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PubMed1995

In Finland insulin gene region encoded susceptibility to IDDM exerts maximum effect when there is low HLA-DR associated risk. DiMe (Childhood Diabetes in Finland) Study Group.

An association between insulin-dependent diabetes mellitus (IDDM) and polymorphisms of the insulin gene on chromosome 11p15 (INS) is a consistent finding in Europid populations. While one study suggested that the INS association is restricted to HLA-DR4-positive individuals, studies in other Europid populations have shown the disease-associated INS genotype to confer susceptibility independently of HLA-DR. We have investigated the role of INS in susceptibility to IDDM in Finland, which has the highest incidence of diabetes mellitus in the world, at two polymorphic restriction sites, 5' and 3' to the insulin gene. From the DiMe (Childhood Diabetes in Finland) Study we studied 154 diabetic children without regard to HLA-DR type; 108 DR4 positive/non-DR3 diabetic children; 39 DR3 positive/non-DR4 diabetic children; 30 DR4/DR3 positive diabetic children; 31 non-DR4/non-DR3 diabetic children; 96 matched DiMe control subjects and 86 other healthy, non-diabetic Finnish control subjects. We found an overall association between IDDM and INS in the high-risk Finnish population only with the 5' polymorphism and identified an INS haplotype negatively associated with IDDM in Finland. However, among diabetic subjects with a reduced HLA-associated susceptibility (non-DR4/non-DR3) both 3' and 5' INS loci showed an association with IDDM (p values 0.02 and 0.0002, respectively). Thus, in the Finnish population insulin gene-encoded susceptibility to IDDM exerts a maximum effect in those with reduced HLA-associated risk.

Adolescent↗

PubMed1983

A comparison of some psychological and physiological effects exerted by zetidoline (DL308) and by oxazepam.

In a double-blind, balanced crossover study, eight healthy male volunteers ingested either DL-308 (10 mg), DL-308 (20 mg), oxazepam (30 mg) or placebo. Subjective estimates of coordination and anxiety, objective performance measurements and cardiovascular measurements were taken at 1, 3, 5 and 8 h after ingestion. DL-308 (20 mg) exerted a strong sedative effect as judged by self-reported coordination scores and performance on logical reasoning and reaction time tests. The effect was evident almost immediately and, on the coordination and reasoning tests, lasted up to 8 h following ingestion. Attention is drawn to the need to extend performance testing in order to maximise test sensitivity. No drug had any consistent or strong influence on cardiovascular measures.

Adult↗

PubMed1984

Natriuretic factor exerts a ouabain-like activity in the rat colon in vitro.

A previously described natriuretic factor (NF) found in urine from man receiving a high salt diet has been postulated to be of hormonal nature. This factor inhibits Na-K ATPase and binds to ouabain receptors. In order to investigate if NF exerts its physiological activity through the Na-K ouabain sensitive pump, its capacity for inhibiting sodium transport has been tested in an in vitro rat colon preparation. Colonic mucosa from rats fed 0.55, 3.55, and 6.55 mmol Na a day were mounted in an Ussing chamber. Inhibition of short-circuit current (SCC) and PD was observed only when NF was added to the serosal side of the membrane and was similar to that observed with ouabain. In rats fed a low or normal salt diet, inhibition of SCC and PD starts after a lag period of 10 min and reaches its maximum inhibition (about 60%) after 90 min. By contrast colonic mucosa from rats receiving a high salt diet exhibits a higher SCC and PD (basal values) and inhibition of the sodium transport starts immediately after addition of NF to the bathing solution. The data demonstrate the similarity of physiological action of ouabain and natriuretic factor on the sodium transport by the colon in vitro. Experiments with rats receiving a high salt diet suggest that by contrast to the kidney, NaCl-dependent cotransport is strongly stimulated by the salt intake in the colon and could be directly inhibited by ouabain or a ouabain-like substance i.e. NF.

Animals↗

PubMed1988

Effect of sustained-release verapamil therapy on the blood pressure at rest and on the pressor response to isometric exertion in hypertensive patients.

