Long-term effects of perindopril on metabolic parameters and the heart in the spontaneously hypertensive/NIH-corpulent rat with non-insulin-dependent diabetes mellitus and hypertension

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic model that exhibits both non-insulin-dependent diabetes mellitus (NIDDM) and hypertension. To determine the impact of long-term treatment with the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the glucose metabolism, lipid levels, and heart in this model, studies were performed in three groups of SHR/N-cp rats maintained on a diet containing 54% carbohydrate with 18% sucrose and 36% starch. One group of obese rats received PE (0.5 to 1.0 mg/kg body weight/d) for 3 to 4 months, a second group of obese rats received no treatment, and a third group of lean rats were used as controls. The mean systolic blood pressure (SBP) increased gradually in both untreated obese and lean rats, with lean animals showing slightly higher levels compared with untreated obese rats. By contrast, SBP was reduced to normal levels in PE-treated obese rats throughout the treatment period. Compared with lean rats, obese rats showed significantly higher body weight and fasting serum levels of glucose, insulin, total cholesterol (TC), and triglyceride (TG). However, no significant differences were observed in these metabolic parameters between PE-treated and untreated obese rats. Plasma renin activity measured at the end of the treatment period was significantly higher in PE-treated rats compared with untreated obese and untreated lean rats. The mean heart weight and left ventricular weight, expressed in absolute terms or indexed to body weight, were significantly lower in PE-treated versus untreated obese and untreated lean rats. To further determine whether glucose metabolism is directly affected by PE treatment, in vitro glycogen synthesis was evaluated in isolated soleus muscles obtained from three additional groups of animals. The basal rate of muscle glycogen synthesis was significantly lower in obese compared with lean rats (P < .05), but did not differ between PE-treated and untreated obese rats. Maximal insulin-stimulated glycogen synthesis increased threefold in PE-treated obese rats, but this increase did not differ from the increases observed in untreated obese and lean rats. In conclusion, the present study shows that long-term PE treatment in obese SHR/N-cp rats with NIDDM and hypertension effectively controlled systemic arterial pressure and resulted in a significant reduction in left ventricular weight. However, these favorable effects of PE were not associated with significant improvement in glucose tolerance, hyperinsulinemia, and hyperlipidemia in this model. PE also had no direct stimulatory effects on either basal or insulin-mediated glycogen synthesis in the isolated soleus muscle of obese rats, perhaps because of the severe insulin-resistant state of the animals. Our results support the clinical observations that antihypertensive therapy with ACE inhibitors has neutral effects on glucose metabolism and insulin sensitivity in patients with combined hypertension and NIDDM.     

Magnolol decreases body temperature by reducing 5-hydroxytryptamine release in the rat hypothalamus

1. The effects of magnolol, isolated and purified from the cortex of Magnolia officinalis Rehd. et Wils, on thermoregulation and hypothalamic release of 5-hydroxytryptamine (5-HT) by in vivo microdialysis were assessed in normothermic rats and in febrile rats treated with interleukin-1 beta. 2. Intraperitoneal administration of magnolol (25-100 mg/kg) produced a decrease in colon temperature, an increase in foot skin temperature, a decrease in metabolic rate and a decrease in the endogenous release of 5-HT in the rat hypothalamus. 3. Depletion of rat brain 5-HT, produced by intracerebroventricular pretreatment with 5,7-dihydroxytryptamine, attenuated the magnolol-induced hypothermia, cutaneous vasodilation and decreased metabolism. 4. Intracerebroventricular administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine (a 5-HT2 receptor agonist; 5-10 micrograms/5 microL) increased basal colon temperature and reversed the magnolol-induced hypothermia. 5. The increases in both colon temperature and hypothalamic 5-HT release produced by interleukin-1 beta injection were attenuated by treatment with magnolol. 6. The data suggest that magnolol decreases body temperature (due to increased heat loss and decreased heat production) by reducing 5-HT release in rat hypothalamus.     

