An HLA-DRB α-helix motif shared by DR11 and DR8 alleles is implicated in the pluriallelic restriction of peptide-specific T-cell lines

The T-cell recognition of HLA-DR-peptide complexes is generally restricted by the polymorphism of the DRB molecules but pluriallelic restriction has been described. The molecular basis of restriction and promiscuity of such peptide-specific responses is poorly understood. We isolated a panel of T-cell lines specific for the tetanus toxin peptide p2 (TT830-843) exhibiting pluriallelic restriction by DR11 and DR8 alleles. Fine restriction specificity of the T-cell lines was examined in functional assays against DR oligotyped APCs expressing different variants of DR11 and DR8 alleles. Our results show that (a) polymorphisms between serologically related alleles are relevant in terms of restriction of the peptide-specific T-cell response; in some instances, a single amino acid substitution can determine the restriction of a T-cell line; (b) different patterns of restriction are not the result of specific differences in DR-p2 binding as p2 peptide binds to all DR11 and DR8 alleles tested (DRB1^* 1101, -1102, -1103, -1104, 110X, -0801, -0802, -0803, and -0806); and (c) pluriallelic restriction of the peptide-specific T-cell responses correlates with the presence of a DRB1 α-helix motif (67-71-86) shared by some DR11 and DR8 alleles. Possible implications of pluriallelic restriction of peptide-specific T-cell response in autoimmune disorders associated with DR11 and DR8 are discussed.     

Update on managing hypercholesterolemia. The new NCEP guidelines.

1. The Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATPIII) will significantly increase the number of Americans treated for hypercholesterolemia. 2. The ATPIII focuses on lowering low density lipoprotein cholesterol as a primary initiative and using exercise, diet, and pharmacotherapy as a means for lowering coronary heart disease and risks. 3. The new guidelines list low density lipoprotein cholesterol levels of less than 100 mg/dL as optimal for all clients. 4. The ATPIII places increased attention on high triglyceride levels (> 200 mg/dL) and on early detection and appropriate aggressive treatment for clients at risk for coronary heart disease and events.     

Transjugular intrahepatic portosystemic shunt before abdominal surgery in cirrhotic patients: a retrospective, comparative study.

Surgery in cirrhotic patients is associated with high morbidity and mortality related to portal hypertension and liver insufficiency. Therefore, preoperative portal decompression is a logical approach to facilitate abdominal surgery and hopefully to improve postoperative survival. The present study evaluated the clinical outcomes of 18 patients (mean age 58 years) with cirrhosis (seven alcoholics and 11 nonalcoholics) who underwent transjugular intrahepatic portosystemic shunt (TIPS) placement before antrectomy (n=5), colectomy (n=10), small-bowel resection (n=1), pancreatectomy (n=1) and nephrectomy (n=1). TIPS was performed a mean (+/-SD) of 72+/-21 days before surgery and induced a marked mean decrease in portohepatic gradient from 21.4+/-3.9 mmHg to 8.4+/-3.4 mmHg. Cirrhotic patients (n=17) who underwent elective abdominal surgery without preoperative TIPS placement were used as the control group. Both groups were matched for age, etiology of cirrhosis, indications for surgery, type of surgery and coagulation parameters. The mean Pugh score was significantly higher in the TIPS group (7.7 versus 6.2). No significant differences were observed for operative blood loss, postoperative complications, duration of hospitalization and one-month (83% versus 88%) or one-year (54% versus 63%) cumulative survival rate. Analysis using the Cox proportional hazards model showed that neither TIPS placement nor preoperative Pugh score were independent predictors for survival. The present study suggests that preoperative TIPS placement does not improve postoperative evolution after abdominal surgery in cirrhotic patients with good or moderately impaired liver function.     

Influence of hospital characteristics on operative death and survival of patients after major cancer surgery in Ontario.

BACKGROUND: There is a lack of information from Canadian hospitals on the role of hospital characteristics such as procedure volume and teaching status on the survival of patients who undergo major cancer resection. Therefore, we chose to study these relationships using data from patients treated in Ontario hospitals. METHODS: We used the Ontario Cancer Registry from calendar years 1990-2000 to obtain data on patients who underwent surgery for breast, colon, lung or esophageal cancer or who underwent major liver surgery related to a cancer diagnosis between 1990 and 1995 in order to assess the influence of volume of procedures and teaching status of hospitals on in-hospital death rate and long-term survival. For each disease site and before observing patient outcomes data, volume cut-off points were selected to create volume groups with similar numbers of patients. Teaching hospitals were those directly affiliated with a medical school. Logistic regression and proportional hazards models were used to consider the clustering of data at the hospital level and to assess operative death and long-term survival. We also used 4 measures to gauge the degree of procedure regionalization across the province including (1) the number of hospitals performing a procedure; (2) the percentage of patients treated in teaching hospitals; (3) the percentage of rural patients treated in higher volume procedure hospitals; and (4) median distances travelled by patients to receive care. RESULTS: The number of patients in our cohorts who underwent resection of the breast, colon, lung, esophagus or liver was 14 346, 8398, 2698, 629 and 362, respectively. Surgery in a high-volume versus a low-volume hospital did not have a statistically significant influence on the odds of operative death for patients who underwent colon, liver, lung or esophageal cancer resection. The risk of long-term death was increased in low-volume versus high-volume hospitals for patients who underwent resection of the breast (hazard ratio [HR] 1.2, 95% confidence interval [95% CI] 1.0-1.4, p < 0.05), lung (HR 1.3, 95% CI 1.1-1.6, p < 0.01) and liver (HR 1.7, 95% CI 1.0-2.7, p = 0.04). There were no significant differences in the odds of operative (in-hospital) death or risk of long-term death among patients treated in teaching compared with nonteaching hospitals. There was more regionalization of liver, lung and esophageal operations versus breast and colon operations. CONCLUSIONS: Increased hospital procedure volume correlated with improved longterm survival for patients in Ontario who underwent some, but not all, cancer resections, whereas hospital teaching status had no significant impact on patient outcomes. Across the province, further regionalization of care may help improve the quality of some cancer procedures.     

