Donor hyperglycemia as a minor risk factor and immunologic variables as major risk factors for pancreas allograft loss in a multivariate analysis of a single institution''s experience.

The impact of multiple donor and recipient variables on functional survival of 307 cadaveric pancreas allografts transplanted in 253 recipients at the authors' institution between July 25, 1978 and September 4, 1990 was determined using the Cox proportional hazards regression model. Relative risk of graft loss was calculated for all cases as well as for technically successful (TS) ones. Factors with an impact in descending order of significance for TS cases were immunosuppression (RR = 3.9 for double-drug versus triple-drug maintenance, p less than 0.0001); recipient category (RR = 2.4 for pancreas alone versus simultaneous pancreas/kidney, p = 0.009); retransplantation (RR = 1.8 for retransplants versus primary grafts, p = 0.007); donor hyperglycemia (RR = 1.7 for blood glucose greater than or equal to 200 versus less than 200 mg/dL, p = 0.02); human leukocyte antigen (HLA) matching (RR = 2.1 for poor versus a good match, p = 0.04). A logistic regression analysis also was performed to determine which factors predisposed to technical failure; none were identified. To make the model as relevant as possible to their current program, the authors analyzed only the bladder-drained cases (n = 221; 1984 to 1990). All patients received triple therapy. Recipient category, retransplantation, donor hyperglycemia, and degree of HLA matching remained as significant risk factors. Construction of estimated survival curves showed that the results of retransplantation were significantly improved, and the penalty incurred by using hyperglycemic donors was partially ameliorated by using well-matched donors. Because preservation times up to 30 hours did not exert an adverse effect on outcome, an argument is made to share pancreata between centers to achieve good matches.     

The role of intestinal flora on the interactions between nonparenchymal cells and hepatocytes in coculture

Kupffer cells are exposed directly to a number of factors in the portal circulation that can modify or regulate their responses to septic stimuli. The gut represents a potential source of a number of these factors including endotoxin, lymphokines, and prostaglandins. We examined Kupffer cells from germfree rats and germfree rats exposed to endotoxin or bacteria via their GI tracts to determine the importance of the intestinal flora in maintaining or modulating Kupffer cell responses. Kupffer cells from germfree animals were reduced in numbers and failed to respond to LPS in Kupffer cell: hepatocyte coculture. When germfree rats were exposed to bacterial endotoxin or bacteria via the gastrointestinal tract their Kupffer cells increased in numbers to normal and the cells responded to LPS in culture. Intestinal overgrowth with Escherichia coli for 2 days activated the Kupffer cells and significantly increased Kupffer cell sensitivity to LPS. These data suggest that the environment of the gastrointestinal tract is important for normal Kupffer cell responses and that intestinal bacterial overgrowth can modify Kupffer cell responses to septic stimuli.     

Localization of Helicobacter pylori urease and heat shock protein in human gastric biopsies.

Helicobacter pylori is a spiral, gram-negative bacterium which causes chronic gastritis and plays a critical role in peptic ulcer disease, gastric carcinoma, and gastric lymphoma. H. pylori expresses significant urease activity which is an essential virulence factor. Since a significant fraction of urease activity is located on the surface of the bacterium, the urease molecule is a logical choice as an antigen for a vaccine; currently recombinant urease apoenzyme is being tested as a vaccine in phase II clinical trials. We have recently demonstrated that urease and HspB (a homolog of the GroEL heat shock protein) become associated with the surface of H. pylori in vitro in a novel manner: these cytoplasmic proteins are released by bacterial autolysis and become adsorbed to the surface of intact bacteria, reflecting the unique characteristics of the outer membrane. To determine if similar mechanisms are operative in vivo, we determined the ultrastructural locations of urease and HspB within bacteria present in human gastric biopsies. Our results demonstrate that both urease and HspB are located within the cytoplasm of all bacteria examined in human gastric biopsies. Interestingly, a significant proportion of the bacteria examined also possessed variable amounts of surface-associated urease and HspB antigen (from 5 to 50% of the total antigenic material), indicating that in vivo, H. pylori has surface characteristics which enable it to adsorb cytoplasmic proteins. This is consistent with our altruistic autolysis model in which H. pylori uses genetically programmed bacterial autolysis to release urease and other cytoplasmic proteins which are subsequently adsorbed onto the surface of neighboring viable bacteria. These observations have important implications regarding pathogenesis and development of vaccines for H. pylori.     

