conditions may not be expected to have a substantial preventive effect on colorectal neoplasia in comparison with the adverse effect of smoking and alcohol. This may be explained by an increased risk of colorectal neoplasia for patients with conditions for which NSAIDs or ASA are being prescribed.

Recovery following treatment of descending thoracic aortic disease. A comparison between endovascular repair and open surgery.

AIM: The aim of this study was to compare the postoperative course in patients treated by endovascular repair (endo) with patients treated by open surgery (open) for descending thoracic aortic disease. METHODS: Twenty-five patients treated with stent grafting for aneurysmal disease or type B dissection were compared with 35 historical controls treated by open surgery. Stay in the intensive care unit, need for artificial ventilation and to where the patient had been discharged, were noted. Pain medication, use of nasogastric tube, time until total oral nutrition, mobilization and the patients' mental condition in the postoperative period, were studied in the patients charts and the nursing reports. RESULTS: Time on the intensive care unit or intermediate care unit was median 45 h in the endo group compared with 192 h in the open group. Eighty percent of the patients in the endo group were discharged directly to their homes in contrast to 23% after open surgery. In the endo group 67% of the patients started oral nutrition on the 1st postoperative day compared to 10% in the open group. There was a significantly faster mobilization in the endo group. CONCLUSIONS: There was a significantly shorter recovery after stent grafting for descending thoracic aortic disease compared to patients operated with open surgical technique.

Molecular signatures of mRNAs and miRNAs as prognostic biomarkers in pancreatobiliary and intestinal types of periampullary adenocarcinomas.

Periampullary adenocarcinomas include four anatomical sites of origin (the pancreatic duct, bile duct, ampulla and duodenum) and most of them fall into two histological subgroups (pancreatobiliary and intestinal). Determining the exact origin of the tumor is sometimes difficult, due to overlapping histopathological characteristics. The prognosis depends on the histological subtype, as well as on the anatomical site of origin, the former being the more important. The molecular basis for these differences in prognosis is poorly understood. Whole-genome analyses were used to investigate the association between molecular tumor profiles, pathogenesis and prognosis. A total of 85 periampullary adenocarcinomas were characterized by mRNA and miRNA expressions profiling. Molecular profiles of the tumors from the different anatomical sites of origin as well as of the different histological subtypes were compared. Differentially expressed mRNAs and miRNAs between the two histopathological subtypes were linked to specific molecular pathways. Six miRNA families were downregulated and four were upregulated in the pancreatobiliary type as compared to the intestinal type (P < 0.05). miRNAs and mRNAs associated with improved overall and recurrence free survival for the two histopathological subtypes were identified. For the pancreatobiliary type the genes ATM, PTEN, RB1 and the miRNAs miR-592 and miR-497, and for the intestinal type the genes PDPK1, PIK3R2, G6PC and the miRNAs miR-127-3p, miR-377* were linked to enriched pathways and identified as prognostic markers. The molecular signatures identified may in the future guide the clinicians in the therapeutic decision making to an individualized treatment, if confirmed in other larger datasets.

Half dose of OKT3 is efficient in treatment of steroid-resistant renal allograft rejection.

Rejection episodes in renal allograft recipients are usually efficiently treated with high doses of intravenous methylprednisolone. Rejection therapy with OKT3 is often reserved for steroid-resistant episodes. However, the optimal dose of OKT3 in the treatment of steroid-resistant rejection is not known. Therefore, we randomized renal transplant recipients with steroid-resistant rejection to treatment with a standard daily intravenous dose of either 5 mg of OKT3 (n=15) or 2.5 mg of OKT3 (n=15) for 10 days. Circulating T cells (measured as CD2+ cells) were adequately and equally depleted in the two groups. Three grafts were lost due to rejection within the first 3 months following OKT3 administration, one in the 2.5 mg OKT3 group and two in the 5 mg OKT3 group. Two nonimmunologic graft losses occurred in the 2.5 mg OKT3 group. Median serum creatinine values were not different between the two groups, neither at the start (median values: 200 micormol/L in the 5 mg OKT3 group vs. 188 micromol/L in the 2.5 mg group) nor immediately after OKT3 rescue therapy (202 micromol/L vs. 185 micromol/L, respectively). Eight cytomegalovirus infections occurred in each group. Two re-rejection episodes occurred in the 5 mg OKT3 group and one occurred in the 2.5 mg OKT3 group. All responded to treatment. Function of the remaining grafts estimated by serum creatinine after a mean long-term follow-up of 18 months (range, 6-36 months) revealed no differences (185 micromol/L in the 5 mg OKT3 group vs. 170 micromol/L in the 2.5 mg OKT3 group). We conclude that OKT3 treatment of steroid-resistant rejections in renal transplant recipients is equally effective in daily doses of 2.5 mg and 5 mg with respect to reversal rate and long-term outcome.

