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Biomedical subjects

R M Fisher

Publications and source records attributed to R M Fisher.

At least 37 records · Page 2Linked to original sources
PubMed1996

Synthesis and biological activity of metabolites of the antidiabetic, antihyperglycemic agent pioglitazone.

Pioglitazone (5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, 2) is a prototypical antidiabetic thiazolidinedione that had been evaluated for possible clinical development. Metabolites 6-9 have been identified after dosing of rats and dogs. Ketone 10 has not yet been identified as a metabolite but has been added to the list as a putative metabolite by analogy to alcohol 6 and ketone 7. We have developed improved syntheses of pioglitazone (2) metabolites 6-9 and the putative metabolite ketone 10. These entities have been compared in the KKAy mouse model of human type-II diabetes to pioglitazone (2). Ketone 10 has proven to be the most potent of these thiazolidinedinediones in this in vivo assay. When 6-10 were compared in vitro in the 3T3-L1 cell line to 2, for their ability to augment insulin-stimulated lipogenesis, 10 was again the most potent compound with 6, 7 and 9 roughly equivalent to 2. These data suggest that metabolites 6, 7 and 9 are likely to contribute to the pharmacological activity of pioglitazone (2), as had been previously reported for ciglitazone (1).

Animals↗
PubMed1996

Association between the LPL-D9N mutation in the lipoprotein lipase gene and plasma lipid traits in myocardial infarction survivors from the ECTIM Study.

Using polymerase chain reaction (PCR) based techniques, we have identified individuals in the ECTIM study of myocardial infarction survivors (cases) and healthy matched controls who are carriers for a mutation of the gene for lipoprotein lipase (LPL) which alters amino acid 9 from aspartic acid to asparagine (LPL-D9N). The frequency of carriers in the cases from Belfast and France (3 separate centres) was 2.5 and 3.7%, respectively (mean 3.3%, 95% CI 1.9-4.7) and in the controls 2.0 and 2.9%, respectively (mean 2.7%, 95% CI 1.6-3.8%), but this difference was not statistically significant. In the cases, carriers of the allele for LPL-N9 had higher levels of several plasma lipid traits including total triglycerides (TG) (30%), very low density lipoprotein (VLDL) cholesterol (19%), apo E (24%), apo C-III (17%), lipoprotein particles (Lp) containing both apo E and apo B (LpE:B) (32%), and particles containing both apo C-III and apo B (LpCIII:B) (39%), and this effect was consistent in cases both from Belfast and from the French centres combined. By contrast, in the controls there were no differences in any lipid trait between carriers and non-carriers of the mutation that was consistent between the French centres and Belfast. There were no significant differences in the levels of any measured factor between cases and controls that could explain the different effect on plasma lipid traits associated with the mutation. However, compared to the non-carriers, in both cases and controls who carried the mutation, plasma TG concentrations were higher in those whose body mass index (BMI) was above the mean of the sample (26.0 kg/m2), with statistically significant interaction seen between BMI and genotype and levels of apo C-III, and lipoprotein particles containing both apo C-III and apo B (P < 0.02). The data suggest that carriers for the LPL-N9 mutation have a mild genetic predisposition to developing hyperlipidaemia and an atherogenic lipid profile, but that this requires the presence of other genetic or environmental factors for full expression, one of which appears to be increasing obesity.

Adult↗
PubMed1996

Carbohydrate metabolism in insulin resistance: glucose uptake and lactate production by adipose and forearm tissues in vivo before and after a mixed meal.

1. To examine whether insulin resistance in vivo is manifest equally in both muscle and adipose tissues, we measured arteriovenous glucose and lactate fluxes across forearm (muscle) and abdominal subcutaneous (adipose) tissue in nine obese, glucose-intolerant subjects and 13 non-obese subjects of similar age and sex. 2. Compared with non-obese subjects, the forearm of the obese subjects was resistant to insulin stimulation of glucose uptake after a mixed meal. In contrast, adipose tissue showed little evidence of insulin stimulation of glucose uptake, and adipose tissue in subjects in both normal and obese groups behaved very similarly (assessed per 100 g of tissue). 3. For lactate flux, adipose tissue behaved very similarly (per 100 g of tissue) in obese and non-obese subjects, and was a consistent lactate exporter. 4. We conclude that insulin resistance of glucose uptake observed in the forearm of obese subjects is not evident in adipose tissue. Adipose tissue glucose uptake in obese, insulin-resistant subjects is similar to that in lean control subjects, although it occurs at elevated circulating insulin and glucose concentrations.