The effect of a new formulation of verapamil sustained release (SR) 240 mg tablets on resting blood pressure (BP) and on the pressor response to isometric exertion have been examined in a single-blind, placebo-controlled, cross-over study in 12 hypertensive patients (mean age 45 years). SR verapamil and placebo were administered every 12 h for 6 consecutive weeks. At the end of each period of treatment BP and heart rate (HR) were measured at rest and during isometric exercise, performed as a handgrip (HG) test for 3 min at 30% of the maximum voluntary contraction. There was a significant reduction in resting systolic and diastolic BP, with no change in HR. BP and HR at peak exercise were lower after verapamil than after placebo, but the maximal absolute increase did not change during verapamil therapy. The results are compatible with a role of SR verapamil b.d. in reducing resting BP in hypertension, and in lowering very high pressure at the peak of a HG test, without modifying the physiological reactivity of cardiovascular system.

Adult↗

PubMed1996

The use of ratings of perceived exertion for regulating exercise levels in rowing ergometry.

The purpose of this study was to examine the validity of the use of ratings of perceived exertion (RPE) to estimate and regulate exercise intensity during rowing ergometry. Nine competitive male rowers [mean age 28.6 years, (SD 6.3)] completed two rowing trials on an ergometer. The first trial (estimation) consisted of an incremental protocol designed to elicit a range of work outputs (WO) and heart rates (HR). The subjects indicated their perception of effort using a 15-point scale at each intensity level. In the second trial (production), 7-14 days later, the subjects were asked to produce exercise intensities corresponding to five levels of RPE: 15, 11, 17, 13, and 19. Data analysis revealed high Pearson correlation coefficients between HR and RPE (r = 0.95, P < 0.01) and WO and RPE (r = 0.96, P < 0.01) during the estimation trial. In addition, significant correlations (P < 0.01) were obtained between the estimation and production trials for HR (r = 0.82) and WO (r = 0.84). Posthoc analysis of variance revealed that the observed differences in mean HR were not significant (P > 0.05) at three of the five intensity levels (RPE 15, 17 and 19), but were at the two lowest RPE levels (11 and 13). Significant mean differences in WO were seen at all but RPE 17. These data support the validity of the RPE scale as a measure of physiological strain among competitive male rowers, and offer support for its use as a method of regulating the intensity of rowing ergometry, especially at higher levels.

Adult↗

PubMed1990

Nonsteroidal antiinflammatory drugs exert differential effects on neutrophil function and plasma membrane viscosity. Studies in human neutrophils and liposomes.

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit neutrophil functions via mechanisms separate from their capacity to inhibit prostaglandin synthesis. We have studied discrete events in the process of signal transduction: NSAIDs but not a related analgesic drug (acetaminophen), inhibited aggregation in response to the chemoattractants f-Met-Leu-Phe (FMLP), leukotriene B4, and C5a. NSAIDs, but not acetaminophen, inhibited binding of radiolabeled FMLP to purified neutrophil membranes. Gpp(NH)p, a GTPase insensitive analog of GTP, also inhibited the binding of FMLP but, paradoxically, enhanced superoxide anion generation and lysozyme release. The inhibition of ligand binding by NSAIDs did not correlate with their capacity to inhibit FMLP-induced increments in diacylglycerol (DG): piroxicam, but not salicylate effectively inhibited appearance of label ([3H]arachidonate, [14C]glycerol) in DG. Finally, NSAIDs exerted differential effects on the viscosity of neutrophil plasma membranes and multilamellar vesicles (liposomes): membrane viscosity was increased by piroxicam and indomethacin, decreased by salicylate, and unaffected by acetaminophen. Thus, the different effects of NSAIDs on discrete pathways are not due to their shared capacity to reduce ligand binding but rather to a capacity to uncouple postreceptor signaling events that depend upon the state of membrane fluidity.

Acetaminophen↗

PubMed1985

Investigations on myelinogenesis in vitro: a study of the critical period at which thyroid hormone exerts its maximum regulatory effect on the developmental expression of two myelin associated markers in cultured brain cells from embryonic mice.