Cell death initiated by 3-deazaadenosine in HL-60 cells is apoptosis and is partially inhibited by homocysteine.

Cell death initiated by the adenosine analog 3-deazaadenosine (c3 Ado) was studied in human promyelocytic leukemia HL-60 cells. A rapid decrease in cell number was seen after 4-hr exposure to 50-100 microM c3 Ado. The dominating mode of cell death was apoptosis as demonstrated by condensation and fragmentation of the nucleus, formation of apoptotic bodies and endonucleolytic degradation of DNA. Four hour treatment with 100 microM c3 Ado resulted in a reduction of early S-phase cells, and appearance of cells with a lower DNA and protein content than that of the G1 population. Whereas 25 and 50 microM c3 Ado only initiated apoptosis in S-phase cells, 75 and 100 microM c3 Ado also initiated apoptosis in G1- and G2 + M-phase cells, suggesting different mechanisms for cell death at different concentrations. Apoptosis initiated by 100 microM c3 Ado was completely inhibited by 1 mM ZnCl2. Addition of homocysteine thiolactone (Hcy) partly inhibited cell death by c3 Ado. Light microscopic examination of cultures treated with 100 microM c3 Ado and 1 mM Hcy showed nuclear condensation and fragmentation consistent with the first stage in apoptosis, however, only a minor formation of apoptotic bodies took place in these cultures compared to that observed in cultures treated with 100 microM c3 Ado alone. The modifying action of Hcy on c3 Ado initiated apoptosis in HL-60 cells and this suggests that c3 Ado and 3-deazaadenosylhomocysteine (c3 AdoHcy) interact with different targets during initiation and progression of cell death in this cell line.

Remote frozen section service: a telepathology project in northern Norway.

We discuss the organization of a remote frozen section service in northern Norway. The service is operated by remote control of a motorized video-microscope located at Kirkenes Hospital, at a distance of more than 400 km from the workstation at the University Hospital in Tromsø. The video images of the frozen section are transmitted via a two-way telephone and video telenetwork with a 2 Mbit/s capacity. The images are displayed on monitors and diagnosed by pathologists in Tromsø. To date, 17 patients have been examined by remote frozen section. Correct benign versus malignant diagnoses have been given in all 17 cases compared with final diagnoses based on formalin-fixed and paraffin-embedded material. The average time taken for examining each frozen section was 15 minutes (range, 5 to 30 minutes). In none of the cases was the interpretation of the slides difficult due to deficient quality of the video images. For small hospitals with limited availability of local pathology services and for hospitals with a deficiency of specialists, telepathology may be a worthwhile substitute.

Current status of telepathology.

Telepathology is moving from the experimental stage to become a regular feature of pathology practice. This has been made possible by technical advances in telecommunications and image processing. Since 1990 the University Hospital of Tromsø has provided local hospitals in northern Norway with a remote frozen section service and with access to video conferences for the review of microscopic findings and for the discussion of major diagnostic issues. Several other hospitals in Norway are now participating in this development and practical relations among pathology laboratories for the purpose of consultation and education will be the next step in the procedure. Similar developments in telepathology have taken place in other countries. Standardization of network and telepathology workstations will be needed before extensive international collaboration can be achieved. Progress in high quality video devices, high capacity telecommunication lines and improved image compression techniques will increase the usage of telepathology services and make them cost-effective. Thus, telepathology will contribute to the development of pathology services in the next century.

Forensic pathology in northern Norway. Requested medico-legal autopsies in the counties of Finnmark and Troms 1973-1992.