Adipose Tissue↗
PubMed1996

Periprandial systemic and regional lipase activity in normal humans.

An assay for plasma lipoprotein lipase activity was used without prior injection of heparin to study arteriovenous differences of lipases across skeletal muscle and adipose tissue of normal male volunteers. Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities and triglyceride?concentrations were measured in arterial plasma and in venous effluent plasma from forearm skeletal muscle and subcutaneous abdominal adipose tissue, in the postabsorptive state and after a mixed meal. Triglyceride clearance by the tissues was greater across adipose tissue than across muscle. There were no arteriovenous differences for HTGL activity. In the postabsorptive state skeletal muscle released LPL activity, but adipose tissue did not. Postprandially the arterial LPL and HTGL activities did not change. LPL activity in adipose tissue venous effluent rose, whereas that in muscle venous effluent decreased. These results show that the release of LPL from subcutaneous adipose and forearm tissues is regulated differently, reflecting in vivo differences in LPL regulation at the tissue level.

Absorption↗
PubMed1995

Human triacylglycerol-rich lipoprotein subfractions as substrates for lipoprotein lipase.

In order to test the hypothesis that lipoprotein lipase (LPL) acts preferentially on larger lipoprotein particles, we determined the susceptibility of triacylglycerol-rich lipoprotein (TRL) subfractions to hydrolysis by LPL in vitro. Chylomicrons (Sf > 400), very low density lipoproteins (VLDL)1 (Sf 60-400) and VLDL2 (Sf 20-60) were isolated from six subjects with a range of plasma-triacylglycerol (TAG) concentrations following an overnight fast and for up to 6 h after the consumption of a mixed meal (41% fat). The percent of TRL-TAG hydrolysed by LPL in subfractions isolated following overnight fast was VLDL1 > VLDL2 (46.8 +/- 10.2 vs. 25.9 +/- 7.4%, P = 0.006) and 3 h after the meal it was chylomicrons > VLDL1 > VLDL2 (81.0 +/- 12.6 vs. 52.8 +/- 10.2 vs. 27.7 +/- 6.2%, chylomicrons vs. VLDL1 and VLDL1 vs. VLDL2, both P < or = 0.005). The percent of VLDL1-TAG hydrolysed increased both within and between subjects as VLDL1-TAG concentrations increased. This relationship could be explained by the positive correlation observed between VLDL1-TAG and VLDL1-TAG:apolipoprotein B. In conclusion, increasing the size and TAG content of a lipoprotein particle increases its susceptibility to hydrolysis by LPL.

Adult↗
PubMed1995

Impaired postprandial clearance of triacylglycerol-rich lipoproteins in adipose tissue in obese subjects.

Adipose tissue is an important site of clearance of circulating triacylglycerol (TAG), especially in the postprandial period. Postprandial lipemia is usually increased in obesity. We studied the extraction of TAG from plasma and TAG-rich lipoproteins (TRLs) in subcutaneous adipose tissue in 11 control and 8 obese subjects before and after a mixed meal. Clearance of plasma TAG and very low-density lipoprotein (VLDL)-TAG was decreased in the obese subjects after an overnight fast. After the meal, chylomicron-TAG extraction increased in the control group whereas VLDL-TAG clearance decreased; these changes were not seen in the obese group, in whom the VLDL particles appeared to be better able to compete with the chylomicrons for clearance by lipoprotein lipase. In the control subjects, removal of TAG from the TRL in the postprandial period was accompanied by a shift toward addition of cholesterol to the high-density lipoprotein (HDL) fraction; this was not observed in the obese subjects. We conclude that disturbed TRL-TAG clearance in adipose tissue is related both to the elevated plasma TAG concentrations and the depressed HDL-cholesterol concentrations typical of obesity.

Adipose Tissue↗
PubMed1995

Interaction of the lipoprotein lipase asparagine 291-->serine mutation with body mass index determines elevated plasma triacylglycerol concentrations: a study in hyperlipidemic subjects, myocardial infarction survivors, and healthy adults.