Cultures of cells dissociated from embryonic mouse brain were used to assess the period in which thyroid hormone exerts its maximum influence on the regulation of the expression of two myelin associated metabolites, sulfolipids and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP-ase). Cultures were grown for a specified number of days on a medium containing normal calf serum and then a portion were switched to a medium containing hypothyroid calf serum for 2 days. One half of these cultures were then supplemented with 50 nM triiodothyronine and growth was continued in all cultures for 3 more days. The cells were then assayed for CNP-ase activity and for their ability to incorporate 35SO4 into sulfolipids. Studies with both myelin markers showed that in the earlier culture ages of 5, 8, and 11 days, thyroid hormone was able to fully restore the activities when added to cultures grown on hypothyroid calf-serum. In contrast, in the intermediate age range (15, 19, and 22 days) the restoration was partial, while in the higher ages, there was practically negligible restoration with T3. Since the culture system eliminates the possibility of a blood brain barrier and drastically decreases the complicity of other hormones, the lack of a myelinogenic response to thyroid hormone after a certain age must be attributed to the loss of sensitivity of the oligodendroglia to T3 possibly through genetic programming.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed1988

Do vanadium ions exert any specific effect on brain protein phosphorylation.

It has been shown previously (1) that vanadate stimulates phosphorylation of the overall proteins from the synaptic membranes of rat cerebral cortex. The aim of the present experiments was to investigate whether the action of vanadate and also of vanadyl ions could exert any specific effect on endogenous phosphorylation of proteins from subcellular fractions of the rat brain cortex. Both vanadate and vanadyl ions stimulate phosphorylation of the overall proteins from synaptic membranes and to lesser extent from mitochondria. An attempt was made to estimate the contribution of inhibition of ATPase activity to nonspecific stimulation of phosphate labeling in the synaptic membrane fraction. A band of Mr approx. 37 kDa from synaptic membranes was particularly sensitive to vanadate. In mitochondria both vanadate and vanadyl caused a marked, concentration dependent inhibition of phosphorylation of a band corresponding to Mr approx. 34 kDa. The effect was confined exclusively to the mitochondrial fractions (total, perikaryal and two synaptic types). It was absent in all subcellular fractions tested, including the nuclear one. Phosphorylation of the mitochondrial 34 kDa band is not influenced by cyclic AMP, Ca-calmodulin, shift of pH from 6.6 to 8.1. Alkaline hydrolysis removed almost all phosphate-labeled bands of mitochondria, including that of 34 kDa.

Adenosine Triphosphate↗

PubMed1994

The benzodiazepine inverse agonist RO19-4603 exerts prolonged and selective suppression of ethanol intake in alcohol-preferring (P) rats.

The time course of the benzodiazepine (BDZ) inverse agonist RO19-4603 in antagonizing ethanol (EtOH) intake was investigated in alcohol-preferring (P) rats (n = 7) maintained on 24-h continuous free-choice access to EtOH (10% v/v), water, and food. After fluid intakes had stabilized over several weeks, animals were injected with Tween-80 vehicle solution or RO19-4603 (0.075, 0.150, and 0.30 mg/kg). EtOH and water intakes were determined at 8- and 24-h intervals. RO19-4603 caused a marked attenuation of EtOH drinking with each of the doses tested. EtOH intake during the 8-h following 0.075, 0.150, and 0.30 mg/kg RO19-4603 was decreased by approximately 36, 74, and 57%, respectively. Intakes during the 24-h interval were similar to the vehicle control condition. However, 32 h post-drug administration, EtOH intakes were reduced to approximately 27, 31, and 29% following the 0.075, 0.150 and 0.30 mg/kg doses, respectively. To further confirm the reliability of the RO19-4603 dose-response effect, and its selectivity for EtOH, the highest dose condition (0.30 mg/kg) was tested twice. The second 0.30 mg/kg dose condition exerted a profile of effects similar to the initial treatment; 8 h following administration, intake was decreased to 60% of the control level, and 32 h post-drug administration intake was decreased to approximately 46% of the controls. These decreases were evidently selective in comparison with water, since water drinking showed compensatory increases which paralleled the decreased EtOH consumption. Dose-response comparisons indicated that 0.150 mg/kg approaches the maximum effective dose, since the 0.30 mg/kg dose of RO19-4603 did not produce an additional decrease in EtOH intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Deterrents↗

PubMed1994

Flumazenil exerts intrinsic activity on sleep EEG and nocturnal hormone secretion in normal controls.