Analgetic and antiinflammatory 7-aroylbenzofuran-5-ylacetic acids and 7-aroylbenzothiophene-5-ylacetic acids

A number of 7-benzoylbenzofuran-5-ylacetic acids and 7-benzoylbenzothiophene-5-ylacetic acids were synthesized. The compounds were generally only 1/2 to 3 times as potent as phenylbutazone in the rat paw edema antiinflammatory assay. However, they show greater activity as analgetic agents. The most active compound is 7-[4-(methylthio)-benzoyl]benzofuran-5-ylacetic acid (5g) having 57 times the potency of aspirin in the mouse writhing analgetic assay. This compound caused virtually no gastric ulceration in rats at doses of up to 90 mg/kg.     

Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by microdialysis

In vivo microdialysis was used to measure changes in extracellular concentrations of catecholamines and indolamines in freely moving rats in response to administration of endotoxin (lipopolysaccharide, LPS). Dialysis probes were placed stereotaxically in either the medial hypothalamus or the medial prefrontal cortex. We used a repeated-measures design in which each rat received LPS or saline, and each subject was retested with the other treatment one week later. With the dialysis probes in the medial hypothalamus, intraperitoneal (ip) administration of LPS (5 μg) increased dialysate concentrations of norepinephrine (NE, 187%), dopamine (DA, 119%), and all their measured catabolites, except normetanephrine. Dialysate concentrations of NE and DA were elevated significantly in the fourth or fifth (20 min) collection period with a peak response at around 2 hr. They returned to baseline by about 4 hr. When the dialysis probes were placed in the medial prefrontal cortex, the same dose of LPS also elevated dialysate concentrations of NE and DA, but the increases were much smaller (ca. 20%). However, a dose of 100 μg LPS increased dialysate concentrations of NE and DA from the medial prefrontal cortex to an extent comparable to that of the 5 μg dose in the hypothalamus, and the response was more prolonged. Dialysate concentrations of serotonin could not be measured reliably, but those of its catabolite, 5-hydroxyindoleacetic acid (5-HIAA), were also elevated in both regions. The peak of 5-HIAA occurred at around 4 hr. Pretreatment of the rats with indomethacin (10 mg/kg ip) completely prevented the changes due to 100 μg LPS in the medial prefrontal cortex. These results support earlier neurochemical data suggesting that LPS stimulates the release of both DA and NE in the brain, and probably also release of serotonin. © 1995 Wiley-Liss, Inc.     

Effects of antipsychotic drugs on latent inhibition: sensitivity and specificity of an animal behavioral model of clinical drug action

Latent inhibition (LI) of a conditioned emotional response (CER) has been proposed as a quantitative measure of selective attention. We have assessed the parallels of the pharmacology of LI in rats with the clinical pharmacology of schizophrenia. Drug and vehicle treated rats were divided into groups and preexposed 20 times to cage illumination as a CS, or not preexposed. All groups were conditioned with 2 CS-footshock pairings. The following day CER, as measured by interruption of drinking in response to CS presentation, was recorded. LI was observed as a decreased CER in preexposed relative to non-preexposed animals. LI was enhanced by haloperidol 0.3 mg/kg after 7 or 14 daily treatments, but not after a single acute dose. Haloperidol doses of 0.3 and 0.03 mg/kg enhanced LI, while doses of 0.003 and 3.0 mg/kg had no effect. Haloperidol enhancement of LI was unaffected by the coadministration of the anticholinergic agent trihexyphenidyl. Enhancement of LI is exhibited by the antipsychotic drugs fluphenazine, chlorpromazine, thiothixene, thioridazine, mesoridazine, and metoclopramide but not clozapine. The non-antipsychotic drugs pentobarbital, imipramine, chlordiazepoxide, trihexyphenidyl, and promethazine failed to enhance LI. LI exhibits striking parallels to the clinical pharmacology of schizophrenia.Preliminary data were presented in part at the Society for Neuroscience Annual Meeting, Phoenix, AZ, 1989     

Phase I study of 4′-deoxydoxorubicin (esorubicin) in children with malignant solid tumors

Summary 4 -Deoxydoxorubicin was given to 15 patients with drug-resistant pediatric malignant solid tumors with the objectives of determining the maximum tolerated dosage and dose-limiting toxicity. Maximum tolerated dosage was 36 mg/m₂ given IV once every 3 weeks. Dose limiting toxicity was myelosuppression, which was severe and prolonged. Therapeutic benefits were not observed for these patients.     

Evidence-based patient choice: a prostate cancer decision aid in plain language

Background  

Decision aids (DA) to assist patients in evaluating treatment options and sharing in decision making have proliferated in recent years. Most require high literacy and do not use plain language principles. We describe one of the first attempts to design a decision aid using principles from reading research and document design. The plain language DA prototype addressed treatment decisions for localized prostate cancer. Evaluation assessed impact on knowledge, decisions, and discussions with doctors in men newly diagnosed with prostate cancer.