The aim of this study was to analyse medico-legal autopsy rates among Norwegian citizens who died in the two northernmost counties of Norway during the 20-year period 1973-1992. Medico-legal autopsy rate was defined as the number of medico-legal autopsies divided by the total number of deaths. The rates were calculated according to year of death, manner of death, sex, age, police district and county. The material included 1539 medico-legal autopsies. In the total 20-year period 37.9% (n = 1113) of the violent deaths and 1.2% (n = 426) of the natural deaths were subjected to medico-legal autopsy. The annual rates increased gradually up to 1987. In the last 5-year period 51.7% of the violent deaths and 2.1% of the natural deaths were subjected to medico-legal autopsy. Among violent deaths in this period the medico-legal autopsy rates were: suicides 65.7%, motor vehicle traffic accidents 58.3%, falls 8.6%, and other violent deaths 77.1%. Females dying after a fall and due to natural causes were significantly less frequently than males subjected to medico-legal autopsy. These two categories of death also revealed a significant decrease in autopsy rate with increasing age (age group 0-29, 30-59 and > or = 60 years) in each 5-year period. In cases of violent death the medico-legal autopsy rate according to police district varied from 24.1% to 88.9% in the last 5-year period. In conclusion, medico-legal autopsy rates depended on manner of death, sex, age and police district, besides changes in legislation.

Lipid entrapment and cellular changes in the rat myocard, lung and liver after long-term parenteral nutrition with lipid emulsion. A light microscopic and ultrastructural study.

We have demonstrated organ damage after long-term administration of lipid-based parenteral nutrition, possibly initiated by intravascular pooling of lipid and phagocytes, in both rats and pigs. To evaluate whether accumulation of lipid could simply be caused by mechanical filtration, a comparative study of three separate capillary beds was performed. Rats were given lipid emulsion (n = 5) or isotonic saline (n = 4) through central venous catheters for 3 weeks. Using both light and electron microscopy, lipid accumulation and structural changes in the rat myocard were compared to those in the lung and liver. The study provides evidence that within myocardial capillaries both peripheral blood monocytes and endothelial cells performed phagocytosis of lipid droplets following administration of lipid emulsion, but no large-scale intravascular pooling of lipid resulted. Morphometry of the myocard detected no lipid increase in the myocytes from the rats given lipid emulsion compared with controls and in neither were there any stigmata of vasculitis or myocardial damage, in contrast to the lung and liver, where intravascular pooling of lipid and phagocytes was seen. This indicates that phagocytosis was an important mechanism involved in entrapment and elimination of lipid.

Pulmonary intravascular macrophages appear in rats after long-term administration of lipid emulsion and amino acid solution. An ultrastructural morphometric study.

Intravascular macrophages have rarely been seen in normal lungs of humans and rats, but in rats endotoxaemia has induced their presence. To study whether substrates used for parenteral nutrition could have a similar stimulatory effect on mononuclear phagocytes, rats were given lipid emulsion (n=5), amino acid solution (n=5), or isotonic saline (n=5) through central venous catheters for 3 weeks. Structural changes in the lung microvessels were evaluated using electron microscopy. The areal fraction of pulmonary intravascular mononuclear phagocytes was 19.6% (SD=8.2) in rats given lipid emulsion (p<0.05) and 8.2% (SD=8.2) in rats given amino acid solution n.s. compared to 2.4% (SD= 4.0) in rats given saline. The increase in areal fraction was mainly due to an increase in cell numbers. In rats given lipid emulsion the intravascular phagocytes were only slightly larger than in rats given saline, but had the morphological features of mature macrophages. The study demonstrates that lipid emulsion recruits pulmonary intravascular macrophages in rats, indicating a stimulatory effect on the mononuclear phagocyte system. The effect was less pronounced with amino acid solution.

Morphological modifications of apoptosis in HL-60 cells: effects of homocysteine and cytochalasins on apoptosis initiated by 3-deazaadenosine.

