Immunologic tolerance: role of the regional lymph node.

Dansyl chloride, a skin setnsitizer when injected in complete Freund's adjuvant, induced marked tolerance and no sensitization when applied to the intact skin of guinea pigs. Application of this chemical to alymphatic skin islands failed to induce tolerance or sensitization. Lymnphatic connections between skin and regional lymph nodes were essential for the developmnent of ismmunologic toleance.

Tuberculin-active carbohydrate that induces inhibition of macrophage migration but not lymphocyte transformation.

A tuberculin carbohydrate fraction, GAE, in sensitized animals induced a delayed type of skin reactivity and inhibited the migration of macrophages but failed to stimulate lymphocyte transformation in vitro. Tuberculin protein-containing fractions were active in each test. These results show that in vitro lymphocyte transformation is not necessarily a corollary of delayed type hypersensitivity.

Body size in early life and risk of epithelial ovarian cancer: results from the Nurses' Health Studies.

Adult body mass index (BMI) has been associated with ovarian cancer risk, but few studies have examined body size earlier in life. We prospectively examined associations of body fatness at ages 5 and 10, BMI at age 18, height, and birthweight with risk of epithelial ovarian cancer in the Nurses' Health Study (NHS: 110 311 women, 735 cases) and Nurses' Health Study II (NHSII: 113 059 women, 137 cases). Cox proportional hazards regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs). There was a weak inverse association between average body fatness at ages 5 and 10 and risk in the NHS (RR for heaviest vs most lean=0.81, 95% CI: 0.53-1.24, P for trend=0.04) and a nonsignificant positive association in the NHSII (RR=2.09, 95% CI: 0.98-4.48, P for trend=0.10), possibly due to differences in age and menopausal status. Height was positively associated with risk in both cohorts (RR for >or=1.75 vs <1.6 m=1.43, 95% CI: 1.05-1.96, P for trend=0.001). Body mass index at the age of 18 years and birthweight were not associated with risk. Further research should examine the biological mechanisms underlying the observed associations.

In vitro studies of poison oak immunity. I. In vitro reaction of human lymphocytes to urushiol.

Poison oak, ivy, and sumac dermatitis is a T-cell-mediated reaction against urushiol, the oil found in the leaf of the plants. This hapten is extremely lipophilic and concentrates in cell membranes. A blastogenesis assay employing peripheral blood lymphocytes obtained from humans sensitized to urushiol is described. The reactivity appears 1--3 wk after exposure and persists from 6 wk to 2 mon. The dose-response range is narrow, with inhibition occurring at higher antigen concentrations. Urushiol introduced into the in vitro culture on autologous lymphocytes, erythrocytes and heterologous erythrocytes produces equal results as measured by the optimal urushiol dose, the intensity of reaction, and the frequency of positive reactors. This suggests that the urushiol is passed from introducer to some other presenter cell. Although the blastogenically reactive cell is a T cell, there is also a requirement for an accessory cell, found in the non-T-cell population, for reactivity. Evidence is presented that this cell is a macrophage.

Sodium-dependent and inhibitor-insensitive uptake of adenosine by mouse peritoneal exudate cells.

[8-3H]Adenosine uptake in mouse peritoneal exudate cells, harvested following i.p. challenge with Complete Freund's Adjuvant from BALB/c mice, was found to be insensitive to common nucleoside transport inhibitors such as dilazep or 6-[(4-nitrobenzyl)mercapto]purine ribonucleoside and to require sodium ion, being inactive when sodium was replaced by lithium or potassium. These findings also applied to the adherent (macrophages) and nonadherent (polymorphonuclear cells) cell fractions prepared from the peritoneal cell mixture. Uptake was inhibited by several nucleosides including deoxyadenosine, inosine, uridine, thymidine and, to a lesser extent, by the adenosine analog tubercidin, while adenine, fructose, glucose and ribose were without effect. Uptake [8-3H]adenosine was fully matched by rapid intracellular phosphorylation to AMP, ADP and ATP. Inosine was a substrate for the transporter, but tubercidin was not. The system clearly is distinct from carrier-mediated, nonconcentrative transport and has similarities to concentrative, sodium-dependent nucleoside transporters described in other cell types.

Physics at the [Formula: see text] linear collider.

A comprehensive review of physics at an [Formula: see text] linear collider in the energy range of [Formula: see text] GeV-3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.

The induction of immune tolerance in delayed contact sensitivity by the use of chemically related substances of low immunogenicity.