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using ¹⁸⁶Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ¹⁸⁶Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ¹⁸⁶Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 10⁹/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of ¹⁸⁶Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of ¹⁸⁶Re-HEDP has been initiated.     

Human xenoreactive natural antibodies of the IgM isotype activate pig endothelial cells

Abstract: Preformed, xenoreactive natural antibodies (XNA) and complement (C) are involved in the initiation of vascular rejection of organs transplanted between discordant species, presumably by stimulating donor organ endothelial cells (EC). Although C is known to play a role in the activation of EC, it has not been clear whether the antibodies serve only to anchor the initial components of C, and thus permit the C cascade to proceed, or whether the antibodies themselves deliver a signal to the EC. We have tested affinity-purified human IgM containing XNA (IgM-XNA) for its ability to stimulate in vitro the up-regulation of genes in pig EC. Northern blot analysis shows that IgM, which contains XNA, stimulates mRNA accumulation for certain genes (including IL-8, PAI-1, and ECI-7, a new gene that we have found is associated with EC activation), but not others known to be up-regulated in response to TNF, IL-1 or LPS. Our results show that XNA provide a signal to EC, and thus may themselves participate in activation of EC and consequent vascular rejection.     

Thymidylate synthase activity,folates, and glutathione system in head and neck carcinoma and adjacent tissues

Background. Head and neck squamous cell carcinomas (HNSCC) present variable aggressiveness and chemosensitivity. Because the glutathione (GSH) system and thymidylate synthase (TS) are involved in the resistance to the main drugs used in HNSCC (cisplatin and 5-FU), we studied these systems in tumors and normal mucosae. Methods. Tumor samples and normal adjacent mucosae were collected from 37 untreated HNSCC patients. GSH and glutathione S-transferase (GST) activity were assayed by spectrophotometry, whereas TS activity and folates were determined by radioassays. Results. Mean GSH levels were higher in tumors (15.2 ± 8.2 nmol/mg protein) than in mucosae (8.3 ± 4.1 nmol/mg protein) (p = 0.005, paired t test). GST activity was also higher in tumors (394 ± 194 nmol/min/mg protein) than in mucosae (261 ± 132 nmol/min/mg protein) (p = 0.0003). TS activity was markedly higher in tumors (9.2 ± 21.5 pmol/min/mg protein) compared to that of mucosae (0.9 ± 1.2 pmol/min/mg protein) (p = 0.0001). Folate levels in tumors and mucosae were similar (1.2 ± 1.1 and 0.8 ± 0.9 pmol/mg protein, respectively; p = 0.1, NS). In relation to clinical stage and tumor size, a statistical difference was found in GSH and GST values between tumors and mucosae for stage IV and T3/T4. The increase in tumor TS compared to that of mucosae was significant for all clinical stages, tumor sizes, and nodal involvement. Conclusions. These data enhance our understanding of the enzymatic systems involved in cisplatin and 5-fluorouracil (5-FU) resistance in HNSCC and normal mucosae and may help to elucidate tumor behavior and interpatient differences in drug sensitivity. © 1994 John Wiley & Sons, Inc.     

Gangliosides and sialoglycoproteins in hypothalamus of normal, postnatal, and pre- and postnatal protein undernourished rats.

Total ganglioside and sialoglycoprotein concentrations were determined in the hypothalamus of normal (diet: 25% casein), postnatal undernourished (diet: 8% casein since birth), and pre- and postnatal undernourished rats (diet: 8% casein since pregnancy). Hypothalamic weights for the two low protein diet groups were lower than for the normal diet groups at all ages studied. Total hypothalamic ganglioside and sialoglycoproteins (mumol NANA) of postnatal undernourished rats were lower than control at day 10, while in pre- and postnatal undernourished rats this difference occurred at day 7. The reduction in gangliosides and sialoglycoprotein contents was not solely a consequence of the decrease in hypothalamic weight since, when the data were expressed as nmol NANA/mg tissue, similar reductions were observed principally in the pre- and postnatal protein undernutrition group. These results suggest that the effects of pre- and postnatal undernutrition on hypothalamic gangliosides and sialoglycoproteins are more pronounced than those that occur as a result of postnatal undernutrition.