A mutation in the lipoprotein lipase (LPL) gene, resulting in the substitution of asparagine by serine at residue 291 (LPL-S291), was found to occur in young survivors of a myocardial infarction from Sweden, combined hyperlipidemic subjects from the United Kingdom, and type III hyperlipidemic subjects from Germany at allelic carrier frequencies no different from those found in companion healthy control subjects (3.63 vs. 3.37; 1.85 vs. 1.60; and 2.00 vs. 1.56%, respectively). In a group of 620 healthy middle-aged men from the United Kingdom with baseline and three subsequent annual lipid measurements, mean plasma triacylglycerol (TG), (but not plasma cholesterol) concentrations in carriers of the mutation were significantly elevated over non-carriers (1.95 vs. 1.61 mmol/l, P = 0.05, and 5.83 vs. 5.65 mmol/l, P = 0.29, respectively). When these healthy control subjects were divided according to tertiles of body mass index (BMI), as expected, non-carriers whose BMI was in the upper two tertiles (BMI > or = 25.0 kg/m2) had higher plasma TG concentrations than those in the lowest tertile (1.90 vs. 1.54 mmol/l), but this difference was much greater in LPL-S291 carriers (2.33 vs. 1.36 mmol/l, P = 0.01, BMI x genotype interaction, P = 0.02). To confirm this effect, a second group of 319 healthy subjects from the United Kingdom was screened for LPL-S291. The allelic frequency of the mutation was found to be 1.88% and the effect on plasma lipid concentrations was very similar to that observed in the first control group (plasma TG, 2.31 vs. 1.27 mmol/l, P < 0.001 for LPL-S291 carriers vs. non-carriers, respectively). As before, those carriers whose BMI was in the top two tertiles for this sample (BMI > or = 23.3 kg/m2) had higher plasma TG concentrations than non-carriers (2.31 vs. 1.42 mmol/l). Thus, the LPL-S291 variant may predispose individuals to elevated plasma TG concentrations under conditions such as increased BMI.

Adolescent↗
PubMed1994

Fasting plasma triacylglycerol concentrations predict adverse changes in lipoprotein metabolism after a normal meal.

The changes in lipoprotein metabolism which follow the ingestion of a large fat load have been well described. The hypothesis was tested that similar changes in lipoprotein metabolism would occur after a relatively normal meal. Plasma and lipoprotein triacylglycerol, cholesterol and apolipoprotein concentrations were determined in twenty subjects (ten female) given a mixed meal containing approximately one-third of the daily intake of major nutrients in the typical Western diet. Fasting plasma triacylglycerol concentrations (range 0.38-2.70 mm/l) and the postprandial rise in plasma triacylglycerol varied considerably between subjects and were significantly associated (P < 0.01). The rise in plasma triacylglycerol corresponded to marked increases in the triacylglycerol concentration of the triacylglycerol-rich lipoproteins (TRL; chylomicrons and very-low-density lipoproteins). TRL cholesterol also increased after the meal. An increase in high-density-lipoprotein (HDL)-triacylglycerol following the meal was accompanied by a decrease in HDL-cholesterol concentration, presumably due to the action of the cholesteryl-ester transfer protein. The increases in HDL-triacylglycerol and in TRL-cholesterol were correlated with the postprandial rise in triacylglycerol in the TRL (P < 0.01). We conclude that potentially adverse changes occur in both triacylglycerol-rich and high-density lipoproteins following a typical mixed meal, as they do after large fat loads. The changes are exaggerated in those subjects with greater fasting plasma triacylglycerol concentrations.

Adult↗
PubMed1993

Communicating bronchopulmonary foregut malformation associated with esophageal atresia and tracheo-esophageal fistula.

We report on two neonates who had esophageal atresia with a distal tracheo-esophageal fistula (type III) and a second fistula between the distal esophagus and an intralobular sequestrated lung segment. In both patients the bronchopulmonary foregut malformation became evident only when the entire esophagus was in continuity following primary repair and a contrast swallow was performed to evaluate the anastomotic site.

Abnormalities, Multiple↗
PubMed1993

Post-prandial VLDL subfraction metabolism in normal and obese subjects.

The metabolic behaviour of very low density lipoprotein subfractions Sf 60-400 (VLDL1) and Sf 20-60 (VLDL2) was studied in five normal weight and five obese subjects following an overnight fast and after the consumption of a mixed meal. The VLDL1 showed increases in triacylglycerol (TG) and cholesterol concentrations after the meal, while the VLDL2 response was much smaller. The obese individuals had higher concentrations of TG, apolipoprotein B and cholesterol in both VLDL subfractions, but when the TG and cholesterol were expressed in terms of their content per VLDL particle, there was no difference between control and obese subjects. The abnormality in the obese group was identified as an elevated number of VLDL particles, of normal composition, which may predispose these individuals to coronary heart disease.

Adult↗
PubMed1992

Chest injuries in children: an analysis of 100 cases of blunt chest trauma from motor vehicle accidents.