Immune tolerance in delayed contact sensitivity to pentadecylcatechol can be induced by a series of derivatives substituted in the 6 position of the ring. Some of these derivatives have the property of being very poor sensitizers and having very low dermal toxicity. Thus, sensitization and tolerance have different biologic mechanisms and are associated with different properties of these chemicals.

Modified emory functional ambulation profile: an outcome measure for the rehabilitation of poststroke gait dysfunction.

BACKGROUND AND PURPOSE: The modified Emory Functional Ambulation Profile (mEFAP) is an easily administered test that measures the time to ambulate through 5 common environmental terrains with or without an assistive device or manual assistance. The mEFAP was evaluated for its interrater reliability, test-retest reliability, concurrent validity, and sensitivity to change during outpatient rehabilitation for poststroke gait dysfunction. METHODS: Twenty-six poststroke patients were followed up prospectively in a rehabilitation day-treatment program. The mEFAP, Berg Balance Test (BBT), and 7-item mobility subsection of the Functional Independence Measure + Functional Assessment Measure (FAMm) were completed at admission and discharge. RESULTS: mEFAP interrater reliability (intraclass coefficient [ICC] 0.999) and test-retest reliability (ICC 0.998) were high. The BBT demonstrated high interrater (ICC 0.992) but poor test-retest (ICC 0.605) reliability. Initial and final scores comparing the mEFAP with the BBT (r=-0.735, r=-0.703) and the mEFAP with the FAMm (r=0.685, r=-0.775) were strongly correlated. Improvement on the mEFAP correlated with improved BBT performance (r=-0.524). There was no correlation between overall change observed on the FAMm and change on the mEFAP (r=-0.145). Total mEFAP and all mEFAP subtask scores improved over time (P:<0.0001). CONCLUSIONS: The mEFAP is a reliable gait-assessment tool for patients with stroke and is sensitive to change in ambulation speed.

Biliary cystadenocarcinoma of the liver: the need for complete resection.

We report on a patient with biliary cystadenocarcinoma and review 112 previously published cases of this rare cystic hepatic neoplasm. This tumour mainly occurs in women at a ratio of 62% (female) to 38% (male), and at an average age of 56.2 years (range 18-88 years). The origin of these neoplasms is intrahepatic in 97% of cases and extrahepatic in the remaining 3%. The clinical symptoms are nonspecific and are not distinctive from benign cystic liver lesions unless invasive growth of the tumour occurs or distant metastases are present. Sonography and computed tomography (CT), as well as magnetic resonance imaging (MRI) demonstrate the multilocular nature of the tumour with septal or mural nodules. Discrete soft tissue masses, thick and coarse calcifications and varying density on CT or intensity on MRI within the loculi are additional non-specific imaging findings. The best therapeutic result with a 5-year survival rate of 100% and a recurrence rate of only 13% was achieved by complete excision (n = 16). Surgical removal of the tumour by complete excision is, therefore, the treatment of choice for biliary cystadenocarcinomas.

Carcinoid of the pancreas: clinical characteristics and morphological features.

The classical carcinoid tumour (WHO) of the pancreas is extremely rare and its diagnosis may puzzle physicians and pathologists. Here, 29 previously published cases of pancreatic carcinoid tumours, including one new case, are reviewed. Literature research was done using MedLine from 1966 to 1995. Pancreatic carcinoids produce an atypical carcinoid syndrome. Skin flushing was reported in only 34%. The main symptom was pain, followed by diarrhoea and weight loss. Elevated urinary 5-HIAA levels were found in 85% (17/20). The immunocytochemical sensitivity for serotonin was 100% (11/11). The diagnosis of pancreatic carcinoid tumour is based on the typical endocrine histological features together with increased serotonin metabolism. Generally, the slow growth rate and late invasion of adjacent organs render local resection possible, but the high incidence of distant metastases (69%) prevents long-term survival in the majority of patients. The possible role of the Octreoscan, a new radionuclide imaging technique, is discussed with regard to this tumour entity.

Relaxation of guinea-pig fundic strip by adenosine, adenosine triphosphate and electrical stimulation: lack of antagonism by theophylline or ATP treatment.

