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The level of cathepsin B (Cat B) was determined in sera obtained preoperatively from 325 patients with colorectal cancer using an ELISA. Control sera from 90 healthy blood donors were analyzed. The levels of Cat B detected included all forms that were present in the sera, i.e., mature enzyme, precursor molecule, and enzyme-inhibitor complexes. The level of Cat B was significantly increased in sera of patients with colorectal cancer. The median level was 10.7 ng/ml versus 2.1 ng/ml in controls (P < 0.0001). A correlation between Cat B serum level and advanced Dukes' stage (P < 0.003) was found, whereas no associations have been found with age, sex, or level of carcinoembryonic antigen (CEA). In survival analysis, the patients with high serum Cat B experienced significantly lower survival probability. At the optimal cutoff value of 9.4 ng/ml, the relative hazard ratio was 1.8 (95% confidence interval, 1.1-2.8; P = 0.016) in the univariate Cox proportional hazards model. The median observation time was 4.4 years (range, 3.2-5.5 years). In multivariate analysis, Dukes' stage was the strongest prognostic variable, followed by age, whereas serum Cat B and CEA were not significant prognostic factors in this model, in accordance with their association with Dukes' stage. When the data for Cat B and CEA were combined, CEA-positive patients were further separated by Cat B into high- and low-risk groups. Patients with high serum levels of both molecules had significantly shorter survival (relative hazard ratio of 2.2; 95% confidence interval, 1.5-3.2; P < 0.0001), as compared with patients with low levels of both molecules.

The purpose of this study was to investigate histamine and skin mast cells in psoriasis before and during 6 months of treatment with high-dose ranitidine. Sixteen psoriasis patients, presenting a mean PASI score of 15.4, were compared with 13 age- and sex-matched healthy controls. Resting extracellular skin levels of histamine and histamine release to mast cell secretagogues, as measured by the microdialysis technique, were increased in involved psoriasis skin compared to normal skin in the controls. Plasma histamine, but not basophil histamine release, was significantly increased in the patients. Mast cells and lymphocytes were significantly increased in numbers in involved versus non-involved skin in the patients, the lymphocytes being predominantly T-lymphocytes expressing HLA-DR activation. During 6 months of ranitidine treatment, mean PASI score of 15.4 decreased to 5.8. The lymphocyte infiltration, but not mast cell numbers, was significantly reduced during treatment, and histamine release to mast cell secretagogues was normalized. These observations suggest that skin mast cells in active psoriasis are functionally hyperreactive. The biochemical findings together with the clinical effect of ranitidine indicate that histamine may be involved in the pathophysiology of psoriasis.

Open laparotomy is followed by profound changes in endocrine metabolic function and various host defense mechanisms, impaired pulmonary function, and hypoxemia, all of which may be important for the development of postoperative infectious complications. Laparoscopic surgery, however, leads to a reduced inflammatory response (C-reactive protein and interleukin-6), a reduced immunomodulatory response, improvement in pulmonary function, and less hypoxemia, whereas classic endocrine metabolic responses are less influenced or not influenced compared with similar open operation. The clinical implications of laparoscopic surgery on postoperative infectious complications have not been assessed in large-scale prospective, randomized studies, except in appendectomy, in which a reduced incidence of wound infection has been demonstrated. Data from cholecystectomy and colorectal surgery suggest a reduction in wound complications, whereas the sparse data on intraperitoneal infections and sepsis are not conclusive. Thus, laparoscopic surgery modifies the injury response and reduces the risk of infectious complications. If integrated into an accelerated rehabilitation program, further improvement may result. The impact of these findings on prophylactic antibiotic regimens cannot be assessed from available data and requires evaluation in prospective clinical studies.

Objective and Design: To study the potential effect of ranitidine on postoperative infectious complications following emergency colorectal surgery. A randomized, placebo-controlled, double-blind trial was carried out in three university clinics and two county hospitals in Denmark., Patients and Treatment: One hundred and ninety-four consecutive patients undergoing acute colorectal surgery for perforated and/or obstructed large bowel were randomized in a double-blind fashion to receive ranitidine 100 mg i.v. twice a day commencing at induction of anesthesia and continued for five days (group I) or i.v. placebo (group II). All patients were given 1.5 g metronidazole plus 3.0 g cefuroxime at the time of surgery. Patients with perforation of the colon or rectum were given metronidazole and cefuroxime for further 3 days. All patients were assessed daily until discharge from the hospital. Thirty patients were withdrawn from the study (for reasons such as other diagnosis, refused to continue, medication not given as prescribed)., Main Outcome Measures: Patients were observed for signs of infectious complications; such as wound infection, intra-abdominal abscess, septicemia, and pneumonia., Results: Both groups were similar with respect to age, sex, weight, duration of surgery, blood transfusions, and site of the procedure, as well as the histologic nature of the underlying disease process. However, the Mannheim Peritonitis Index (MPI) was significantly higher in group I compared with group II (p < 0.05). Wound infection, intraabdominal abscess, septicemia, and pneumonia were 12.9%, 5.2%, 3.8% and 14%, respectively in group I. In group II, the infectious complications were 16.1%, 6.8%, 6.9% and 22%, respectively. Twelve patients (13.8%) in the placebo group developed more than one complication compared with 5 patients (6.5%) in the ranitidine group., Conclusion: Ranitidine may have a beneficial effect on postoperative infectious complications in patients following acute colorectal surgery.

Objectives: TNF-alpha and IL-2 are important cytokines in macrophage and T-lymphocyte activity against infection and dissemination of malignant cells. We studied the influence of supernatants from stored whole blood and buffy-coat-depleted SAGM (saline, adenine, glucose and mannitol) blood in stimulating TNF-alpha and IL-2 release in an ex vivo assay., Methods: Supernatants of 10 units of whole blood and 10 units of SAGM blood were collected after 1, 21 and 35 days of standard blood bank storage. Heparinized blood from 20 healthy volunteers (as 'recipients'), corresponding in ABO and Rh type to the stored blood, were used in a culture system with LPS and PHA as stimulators of TNF-alpha and IL-2 release. The effect of added supernatants, from either stored whole blood or SAGM blood, on cytokine release was evaluated compared to saline as control. TNF-alpha concentration was analyzed by ELISA after culture for 24 h and IL-2 after 72 h, respectively., Results: Supernatants from both stored whole blood and SAGM blood showed a significant decrease in both LPS- and PHA-stimulated TNF-alpha release that was dependent on storage time. IL-2 was not detected in response to LPS stimulation. PHA-stimulated IL-2 release was significantly reduced and related to storage time of both whole blood and SAGM blood., Conclusions: Recipient cytokine release induced by blood transfusion seems to be dependent on storage time. This may have implications in transfusion-induced immune modulation.

