U-83836E prevents kainic acid-induced neuronal damage

Tsukuba College of Technology is the first national university established as an institute of higher education for the visually and hearing impaired. We have been systematically conducting a University Personality Inventory (UPI) survey on our students since 1989 to understand their mental health. In this study, we compared the UPI scores of the new students of Tsukuba College of Technology in 1993 and 1994 with unimpaired students from the University of Tsukuba (control group), but found no significant difference in the UPI scores of the visually impaired and the control group. However, we noticed a significant difference in the average UPI scores between the hearing impaired and the control group. The visually impaired group were divided into four subgroups, UPI scores descended in order from degree 1 (total blindness), to degrees 2 and 3 (amblyopia), to degree 4 (visual acuity > or = 0.3). The UPI scores of the degree 4 subgroup were significantly lower than those of the control group. An investigation of the items for which the check rate was at least 50% showed that the visually impaired students had a variety of psychological problems, most of which seemed to concern depression or anxiety as did the normal control group. The number of affirmative responses increased with low visual acuity. The only one belonging to the 'lie' scale item was observed in the group of hearing impaired students. Thus, comparing these three groups from the viewpoint of mental health, we noticed the hearing impaired group was slightly different from the other two groups, but the visually impaired group was similar to the normal control group.     

Estradiol prevents kainic acid-induced neuronal loss in the rat dentate gyrus

The neuroprotective role of 17beta-estradiol in the hippocampal dentate gyrus of adult rats treated with kainic acid has been investigated. The systemic injection of a single low dose (7 mg/kg) of kainic acid to ovariectomized rats produced a marked loss of Nissl-stained and somatostatin-immunoreactive hilar neurons. A single simultaneous systemic dose of estradiol (150 microg per animal) prevented the kainic acid-induced decrease in Nissl-stained and somatostatinergic hilar neurons. These results indicate that estradiol may protect adult hilar neurons in vivo from neurotoxic-induced cell death.     

Interferon-alpha prevents endotoxin-induced mortality in mice

Endotoxins, the lipopolysaccharide (LPS) moieties on the bacterial cell wall, cause many of the pathological features of Gram-negative septicemia. Tumor necrosis factor (TNF), primarily a product of monocyte/macrophages, has been shown to mediate many of the pathophysiological effects of endotoxin. Kupffer cells, the largest macrophage population in the body, release TNF when stimulated by LPS in vitro. A recombinant human hybrid interferon-alpha A/D (rIFN-alpha) markedly inhibited this LPS-elicited TNF production by Kupffer cells. The effects of rIFN-alpha were further tested in C57BL/6 mice receiving a lethal dose (400 micrograms/mouse) of LPS. All LPS-treated mice died within 2 days. Pretreatment with rIFN-alpha 1 h before LPS challenge improved the survival at 3 days to 22% (5/23, p < 0.04). In contrast, rIFN-alpha was more effective when administered 20 min after LPS injection, increasing the survival rate to 81% (13/16, p < 0.0001). TNF mRNA expression in the liver and spleen 50 min after LPS challenge, and plasma TNF 1.5 h after LPS were also reduced by either pretreatment or post-treatment with rIFN-alpha. Subsequently, experiments were carried out to test the efficacy of delayed rIFN-alpha treatment. A significant protective effect was still apparent when rIFN-alpha was administered 6, 10 and even 14 h (81%, 62% and 28% survival, respectively) after LPS challenge when serum TNF levels had already returned to near baseline. These experimental results suggest that rIFN-alpha might have a therapeutic potential for the prevention and treatment of the deleterious effects associated with endotoxemia besides mechanisms initially blocking TNF production.     

Hemostasis in fatty liver

A controlled, double-blind trial on 42 children showed that a dentrifrice containing 0,25% fluorine clearly prevented caries when used continuously for 2 years. This effects was greater than that of a similar toothpaste containing fluorine. Tolerance was excellent.     

Endotoxin modulates arachidonic acid-induced glycogenolysis in the perfused rat liver

Effects of endotoxin on arachidonic acid (AA)-induced hepatic glycogenolysis were examined in perfused rat liver. In normal rat liver, infusion of AA increased oxygen consumption and glucose production concurrently. In rats injected with lipopolysaccharide (LPS) 6 h before, AA increased glucose production but suppressed oxygen consumption. The changes in LPS-injected rat were abolished by a thromboxane (Tx) A2 receptor antagonist. The release of Tx B2 by AA increased after LPS-injection. These results suggest that priming of hepatic macrophage by endotoxin in vivo enhances Tx synthesis, resulting in modulating hepatic glycogenolysis.     

