Relationship of blood thromboxane-B2 (TxB2) with lipid peroxides and effect of vitamin E and placebo supplementation on TxB2 and lipid peroxide levels in type 1 diabetic patients

OBJECTIVE: To study the effect of vitamin E supplementation on platelet hyperaggregability in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Written informed consent according to the Institutional Review Board on Human Experimentation guidelines was obtained from diabetic patients (n = 29) and their age-matched normal siblings (n = 21) to participate in this study. Diabetic patients were supplemented with DL-alpha-tocopherol (vitamin E) capsule (orally, 100 IU/day) or placebo for 3 months in a double-blind clinical trial. Alternate diabetic patients were assigned to vitamin E or placebo during regular visits to the clinic. Fasting blood was collected from each diabetic patient before the start and after the vitamin E or placebo supplementation. Platelet aggregability was assessed by competitive enzyme-linked immunosorbent assay of the blood TxB2 (a stable thromboxane metabolite). Plasma vitamin E and MDA (malondialdehyde, a product of lipid peroxidation) was assessed by high-performance liquid chromatography. Data were analyzed statistically on 12 diabetic patients on vitamin E and 12 on placebo supplementation. RESULTS: Diabetic patients (n = 29) had 62% higher (P < 0.05) levels of TxB2 and 15% higher levels (P < 0.05) of MDA in comparison to normal subjects (n = 21). Plasma TxB2 levels had a significant correlation with MDA levels (r = 0.45, P < 0.02) but not with the HbA1 (r = -0.08), glucose (r = -0.13), duration of diabetes (r = -0.04), or age (r = 0.12) of diabetic patients. Vitamin E supplementation lowered MDA levels by 30% (P < 0.04), TxB2 levels by 51% (P < 0.03), and triglyceride levels by 22% (P < 0.04) in diabetic patients. There were no differences in these parameters before versus after placebo supplementation. CONCLUSIONS: The elevated blood level of TxB2 (hyperaggregability of platelets) is significantly related to the level of lipid peroxidation products (oxidative stress) in type 1 diabetic patients. Supplementation of modest doses of vitamin E (100 IU/day) significantly lowers blood TxB2 and lipid peroxidation products levels in type 1 diabetic patients.     

Calbistrins, novel antifungal agents produced by Penicillium restrictum. I. Production, taxonomy of the producing organism and biological activity

Over a 14-year period, from 1971 to 1985, there were 15 patients referred to the Princess Margaret Hospital in Toronto for postoperative radiotherapy to the cervical lymph nodes following radical neck surgery for metastatic cancer. An intensive investigation failed to yield a primary site in any patient. All of the patients had extensive neck disease with significant indications for postoperative radiotherapy (massive neck nodes, invasion of extra nodal structures or fixation to unresectable adjacent structures). Of this highly selected group of patients with advanced neck disease: 4/15 (27%) died within one year of uncontrolled local disease, a further 2/15 (13%) died within four years of metastatic/recurrent disease, 6/15 (33%) died of intercurrent disease and 3/15 (20%) were alive with at least four years follow-up. Although all patients presented with advanced disease, survival and significant palliation was possible in this select group of patients.     

Endosonographic evaluation of the rectum in children with extrahepatic portal venous obstruction

OBJECTIVE: To determine the mechanism of the adverse relationship between perioperative blood transfusion and lung cancer recurrence, by focusing on endothelial cell adhesion molecules (CAMs), which are thought to play a role in distant tumor cell implantation. DESIGN AND OUTCOME MEASURES: Murine endothelial cells were cocultured with allogeneic leukocytes, syngeneic leukocytes, and syngeneic lung carcinoma cells for 60 hours. The percentage of endothelial cells expressing vascular CAMs (VCAMs) and intercellular CAMs (ICAMs) was quantified during this time using indirect immunofluorescence and flow cytometry. Tumor cell adhesion to the endothelium was quantified for 6 hours using cells labeled with sulfur 35 and a scintillation counter. SETTING: Laboratory. MATERIALS: C57/BL and Balb/C mice. RESULTS: Vascular CAM was not expressed on the endothelium, but ICAM was preferentially expressed without stimulation. Tumor-cell adhesion and endothelial ICAM expression were inversely related. After 15 hours of coculture, tumor cell adhesion was four-fold greater in the experimental group than in the control, and coincident endothelial ICAM expression was fourfold lower. CONCLUSION: Endothelial cell ICAM expression is negatively correlated with metastatic potential.     