Measurement of urokinase receptor (uPAR) in tumor extracts has prognostic value, but assay of the soluble uPAR (suPAR) in peripheral blood may offer wider applications in cancer patient management. A tumor extract uPAR ELISA was modified to eliminate nonspecific plasma protein interference, enabling specific detection of suPAR in plasma and sera with >90% recovery of added calibrator. suPAR concentrations in citrate plasma correlated with sera in 93 healthy blood donors (r = 0.84, P <0.0001), with a median value for both of 1.2 microg/L. The plasma median for 19 advanced breast cancer patients was 2.9 microg/L suPAR, and a similar increase was found for 10 advanced colon cancer patients, consistent with release of suPAR from tumors into blood. Repetitive monitoring of suPAR in cancer patients' blood may have value in assessment of prognosis and tumor recurrence.

The objective of the study was to investigate certain immune parameters in patients undergoing elective colorectal surgery and receiving either whole blood transfusion or leucocyte-filtrated blood. Sixty consecutive patients were randomly allocated to receive either whole blood transfusion or leucocyte-filtrated blood leucocyte when transfusion was indicated. The immune parameters were investigated on the day of surgery and on day 3, 7 and 30 postoperatively. Transfusion with whole blood was followed by a significant decrease in lymphocyte proliferation and CD4+/CD8+ ratio (p < 0.01) as well as a significant increase in soluble interleukin-2 receptor and interleukin-6 (p < 0.01). Furthermore transfusion with whole blood was accompanied by a significant increase in postoperative infectious complications (p < 0.01). Patients transfused with leucocyte-filtrated blood had only minor and passing changes in the immune parameters and developed no infectious complications, indicating that effective leucocyte filtration abolishes transfusion-associated immunosuppression.

Bioactive substances in fresh frozen plasma (FFP) are considered to be related to adverse reactions after transfusion, particularly in septic or traumatized patients. Therefore, we analysed the concentration of various bioactive substances (histamine, eosinophil cationic protein, eosinophil protein X, myeloperoxidase and interleukin-6) in 25 u. of thawed FFP from healthy donors. These were compared with donor plasma concentrations of 24 healthy controls. In addition, we analysed the concentration of the bioactive substances, except interleukin-6, in 25 u. of thawed FFP, which were subjected to leucocyte filtration before freezing and storage. Finally, we analysed the substances in 10 leucocyte non-filtered plasma units before freezing and storage, and after thawing, respectively. Before analyses, which were performed by ELISA and RIA methods, these latter samples were sterile filtered through a 0.20-micron filter. Histamine, eosinophil cationic protein, eosinophil protein X and myeloperoxidase concentrations were significantly greater (P < 0.05) in the 25 u. of FFP compared with normal donor plasma. Pre-storage leucocyte filtration reduced concentrations of the bioactive substances in FFP to concentrations comparable with normal donor plasma concentrations. Interleukin-6 was undetectable in all FFP units and in 21 of the 24 control donors. Histamine, eosinophil cationic protein and myeloperoxidase concentrations were significantly higher (P < 0.05) in samples collected from the 10 u. of FFP after freezing and thawing compared with samples collected before freezing. We conclude that fresh frozen plasma prepared by a conventional separation method contains various leucocyte-derived bioactive substances, which may be reduced by pre-storage leucocyte filtration.

Adverse reactions to transfusion of allogeneic blood may depend on content of leucocytes and platelets and on storage-time of the erythrocyte suspensions. Therefore, we studied the efficacy of prestorage leucocyte reduction by filtration on total content and extracellular accumulation of histamine, eosinophil cationic protein (ECP), eosinophil protein X (EPX), myeloperoxidase (MPO), plasminogen activator inhibitor type-1 (PAI-1) and interleukin-6 (IL-6) in samples obtained from 5 units of SAGM blood, 7 units of plasma-reduced whole-blood and 6 units of whole-blood before and after filtration, respectively. In addition, we analysed supernatants from the same units after storage at +4 degrees C for 0, 21 and 35 d, respectively. The filtration was performed at room temperature within 2-4 h after donation. The substances were analysed by ELISA and RIA methods and we also analysed the donor plasma levels of the same bioactive substances. The total content of histamine, ECP, EPX, and MPO were 10-70-fold higher in all unfiltered erythrocyte products compared to donor plasma concentrations, while PAI-1 content was 15-20-fold higher only in plasma-reduced whole-blood and whole-blood. Prestorage leucocyte filtration significantly reduced the total histamine, ECP, EPX, MPO and PAI-1 content to levels similar to donor plasma levels in plasma-reduced whole-blood and whole-blood, while PAI-1 was still low in filtered SAGM blood. In addition, the levels of extracellular bioactive substances at d 0 after donation and filtration were within the range of concentrations in donor plasma, and there was no time-dependent accumulation during storage for 35 d at +4 degrees C. IL-6 was not detected in either plasma or samples obtained from the blood bags. These results suggest prestorage leucocyte filtration to deplete leucocyte contents to levels, which prevent the previously shown time-dependent accumulation of leucocyte derived bioactive substances in various erythrocyte suspensions. In addition, the PAI-1 results suggest leucocyte filters to reduce the obligatory platelet content in whole-blood products.

Background: Laparoscopic techniques have been evaluated for many operations, but retrospective and prospective studies have failed to show these techniques to be superior to open operations in all patients with colorectal disease. This study compares laparoscopic and open colonic resection in a randomized fashion with special reference to outcome, complications and immunomodulation., Methods: The clinical course, assessment of convalescence parameters, immunofunction and pathological evaluation of the operative specimen were compared in 34 patients with colonic adenocarcinoma. The patients were randomized to either laparoscopic surgery (group 1, n = 18) or open surgery (group 2, n = 16). As five patients were excluded the number of patients was 15 in group 1 and 14 in group 2., Results: Patients in group 1 were discharged earlier (P < 0.05) and suffered less pain (P < 0.01 at rest, P < 0.05 during coughing and mobilization). Surgery was equally radical in the two groups. Intraoperative bleeding, postoperative reduction in pulmonary function, and level of fatigue were identical in the two groups. The immunodepression was more pronounced in patients in group 1 (P < 0.01)., Conclusion: Laparoscopic colonic resection is an acceptable and safe alternative to open procedures; the differences between the two techniques are not marked.