The physiological function of benzodiazepine (BDZ) receptors includes regulation of sleep and neuroendocrine activity. Most of the pharmacological effects of BDZ are blocked by flumazenil. However, recent neurological and behavioral studies suggest that flumazenil has its own central intrinsic activity. This issue was addressed in a study of the sleep EEG and the nocturnal secretion of growth hormone and cortisol in ten normal male controls, who were given flumazenil either alone or in combination with the BDZ agonist midazolam, placebo and midazolam alone. Flumazenil prompted an increase in sleep onset latency, a decrease in slow wave sleep and an increase in wakefulness. Plasma cortisol concentrations after flumazenil administration were lower than after midazolam. Both flumazenil and midazolam decreased nocturnal growth hormone secretion. After simultaneous application of both BDZ receptor ligands the growth hormone blunting was amplified. Our study demonstrates that at the level of the sleep EEG and neuroendocrine activity flumazenil is capable of exerting both agonistic and inverse agonistic or antagonistic effects.

Adult↗

PubMed1976

Specific inhibition of hepatic fatty acid synthesis exerted by dietary linoleate and linolenate in essential fatty acid adequate rats.

Dietary linoleate and linolenate were investigated for their ability to specifically inhibit liver and adipose tissue lipogenesis in meal-fed (access to food 900-1,200 hr), essential fatty acid (EFA) adequate rats. Supplementing a high carbohydrate diet containing 2.5% safflower oil with 3% palmitate 16:0, oleate 18:1, or linoleate 18:2 did not affect in vivo liver or adipose tissue fatty acid synthesis. However, 18:2 addition to the basal diet did result in a significant (P less than 0.05) decline of liver fatty acid synthetase (FAS) and glucose-6-phosphate dehydrogenase (G6PD) activities. When the safflower oil content of the basal diet was reduced to 1%, the addition of 3% 18:2 or linolenate 18:3 significantly (P less than 0.05) depressed hepatic FAS, G6PD, and in vivo fatty acid synthesis by 50%. Addition of 18:1 caused no depression in hepatic FAS activity but did result in a significant (P less than 0.05) decline in liver G6PD activity and fatty acid synthesis which was intermediate between basal and basal +18:2- or +18:3-fed animals. Adipose tissue rates of lipogenesis were completely unaffected by dietary fatty acid supplementation. Similarly, the addition of 3 or 5% 18:3 to a basal diet for only one meal resulted in no change in lipogenesis relative to that in animals fed the basal diet. The data indicate that, like rats fed EFA-deficient diets, dietary 18:2 and 18:3 exert a specific capacity to depress rat liver FAS and G6PD activities and rate of fatty acid synthesis.

Adipose Tissue↗

PubMed1991

The hypercholesterolemic effect of dietary coconut fat versus corn oil in hypo- or hyperresponsive rabbits is not exerted through influencing cholesterol absorption.

In two inbred strains of rabbits with high or low response of plasma cholesterol to dietary saturated versus polyunsaturated fatty acids, the efficiency of intestinal cholesterol absorption was measured. The feeding of a cholesterol-free purified diet containing saturated fatty acids in the form of coconut fat, when compared with a diet containing corn oil as polyunsaturated fatty acids, did not influence the efficiency of cholesterol absorption in the two rabbit strains. Irrespective of the dietary fat source, the hyperresponsive rabbits absorbed cholesterol more efficiently. It is concluded that the hypercholesterolemic effect of dietary coconut fat versus corn oil is not exerted by influencing cholesterol absorption.

Animals↗

PubMed2003

Pulmonary antioxidants exert differential protective effects against urban and industrial particulate matter.

This investigation focuses on the application of an in vitro assay in elucidating the role of lung lining fluid antioxidants in the protection against inhaled particles, and to compare the toxicities of different airborne particulate matter (PM), PM10, collections from South Wales, UK. PM collections from both urban and industrial sites caused 50% oxidative degradation of DNA in vitro at concentrations as low as 12.9 +/- 2.1 microg ml(-1) and 4.9 0.9 mg ml-1 respectively. The primary source of this bioreactivity was found to be the soluble fraction of both particle collections. The coarser PM(10-2.5) fraction also showed greater oxidative bioreactivity than the PM(2.5-0.1) in both cases. When repeated in the presence of a low molecular weight fraction of fresh pulmonary lavage fluid, as well as in artificial lung lining fluid (200 microM urate, glutathione and ascorbate), the DNA damage was significantly reduced in all cases (P < 0.05). The antioxidants exerted a greater effect on the industrial samples than on the urban samples, and on the PM(10-2.5) fractions than on the PM(2.5-0.1) fractions, supporting the previous findings that respirable PM and urban samples contain fewer free radical sources than inhalable PM and industrial samples.