1 Theophylline relaxed isolated strips of guinea-pig stomach fundus in a dose-dependent manner; above 50 to 100 microM responses showed no fade for up to 90 min. 2 Relaxant responses to adenosine, adenosine triphosphate (ATP), noradrenaline, and to electric field stimulation of non-adrenergic inhibitory nerves were not affected in a significant manner in the presence of 50 microM theophylline. 3 In tissues which showed complete fade of initial responses in the continued presence of 50 microM ATP, the effects of stimulation of non-adrenergic inhibitory nerves remained unaltered, suggesting that the ATP receptor has no function in non-adrenergic inhibitory transmission in this tissue. 4 These findings are opposite to those of Okwuasaba, Hamilton & Cook (1977), who claimed that 50 microM theophylline almost fully inhibited relaxation induced by adenosine ATP and nerve stimulation and that ATP-induced fade also abolished sensitivity to inhibitory nerve stimulation.

Competition of nucleoside transport inhibitors with binding of 6-[(4-nitrobenzyl)-mercapto]purine ribonucleoside to intact erythrocytes and ghost membranes from different species.

The potency of nucleoside transport inhibitors, including 6-[(4-nitrobenzyl)-mercapto]purine ribonucleoside (NBMPR), dilazep, mioflazine and its derivatives soluflazine and R57974 as inhibitors of the binding of [3H(G)]NBMPR to intact erythrocytes and respective ghost membranes from human, mouse and hamster was determined. There was no close agreement between the IC50 profiles for the different inhibitors when comparing values obtained for intact cells and membranes from each species, and there was no consistent profile of differences when considering individual drugs and comparing their actions in the three species. Present data also were compared with potency values obtained previously with the same drugs directly in nucleoside transport inhibition studies with erythrocytes from the same species as well as with [3H(G)]NBMPR binding studies in isolated liver and lung membranes from hamster. The overall conclusion from this and previous studies is that the evaluation of relative potencies in screening of potential nucleoside transport inhibitors is best carried out at the level actual nucleoside transport studies in intact cells, since [3H(G)]NBMPR binding studies yield discrepant data.

Binding of [G-3H]6-(4-nitrobenzylmercapto)purine ribonucleoside to isolated membranes. Inhibitory effect of mioflazine and its derivatives.

The binding of [G-3H]-6-(4-nitrobenzylmercapto)purine ribonucleoside [( G-3H]NBMPR) was investigated using a centrifugation assay with membrane preparations from hamster tissues including liver, lung, kidney and heart. Only liver and lung membranes showed high specific binding, with dissociation constants (Kd) values of 2.4 +/- 0.4 and 0.44 +/- 0.05 nM, and maximal binding (Bmax) of 3.7 +/- 0.4 and 1.04 +/- 0.01 pmol/mg, respectively. The binding of [G-3H]NBMPR was inhibited in a concentration dependent manner by unlabelled NBMPR, dilazep and a new group of chemically related nucleoside transport inhibitors, mioflazine, soluflazine and R57974, the latter being the most potent derivative. R57974 displaced bound [G-3H]NBMPR as effectively as unlabelled NBMPR suggesting a common binding site. The assay procedure used appears useful for the rapid screening of the effectiveness of nucleoside transport inhibitors which will be of value for the selection of inhibitors suitable for combination with cytotoxic nucleosides in the treatment of selected cancers or parasitic diseases.

5'-Deoxy-5'-methylthioadenosine: a nucleoside which differentiates between adenosine receptor types.

The activities of an endogenous nucleoside, 5'-deoxy-5'-methylthioadenosine (MTA), on adenosine sensitive sites such as adenosine A1 and A2 receptors and the P-site, as well as on purine nucleoside transport, have been studied. This nucleoside competitively antagonized the A2 receptor-mediated stimulation of neuroblastoma adenylate cyclase, produced a GTP-dependent and 8-p-sulfophenyltheophylline-sensitive inhibition of adenylate cyclase activity in rat cerebellar membranes, and decreased the spontaneous contractile activity of isolated segments of rabbit jejunum. MTA was neither active at the P-site nor did it diminish the binding of [3H]nitrobenzylthioinosine, a nucleoside transport inhibitor. We conclude that (a) MTA is an agonist at the adenosine A1 receptor but an antagonist at the A2 receptor, and (b) the adenosine receptor which causes relaxation of rabbit jejunum is not a neuroblastoma-type A2 receptor which activates adenylate cyclase.

Evaluation of synthetic pseudo cord-factor-like glycolipids for the serodiagnosis of tuberculosis.