Induction of magnetic resonance-visible lipid in a transformed human breast cell line by tetraphenylphosphonium chloride

Proton magnetic resonance spectroscopy (1H MRS) and DNA flow cytometry were used to monitor the effects of the cationic lipophilic phosphonium salt and potential antineoplastic agent tetraphenylphosphonium chloride (TPP) on the transformed human breast cell line HBL-100. TPP treatment for 48 hr was cytostatic at low concentrations and cytotoxic at higher concentrations with an IC50 of 55 microM as measured by Trypan blue exclusion. At micromolar concentrations, TPP caused a significant increase in the methylene MR signal arising from mobile lipid as measured by the ratio of the lipid CH2 peak height to either the CH3 peak height (internal referencing) or the peak height for p-aminobenzoic acid (PABA) as an external reference in a co-axial capillary within the sample. Over the same concentration range, TPP caused a slowing of passage through S phase as demonstrated by a significant depletion of cells in G2/M phase with a concurrent but non-significant increase in cells in S. Time-dependent increases in MR-visible lipid were observed with 2 microM TPP treatment, and the removal of TPP from the culture medium caused no significant reduction in mobile lipid. Two-dimensional 1H-1H COSY spectra of TPP-treated HBL-100 cells revealed concentration-dependent increases in cross-peak volume ratios arising from lipid acyl chains relative to both internal (lysine, polyamines) and external (PABA) standards. Increases in choline and glycerophosphocholine cross-peak volume ratios were observed, indicating that the catabolism or rearrangement of phospholipids may be responsible for the observed MR-visible lipid increases.     

Neuronal signaling systems and ethanol dependence

In recent years there have been remarkable developments toward the understanding of the molecular and/or cellular changes in the neuronal second-messenger pathways during ethanol dependence. In general, it is believed that the cyclic adenosine 3',5'-monophosphate (cAMP) and the phosphoinositide (PI) signal-transduction pathways may be the intracellular targets that mediate the action of ethanol and ultimately contribute to the molecular events involved in the development of ethanol tolerance and dependence. Several laboratories have demonstrated that acute ethanol exposure increases, whereas protracted ethanol exposure decreases, agonist-stimulated adenylate cyclase activity in a variety of cell systems, including the rodent brain. Recent studies indicate that various postreceptor events of the cAMP signal transduction cascade (i.e., Gs protein, protein kinase A [PKA], and cAMP-responsive element binding protein [CREB]) in the rodent brain are also modulated by chronic ethanol exposure. The PI signal-transduction cascade represents another important second-messenger system that is modulated by both acute and chronic ethanol exposure in a variety of cell systems. It has been shown that protracted ethanol exposure significantly decreases phospholipase C (PLC) activity in the cerebral cortex of mice and rats. The decreased PLC activity during chronic ethanol exposure may be caused by a decrease in the protein levels of the PLC-beta 1 isozyme but not of PLC-delta 1 or PLC-gamma 1 isozymes in the rat cerebral cortex. Protein kinase C (PKC), which is a key step in the PI-signaling cascade, has been shown to be altered in a variety of cell systems by acute or chronic ethanol exposure. It appears from the literature that PKC plays an important role in the modulation of the function of various neurotransmitter receptors (e.g., gamma-aminobutyrate type A [GABAA], N-methyl-D-aspartate [NMDA], serotonin2A [5-HT2A], and 5-HT2C, and muscarinic [m1] receptors) resulting from ethanol exposure. The findings described in this review article indicate that neuronal-signaling proteins represent a molecular locus for the action of ethanol and are possibly involved in the neuro-adaptational mechanisms to protracted ethanol exposure. These findings support the notion that alterations in the cAMP and the PI-signaling cascades during chronic ethanol exposure could be the critical molecular events associated with the development of ethanol dependence.     

Silicone oil tamponade to seal macular holes without position restrictions

OBJECTIVE: The authors performed a study to determine the effectiveness and safety of silicone oil as a substitute for gas to fill the vitreous cavity to treat macular holes. DESIGN: Multicenter, nonrandomized, interventional trial. PARTICIPANTS: Thirty-seven consecutive patients chose vitrectomy with silicone tamponade instead of gas to treat 40 eyes with stage-2 to stage-4 idiopathic age-related macular holes. Stage-2 holes constituted 40% of the holes, and stage-3 and stage-4 holes made up 60%. INTERVENTION: All eyes were treated with vitrectomy, manual detachment of the posterior vitreous face (not done for stage-4 holes), autologous serum instillation, and silicone fill of the vitreous cavity. After insertion of the oil, the patients resumed normal activity with no restriction of head or eye position except to avoid faceup position. The oil was removed after approximately 6 weeks. MAIN OUTCOME MEASURES: The authors considered the seal of the macular hole and the preoperative and postoperative logarithm of the minimum angle of resolution (logMAR) visions the most significant measures for comparison to other studies. RESULTS: Eighty percent of all holes and 86% of holes not treated previously were sealed with a single silicone tamponade of the vitreous cavity. The logMAR value of visual acuity improved an average of 0.26 (2.6 lines) to 0.61 (20/81) for all eyes and 0.34 (3.4 lines) to 0.52 (20/66) when the macular hole sealed. Completeness of fill of the vitreous cavity with silicone affected seal of the macular hole. Three of eight eyes in which open holes developed after oil removal had less than 90% fill of the vitreous cavity by silicone. Sixty-nine percent of lenses increased opacity one grade or were removed after silicone tamponade. There were no significant adverse effects arising from silicone tamponade. CONCLUSIONS: Silicone oil tamponade of macular holes is effective and safe. Silicone may be optimal for the treatment of macular holes in persons who must travel, who cannot maintain facedown positioning, or who have monocular vision. The most important factor in the successful closure of the macular hole was the completeness of fill of the vitreous cavity with silicone oil.