Fish oil supplementation prevents diabetes-induced nerve conduction velocity and neuroanatomical changes in rats

Diabetic neuropathy has been associated with a decrease in nerve conduction velocity, Na,K-ATPase activity and characteristic histological damage of the sciatic nerve. The aim of this study was to evaluate the potential effect of a dietary supplementation with fish oil [(n-3) fatty acids] on the sciatic nerve of diabetic rats. Diabetes was induced by intravenous streptozotocin injection. Diabetic animals (n = 20) were fed a nonpurified diet supplemented with either olive oil (DO) or fish oil (DM), and control animals (n = 10) were fed a nonpurified diet supplemented with olive oil at a daily dose of 0.5 g/kg by gavage for 8 wk. Nerves were characterized by their conduction velocity, morphometric analysis and membrane Na, K-ATPase activity. Nerve conduction velocity, as well as Na,K-ATPase activity, was improved by fish oil treatment. A correlation was found between these two variables (R = 0.999, P < 0.05). Moreover, a preventive effect of fish oil was observed on nerve histological damage [endoneurial edema, axonal degeneration (by 10-15%) with demyelination]. Moreover, the normal bimodal distribution of the internal diameter of myelinated fibers was absent in the DO group and was restored in the DM group. These data suggest that fish oil therapy may be effective in the prevention of diabetic neuropathy.     

Involvement of lipid peroxidation in free fatty acid-induced isolated rat pancreatic acinar cell injury

Ophthalmologists play a relatively peripheral role in medical student and resident education. A review of the evolution, funding, and administration of medical education in the United States lends insight into why this is so. The author reviews the current status of education in ophthalmology for medical students and residents; the development of an ophthalmology curriculum; alternatives to the traditional medical school curriculum and how these have been incorporated into ophthalmic education; and the effect of new trends in medical education and pressures created by health care reform on the education of medical students and residents. The role of ophthalmologists in the general practice of medicine and in teaching doctors about the eye is discussed. Finally, the opportunity that the current climate presents for ophthalmologists to define their role in health care through education is considered.     

Nonesterified fatty acids induce transmembrane monovalent cation flux: host-guest interactions as determinants of fatty acid-induced ion transport

Nonesterified fatty acids are key intermediates in cellular metabolism whose intracellular concentration is regulated by multiple anabolic, catabolic, and oxidative enzymatic cascades. Herein, we demonstrate that fatty acids induce transmembrane monovalent cation flux with an apparent rate constant kapp = 10(-)4 - 10(-)3 s-1. Fatty acid-induced cation efflux exploits the ionic association of the cation with the carboxylate anion of the fatty acid and the subsequent transmembrane flip-flop of the fatty acid-cation complex. Rates of fatty acid-induced transmembrane cation flux were dependent upon complex host-guest interactions between the fatty acid-cation complex and the phospholipid constituents which comprise the membrane bilayer including (1) the degree of unsaturation of the fatty acid guest and the regiospecificity and stereospecificity of its olefinic linkages; (2) the phospholipid subclass and individual molecular species which constitute the host membrane phospholipids; (3) impedance matching of host and guest hydrophobic characteristics; and (4) the cholesterol content of the membrane bilayer. Arrhenius analysis demonstrated that fatty acid-induced K+ efflux was facilitated largely by changes in the entropy of activation of ion translocation and not the energy of activation. Moreover, Arrhenius analysis demonstrated that the energy of activation of ion translocation was phospholipid subclass specific. For example, arachidonic acid-induced cation efflux in membranes comprised of 16:0-18:1 plasmenylcholine possessed an Ea = 5.3 +/- 0.4 kcal/mol, while that for 16:0-18:1 phosphatidylcholine was 7.2 +/- 0.5 kcal/mol. Electrophysiologic measurements of planar lipid membranes containing 10 mol % arachidonic acid as a substitutional impurity confirmed the ability of physiologically relevant amounts of fatty acid to induce ion translocation with a specific conductance of 2.6 +/- 0.3 microS/cm2. Collectively, these results demonstrate that fatty acids facilitate transmembrane cation flux by an ion carrier type mechanism and suggest that fatty acid-mediated ion transport contributes to the leakage current present in many cell types and thus potentially modulates cellular responsivity during signal transduction where the intracellular content of fatty acids changes dramatically.     

IL-12 prevents neonatal induction of transplantation tolerance in mice

We investigated the effect of IL-12 on the induction of transplantation tolerance by neonatal injection of allogenic cells. We first observed that injection of newborn BALB/c mice with IL-12 and (A/J x BALB/c)F1 spleen cells prevented the Th2 alloimmune response induced by neonatal inoculation of F1 cells alone and allowed the differentiation of T cells secreting high amounts of IL-2 and IFN-gamma in mixed lymphocyte cultures with donor-type stimulators. Furthermore, IL-12 administration resulted in the emergence of anti-donor cytotoxic T lymphocyte responses although at lower levels than in control uninjected mice. In parallel, we found that mice injected at birth with IL-12 and F1 cells did not develop chimerism and were able to reject a donor-type skin graft as efficiently as control mice. We conclude that IL-12 inhibits the Th2 polarization of the newborn response to alloantigens and prevents thereby the establishment of transplantation tolerance.     