Air Pollutants↗

PubMed1996

Transverse forces exerted on the maxillary incisors during laryngoscopy.

PURPOSE: In this study the effect of level of experience of the intubator on the forces applied by the Macintosh laryngoscope on the maxillary incisors in both the axial and transverse direction were investigated. METHODS: Five groups of different levels of experience (15 per group), staff anaesthetists, residents, nurse anaesthetists, surgeons and students, performed one laryngoscopy and subsequent intubation on an intubation manikin equipped with sensors to measure these forces. RESULTS: Maximal transverse forces oriented toward the base of the skull (Fmtpmax) were between 0 and 10 N in 46 cases (61%), between 10 and 20 N in 21 (28%) and > or = 20 N (maximum 46.5 N) in eight cases (11%). The maximal values of the transverse forces oriented toward the intubator (Fmtnmax) were between 0 and 10 N in 69 cases (92%), between 10 and 20 N in 3 (4%) and > or = 20 N (maximum 36.4 N) in 3 (4%). Level of experience was related to Fmtpmax (Spearman: P = 0.04, r = 0.24). In addition, Fmtnmax was less in experienced intubators (anaesthetist and residents) than in inexperienced intubators (all other groups) (Student's t test: P = 0.04). CONCLUSION: In contrast to the effect on forces exerted in the axial direction, experience proved to have a beneficial effect on the forces in the transverse direction.

Humans↗

PubMed1995

Does experience influence the forces exerted on maxillary incisors during laryngoscopy? A manikin study using the Macintosh laryngoscope.

The influence of the level of experience of the laryngoscopist on the duration of laryngoscopy, the forces exerted on the tongue and on the maxillary incisors during laryngoscopy, were investigated. Five groups (anaesthetists, residents in anaesthesia, nurse anaesthetists, surgeons and medical students), each consisting of 15 individuals, participated in the study. An intubation manikin was used with a laryngoscope modified so that the forces applied during laryngoscopy could be measured. The mean duration of laryngoscopy in these groups was 23.4 sec, 17.6 sec, 27.1 sec, 26.8 sec and 42.7 sec, respectively. The maximally applied forces on the tongue were 71.7 N, 60.5 N, 65.9 N, 74.2 N and 69.7 N, respectively. The maximally applied forces on the maxillary incisors were 49.9 N, 36.3 N, 41.1 N, 58.3 N and 53.9 N, respectively. These results indicate the level of experience has a significant influence on the duration of laryngoscopy but seems to have little influence on the forces applied to the tongue and the maxillary incisors.

Anesthesiology↗

PubMed2000

Testicular Sertoli cells exert both protective and destructive effects on syngeneic islet grafts in non-obese diabetic mice.

AIMS/HYPOTHESIS: Testicular Sertoli cells protect allogeneic islet grafts from rejection after transplantation into animals with chemically induced diabetes. The aims of this study were to determine whether Sertoli cells can protect syngeneic islets from autoimmune destruction after transplantation into non-obese diabetic (NOD) mice and, if so, whether protection is due to Sertoli cell expression of Fas ligand (FasL), believed to be the mechanism that protects against allograft rejection. METHODS: We compared the survival of syngeneic islets transplanted under the renal capsule of nonobese diabetic mice, alone and together with purified Sertoli cells prepared from testes of newborn nonobese diabetic mice. Additionally, we examined the composition of the islet and Sertoli cell co-transplants by immunohistochemistry to determine whether islet graft survival correlated with Sertoli cell expression of Fas ligand. RESULTS: Sertoli cell doses of 1, 2 and 4 x 10(6) cells produced a dose-dependent prolongation of median islet graft survival from 11 days (islets alone) to 32 days (islets + 4 x 10(6) Sertoli cells); addition of 8 x 10(6) Sertoli cells to the islet grafts decreased, however, median survival to 8 days. Immunohistochemical analysis of the islet and Sertoli cell co-transplants showed a correlation between Fas ligand expression by Sertoli cells and graft infiltration by neutrophilic leucocytes, leading to islet beta-cell destruction and diabetes recurrence. CONCLUSION/INTERPRETATION: Sertoli cells exert opposing effects on survival of syngeneic islet grafts in nonobese diabetic mice: Fas ligand-dependent neutrophil infiltration and graft destruction, and Fas ligand-independent protection of the graft from autoimmune destruction.