Objective: To study the effect of preoperative treatment with a single high-dose glucocorticoid on the systemic and immunologic responses, wound healing, and convalescence after colonic surgery., Design: Double-blind, placebo-controlled, randomized trial., Setting: Department of surgery in a university hospital., Patients: Thirty patients scheduled for open colonic resection; 6 patients were excluded from the study (N = 24)., Interventions: Patients were randomized to either of 2 treatment regimens: methylprednisolone sodium succinate 90 minutes before induction of anesthesia and epidural analgesia (group 1, n = 12), or placebo 90 minutes before anesthesia and epidural analgesia (group 2, n = 12)., Main Outcome Measures: Assessments of pain, pulmonary function, convalescence, and various injury and wound-healing factors were done several times until 10 days after surgery., Results: Conventional reduction in pulmonary function and mobilization was improved in group 1. Interleukin-6 and C-reactive protein levels increased significantly less in group 1, as delayed-type hypersensitivity was abolished in group 1. Plasma cascade system activations were significantly less pronounced in group 1. Reduction of collagen turnover was observed in group 1, but without detrimental effects on collagen accumulation., Conclusion: Treatment with a single high-dose glucocorticoid before colonic surgery may improve postoperative pulmonary function and mobilization and reduce plasma cascade system activations, the inflammatory response, and immunofunction, but without detrimental effects on wound healing.

Evidence has emerged that suggests adverse effects to perioperative homologous blood transfusion are related to the age of the blood products. Recently, time-dependent accumulation of bioactive substances in red cell suspensions, standard platelet concentrates and fresh frozen plasma during storage have been shown. The potential adverse effects of these bioactive substances were analysed in a burn trauma patient. A patient with 40 per cent second and third degree burn trauma without other injuries underwent a two-step transplantation operation. Samples for analyses of histamine, eosinophil cationic protein (ECP), eosinophil protein X (EPX), neutrophil myeloperoxidase (MPO) and interleukin 6 (IL-6) were drawn frequently from the patient before, during and after the operations, and from all transfused red cell, platelet and fresh frozen plasma units. Urine was sampled every hour during the first operation for analyses of ECP and EPX excretion. All analyses were performed by ELISA and RIA methods, and results compared to patient outcome. The patient received a total of 48 and 8 SAGM blood, 6 and 0 platelet and 12 and 4 fresh frozen plasma units at the two operations, respectively. Transfused products contained a total of 64.54 nmol and 17.50 nmol histamine, 115518 ng and 25764 ng ECP, 174457 ng and 38770 ng EPX, 6950915 ng and 1505125 ng MPO, and 14740 pg and 5600 pg IL-6 at the two operations, respectively. The accumulation of the substances in patient plasma correlated to postoperative septic reactions, without any disclosure of bacteraemia after the first operation, while the accumulation at the second operation correlated to the septic reaction and Pseudomonas aeruginosa infection. Time-dependent accumulation of bioactive substances in blood products during storage may be related to the development of post-transfusion adverse effects.

We report the results of an open, prospective study of 20 patients with moderate to severe psoriasis (median PASI score: 15.7) treated with oral ranitidine 300 mg twice daily for six months. No other medication was allowed during the study period. The median PASI score was reduced to 14.5, 9.1 and 5.7 after one, three and six months of treatment, respectively (p < 0.00001). A mild to moderate worsening was observed in 15 patients within the first month of treatment, but this was not followed by exclusion from the study, and long-term treatment improved disease status in most patients. Eight patients continued therapy with ranitidine 300 mg twice daily after the study was completed. None of these patients relapsed during a follow-up period of 12-18 months. The results of the present study suggest that ranitidine may be beneficial in the treatment of some patients with psoriasis.

We present a simple nonradioactive assay based on polymerase chain reaction (PCR) in combination with denaturing gradient gel electrophoresis (DGGE), which allows comprehensive mutation scanning of the entire coding sequence and splice junctions of the p53 gene in one analytical step. The key features of the present method are (1) all fragments can be amplified using one common PCR protocol; (2) all fragments can be scanned for mutations on a single "broad-range" denaturing gradient gel; and (3) all fragments were tailored by the attachment of appropriate GC clamps and otherwise manipulated to consist of only two melting domains in order to maximize resolution of mutations by DGGE. The entire procedure starting with a sample of genomic DNA can be completed within 6 hr and has the potential to detect any sequence variation, irrespective of its location in the p53 gene. The mutation detection sensitivity was demonstrated by the analysis of 26 constructed control mutations distributed over the whole of the p53 gene. We have applied the method to genetic diagnosis in 43 cases of colorectal cancer. Overall, a point mutation, microdeletion, or microinsertion was found in 26 (61%) of the tumors. In addition to missense and frameshift mutations within exons 4-8, a 20-bp insertion in exon 11 was found in one sample, illustrating the importance of comprehensive gene scanning for reliable diagnosis.

Background: The mechanisms of the detrimental effects of perioperative allogeneic blood transfusion are still unclear. Previous studies have suggested a higher incidence of adverse effects after the use of blood stored for prolonged time. Therefore, a possible time-dependent release of various white cell- and platelet-derived bioactive substances in stored human red cell suspensions was studied., Study Design and Methods: Whole blood (6 units), plasma-reduced whole blood (6 units), and saline-adenine-glucose-mannitol blood (6 units) from 18 unpaid, normal blood donors were stored under standard blood bank conditions at 4 degrees C for 35 days. After refrigeration, samples were collected from all blood bags on Days 0, 2, 5, 9, 14, 21, 28, and 35 of storage. Extracellular concentrations of eosinophil cationic protein, eosinophil protein X, plasminogen activator inhibitor 1, myeloperoxidase, and interleukin 6 were analyzed by enzyme-linked immunosorbent assay and radioimmunoassay. The total intracellular and donor plasma levels of these substances also were analyzed at the time of blood donation., Results: Eosinophil cationic protein, eosinophil protein X, and myeloperoxidase increased 10- to 25-fold (p < 0.05) in a time-dependent manner in whole blood, plasma-reduced whole blood, and saline-adenine-glucose-mannitol blood during storage for 35 days. Plasminogen activator inhibitor 1 increased threefold to sixfold (p < 0.05) in whole blood and plasma-reduced whole blood, but not in saline-adenine-glucose-mannitol blood. Interleukin 6 was not detected in either plasma or samples obtained from the blood bags., Conclusion: Stored whole blood, plasma-reduced whole blood, and saline-adenine-glucose-mannitol blood may release white cell- and platelet-derived bioactive substances in a time-dependent manner, which may be related to the detrimental effects of perioperative blood transfusions. Therefore, prestorage white cell reduction should be considered for further improvement of red cell suspensions.

