Genetic variation among 129 substrains: practical consequences.
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Animals↗
Biomedical subjects
J Mann
Publications and source records attributed to J Mann.
Role of alpha9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation.
Cochlear outer hair cells (OHCs) express alpha9 nACh receptors and are contacted by descending, predominately cholinergic, efferent fibers originating in the CNS. Mice carrying a null mutation for the nACh alpha9 gene were produced to investigate its role(s) in auditory processing and development of hair cell innervation. In alpha9 knockout mice, most OHCs were innervated by one large terminal instead of multiple smaller terminals as in wild types, suggesting a role for the nACh alpha9 subunit in development of mature synaptic connections. Alpha9 knockout mice also failed to show suppression of cochlear responses (compound action potentials, distortion product otoacoustic emissions) during efferent fiber activation, demonstrating the key role alpha9 receptors play in mediating the only known effects of the olivocochlear system.
Animals↗
Analysis of furanone, pyranone, and new heterocyclic colored compounds from sugar-glycine model Maillard systems.
Aqueous sugar (xylose or glucose)-glycine model systems were refluxed for 2 h with the pH maintained at 5. Reverse-phase HPLC of the total reaction products gave two resolved peaks (one of which was colored) for the xylose system and five resolved peaks (two of which were colored) for the glucose system. The components responsible for these peaks were isolated from the ethyl acetate extracts by semipreparative HPLC. Using mainly NMR, the colored compound from the xylose system was identified as the new 2-acetyl-6-(hydroxymethyl)-5,6-dihydro-4H-pyridinone. The colored compounds from the glucose system were most likely to be two novel cis/trans ring isomers of the related new compound 2-acetyl-6-hydroxy-7-(hydroxymethyl)-1,5,6,7-tetrahydro-4H-azepinone+ ++. These compounds are the first one-ring structures isolated from sugar-amino acid model systems that are reported to be colored. Two of the colorless components of the glucose system were identified, mainly by NMR experiments, as the related compounds 4-hydroxy-2-(hydroxymethyl)-5-methyl-3(2H)-furanone and 2, 3-dihydro-3,5-dihydroxy-6-methyl-4H-pyranone. The remaining compound from the glucose system and the colorless compound from the xylose system were identified as 5-(hydroxymethyl)furfural and 4-hydroxy-5-methyl-3(2H)-furanone, respectively.
Carbohydrates↗
Nutrition education for medical students: the University of Otago experience.
Nutrition education for medical students in the University of Otago, New Zealand, has been adapted to comply with the newly introduced system-based teaching. Clinical cases provide the focus for class demonstrations, tutorials, self-directed learning and a limited number of lectures. In the preclinical curriculum nutrition is taught primarily in the Metabolism, Blood, Heart and Circulation, Endocrine and Cancer modules. The concept of nutrient requirements for growth and development and the maintenance of health; the various methods used for assessing dietary intakes and nutritional status as well as nutrition issues relevant to obesity are covered in the Metabolism module. The role of nutritional factors in the aetiology of disease is stressed in the other modules. Emphasis in the clinical curriculum is on the dietary management of some disease states. Students are also given insights into nutrition research and public health aspects of nutrition. This integration of nutrition teaching into the curriculum has been extremely well received by students but is labour intensive.
Adult↗
Glycaemic control, muscle glycogen and exercise performance in IDDM athletes on diets of varying carbohydrate content.
The aim of this study was to examine the effects of a high carbohydrate diet on glycaemic control, resting muscle glycogen levels and exercise performance in athletes with insulin dependent diabetes (IDDM). Seven trained (mean +/- S.D., VO2max 50.3 +/- 7.4 ml/kg/min) IDDM males consumed a high carbohydrate diet (HCD) or a normal mixed diet (NMD) for 3 week periods in a randomised crossover trial with a one week wash-out. Carbohydrate provided 59% or 50% of total energy intake, respectively, on the two diets. Fasting plasma lipids, mean blood glucose (over 96 h), fructosamine and muscle glycogen were measured and insulin use recorded. Exercise performance was evaluated by a 15 min time trial following a 50 min pre-loading block. Statistical significance was assessed using two tailed paired Student t-tests. Mean blood glucose was 10% higher on HCD than NMD (p = 0.005), fructosamine levels were 375 +/- 54 and 353 +/- 51 (mol/L on HCD and NMD, resp., p = 0.04) and daily insulin requirements were 15% higher on HCD than NMD (p = 0.02). Fasting blood lipids were similar on the two diets. Muscle glycogen was significantly lower on HCD than NMD (88.2 +/- 19.2 and 95.6 +/- 14.6 mmol/kg ww, respectively, p = 0.02). Exercise completed during the time trial was 6% less on HCD than on NMD (p = 0.007). An increased carbohydrate intake for three weeks, in IDDM athletes, is associated with a deterioration in glycaemic control, increased insulin requirements, decreased muscle glycogen and reduced exercise performance. These data do not support recommendations for IDDM athletes to consume a high carbohydrate diet, at least not when glycaemic control worsens upon following this advice, as was observed in this short-term study.