Animals↗

PubMed2001

Glucose and insulin exert additive ocular and renal vasodilator effects on healthy humans.

AIMS/HYPOTHESIS: There is evidence that insulin and glucose cause renal and ocular vasodilation. There is, however, currently no data on the effect of combined hyperglycaemia and hyperinsulinaemia on the renal and ocular blood flow seen in diabetic patients on insulin therapy. METHODS: We carried out two different 3-way crossover studies in healthy subjects (each, n = 9). In study one, hyperglycaemic clamps (5.6 mmol/l, 11.1 mmol/ 1, 16.7 mmol/l) were carried out during placebo or insulin (dose 1: 1 mU/kg/min; dose 2: 2 mU/kg/min) infusion. The second study was identical but endogenous insulin secretion was blocked with somatostatin. The renal plasma flow, glomerular filtration rate and pulsatile choroidal blood flow were measured using the paraaminohippurate method, the inulin method and a laser interferometric measurement of fundus pulsation amplitude, respectively. RESULTS: Insulin increased renal plasma flow and fundus pulsation amplitude but not the glomerular filtration rate. Hyperglycaemia increased all the renal and ocular parameters studied. Haemodynamic effects of glucose and insulin were additive when somatostatin was co-administered but not under basal conditions. CONCLUSIONS/INTERPRETATION: Glucose and insulin can exert additive vasodilator properties on renal and ocular circulation. To find out whether this observation is related to the increased regional perfusion in diabetes longitudinal studies on patients with Type I (insulin-dependent) diabetes mellitus are needed.

Adult↗

PubMed2003

Omega-3 vs. omega-6 lipid emulsions exert differential influence on neutrophils in septic shock patients: impact on plasma fatty acids and lipid mediator generation.

OBJECTIVE: To compare the effects of a conventional omega-6 lipid infusion and a fish oil based (omega-3) lipid infusion for parenteral nutrition on neutrophil function, lipid mediators, and plasma free fatty acids. DESIGN AND SETTING: Open-label, randomized, pilot study in a university hospital medical intensive care unit and experimental laboratory. PATIENTS AND PARTICIPANTS: Ten patients with septic shock and eight healthy controls. INTERVENTIONS: Patients (five per group) requiring parenteral nutrition received intravenously either a omega-3 or a omega-6 lipid emulsion for a 10-day period. MEASUREMENTS AND RESULTS: At baseline levels of plasma free fatty acids were elevated several-fold, including high concentrations of the omega-6 lipid precursor arachidonic acid (AA). Neutrophils isolated from septic patients displayed markedly reduced responsiveness to ex vivo stimulation, including lipid mediator generation [leukotrienes (LT), PAF], respiratory burst, and phosphoinositide hydrolysis signaling. Under the omega-6 lipid infusion regimen abnormalities in plasma free fatty acids and impairment of neutrophil functions persisted or worsened. In contrast, a rapid switch in the plasma free fatty acid fraction to predominance of the omega-3 acids eicosapentaenoic acid and docosahexaenoic acid over AA occurred in response to omega-3 lipid infusion. LTB(5), in addition to LTB(4), appeared upon neutrophil stimulation originating from these patients, and neutrophil function was significantly improved in the omega-3 lipid group. CONCLUSIONS: omega-3 vs. omega-6 lipid emulsions differentially influence the plasma free fatty acid profile with impact on neutrophil functions. Lipid-based parenteral nutrition in septic patients may thus exert profound influence on sequelae and status of immunocompetence and inflammation.

Adult↗