Diagnosis of fatty liver in dairy cows

From 27 dairy cows with a mean milk yield of 6900 kg FCM (4% milk fat) per 305 day lactation period liver bioptates 2 weeks post partum (p.p.), milk samples 2, 4 weeks p.p., blood samples 0 (partus), 2, 4 week p.p., measurement of backfat thickness 2 weeks prior to calving, 0, 6, 17 weeks p.p. were taken and body weight and milk yield were determined. Fertility results and disorders appearance were recorded too. Total lipid and triglyceride content were analysed in liver tissue. Acetone concentration was determined in milk and 15 clinical-chemical parameters were elucidated in blood samples. Liver fat concentration shows a great variability from 3.9% to 24%. There is no strong reference value for the distinction between physiological and pathological liver fat concentration. Assessment as to whether increased liver fat levels in dairy cow are indicative of liver damage due to a pathological process should include detection of liver cell damage on the basis of plasma enzymes with closest possible specificity of liver. Glutamate-dehydrogenase (GLDH) is recommended. Liver fat content clearly could be defined exclusively from investigation of liver tissue rather than from analysis of blood or milk parameters. Measurement of backfat thickness provided useful information on the post partum lipolysis rate with a good correlation to liver fat (r to -0.72).     

Acute fatty liver of pregnancy

Acute fatty liver is a rare but potentially fatal complication of the third trimester of pregnancy. Significant improvements in morbidity and mortality have been reported in the last several years. Despite accumulation of more data about the disease, the exact pathogenesis is unknown. Many women are initially misdiagnosed with other more common causes of liver dysfunction during pregnancy. It is possible that acute fatty liver is an atypical form of preeclampsia because 30% to 40% of women with acute fatty liver also have preeclampsia. Supportive care and expeditious delivery represent the only known treatment. More data are needed about acute fatty liver of pregnancy, but the rare nature of the disease and the likelihood that most cases are not reported in the literature limit the ability systematically to study causation, disease process, and treatment options. Because of the serious condition of most women who develop acute fatty liver of pregnancy, collaboration between critical care and perinatal care providers is essential for optimal maternal-fetal outcomes.     

A metalloproteinase inhibitor prevents lethal acute graft-versus-host disease in mice

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD), which is a major complication after allogeneic bone marrow transplantation. We examined here the ameliorating effect of a metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a lethal acute GVHD model in mice. Administration of KB-R7785 into (BALB/c x C57BL/6) F1 that received C57BL/6 spleen cells markedly reduced the mortality and weight loss in association with minimal signs of GVHD pathology in the liver, intestine, and hematopoietic tissues. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-alpha antibody. Our results suggest that KB-R7785 could be a potent therapeutic agent for GVHD.     

Inactivation of Kupffer cells prevents early alcohol-induced liver injury

It is well recognized that consumption of alcohol leads to liver disease in a dose-dependent manner; however, the exact mechanisms remain unclear. Hypoxia subsequent to a hypermetabolic state may be involved; therefore, when it was observed recently that inactivation of Kupffer cells prevented stimulation of hepatic oxygen uptake by alcohol, the idea that Kupffer cells participate in early events that ultimately lead to alcohol-induced liver disease became a real possibility. The purpose of this study was to test that hypothesis. Male Wistar rats were exposed to ethanol continuously by means of intragastric feeding for up to 4 weeks using the model developed by Tsukamoto and French. In this model, ethanol causes fatty liver, necrosis and inflammation--changes characteristic of alcohol-induced liver disease in human beings. Kupffer cells were inactivated by twice weekly treatment with gadolinium chloride (GdCl3), a selective Kupffer cell toxicant. AST levels were elevated to 192 +/- 13 and 244 +/- 56 IU/L in rats exposed to ethanol for 2 and 4 wk, respectively (control value, 88 +/- 7). This injury was prevented almost completely by GdCl3 treatment. Fatty changes, inflammation and necrosis were also all reduced dramatically by GdCl3 treatment. The average hepatic pathological score of rats treated with ethanol for 4 wk was 4.3 +/- 0.6, which was reduced significantly in ethanol- and GdCl3-treated rats to 1.8 +/- 0.5 (p < 0.05). Rates of ethanol elimination were elevated 2- to 3-fold in rats exposed to ethanol for 2 to 4 wk. This elevation was blocked by GdCl3 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice

Vincristine is a commonly used antitumor agent whose major dose-limiting side-effect is a mixed sensorimotor neuropathy. To assess whether insulin-like growth factor-I (IGF-I), a neurotrophic agent that supports the survival of motoneurons and enhances regeneration of motor and sensory neurons, could prevent the peripheral neuropathy produced by vincristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 x /week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mice treated with vincristine alone, there was evidence of a mixed sensorimotor neuropathy as indicated by changes in behavior, nerve conduction and histology. Caudal nerve conduction velocity was significantly slower in mice treated with vincristine alone as compared with vehicle-treated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but not toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristine-treated mice prevented the neurotoxic effects of vincristine as measured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I partially ameliorated the neuropathy induced by vincristine as this dose only prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. These results suggest that IGF-I prevents both motor and sensory components of vincristine neuropathy and may be useful clinically in preventing the neuropathy induced by vincristine treatment.     

De novo non-alcoholic fatty liver disease following orthotopic liver transplantation

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized clinico-pathologic entity typically associated with obesity, type II diabetes and hyperlipidemia. It has been noted to recur after orthotopic liver transplantation (OLT). We report four patients who developed de novo NAFLD within 3 months of OLT without the typical predisposing factors of diabetes mellitus or obesity. Three of the four patients underwent OLT for hepatitis C-related cirrhosis, and the other for alcoholic cirrhosis. Examination of the liver explants revealed no evidence of steatosis. No surreptitious alcohol use or a drug-induced process could be identified in these patients. Treatment of recurrent hepatitis C infection in one patient with interferon and ribavirin led to sustained suppression of the viral RNA to undetectable levels, but no improvement in histology or liver enzymes. All four patients had histologic evidence of preservation injury on the initial post-OLT biopsies, but the significance of this finding in relationship to the development of NAFLD is unknown. NAFLD can develop without any of the known predisposing conditions after transplantation, and this raises further questions about the pathogenesis of this condition.     

The integrin ligand echistatin prevents bone loss in ovariectomized mice and rats

Integrins that bind RGD (arginine-glycine-aspartic acid) containing peptides, especially the vitronectin receptor alpha(v)beta3, have been implicated in the regulation of osteoclast function. Echistatin, an RGD-containing snake venom peptide with high affinity for beta3 integrins, as well as nonpeptide RGD mimetics, were shown to inhibit osteoclastic bone resorption in vitro and in vivo. To evaluate the role of RGD-binding integrins in bone metabolism, we examined by several methods the effects of echistatin on ovariectomy (OVX)-induced bone loss in mice and rats. First, we confirmed that echistatin binds in vitro with high affinity (Kd, 0.5 nM) to alpha(v)beta3 integrin purified from human placenta and established a competitive binding assay to measure echistatin concentrations in serum. We find that echistatin infused for 2 or 4 weeks at 0.36 microg/h x g body weight (approximately 50 nmol/day x mouse) completely prevents OVX-induced cancellous bone loss in the distal femora of ovariectomized mice. Echistatin has no effect on uterine weight, body weight, and femoral length changes induced by OVX, nor does it cause any apparent changes in major organs other than bone. In OVX rats, echistatin infusion at 0.26 microg/h x g for 4 weeks effectively prevents bone loss, evaluated by dual energy x-ray absorptiometry of the femur, by femoral ash weight, and by bone histomorphometry of the proximal tibia. At effective serum concentrations of 20-30 nM, measured at the end of the infusion period, echistatin maintains histomorphometric indices of bone turnover at control levels but does not decrease osteoclast surface. In conclusion, these results provide in vivo evidence, at the level of bone histology, that RGD-binding integrins, probably alpha(v)beta3, play a rate-limiting role in osteoclastic bone resorption and suggest a therapeutic potential for integrin ligands in the suppression of bone loss.     

Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice

The purpose of this study was to determine the relative importance of the metabolic effects of insulin for diabetes prevention by administering insulin or an inactive insulin analog by daily subcutaneous injections to prediabetic mice. A recombinant monomeric human insulin analog, which does not bind to the insulin receptor as a consequence of an alteration of a single amino acid at position 25 of the B chain, was shown to be equally effective at diabetes prevention as was intact insulin. In contrast to native insulin, the insulin analog did not cause hypoglycemia after subcutaneous injection. The insulin analog, however, protected young adult mice from diabetes, even when it was initiated after the onset of extensive lymphocytic infiltration of the islets. Thus, preventative therapy by daily subcutaneous injections of insulin does not require the hypoglycemic response, or binding to the insulin receptor to prevent the onset of type I diabetes.