Unlabelled: Two commercially available bacterial filters to be used as part of the mechanical ventilation unit during anaesthesia were tested for hygienic criteria. Manufacturers claim that bacterial breathing filters have a filtration capacity of about 99.995%, so that there would be no need for thermal disinfection of tubing and ventilation circuits after each use. One filter is designed for a single use only, the other can be used up to 24 times after sterilisation. Both filters consist of hydrophobic glass fibres., Methods: During simulated mechanical ventilation for 24 h, an alcoholic suspension of Bacillus subtilis was atomized in front of the filters tested. A gelatin membrane filter was integrated in the ventilation circuit and captured the filtered gas behind the test filter., Results: During simulated mechanical ventilation for 24 h, the filtration capacity of both the disposable and reusable filters (Table 2) did not confirm the manufacturers' short-term technical findings over 8 s (DIN-EN 143)., Conclusions: The use of bacterial filters during mechanical ventilation reduces the probability of bacterial contamination, but does not make sterilisation of the tubes and ventilation circuit unnecessary.

In a randomized study the effect of whole blood transfusion versus bedside leucocyte-depleted blood transfusion on lymphocyte proliferation, CD4+:CD8+ ratio, and levels of soluble interleukin 2 receptor (sIL-2R) and interleukin (IL) 6, as well as on the development of postoperative wound infection and intra-abdominal abscess, was assessed in 60 patients undergoing elective colorectal surgery. Transfusion with whole blood induced a significant decrease in lymphocyte proliferation and CD4+ :CD8+ ratio (P < 0.01) as well as a significant increase in sIL-2R and IL-6 levels (P < 0.01). Furthermore, transfusion with whole blood was accompanied by a significant increase in postoperative infectious complications (P < 0.01). In patients transfused with leucocyte-depleted blood only slight and transient changes were observed, which were not significantly different from those observed in non-transfused patients.

Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory response, immune reaction, coagulation cascade, and cardiovascular function. Furthermore, histamine may play a major role in the growth of normal and malignant tissue as a regulator of proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases.

Perioperative transfusion of whole blood has been shown to amplify trauma-induced immunosuppression, which could be attenuated by perioperative administration of histamine2 receptor antagonists. Supernatants from different blood products were, therefore, analysed for histamine content during storage. Whole blood (six units), plasma-reduced whole blood (six units), and plasma- and buffy coat-reduced (saline-adenine-glucose-mannitol) (SAGM) blood (six units) from unpaid healthy donors were stored in the blood bank for 35 days at 4 degrees C. Plasma histamine and total cell-bound histamine content at donation, and histamine concentration in samples drawn from the units on days 0, 2, 5, 9, 14, 21, 28 and 35 were analysed with an enzyme-linked immunosorbent assay. Median plasma histamine concentration was 4.8 (range 1.9-14.3) nmol/l (n = 18). Median total cell-bound histamine content was 417.0 (range 176.0-910.0) nmol/l in whole blood and 475.0 (range 360.0-1560.0) nmol/l in plasma-reduced whole blood, while it was undetectable in SAGM blood. Spontaneous histamine release increased in a time-dependent manner from a median of 6.7 (range 2.2-17.4) nmol/l at the time of storage to 175.0 (range 33.0-485.0) nmol/l at day 35 in whole blood, from 18.8 (range 8.2-38.5) to 328.5 (range 224.0-1137.0) nmol/l in plasma-reduced whole blood, and from 0.5 (range 0.5-1.5) to 2.2 (range 1.4-6.9) nmol/l in SAGM blood. These results show spontaneous histamine release during storage of human blood products which contain full amount of leucocytes, and this may play a significant role in detrimental effects of blood transfusion.

We report the results of an open, prospective study on the efficacy of systemic ranitidine in the treatment of psoriasis. Twenty patients suffering from moderate to severe psoriasis were included in the study. The median pretreatment PASI score was 15.7 (range 6.0-24.7). The patients were treated with oral ranitidine 300 mg twice a day for 6 months; no other medication was allowed during the study period. Eighteen patients completed the study. The median PASI score was reduced from 15.7 to 14.5, 9.1 and 5.7, after 1, 3 and 6 months of treatment, respectively (P < 0.00001). A significant reduction in PASI score was evident at 3 months of treatment. A mild to moderate deterioration occurred in 15 patients within the first month of treatment, but this was followed by improvement during prolonged treatment in most patients. No other clinical and/or biochemical side-effects were observed. Eight patients continued therapy with ranitidine after the study was completed, and none of these patients relapsed during a follow-up period of 12-18 months. The results of the present study suggest that ranitidine may be a beneficial and safe treatment for psoriasis. In addition, high-dose, long-term ranitidine treatment appears to be free from severe adverse effects.

We previously observed that human, recombinant interleukin-2 in a pharmacologic dose (200 u/ml) induced histamine release from monocyte-depleted peripheral blood mononuclear cells in vitro. Therefore, we studied the role of various pharmacologic doses of rIL-2 on in vitro histamine release. Peripheral blood mononuclear cells (5 x 10(6) cells/ml), which also contain basophils, from 13 patients scheduled for elective colorectal cancer surgery and 10 age and sex matched healthy volunteers were stimulated with rIL-2 in concentrations of 0, 50, 100, 200, 450, 900, 1,800 and 3,600 u/ml, respectively, for 1, 24 and 48 hours under standard conditions. Histamine was analysed in supernatants using the glass fiber method. Simultaneously, total cell-bound histamine was analysed in lysate from 5 x 10(6) mononuclear cells from all patients and volunteers, thus allowing determination of percent histamine release. Supernatant histamine concentration from unstimulated cells was 17.2 +/- 1.5 ng/ml in patients compared to 7.9 +/- 1.0 ng/ml in volunteers (#p < 0.05) after 1 hour stimulation, and no further increase was observed after 24 and 48 hours, respectively. Histamine concentration increased significantly in the supernatant from cells stimulated by rIL-2 in a dose-dependent manner both in patients and volunteers. Total cell-bound histamine was 49.3 +/- 4.1 ng/ml in patients compared to 78.5 +/- 7.7 ng/ml in volunteers (p < 0.05). Therefore, both spontaneous and rIL-2-induced histamine release was significantly enhanced in cancer patients compared to volunteers (*p < 0.05). These data suggest that rIL-2 in high pharmacologic doses stimulates in vitro histamine release in a dose-dependent manner in both cancer patients and volunteers. This may in part explain the severe toxicity observed during high-dose rIL-2 therapy.