Excitotoxic neurodegeneration induced by deprivation of oxygen and glucose in isolated retina

PURPOSE: Ischemic neurodegeneration contributes to many retinal diseases. An isolated retina model has been used to examine the neuronal cell death induced by deprivation of oxygen and glucose (simulated ischemia) as a model for ischemic disease. METHODS: Neurodegeneration in the isolated chick embryo retina was induced by simulated ischemia and assessed using biochemical (lactate dehydrogenase release) and morphologic (light microscopy) techniques. RESULTS: Simulated ischemia led to lactate dehydrogenase release gradually in a period of 6 to 24 hours. Light microscopic observations demonstrated morphologic cell degeneration well before lactate dehydrogenase release occurred. N-Methyl-D-aspartate (NMDA) and non-NMDA receptor blockers individually provided partial protection, and the combination was fully protective. No protection was provided if the antagonists were added after simulated ischemia. When NMDA receptors were blocked by MK-801, cyclothiazide, an inhibitor of desensitization at non-NMDA receptors, enhanced lactate dehydrogenase released after 1 or 2 hours of simulated ischemia. Low concentrations of glucose effectively prevented lactate dehydrogenase release, despite anoxic conditions. CONCLUSIONS: The isolated retina provided a convenient system to characterize quantitatively ischemic cell death. Retinal ischemic neurodegeneration is an excitotoxic process that involves overactivation of NMDA and non-NMDA glutamate receptors. Blockade of both of these receptor subtypes was necessary for complete neuroprotection. Receptor desensitization played a protective role. If even low concentrations of glucose were delivered to an ischemic retina in vitro, substantial neuroprotection could be achieved. This may have implications for the management of acute retinal ischemic episodes.     

Dual role of dendritic cells in the induction and down-regulation of antigen-specific cutaneous inflammation

We have previously reported that contact sensitivity (CS) to dinitrofluorobenzene (DNFB) in C57BL/6 mice was mediated by MHC class I-restricted CD8+ T cells and down-regulated by MHC class II-restricted CD4+ T cells. In this study, we analyzed the contribution of dendritic cells (DC) in the induction of these two T cell subsets endowed with opposite functions. Hapten-pulsed skin- and bone marrow-derived DC, obtained from either normal C57BL/6 mice or from MHC class II (I+ II-) and MHC class I (I- II+)-deficient mice, were tested for their ability to prime normal mice for CS to dinitrofluorobenzene. Expression of MHC class I molecules by transferred DC was mandatory both for the induction of CS and for the generation of hapten-specific CD8+ T cells in lymphoid organs. I+ II- DC were as potent as I+ II+ DC in priming for CS, demonstrating that activation of effector CD8+ T cells can occur independently of CD4+ T cell help. I- II+ DC could not immunize for CS, although they could sensitize for a delayed-type hypersensitivity reaction to protein Ags. Moreover, I- II+ DC injected simultaneously with cutaneous sensitization down-regulated the inflammatory response, suggesting that hapten presentation by MHC class II molecules could prime regulatory CD4+ T cells. These results indicate that DC can present haptenated peptides by both MHC class I and class II molecules and activate Ag-specific CD8+ effector and CD4+ regulatory T cell subsets, concurrently and independently.     

Effects of nimesulide on constitutive and inducible prostanoid biosynthesis in human beings

BACKGROUND: The aim of this study was to test the hypothesis that nimesulide, a nonsteroidal antiinflammatory drug, or its principal metabolite 4-hydroxynimesulide, is a selective inhibitor of prostaglandin H synthase-2 in human beings. METHODS: Heparinized whole blood samples obtained from healthy subjects were incubated with lipopolysaccharide (10 micrograms/ml) for 24 hours at 37 degrees C and prostaglandin E2 was measured in plasma as an index of monocyte prostaglandin H synthase-2 activity. The production of thromboxane B2 in whole blood allowed to clot at 37 degrees C for 60 minutes was assessed as an index of platelet prostaglandin H synthase-1 activity. We also measured the urinary excretion of 11-dehydrothromboxane B2, prostaglandin E2, 6-ketoprostaglandin F1 alpha, and thromboxane B2 as in vivo indexes of cyclooxygenase activity. All prostanoids were measured by previously validated radioimmunoassay techniques. RESULTS: In the whole blood assays in vitro, nimesulide was twentyfold more potent than 4-hydroxynimesulide toward the two isozymes and both compounds displayed a twentyfold preference for prostaglandin H synthase-2 versus prostaglandin H synthase-1. The administration of a single oral dose of 100 mg nimesulide to six healthy subjects significantly (p < 0.01) reduced monocyte prostaglandin H synthase-2 and prostaglandin H synthase-1 activity ex vivo by more than 90% and 50%, respectively, up to 6 hours. At 24 hours, prostaglandin H synthase-2 but not prostaglandin H synthase-1 activity was significantly reduced by 49% (p < 0.05). Nimesulide significantly (p < 0.05) reduced the urinary excretion of 11-dehydrothromboxane B2 and 6-ketoprostaglandin F1 alpha by approximately 30% and 25%, respectively, while not affecting that of prostaglandin E2 and thromboxane B2. CONCLUSIONS: Nimesulide is a potent inhibitor of human monocyte prostaglandin H synthase-2. However, despite a twentyfold selectivity ratio, therapeutic plasma levels of nimesulide are sufficiently high to cause detectable inhibition of platelet prostaglandin H synthase-1.     