A number of glycolipids were evaluated in an ELISA test for their serodiagnostic usefulness in tuberculosis. One hundred and twelve (112) sera belonging to bacteriologically confirmed TB patients, patients with pathologies other than tuberculosis and healthy individuals were examined against several synthetic "mirror" pseudo cord factors (analogues of trehalose-6,6'-dimycolate or TDM) using natural cord factor and another recently described natural glycolipid (SL-IV) of Mycobacterium tuberculosis as control antigens. Analysis of the results shows that all synthetic "mirror" pseudo cord factors, except one with a short 8-carbon chain, were better recognized by the sera of tuberculosis patients than natural cord factor, with sensitivity and specificity values in the ELISA test similar to those reported for M. tuberculosis species-specific SL-IV. Of all antigens tested in this study, BDA. TDA, a bis(N,N-dioctadecylamide) of "trehalose dicarboxylic acid", [(alpha-D-glucopyranosyluronic acid) (alpha-D-glucopyranosiduranic acid)], showed the highest serodiagnostic discriminating power (93% sensitivity and specificity). We postulate that either these artificial molecules are cross-reactants of similarly structured native glycolipids of M. tuberculosis or that they bear closer resemblance to actual phagosome-lysosome-modified antigens than to native mycobacterial ones.

Screening of synthetic trehalose 6,6'-diesters and trehalose 6-monoesters as potential immunoreactants for the serodiagnosis of tuberculosis.

The absence of serological cross-reactivity between trehalose 2,3-diester (DAT, formerly SL-IV) and synthetic trehalose 6,6'-diesters and trehalose 6-monoesters was established by ELISA testing using polyclonal immune sera raised in rabbits sensitized with "DAT". From the screening of fifteen synthetic trehalose 6,6'- and 6-esters, "mirror" pseudo cord factor no. 1, "mirror" amides no. 5 and 6, cord factor analogues 7 and 8 and trehalose 6-monoesters 10 and 11 were selected for future, more extensive serological analysis. Paired comparisons of analogues among these fifteen substances showed that serodiagnostic discrimination power was more a function of the carbon chain length of their substituent groups--as well as of their position--than of the "mirror" constitution of the molecules. More exhaustive testing of these seven compounds is needed to select the synthetic product most efficient in the ELISA serodiagnosis of tuberculosis.

Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2.

ErbB3 is a transmembrane signaling molecule that shares close structural homology with epidermal growth factor receptor (EGFR), erbB2, and erbB4. They have all been implicated in cell transformation and tumor pathogenesis, but very little is known about the role of erbB3 in normal colon and colorectal cancer. Therefore, in the current study, we determined whether erbB3 is found in normal human colon and whether its expression is altered in colorectal cancer. Because of some evidence that erbB3 might interact with erbB2 and EGFR, respectively, by heterodimerization, we also included erbB2 and EGFR analysis with special regard to coexpression. The study was performed on 35 patients operated on for colorectal carcinoma. The normal human colon showed weak erbB3 and erbB2 immunostaining, predominantly in surface epithelial cells. EGFR immunoreactivity in normal colon varied from weak to strong. In contrast, in 31 of 35 (89%) and in 29 of 35 (83%) colonic cancers, moderate to strong immunoreactivity for erbB3 and erbB2, respectively, was present in most epithelial cancer cells. A concomitant erbB3 and erbB2 immunostaining advantage could be found in 77% of cancerous tissues in comparison with the normal colon. No difference in EGFR immunostaining was evident between normal colon and cancer. Northern blot analysis showed an increase in erbB3 and erbB2 mRNA levels in 64% of cancers in comparison with normal colon samples. By densitometry, 2.3-fold and a 1.5-fold significant increases in erbB3 and erbB2 mRNA levels, respectively, were calculated in the cancerous tissues. Eighty-five percent of cancers with erbB3 mRNA overexpression showed an increase in erbB2 mRNA. Southern blot analysis did not indicate any gene amplification or rearrangement responsible for erbB2 or erbB3 overexpression. EGFR, however, was decreased in cancer on mRNA level. These findings indicate that erbB2 and erbB3, but not EGFR, may contribute to tumor growth and disease progression in colon cancer. The correlation between increased erbB2 and erbB3 expression in both Northern blots and immunohistochemical analysis suggests a co-overexpression of erbB2 and erbB3 and might support the hypothesis that these two growth factor receptors act together by heterodimer formation.

Comparison of outcome between extended and nonextended liver resections for neoplasms.