Adolescent↗
Mortality in vegetarians and nonvegetarians: detailed findings from a collaborative analysis of 5 prospective studies.
We combined data from 5 prospective studies to compare the death rates from common diseases of vegetarians with those of nonvegetarians with similar lifestyles. A summary of these results was reported previously; we report here more details of the findings. Data for 76172 men and women were available. Vegetarians were those who did not eat any meat or fish (n = 27808). Death rate ratios at ages 16-89 y were calculated by Poisson regression and all results were adjusted for age, sex, and smoking status. A random-effects model was used to calculate pooled estimates of effect for all studies combined. There were 8330 deaths after a mean of 10.6 y of follow-up. Mortality from ischemic heart disease was 24% lower in vegetarians than in nonvegetarians (death rate ratio: 0.76; 95% CI: 0.62, 0.94; P<0.01). The lower mortality from ischemic heart disease among vegetarians was greater at younger ages and was restricted to those who had followed their current diet for >5 y. Further categorization of diets showed that, in comparison with regular meat eaters, mortality from ischemic heart disease was 20% lower in occasional meat eaters, 34% lower in people who ate fish but not meat, 34% lower in lactoovovegetarians, and 26% lower in vegans. There were no significant differences between vegetarians and nonvegetarians in mortality from cerebrovascular disease, stomach cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, or all other causes combined.
Adolescent↗
Effects of valsartan on left ventricular diastolic function in patients with mild or moderate essential hypertension: comparison with enalapril.
OBJECTIVE: This study compares the effects of an AT1 angiotensin II receptor antagonist (valsartan) with those of an ACE inhibitor (enalapril) on left ventricular (LV) diastolic function in patients with mild or moderate essential hypertension and no evidence of LV hypertrophy at echocardiography. METHODS: A total of 24 patients (16 men, mean age 47 +/- 8 years) underwent radionuclide ambulatory monitoring (Vest) of LV function at rest and during upright bicycle exercise testing before and after two 4-week treatment periods with valsartan (80-160 mg/day orally) and enalapril (20-40 mg/day orally) according to a double-blind, crossover randomization scheme. RESULTS: In the overall population no differences between the two treatments were found in LV peak filling rate (PFR) either at rest or at peak exercise. In a subgroup analysis it was found that baseline PFR was normal (= 2.5 EDV/sec) in 12 patients (subgroup A) and impaired (< 2.5 EDV/sec) in the remaining 12 (subgroup B). In both subgroups, valsartan and enalapril induced a significant and comparable reduction of systolic and diastolic blood pressure. In subgroup A, valsartan and enalapril did not induce significant changes in PFR. In subgroup B, valsartan increased PFR both at rest (from 2.0 +/- 0.3 to 2.4 +/- 0.3 EDV/sec, P < 0.01) and at peak exercise (from 4.1 +/- 1.1 to 4.4 +/- 1.0 EDV/s, P < 0.05), whereas enalapril did not change PFR either at rest (2.0 +/- 0.4 EDV/s, P < 0.01 versus valsartan) or at peak exercise (3.7 +/- 1.1 EDV/sec, P < 0.05 versus valsartan). CONCLUSIONS: Valsartan-induced renin-angiotensin system blockade is able to improve LV filling in patients with mild or moderate essential hypertension and impaired diastolic function. These findings support the hypothesis of a contribution of the renin-angiotensin system in the control of LV diastolic function in these patients.
Adult↗
Gamma interferon (IFN-gamma) receptor null-mutant mice are more susceptible to herpes simplex virus type 1 infection than IFN-gamma ligand null-mutant mice.