Prolongation of allograft survival by 1,25-dihydroxyvitamin D3

BACKGROUND: 1,25-Dihydroxyvitamin D3, the hormonal form of vitamin D, is now believed to play a significant role in the immune responses, both in vitro and in vivo, preventing the development of several autoimmune diseases. These studies suggest that 1,25-dihydroxyvitamin D3 may be effective in prolonging allograph survival. METHODS: To test the hypothesis that 1,25-dihydroxyvitamin D3 would prolong allograft survival, neonatal heart grafts were transplanted to allogeneic recipients receiving either 19-nor-1,25-dihydroxyvitamin D2 (200 ng/day) or 1,25-dihydroxyvitamin D3 (50 ng/mouse/day) orally through the diet. The efficacy of 1,25-dihydroxyvitamin D3 in prolonging graft survival in a vascularized model was determined by heterotopic ACI to Lewis heart transplants. RESULTS: The provision of exogenous 1,25-dihydroxyvitamin D3 or an analog, 19-nor-1,25-dihydroxyvitamin D2, to mice markedly prolonged the survival of neonatal mouse heart allografts. Similar results were obtained with a vascularized heterotopic heart transplant model in rats. Cyclosporine at a maximum 25 mg/kg dose for mice proved less effective than 1,25-dihydroxyvitamin D3. Graft survival in mice differing at class I and class II loci (B10.A(4R) --> C57BL/10) increased from 13.0+/-1.1 days to 51.0+/-5.6 days and was significantly better than cyclosporine monotherapy (33.2+/-3.6). Rat heart survival in a high responder strain combination (ACI --> Lewis) increased from 6.2+/-0.3 to 25.2+/-2.8 days. The increased survival of the transplants brought about with 1,25-dihydroxyvitamin D3 was not accompanied by hypercalcemia in rats. CONCLUSION: These results suggest that 1,25-dihydroxyvitamin D3 can be used as an effective agent in preventing graft rejection.     

Neuromuscular effects of rocuronium during sevoflurane, isoflurane, and intravenous anesthesia

The potency and time course of action of rocuronium were studied in patients anesthetized with 66% nitrous oxide in oxygen and 1.5 minimum alveolar anesthetic concentration of sevoflurane or isoflurane, or a propofol infusion. Potency was estimated by using the single-bolus technique. Neuromuscular block was measured by stimulation of the ulnar nerve and by recording the force of contraction of the adductor pollicis muscle. The mean (95% confidence limits) of the 50% and 95% effective doses were estimated tobe 142 (129-157) and 265 (233-301) microg/ kg, 165 (146-187) and 324 (265-396) microg/kg, and 183 (163-207) and 398 (316-502) microg/kg during sevoflurane, isoflurane, and propofol anesthesia, respectively (P < 0.05 for sevoflurane versus propofol). The mean +/- SD times to onset of maximal block after rocuronium 0.6 mg/kg were 0.96 +/- 0.16, 0.90 +/- 0.16, and 1.02 +/- 0.15 min during sevoflurane, isoflurane, and propofol anesthesia, respectively. The respective times to recovery of the first response in the train-of-four (TOF) stimulation (T1) to 25% and 90% were 45 +/- 13.1 and 83 +/- 29.3 min, 35 +/- 6.1 and 56 +/- 15.9 min, and 35 +/- 9.2 and 55 +/- 19.4 min. The times to recovery of the TOF ratio to 0.8 were 103 +/- 30.7, 69 +/- 20.4, and 62 +/- 21.1 min, and the 25%-75% recovery indices were 26 +/- 11.7, 12 +/- 5.0, and 14 +/- 6.9 min, respectively. There were no differences among groups in the times for onset of action or to recovery of T1 to 25%. However, the times for recovery of T1 to 90%, TOF ratio to 0.8, and recovery index in the sevoflurane group were all significantly longer compared with the other two groups (P < 0.05, < 0.01, and < 0.01, respectively). We conclude that the effects of rocuronium, especially duration of action, are significantly enhanced during sevoflurane compared with isoflurane and propofol anesthesia. IMPLICATIONS: In routine clinical use, the effects of rocuronium are enhanced by sevoflurane, in comparison with isoflurane and propofol anesthesia, and the recovery is slower. Particular attention should be paid to monitoring of neuromuscular block during sevoflurane anesthesia.     