BACKGROUND: An aggressive approach to liver resection for neoplasms was adopted during a 5-year period. The results were evaluated by comparing the outcome between extended and nonextended liver resections. METHODS: Among 73 consecutive patients undergoing liver resections for neoplasm or suspicion of neoplasm, 33 underwent extended liver resections (26 extended right lobectomies and 7 extended left lobectomies) and 40 underwent resections of lesser extent. Mortality, morbidity, and survival between the two groups were compared. RESULTS: Overall morbidity was 21% and perioperative mortality was 5.4%. Morbidity and mortality were not significantly different between extended and nonextended liver resections (24% vs 18% and 6.1% vs 5.0%, respectively). Liver resections for extrahepatic cholangiocarcinomas were found to be associated with a higher morbidity (6 of 10) and mortality (2 of 10) when compared with liver resections for noncholangiocarcinomas. Bile leaks occurred mainly in patients with cholangiocarcinomas (4 of 6) and contributed to an increased overall morbidity in this series. After a median follow-up of 31 months, there was no difference in survival between extended and nonextended liver resections. CONCLUSIONS: Extensive liver resections for neoplasms can be carried out without significant increase in the operative risk. Short-term survival is comparable between patients undergoing extended and nonextended liver resections.

Incidence of port site recurrence after laparoscopic cholecystectomy for preoperatively unsuspected gallbladder carcinoma.

BACKGROUND: We sought to determine the incidence of recurrence of carcinoma at the port site and the outcome of patients with such recurrences after exploratory laparoscopy/laparoscopic cholecystectomy for unsuspected gallbladder carcinoma and analyzed aspects of the laparoscopic procedure associated with recurrences at the port site. METHODS: Thirty-seven patients with preoperatively unknown adenocarcinoma of the gallbladder were analyzed. The patients were part of a large prospective study of the Swiss Association of Laparoscopic and Thoracoscopic Surgery including 10,925 patients undergoing laparoscopic cholecystectomy. RESULTS: Preoperatively undiagnosed adenocarcinoma of the gallbladder is rarely encountered in patients undergoing laparoscopic cholecystectomy (0.34%). The incidence of recurrence of carcinoma at the port site in these patients is 14% (5 of 37) and is similar whether the primary tumor is confined to the gallbladder (T1/T2) or locally advanced (T3/T4). The recurrences at the port site were diagnosed within 6 to 16 months (median 10 months) after the operation. Patients with an intraoperative perforation of the gallbladder had a higher incidence of recurrences at the port site (40%) than had patients without perforation (9%; P = .13). All patients with recurrences at the port site had distant metastases and all died of the disease 12 to 35 months (median 19 months) after cholecystectomy; all patients with such recurrences and stage T1/T2 tumors subsequently had peritoneal metastases. CONCLUSIONS: Patients with a preoperatively undiagnosed adenocarcinoma of the gallbladder undergoing laparoscopy or laparoscopic cholecystectomy have a high incidence of recurrences at the port site, and the incidence increases when a gallbladder perforation occurs during the operation. All patients with such recurrences died of the disease. The diagnosis of an isolated recurrence at the port site may therefore be an indicator of disseminated disease in most cases.

Conservative surgical treatment of diffuse peritonitis.

BACKGROUND: Peritonitis is, even today, a significant source of death and complications. The objective of this study was to determine the morbidity and mortality rates, the incidence of reoperations, and the need for additional treatment strategies (on demand) in patients with diffuse peritonitis. METHODS: Prospective analysis including all patients (n = 258) with diffuse peritonitis admitted to our surgical service between November 1993 and April 1998 who underwent a uniform surgical treatment concept of peritonitis including early intervention, source control, and extensive intraoperative lavage. RESULTS: The 258 patients with diffuse peritonitis averaged a mean Mannheim Peritonitis Index of 27.1 points (range, 11-43 points). Source control at the initial operation was possible in 230 of the patients (89%), of those, 21 patients (9%) needed reintervention. In 28 patients (11%), source control was not possible at the initial operation. Twenty of these patients (71%) had to undergo additional treatment strategies (on demand) such as continuous lavage and/or laparostomy. Overall 228 of the 258 patients (88%) needed just 1 initial surgical intervention. The overall morbidity rate was 41%; the rate of reoperation was 12%, and the hospital mortality rate was 14%. CONCLUSIONS: A conservative surgical treatment concept supplemented with "extensive" intraoperative lavage reduces the reoperation rate compared with other treatment standards of peritonitis and achieves a low mortality rate in patients with diffuse peritonitis.