Using electron microscopy, confocal laser scanning microscopy and measurements of intact DNA we have studied the morphology and DNA degradation of human leukaemia HL-60 cells undergoing drug initiated apoptosis. Apoptosis was initiated by 100 microM 3-deazaadenosine (c3Ado), 25 microM c3Ado plus 1 mM homocysteine thiolactone (Hcy) and 100 microM c3Ado plus 5 micrograms/ml cytochalasin B (CB). Two different phenotypes of apoptotic cells (APC), blebbed and non-blebbed, were present in the cultures. Blebbed APC dominated in cultures exposed to c3Ado, whereas most APC in cultures treated with c3Ado plus Hcy and all the APC in cultures treated with c3Ado plus CB displayed a non-blebbed phenotype. A more pronounced reduction of the chromatin/cytoplasm ratio, lower volume fractions of uncondensed chromatin and higher volume fractions of highly condensed chromatin (micronuclei) were found in cultures exposed to c3Ado and c3Ado plus Hcy when compared with cultures exposed to c3Ado plus CB. A partial inhibition of c3Ado apoptosis by CB was confirmed by measurements of intact DNA. The inhibitory effect of CB was not reproducible by CE, indicating that CB exerts its effect by an actin independent mechanism. Both blebbed and non-blebbed APC displayed nuclear fragmentation, segregation of organelles and cytoplasmic vesiculation, suggesting that the differences between the phenotypes were restricted to the cytoplasmic membrane. We were not able to demonstrate the presence of F-actin by fluorescein isothiocyanate-phalloidin staining in blebbed APC nor in non-blebbed APC in cultures treated with c3Ado plus Hcy. Non-blebbed APC in cultures treated with c3Ado plus CB displayed foci of F-actin at the internal part of the cytoplasmic membrane. This suggests that F-actin is preserved by the mechanism by which CB inhibits blebbing, and may indicate that blebbing of the cytoplasmic membrane during apoptosis is associated with F-actin deficiency rather than a result of actin-myosin interactions.

Effect of nitroglycerin on spinal cord ischemia after thoracic aortic cross-clamping.

BACKGROUND: Thoracic aortic cross-clamping with the use of sodium nitroprusside (SNP) has been shown to cause a decrease in spinal cord perfusion pressure and an increased incidence of paraplegia. Nitroglycerin is frequently used in this setting. This study investigated the effects of nitroglycerin and SNP on spinal cord ischemia. METHODS: Three-groups of 8 mongrel dogs underwent thoracic aortic cross-clamping for 45 minutes. Proximal pressure was maintained between 95 and 100 mm Hg with SNP, nitroglycerin, or phlebotomy. All animals were neurologically evaluated 24 hours later by a blinded observer, and the findings were confirmed by histopathologic study. Statistical analysis (p value of less than 0.05) of measured hemodynamic data was by analysis of variance and of Tarlov scores, the Mann-Whitney U test. RESULTS: Distal aortic pressures (p < 0.001), Tarlov scores, and spinal cord perfusion pressures (p < 0.01 and p < 0.05 for SNP group and nitroglycerin group, respectively) were significantly higher in the phlebotomy group compared with the SNP and NTG groups. Cerebrospinal fluid pressures were significantly lower in the phlebotomy group compared with the SNP group (p < 0.001). CONCLUSIONS: The use of either NTG or SNP was associated with a high incidence of paraplegia. Nitroglycerin appears to be no safer than SNP when used during thoracic aortic cross-clamping.

Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat.

To examine directly the hepatic and renal toxicity of 7-hydroxymethotrexate (7-OH-MTX) without interference of the parent compound methotrexate (MTX), we purified and gave 100 mg/kg 7-OH-MTX to rats, a dose resulting in serum levels of 7-OH-MTX comparable with those achieved in the clinic after the administration of high-dose MTX (HD-MTX). After only 5 h, the 7-OH-MTX-treated rats demonstrated 2.6-fold increases in serum creatinine values and 2-fold elevations in serum aspartate aminotransferase (ASAT) levels as compared with the controls. Morphologic evidence of toxicity, however, was apparent only in the kidneys. Intraluminal cellular debris containing membranous material and deteriorated organelles was seen, but no precipitate of the delivered drug. The peak serum concentration of 7-OH was up to 939 microM, and concentrations of 7-OH-MTX declined triphasically, showing a t1/2 alpha value of 2.45 min, a t1/2 beta value of 30.5 min, and a terminal half-life (t1/2 gamma) of 240 min. The total clearance value was 14.5 ml min-1 kg, and the postdistributional volume of distribution (V beta) was 5070 ml/kg. Our results may indicate a direct toxic effect of 7-OH-MTX on kidney and liver cells.

Variant gamma-glutamyltransferase in colorectal carcinoma and liver metastasis. A case study.

Two variant forms of gamma-glutamyltransferase have recently been demonstrated in colorectal carcinoma. They differed from the enzyme in normal colon mucosa by altered sialic acid content, and Concanavalin A affinity. A search for a variant gamma-glutamyltransferase was undertaken in liver metastasis from one patient with colorectal carcinoma. The enzyme in the metastatic tissue was clearly different from the normal liver enzyme and apparently identical to the variant enzyme in the primary tumor. Thus, the variant form appears to be related to the neoplastic transformation. However, as antigenic properties of the metastatic enzyme were apparently identical to those of the normal liver enzyme, they will not be true isoenzymes.