Background: The skin microdialysis technique makes it possible to measure histamine release in intact human skin in vivo directly. In this study we have used the microdialysis technique to characterize histamine release by codeine after intracutaneous injections and following skin challenge by a novel atraumatic delivery technique., Objective: The purpose of the study was to compare histamine release in human skin by codeine, delivered by an intraprobe drug delivery system (IPD) and intracutaneous injections (ICT), with respect to dose-response relations, kinetics of histamine appearance and decay, correlations between histamine release and skin responses, and reproducibility., Methods: Hollow dialysis fibres were inserted intradermally in 12 healthy subjects. Twelve fibres were inserted in each subject, six fibres in each arm. Each fibre was perfused at a rate of 3 microM/min, and samples were collected in 2 min fractions. By the IPD technique, codeine was administered to the skin by adding codeine to the perfusion medium. Sequential IPD challenges were performed in one arm, and ICTs were done on the other arm., Results: Sixfold serial dilutions of codeine (0.01-3 mg/mL) caused a significant dose-related histamine release by ICT and IPD. Peak histamine release was found within the first 4 min after skin challenge by ICT and IPD, followed by a fast decline with a dialysate histamine half life of approximately 2-3 min. Peak histamine release was linearly correlated with cumulative release of the 20 min sampling period, and histamine release correlated with weal size. The coefficient of variation on peak histamine release was 18.9% and 4.8% for codeine ICT and IPD, respectively., Conclusion: We have described in detail codeine-induced histamine release in intact human skin in vivo by the microdialysis technique. It was possible to administer codeine atraumatically to the skin by intraprobe delivery. The skin microdialysis technique opens up possibilities for measurement of inflammatory mediators release in normal and diseased skin, and it will be possible to deliver immunopharmacologically active drugs to the skin by intraprobe delivery.

Patients with B cell chronic lymphocytic leukemia (B-CLL) have decreased capacity to mount relevant antibody responses upon immunization, and development of hypogammaglobulinemia is part of the natural history of the disease. We investigated the influence of histamine type-2 (H2) receptor blockade by ranitidine on the in vivo antibody production in B-CLL patients following vaccination. Anti-polysaccharide antibodies in B-CLL patients, vaccinated with a tetanus-toxoid conjugated vaccine against Haemophilus influenzae type-B (Hib), reached long-term protective levels in more than 90% of B-CLL patients randomized to ranitidine treatment, as compared to 43% of the untreated patients (P = 0.024). No difference in the response to vaccination against influenza virus types A and B protein could be detected between the two groups. Plasma histamine levels were 2-fold to 20-fold higher in 23 out of 31 B-CLL patients, compared to normal controls, and these levels showed a significant positive correlation to disease duration. These findings indicate the possibility of improving in vivo antibody production against a highly relevant pathogen in B-CLL patients by histamine type-2 receptor blockade, and the combined finding of an immune-stimulatory effect of ranitidine and increased plasma histamine levels, strongly suggests the involvement of histamine in the pathogenesis of B-CLL immunodeficiency.

The histamine H-2-receptor antagonist ranitidine hydrochloride has been shown to alleviate trauma-, blood transfusion- and sepsis-induced immunosuppression. We evaluated the effect of ranitidine on the postoperative impairment of monocyte and neutrophil function in 24 patients undergoing major elective abdominal surgery. The patients were randomized to receive postoperative adjuvant treatment with ranitidine hydrochloride (100 mg) administered intravenously twice daily for four days, followed by oral ranitidine hydrochloride (150 mg) administered twice daily for five days (n = 11), or no adjuvant treatment (n = 13). Blood monocyte and neutrophil chemotaxis and chemiluminescence were analyzed before the operation and on post-operative days one, three and nine. Monocyte chemotaxis to C5a in the 13 control patients was significantly decreased on day one compared to day 0. Chemotaxis in the 11 ranitidine-treated patients increased significantly from day 0 to day one (p < .01 between groups). Neutrophil chemiluminescence to zymosan and N-f-methionyl-leucylphenylalanine was significantly increased in control patients on day one compared to day 0 (p < .05), while ranitidine reduced chemiluminescence to zymosan insignificantly on day one (p < .07 between groups). Five of the 13 control patients developed postoperative infectious complications, which were related to decreased monocyte chemotaxis to C5a and increased neutrophil chemiluminescence to zymosan when compared to noninfected patients. A significant difference (P < .05) in chemiluminescence to zymosan between infected and noninfected control patients was observed on day three, before clinical signs of infectious disease could be detected. There were no infectious complications in ranitidine-treated patients. These results support previous studies on the effect of ranitidine in reducing postoperative immunosuppression.

Peripheral venous blood from 12 patients with colorectal cancer and eight healthy volunteers was used to identify the lowest in vitro dose of human, recombinant interleukin-2 (rIL-2) with immunoactivity on NK-cell lysis of K562 tumour cells. Subsequently, this dosage of 200 units/ml rIL-2, which may respond to 10(6) units in vivo, was used alone or in combination with ranitidine (0.02 mg/ml, which may correspond to 100 mg in vivo) to improve in vitro NK-cell activity in peripheral blood from 25 patients with liver metastases from colorectal cancer. A standard 4-hour Cr51-release assay of K562 tumour cells was used for the analyses. Spontaneous NK-cell activity was 19.0% (6.5-33.2), while ranitidine-induced NK-cell activity was 23.6% (7.8-46.2), and without statistical difference from spontaneous activity. Recombinant IL-2-induced NK-cell activity was 37.1% (11.1-71.7) (P < 0.05 compared to spontaneous activity), and rIL-2 plus ranitidine-induced NK-cell activity was 52.7% (18.9-85.6) (P < 0.05 compared to spontaneous and to rIL-2-induced activity, respectively). These results suggest a synergistic increase of low-dose rIL-2-induced NK-cell activity by ranitidine. Therefore, the combination of low-dose rIL-2 and ranitidine may be beneficial to improve post-operative immune competence, and should be considered in future adjuvant treatment regimens of cancer patients.

