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.     

Novel molecular aspects of prostate carcinogenesis.

Prostate adenocarcinoma is one of the most frequently diagnosed forms of cancer in the male population of the Western world. The pivotal role of androgen and its receptor in this disease has been abundantly documented and indeed, chemical castration and treatment with antiandrogens are now standard therapies. However, relapse is often observed after 18-24 months, due to the remarkable ability of prostate tumour cells to adapt to low or undetectable androgen levels. Amplification and mutations of the androgen receptor (AR) gene have been described as well as alterations in cofactor expression and crosstalk with other signalling pathways. Another recent line of research focused on the re-programming of gene expression taking place in prostate tumours. Global expression profiling of normal and cancerous prostate tissues led to the identification of tumour-distinctive patterns. Validation studies are currently underway to identify novel drug targets as well as diagnostic and outcome prediction markers.     

A randomized trial of low-protein diet in type 1 and in type 2 diabetes mellitus patients with incipient and overt nephropathy.

OBJECTIVE: The efficacy of a low-protein diet in the secondary prevention of diabetic nephropathy is not established in patients with type 1 or type 2 diabetes mellitus. To determine whether a low-protein diet slows the decrease in glomerular filtration rate (GFR) and decreases the albumin excretion rate (AER) in diabetic patients with incipient and overt nephropathy, we performed a 2-year prospective, randomized controlled trial comparing the effects of a low-protein diet (0.8 g/kg/day) with a usual-protein diet. SETTING AND PATIENTS: The study was conducted in a University hospital and included 63 type 1 and type 2 diabetic patients with either incipient or overt nephropathy and mild renal failure (prestudy GFR, 80 +/- 20 mL/min). The primary outcome measures were decreased in GFR and 24-hour AER. RESULTS: In the low-protein-diet group, patients were younger (52 +/- 12 versus 63 +/- 9 years old) and more often were type 2 diabetic. During the follow-up period, according to dietary records the low-protein-diet group consumed 16% +/- 3% of total caloric intakes as compared with 19% +/- 4% in the usual-protein-diet group (P < .02), but 24-hour urinary urea excretions did not differ between the two groups. The 2-year GFR decrease was 7 +/- 11 mL/min in the low-protein-diet group and 5 +/- 15 mL/min in the usual-protein-diet group (P = not significant). AER did not increase significantly in the two diet groups during the follow-up period. Blood pressure and glycemic control were similar in the two groups all along the study. The decrease in GFR and AER were also similar in 6 compliant patients according to dietary records and to 24-hour urinary urea excretions from the low-protein-diet group and in 12 patients from the usual-protein-diet group. CONCLUSIONS: A 2-year low-protein diet did not alter the course of GFR or of AER in diabetic patients with incipient or overt nephropathy receiving renin-angiotensin blockers with strict blood pressure control.     

Retentissement osseux de l’anorexie mentale

The objective of this study was to evaluate the epidemiology, diagnosis, pathophysiology, and treatment of bone loss related to anorexia nervosa. Earlier onset and longer duration of anorexia nervosa are associated with more severe bone loss. Osteoporosis develops in 38 to 50% of cases. Bone mineral density measurement by dual-energy X-ray absorptiometry is useful for assessing bone mass, and bone marker assays provide information on bone turnover. Bone loss in anorexia nervosa is probably multifactoriel. Estrogen deficiency was long felt to be the major factor. However, in contrast to postmenopausal osteoporosis, bone loss associated with anorexia nervosa is related mainly to inadequate bone formation, with only a slight increase in bone resorption. This suggests a role for nutritional factors, such as disturbances in the growth hormone-somatomedin C axis (GH/IGF-I) related to malnutrition. The best treatment strategy for correcting bone mass in patients with anorexia nervosa is not agreed on. Resumption of menstrual cycles and weight gain seem necessary but not always sufficient. Studies found no benefits with estrogen therapy, but this was usually given as estrogen–progestin contraceptives. No vast studies evaluating hormone replacement therapy have been reported. Bone formation enhancers such as IGF-I seem to provide the best results, most notably when used in combination with estrogens. This suggests that complex treatment strategies combining bone formation enhancers and bone resorption inhibitors may deserve evaluation.     

A longitudinal study of vergence adaptation in incipient presbyopia

BACKGROUND: To investigate vergence adaptation during the incipient phase of presbyopia, when the amplitude of accommodation approaches the level where the first reading addition is required. The study aimed to assess the ability of the vergence system to counteract changes in the component contributions to the overall vergence response with the decline in the amplitude of accommodation in presbyopia, although previous reports on the nature of changes in accommodative, tonic and proximal vergence are equivocal. METHODS: Using a 'flashed' Maddox rod technique, an assessment of vergence adaptation to 6delta base-out and 6delta base-in prism was made for 28 subjects (aged 35-45 years at the commencement of the study). The measurements were taken four times over a 2-year period. RESULTS: Using a repeated measures analysis of variance, the results show that with the decline in amplitude of accommodation, there is a statistically significant reduction in the magnitude of vergence adaptation to both base-out (p < 0.05) and base-in prism (p < 0.01). CONCLUSIONS: This study shows that with ageing, there is a decrease in the ability of the slow vergence mechanism to overcome a change in fusional vergence demand and would suggest that either the fast component of fusional vergence must cope with any change in fusional vergence demand or that the sum of the accommodative, tonic and proximal vergence responses are virtually stable with age.     

Intravenous Lidocaine Infusion Facilitates Acute Rehabilitation after Laparoscopic Colectomy

Background: Intravenous infusion of lidocaine decreases postoperative pain and speeds the return of bowel function. The authors therefore tested the hypothesis that perioperative lidocaine infusion facilitates acute rehabilitation protocol in patients undergoing laparoscopic colectomy.

Methods: Forty patients scheduled to undergo laparoscopic colectomy were randomly allocated to receive intravenous lidocaine (bolus injection of 1.5 mg/kg lidocaine at induction of anesthesia, then a continuous infusion of 2 mg [middle dot] kg-1 [middle dot] h-1 intraoperatively and 1.33 mg [middle dot] kg-1 [middle dot] h-1 for 24 h postoperatively) or an equal volume of saline. All patients received similar intensive postoperative rehabilitation. Postoperative pain scores, opioid consumption, and fatigue scores were measured. Times to first flatus, defecation, and hospital discharge were recorded. Postoperative endocrine (cortisol and catecholamines) and metabolic (leukocytes, C-reactive protein, and glucose) responses were measured for 48 h. Data (presented as median [25-75% interquartile range], lidocaine vs. saline groups) were analyzed using Mann-Whitney tests. P < 0.05 was considered statistically significant.

Results: Patient demographics were similar in the two groups. Times to first flatus (17 [11-24] vs. 28 [25-33] h; P < 0.001), defecation (28 [24-37] vs. 51 [41-70] h; P = 0.001), and hospital discharge (2 [2-3] vs. 3 [3-4] days; P = 0.001) were significantly shorter in patients who received lidocaine. Lidocaine significantly reduced opioid consumption (8 [5-18] vs. 22 [14-36] mg; P = 0.005) and postoperative pain and fatigue scores. In contrast, endocrine and metabolic responses were similar in the two groups.