Teaching medical faculty how to apply continuous quality improvement to medical education

BACKGROUND: An eight-hour workshop was conducted at a professional meeting in 1996 to introduce medical faculty to the principles of continuous quality improvement (CQI) as they relate to change in medical education and to provide participants with opportunities to use specific tools for applications to education. Four two-hour sessions focused on an introduction to CQI, understanding and mapping processes, identifying change ideas, and testing a change for improvement. TESTING A CHANGE FOR IMPROVEMENT: The goals of the final session were to plan a pilot test of an improvement, identify the steps of the plan-do-study-act (PDSA) cycle, and consider change for improvement in the context of one's own organization. Working in small groups, participants chose a specific change one might try in the following example: improving student performance in a neuroscience course. POSTSESSION EVALUATION AND FOLLOW-UP: Immediately following the workshop sessions, participants represented by administrators in medical education and clinical and basic science teaching faculty completed evaluations on the usefulness and likelihood of their using CQI tools. One year later, of the 32 workshop registrants who were mailed surveys, 15 respondents rated their change in understanding of CQI and their use of CQI techniques. More than 60% of the respondents reported application of CQI principles at their organizations. CQI methods used most frequently included structured team meetings, prioritizing opportunities, and brainstorming. CONCLUSION: The significant application of CQI principles and methods reported by participants one year after a brief intervention supports a need and utility for CQI principles and tools in medical education.     

High-dose therapy with peripheral blood stem cell (PBSC) support using an innovative mobilization regimen in patients with high-risk primary or chemoresponsive metastatic breast cancers

BACKGROUND: Epidemiologic studies are necessary to determine the prevalence of allergic diseases. This varies widely depending on allergen preparations and patients studied. OBJECTIVE: To investigate the prevalence of atopic disease, skin test reactivity, total and specific IgE to common allergens, and other variables in a sample of students from Málaga, southern Spain. METHODS: Three hundred sixty-five students (age 17.9 +/- 1.18) were interviewed by an allergist. Skin prick tests were performed with Dermatophagoides pteronyssinus, Artemisia vulgaris, Plantago lanceolata, Chenopodium album, Olea europaea, Phleum pratense, Parietaria judaica, Cynodon dactylon, Alternaria tenuis, and cat dander. Total and specific IgE to D. pteronyssinus, Olea, and Parietaria were determined. RESULTS: Of all subjects studied, 19.9% suffered from rhinoconjunctivitis, 4.1% rhinoconjunctivitis plus asthma, 3.1% asthma alone, and 0.8% atopic dermatitis; 46.4% had a positive skin test to at least one allergen (28.2% to D. pteronyssinus, 20.4% to Olea, 13.8% to Phleum); and 43% had total IgE > 100 kU/L and 44.7% a family history of atopy. Allergic symptoms were strongly associated with skin test positivities and family allergic history. Patients with asthma or skin prick test positive had higher total IgE values than others (P < .01). There was a significant correlation between specific IgE values and wheal size in skin test. CONCLUSIONS: Our findings confirm the high prevalence of atopic diseases, and the close relationship of skin tests reactivity (or presence of specific IgE) to allergens with symptoms of asthma and rhinitis. The presence of a family history of allergic diseases influences the development of positive skin tests and atopic illness. Dermatophagoides pteronyssinus and pollen of Olea europaea were found to be the most common allergens.     

Criterion validity and the utility of reactive and proactive aggression: comparisons to attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, and other measures of functioning

Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is a clinicopathologic entity that includes proteinuria, azotemia, focal segmental glomerulosclerosis or mesangial hyperplasia, and tubulointerstitial disease. The incidence of HIVAN is increased in black patients and variable depending on the age and geographic area. The objective of this study was to describe relevant clinical and pathological findings in 30 children with HIVAN followed at the Children's National Medical Center in Washington, D.C. Our experience of the last 12 years showed a spectrum of HIVAN that seems to be coincident with the degree of acquired immunodeficiency syndrome (AIDS) symptomatology. By renal sonograms and frequent urinalysis, we identified children undergoing the early stages of HIVAN with enlarged echogenic kidneys, proteinuria, and "urine microcysts". HIVAN did not necessarily progress rapidly to end-stage renal disease. Nephrotic syndrome or chronic renal insufficiency were late manifestations of HIVAN. Children with HIVAN were likely to develop transient electrolyte disorders, heavy proteinuria, and acute renal failure due to systemic infectious episodes or nephrotoxic drugs. HIVAN was associated with other HIV-induced illnesses and high mortality rates. Early detection and careful clinical follow-up of children with HIVAN may reduce the incidence of renal-cardiovascular complications and improve their quality of life.