Background: The mechanism of post-traumatic immunosuppression is still not known in detail. However, histamine released during trauma and major surgery may play a significant role in the process. Previously, we showed that the histamine-2 receptor antagonist (H2RA), ranitidine, reduced trauma-induced suppression of certain immunological parameters., Study Design: The effect of perioperative ranitidine on postoperative change in plasma interleukin-6 (IL-6) and serum C-reactive protein (CRP) levels was assessed in 23 women undergoing elective abdominal hysterectomy. The patients were randomized to receive intravenous ranitidine, 100 mg twice a day from skin incision, for two days, followed by oral ranitidine, 150 mg twice a day, for a further three days, or no ranitidine. Interleukin-6 and CRP were analyzed in plasma and serum, respectively, drawn preoperatively and six, 24, 48, and 120 hours after skin incision., Results: Routine blood analyses, clinical data (except age), duration of surgery, anesthesia, antibiotic prophylaxis, blood loss, and perioperative blood transfusion were similar in the two groups. Interleukin-6 levels were significantly increased in all patients and without difference between the ranitidine-treated and non-ranitidine-treated patients after six, 24, and 48 hours compared to preoperative levels, respectively. C-reactive protein levels were also significantly increased in all patients after 24, 48, and 120 hours, respectively; however, at 48 hours, CRP was significantly reduced in ranitidine-treated patients compared with non-ranitidine-treated patients (p = 0.02)., Conclusions: These results suggest that histamine-2 receptor activation mechanisms may not be involved in postoperative IL-6 synthesis. However, the reduced CRP level in ranitidine-treated patients suggests that H2RAs modulate IL-6 signal transduction in hepatic cells.

Evidence suggests that perioperative allogeneic blood transfusion increases the risk of infectious complications after major surgery and of cancer recurrence after curative operation. This has been attributed to immunosuppression. Several authors have suggested that filtered whole blood and/or red cell concentrate, or leucocyte- and buffy coat-reduced red cells in artificial medium or their own plasma, may reduce postoperative immunosuppression. It was also anticipated that the use of autologous blood might minimize the risk of perioperative transfusion, but studies have unexpectedly shown similar postoperative infectious complications and cancer recurrence and/or survival rates in patients receiving autologous blood donated before operation and those receiving allogeneic blood. Future studies should identify common risk factors associated with blood storage.

The effect of perioperative immunomodulation with the H2-receptor antagonist ranitidine on postoperative changes in soluble interleukin (IL) 2 receptor and soluble CD8 levels was assessed in 24 patients undergoing major elective abdominal surgery. Eleven patients were randomized to receive intravenous ranitidine 100 mg twice daily for 4 days from skin incision, followed by oral ranitidine 150 mg twice daily for a further 5 days; 13 control patients received no ranitidine. Routine blood analysis, clinical data, duration of surgery, anaesthesia, antibiotic prophylaxis and perioperative blood transfusion were similar in the two groups. Serum concentrations of soluble IL-2 receptor and CD8 were measured before operation (day 0) and in the morning of postoperative days 1, 3 and 9 using commercial enzyme-linked immunosorbent assay kits. In patients treated with ranitidine, the serum level of soluble IL-2 receptor increased from day 0 to day 9 (P < 0.01); in control patients it decreased from day 0 to day 1, did not change significantly by day 3 and increased by day 9. The change from day 0 to day 1 was significantly different between the two groups (P < 0.01). Five of the 13 control patients developed postoperative infectious complications. No significant differences were shown in soluble CD8 concentration during the postoperative period. The postoperative change in soluble IL-2 receptor level may reflect lymphocyte activation status; ranitidine appears to promote activation of mainly CD4-positive lymphocytes since serum levels of CD8 were unchanged. Ranitidine may, therefore, improve immune function during major surgery.

Background: The histamine H2-receptor antagonist ranitidine hydrochloride has been shown to improve trauma-, blood transfusion-, and sepsis-induced immunosuppression., Objective: To evaluate the effect of ranitidine on postoperative impairment in monocyte and neutrophil function., Methods: Twenty-four patients undergoing major elective abdominal surgery were randomized to receive adjuvant treatment with ranitidine hydrochloride (100 mg) administered twice a day intravenously from skin incision for 4 days, followed by oral ranitidine hydrochloride (150 mg) administered twice a day for 5 days (n = 11), or no adjuvant treatment (n = 13). Blood monocyte and neutrophil chemotaxis and chemiluminescence were analyzed before the operation and on postoperative days 1, 3, and 9., Results: Monocyte chemotaxis to C5a in the 13 control patients was significantly decreased on day 1 compared with day 0. Chemotaxis in the 11 ranitidine-treated patients increased significantly from day 0 to day 1 (P < .01 between groups). Neutrophil chemiluminescence to zymosan and N-f-methionyl-leucyl-phenylalanine was significantly increased in control patients on day 1 compared with day 0 (P < .05), while ranitidine reduced chemiluminescence to zymosan insignificantly on day 1 (P < .07 between groups). Five of the 13 control patients developed postoperative infectious complications, which were related to decreased monocyte chemotaxis to C5a and increased neutrophil chemiluminescence to zymosan, compared with noninfected patients. A significant difference (P < .05) in chemiluminescence to zymosan between infected and noninfected control patients was observed on day 3 before clinical signs of infectious disease could be detected. There were no infectious complications in ranitidine-treated patients., Conclusion: These results support previous studies on the effect of ranitidine to improve postoperative immunosuppression.

Retrospective studies suggest increased postoperative morbidity among alcohol misusers. We have prospectively studied the risk associated with alcohol intake among patients undergoing surgery. We investigated 15 persons who required colorectal surgery and who were drinking at least five Danish drinks per day. These patients were matched for sex, nutrition, age, weight, cardio-pulmonary disease, diagnosis anesthesia, and surgery to 15 control persons who were consuming no more than two drinks daily. None of the patients showed signs of liver disease. The alcohol group developed more postoperative complications than controls (67 vs 20%, p < 0.05) and hospital stay was prolonged (20 vs 12 days, p < 0.05). Preoperatively, alcohol misusers had reduced left ventricular ejection fraction (54 vs 68%, p < 0.01). Delayed-type hypersensitivity responses were reduced in the alcohol group before (53 mm2 vs 78, p < 0.05) and after (18 mm2 vs 55, p < 0.01) surgery. Alcohol misusers had significantly longer bleeding times. Surgical stress responses, as assessed by changes in plasma cortisol and catecholamines, were higher among alcohol misusers (p < 0.05). Postoperative morbidity was increased in alcohol misusers without signs of liver damage. The mechanisms may include subclinical cardiac insufficiency, immunosuppression, and decreased haemostatic function. Preoperative alcohol consumption may be a more important risk factor for postoperative morbidity than previously thought.