Mouse strains with null mutations in the gamma interferon gene (Ifng) or the gamma interferon receptor gene (Ifngr) have been engineered. The use of these strains as animal models of viral and bacterial infections has enhanced our understanding of the role of gamma interferon (IFN-gamma) in the host immune response. However, direct comparisons between Ifng-/- (GKO) and Ifngr-/- (RGKO) mice have been problematic because previously available strains of these mice have had different genetic backgrounds (i.e., C57BL/6 and BALB/c for GKO mice and 129/Sv//Ev for RGKO mice). To enable direct comparison of herpes simplex virus type 1 (HSV-1) infections in GKO and RGKO mice, we introduced the IFN-gamma null mutation into the 129/Sv//Ev background. We report that, after HSV-1 inoculation, mortality was significantly greater in RGKO mice than in GKO mice (38 versus 23%, P = 0.0001). Similarly, the mortality from vaccinia virus challenge was significantly greater in RGKO mice than in GKO mice. With differences in genetic background excluded as a confounding issue, these results are consistent with the existence of an alternative ligand(s) for the IFN-gamma receptor that is also capable of mediating protection against viral challenge.
Animals↗
Mechanisms of progression in native coronary artery disease: role of healed plaque disruption.
OBJECTIVE: To determine the role of healed plaque disruption in the generation of chronic high grade coronary stenosis. METHODS: Coronary arteries obtained at necropsy were perfuse fixed with formal saline for 24 hours at 100 mg Hg. The percentage lumen diameter stenosis was measured in each 3 mm segment containing a plaque, using the lumen size at the nearest histologically normal segment as the reference point. Each segment was prepared for histological examination and stained with Sirius red and immunohistochemistry for smooth muscle actin. Healed disruption was considered to be present when under polarised light there was a break in the yellow-white dense collagen of the cap filled in by more loosely arranged green collagen. Increased smooth muscle density in the green staining areas was required. Each section was read independently by two observers; any segment with discordant views was considered negative. MATERIAL: 31 men aged 51-69 dying suddenly of ischaemic heart disease. 39 coronary arteries were studied containing 256 separate plaques, after excluding coronary arteries with old total occlusions, an acute culprit thrombotic lesion, diffuse disease without normal arterial segments, and arteries related to old myocardial scars. RESULTS: 16 of 99 plaques causing < 20% diameter stenosis had prior disruption. In the 21-50% stenosis range 16 of 86 plaques showed healed disruption. Stenosis >/= 51% by diameter was present in 71 plaques, 52 of which showed a healed disruption pattern. The difference between stenosis < 50% and stenosis >/= 51% was significant by the chi(2) test (p < 0.001). CONCLUSIONS: Subclinical episodes of plaque disruption followed by healing are a stimulus to plaque growth that occurs suddenly and is a major factor in causing chronic high grade coronary stenosis. This mechanism would explain the phasic rather than linear progression of coronary disease observed in angiograms carried out annually in patients with chronic ischaemic heart disease.
Aged↗
AT(1) receptor antagonism reduces endothelial dysfunction and intimal thickening in atherosclerotic rabbits.
The effects of angiotensin (AT)(1) receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (P<0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (P<0.05) this response in hypercholesterolemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (P<0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.5+/-6% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (P<0.05) intimal lesion to 2.4+/-0.7% and 2.7+/-0.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT(1) receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT(1) receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis.
Angiotensin I↗
Assessing immunization performance of private practitioners in Maine: impact of the assessment, feedback, incentives, and exchange strategy.
INTRODUCTION: A provider-based vaccination strategy that has strong supportive evidence of efficacy at raising immunization coverage level is known as Assessment, Feedback, Incentives, and Exchange. The Maine Immunization Program, and the Maine Chapter of the American Academy of Pediatrics collaborated on the implementation and evaluation of this strategy among private providers. METHODS: Between November 1994 and June 1996, the Maine Immunization Program conducted baseline immunization assessments of all private practices administering childhood vaccines to children 24 to 35 months of age. Coverage level assessments were conducted using the Clinic Assessment Software Application. Follow-up assessments were among the largest practices, delivering 80% of all vaccines. RESULTS: Of the 231 practices, 58 were pediatric and 149 were family practices. The median up-to-date vaccination coverages among all providers for 3 doses of diphtheria-tetanus-pertussis vaccine and 2 doses of oral polio vaccine, and 4 doses of diphtheria-tetanus-pertussis vaccine, 3 doses of oral polio vaccine, and 1 dose of measles-mumps-rubella vaccine at age 12 and 24 months were 90% and 78%, respectively, and did not vary by number of providers in a practice or by specialty. Urban practices had higher coverage than rural practices at 12 months (92% vs 88%). The median up-to-date coverage for 4 doses of diphtheria-tetanus-pertussis vaccine, 3 doses of oral polio vaccine, and 1 dose of measles-mumps-rubella vaccine at 24 months of age improved significantly among those practices assessed 1 year later (from 78% at baseline to 87% at the second assessment). On average, the assessments required 21/2 person-days of effort. CONCLUSIONS: We document the feasibility and impact of a public/private partnership to improve immunization delivery on a statewide basis. IMPLICATIONS: Other states should consider using public/private partnerships to conduct private practice assessments. More cost-effective methods of assessing immunization coverage levels in private practices are needed.