Binding of the urokinase plasminogen activator (uPA) to a specific cell surface receptor (uPAR) plays a crucial role in proteolysis during tissue remodelling and cancer invasion. An immunosorbent assay for the quantitation of uPAR has now been developed. This assay is based on two monoclonal antibodies recognizing the non-ligand binding part of this receptor, and it detects both free and occupied uPAR, in contrast to ligand-binding assays used previously. In a variant of the assay, the occupied fraction of uPAR is selectively detected with a uPA antibody. To be used as a standard, a soluble variant of uPAR, suPAR, has been constructed by recombinant technique and the protein content of a purified suPAR standard preparation was determined by amino acid composition analysis. The sensitivity of the assay (0.6 ng uPAR/ml) is strong enough to measure uPAR in extracts of cultured cells and cancer tissue. Recent studies have shown that a high uPA level in tumor extracts is in some cancers associated with poor prognosis. The present assay will now allow similar prognostic studies of uPAR levels.

121 patients with multilevel, lower extremity arterial occlusive disease were treated by aortofemoral reconstruction and extended profundoplasty. Early and late results of 201 limbs were analyzed according to their preoperative grade of ischemia. In the case of moderate claudication the success rate was 43% postoperatively and 81% after 5 years. When having severe claudication the success rate was 62% and 79% after 5 years. The revascularisation of the deep femoral artery helps developing the collateral arteries, responsible for an improvement after a considerable period of time. In limbs with rest pain we got a success rate of 78% postoperatively and 76% after 5 years. In the case of gangrene the primary success rate was 40% and 68% after 5 years. Angiographically, severe arteriosclerotic lesions were documented in the deep femoral artery and popliteal artery when limb-threatening ischemia was present. Nevertheless, the combined aortofemoral and extended deep femoral artery reconstruction was efficient in treating the multilevel occlusive disease; subsequent femoro-distal bypass was necessary only in case of threatening ischemia for 9.3% of limbs. Our findings show there is no indication for simultaneous aortofemoral and femoro-distal bypass grafting in the treatment of the multilevel disease.

The immunosuppressive chemical drugs cyclosporine A (CsA) and methotrexate (Mx) have recently been shown to be of benefit in several different diseases of autoimmune origin. Cellular immune responses may play a major role in autoimmunity as autoreactive T lymphocytes appear to recognize autoantigens and major histocompatibility complex (MHC) class II restriction molecules presented by non-immune, aberrant cells, subsequently leading to damage on healthy tissues. Psoriasis is suggested to be an autoimmune disease and in severe, uncontrollable psoriasis CsA and Mx are of value in reducing disease activity. Histamine is suggested to be involved in the pathogenesis of psoriasis and the histamine-2 receptor antagonist ranitidine has been shown to be of value to reduce severe psoriatic disease. The finding that CsA and Mx efficiently reduce histamine formation and release raises the possibility, that histamine is one of the molecules involved in pathogenesis of autoimmune diseases. T cell mediated regulation and suppression of autoreactive T cells seem to be ineffective in controlling the enhanced immune reaction in patients where the discrimination between self and non-self is changed. A consequence of this may be induction of interferon-gamma (IFN-g) production and release by cytotoxic T cells, subsequently leading to expression of MHC II molecules on non-immune tissues. As immunotherapy may be of value in some autoimmune diseases the use of histamine-2 receptor antagonists should be evaluated in patients where conventional therapy is ineffective to reduce disease activity.

Retrospective studies suggest that there is an increased postoperative morbidity among alcohol misusers. We have prospectively studied the risk of alcohol intake among patients undergoing surgery. We investigated 15 symptom-free subjects who required colorectal surgery and who were drinking at least 60 g of alcohol per day. These patients were matched for sex, nutrition, age, weight, cardiovascular and pulmonary disease, diagnosis, anaesthesia, and surgery to 15 control subjects who were consuming below 25 g of alcohol daily. Those drinking at least 60 g of alcohol per day developed more postoperative complications than controls (67% vs 20%, p less than 0.05) and hospital stay was prolonged (20 vs 12 days, p less than 0.05). Preoperatively, alcohol misusers had reduced left ventricular ejection fraction (median, 54% vs 68%, p less than 0.01). Delayed hypersensitivity responses were smaller in the alcohol group before (53 mm2 vs 78 mm2, p less than 0.05) and after (18 mm2 vs 55 mm2, p less than 0.01) surgery. Alcohol misusers had longer bleeding times during the first postoperative week (p less than 0.01). Surgical stress responses, as assessed by changes in plasma cortisol and catecholamines, were higher among alcoholics (p less than 0.05). Postoperative morbidity is increased in symptom-free alcohol misusers. The mechanism is probably subclinical cardiac insufficiency, immunosuppression, and decreased haemostatic function. Preoperative alcohol consumption may be a more important risk factor than previously thought.

The effect of the histamine-2 receptor antagonist ranitidine (100 mg intravenously every 12 hours for 72 hours) on postoperative serum antibody responses to preoperative immunization with six limit of flocculation tetanus toxoid and six limit of flocculation diphtheria toxoid was assessed in a double-blind, placebo-controlled randomized study in 26 patients undergoing major abdominal surgery. The preoperative antitetanus antibody level was less than 0.1 IU/ml in all patients, and they were inoculated with both antigens 48 hours before surgery. Serum samples for analysis of antitetanus toxoid and antidiphtheria toxoid were drawn before skin incision and on postoperative days 1, 3, 5, 7, 10, 14, 21, and 28. Ranitidine significantly increased the postoperative antibody response to tetanus toxoid, (p less than 0.01) and insignificantly increased that to diphtheria toxoid vaccination (p less than 0.2) compared with placebo.

The duration of postoperative impairment in cell-mediated immunity was assessed by repeated skin testing with seven delayed type common antigens in 15 patients undergoing major elective abdominal surgery compared to a similar testing regimen in 10 healthy volunteers. All were skin tested four times, with 72-hour intervals, and in the surgical patients the first test was applied 2 days before surgery, followed by tests on postoperative days 1, 4 and 7. The tests were read after 48 h. Postoperatively, the skin test area decreased on day 3 (p less than 0.01) and recurred to preoperative levels on day 9. In contrast, the skin test area in the volunteers increased from test to test (p less than 0.001) during the study, confirming a previous finding of a vaccination effect. These results suggest that the postoperative immunosuppression is maintained for about 6-9 days.

The findings that the immunosuppressant cyclosporine A (CsA) improves psoriasis raise the possibility that cellular immune processes may play a major role in the pathogenesis of this disease. It is broadly agreed that histamine released by mast cells is one of the molecules involved in the pathogenesis. This is supported by the findings that CsA and methotrexate (Mxt) reduce formation and release of histamine. However, the well known side-effects of CsA and Mxt may argue potential use of other agents acting on formation and action of histamine. Such agents may be the histamine-2 receptor antagonists, previously reported to have a clinical effect on psoriasis. But randomised short-term studies have disclosed that these drugs have no beneficial or even an aggravating effect on the disease. This article reports on recent findings of improvement in psoriasis using high doses of the histamine-2 receptor antagonist ranitidine in long-term studies. Also presented are a hypothetical action of histamine in development of psoriasis and a rationale for ranitidine as a potential agent in the therapy of psoriasis.

In a 21-year-old man with open bite, myogenic headache and internal derangement of the temporomandibular joint clinical examination was supplemented by radiographs of the joints, cephalometric analysis, electromyographic recordings of the masticatory muscles and tracking of mandibular movements. His condition was characterized by reduced occlusal stability with contact limited to posterior molars, and weak elevator muscles with increased strain during posture and chewing. The purpose of the treatment was to eliminate symptoms with a reflex-releasing stabilizing splint. Secondly, to increase occlusal stability, primarily with the splint and later through orthodontic treatment aiming at closing the bite in the premolar region because the reduced occlusal stability seemed to be a significant etiologic factor. Treatment with the splint reduced signs and symptoms of craniomandibular disorders. During the following orthodontic treatment, contact was established on both premolars and molars, mainly due to extrusion of mandibular premolars. Analysis showed greater elevator strength and decreased muscular loading after treatment. A splint was used for retention accompanied by muscle training with exercise gum. Permanent training with gum was recommended after the retention period.

The influence of perioperative whole-blood transfusion and transfusion with erythrocyte suspension (SAG-M blood) on postoperative depression of cell-mediated immunity (CMI) was investigated in 67 patients who underwent elective resection for colorectal cancer. Cell-mediated immunity was assessed pre- and postoperatively by skin testing with seven common delayed-type hypersensitivity (DTH) antigens. The postoperative skin-test response decreased more in the patients who received whole blood (15 patients) than in those who received SAG-M blood (16 patients) (60% versus 42%, p less than 0.001) and in those who did not receive a blood transfusion (36 patients) (60% versus 40%, p less than 0.001). The enhanced postoperative immunosuppression in patients who received whole-blood transfusions persisted after matching according to age, sex, height, weight, hemoglobin and serum albumin levels, duration of surgery and diagnosis. Thus, perioperative transfusion with SAG-M blood does not enhance surgically induced immunosuppression as effectively as does transfusion with whole blood.

Multiple myeloma (MM) is characterized by an increased susceptibility to infections and to other malignancies. Selected related immune functions were studied. Spontaneous and interleukin-2-stimulated natural killer (NK) cell activities were normal in 19 patients with MM compared with 62 controls. In contrast, interferon-stimulated NK cells had a significantly lower increase in activity in MM than in controls. The normal improvement in lytic NK cell activity after addition of indomethacin to the mononuclear cell cultures (to inhibit prostaglandin-mediated suppression) was not observed in cultures from MM patients. As reported for other lymphoproliferative disorders, the levels of soluble interleukin-2 receptors in serum were significantly higher in MM (600 U/ml median value) compared with controls (317 U/ml median value), P less than 0.0001, and the concentration of interleukin-2 receptors was significantly correlated with the concentration of monoclonal immunoglobulin in serum. Blood monocyte chemotactic responsiveness was significantly lower in MM patients with both zymosan-activated serum and f-Met-Leu-Phe as cytotaxins, suggesting reduced ability to accumulate at inflammatory foci. In contrast, release of reactive oxygen radicals, believed to be associated with the killing ability of monocytes, was normal after in vitro stimulation.

Tetranectin, a recently described human protein widely distributed in the body and with possible importance for cell growth and differentiation, has previously been observed to be decreased in patients with solid malignant tumors. In patients with multiple myeloma, either untreated or previously treated, serum levels were found to be significantly reduced. A negligible interindividual variation was observed. Levels of serum tetranectin were not correlated with serum albumin, hemoglobin, or M-component. Low levels of tetranectin may be related to the growth and spread of malignant cells or reflect a general catabolic state of chronic disease.

Multiple myeloma is characterized by an increased susceptibility to infections and to other malignancies. In a double-blind, placebo-controlled study the potential impact of immunomodulation by ranitidine was studied in 20 patients with multiple myeloma. Three patients were untreated, while 17 after previous cytotoxic therapy were in a stable phase of their disease. All were without clinical signs of infections and at that time had not been treated with other immunomodulating agents. The patients were randomized to oral ranitidine 300 mg twice a day for 21 days or placebo, and several immunological parameters related to multiple myeloma were studied. The blood monocyte chemotactic response was improved in patients treated with ranitidine, and superoxide anion production increased from 2.02 nmol/min to 3.86 nmol/min (median values), while it was unchanged in patients given placebo (2.19-2.25 nmol/min) (P less than 0.005 between groups). Among ranitidine-treated patients spontaneous NK cell activity was unchanged, while in vitro interleukin-2- and interferon-alpha-stimulated NK cell activity decreased (P less than 0.03, respectively). As production of oxygen radicals constitutes an important mechanism of monocyte killing activity against microorganisms and probably against malignant cells, it is suggested that ranitidine may be of beneficial impact in the treatment of multiple myeloma.

On the basis of the literature and the authors own investigations, the present article provides a brief schematic review of the fraction of the physiological immune response which has hitherto been investigated in connection with surgical trauma. Surgery, anaesthesia and blood transfusion induce temporarily acquired immune suppression and thus a potentially increased risk for postoperative infectious complications and recurrence after cancer surgery. The pathological physiological alterations in immune function which develop as a result of anaesthesia, surgery and perioperative blood transfusion are reviewed. The clinical sequelae of preoperative and postoperative immune suppression are increased morbidity and mortality rates. Future research in this field must, therefore, be focussed on detailed investigation of the mechanisms which lead to postoperative immune suppression and development of methods to prevent these.