Child↗
Nutritional determinants of serum triglycerides.
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Cardiovascular Diseases↗
The future of the global AIDS movement.
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Acquired Immunodeficiency Syndrome↗
Increased thrombotic vascular events after change of statin.
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Anticholesteremic Agents↗
Should folate be added to flour to prevent neural tube defects?
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Adult↗
Lipid-modifying drugs.
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Clinical Trials as Topic↗
The impact of reference pricing on clinical lipid control.
AIM: Reference pricing has recently been introduced into New Zealand in an attempt to curb rising pharmaceutical costs. Although budget savings may be significant, the resulting alteration of established drug prescriptions has the potential to cause harm. We undertook to assess the impact of these changes in patients switching from simvastatin to fluvastatin following the introduction of reference-based pricing in New Zealand. METHODS: The fasting lipid profiles of 262 patients in a defined geographic region were obtained after at least six weeks of fluvastatin therapy. These were compared to mean lipid levels obtained from laboratory databases for the patients while previously receiving simvastatin. RESULTS: There was a significant increase in total cholesterol, LDL cholesterol and triglyceride levels (p < 0.01). The elevation was less pronounced where higher incremental doses of fluvastatin were used, although still significant for LDL cholesterol and total cholesterol (p < 0.01). Those receiving maximal therapy with fluvastatin experienced similar elevations in lipid as did those on lower doses. CONCLUSION: The lipid elevations seen in this audit relate both to the lesser potency of fluvastatin and underdosing. In this high risk population, significant lipid elevations may conceivably produce an excess of vascular events. The responsibility to the taxpayer should be weighed carefully against the ethical responsibility to the individual patient and the potential to do harm. Subtherapeutic treatment may prove more costly than all the savings from reference pricing.
Drug Utilization↗
Structure-activity relationships for triphenylethylene antiestrogens on hepatic phase-I and phase-II enzyme expression.
To better understand the mechanism(s) by which tamoxifen induces rat hepatic CYPIIB2 and suppresses GSTA1, structure-activity studies were performed. Compounds employed in these studies included: tamoxifen, fixed-ring tamoxifen, ethylated fixed-ring tamoxifen, pyrrolidino-tamoxifen, 4-iodotamoxifen, idoxifene, and toremifene. With respect to GSTA1 suppression, tamoxifen, fixed-ring tamoxifen, 4-iodotamoxifen, idoxifene, and toremifene were all potent suppressors of GSTA1, while ethylated fixed-ring tamoxifen and pyrrolidino-tamoxifen were completely without activity. The results suggest that the aminoethoxy side chain plays a crucial role in GSTA1 suppression, and that 4-iodination may potentiate this activity. With respect to induction of CYPIIB2, tamoxifen, fixed-ring tamoxifen, and ethylated fixed-ring tamoxifen were inducers of this enzyme, while toremifene and 4-iodotamoxifen were inactive, suggesting that the aminoethoxy side chain is not a structural determinant of CYPIIB2 induction. Because ethylated fixed-ring tamoxifen, toremifene, and 4-iodotamoxifen had differential activities in the two assays, we conclude that CYPIIB2 induction and GSTA1 suppression by triphenylethylenes are the result of two separate and distinct mechanistic pathways. Structure-activity relationships for GSTA1 suppression and CYPIIB2 induction were compared with previously published relationships for triphenylethylene: 1) estrogen receptor relative binding affinity; 2) calmodulin antagonism; 3) antiuterotrophic activity; and 4) antagonism of MCF-7 cell growth. No clear correlation was observed between the effects on CYPIIB2 and these other four activities, suggesting no relationship between the mechanisms responsible for these effects. Similarly, no precise correlation was observed between GSTA1 suppression and these other activities, although rough similarities were observed for relative binding affinity and antiuterotrophic activity. This suggests that the mechanisms responsible for CYPIIB2 induction and GSTA1 suppression are not related to the mechanisms of action for these other documented activities, and may represent different mechanistic pathways.
Animals↗