One hundred twenty-eight cases of chest injury were seen in a Paediatric Trauma Unit over a 5 1/2-year period. One hundred patients sustained motor vehicle accident (MVA)-related blunt chest injuries, 91 of them as pedestrians. Nine children had blunt chest injuries from falls, 10 had stab wounds (3 assault, 7 accidental), and 9 had gunshot injuries (6 from birdshot used by police during civil disturbance). MVA-related injuries were studied separately, as an etiologically homogeneous group. Sixty-five of these patients were under the age of 6. All but 3 also had serious extrathoracic injuries. The mean injury severity score (ISS) in MVA-related injuries was 25. Eight patients died, all with an ISS of 34 or more, 7 of whom had fatal head injuries. In MVA-related injuries, pulmonary contusion (n = 73) was the most frequent lesion seen, followed by rib fracture (n = 62), posttraumatic effusion (n = 58), pneumothorax (n = 38), and pneumatocele (n = 5). In MVA-related injuries, 18 children required ventilation. Thirty-nine (69%) of 56 children with radiologically evident posttraumatic pleural effusion had intercostal chest drainage. Analysis suggests that lung injury is a central event in MVA-related blunt chest trauma. Primary lung injury, radiologically visible as contusion, is complicated by hematoma, posttraumatic effusion, and pneumothorax.

Accidents, Traffic↗
PubMed1992

An improved technique for processing an overdenture on implants.

This article shows an alternate procedure for making an overdenture on implants. This method helps to eliminate a chairside reline for the dentist by directly incorporating the clips into the heat-cured acrylic resin. The procedure is divided into three main sections. The first section deals with the impressions, casts, and records. The second section relates to the making of the bar, and the third section shows the assembling of the clips.

Acrylic Resins↗
PubMed1992

Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal.

Physiological actions of insulin include suppression of fat mobilization from adipose tissue and activation of adipose tissue lipoprotein lipase. Here, we report measurements of adipose tissue hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) action in vivo in 10 normal and eight obese subjects, with the latter group having varying degrees of glucose intolerance. HSL and LPL actions (per gram of adipose tissue) were similar in the two groups, after an overnight fast. In the normal subjects, HSL action was suppressed after a meal (by 75% +/- 6% between 60 to 300 minutes, P less than .01), and the action of LPL was increased (clearance of circulating triacylglycerol [TAG] increased by 140% +/- 57% at 300 minutes, P less than .05). Despite hyperinsulinemia, these responses were blunted in the obese subjects (P less than .05 for each change being less than in normal group). The adipose tissue of the obese subjects showed continued nonesterified fatty acid (NEFA) release at a time when NEFA mobilization was completely suppressed in the normal group. Both impaired suppression of HSL and low fractional retention of fatty acids for reesterification within the adipose tissue contributed to this abnormal NEFA release. Impaired activation of LPL was associated with a greater absolute increase in plasma TAG concentration postprandially in the obese. In obese subjects, adipose tissue HSL and LPL fail to respond to immunoreactive insulin postprandially, which may be an important maladaptation in terms of lipoprotein metabolism and risk of coronary heart disease.

Adipose Tissue↗
PubMed1991

Peripheral triacylglycerol extraction in the fasting and post-prandial states.

1. Triacylglycerol extraction by subcutaneous adipose tissue and forearm muscle was studied in nine normal subjects after an overnight fast and after the consumption of a mixed meal. 2. There was an inverse correlation between the total plasma fractional triacylglycerol extraction across the adipose tissue and the fasting arterial plasma triacylglycerol concentration. In contrast, there was no correlation between the lower fractional triacylglycerol extraction across the forearm muscle and the fasting plasma triacylglycerol concentration. 3. Chylomicron-triacylglycerol concentrations in arterial(ized) plasma increased post-prandially and peaked at 240-300 min. There was a comparable increase in the very-low-density lipoprotein-triacylglycerol concentration, peaking at 300 min. 4. Clearance of chylomicron-triacylglycerol by adipose tissue increased after the meal (P less than 0.05). In contrast, the clearance of very-low-density lipoprotein-triacylglycerol by adipose tissue decreased post-prandially (P less than 0.05). 5. Although there was significant uptake of chylomicron-triacylglycerol by the forearm muscle post-prandially, this was less than by the adipose tissue. Very-low-density lipoprotein-triacylglycerol was unaffected by passage through the forearm muscle at any time. 6. We conclude that the extraction of lipoprotein-triacylglycerol by human adipose tissue is important in determining the fasting plasma triacylglycerol concentration. Chylomicron-triacylglycerol, appearing in the plasma post-prandially, may compete with very-low-density lipoprotein-triacylglycerol for clearance by adipose tissue lipoprotein lipase, and this mechanism may explain, at least in part, the post-prandial rise in very-low-density lipoprotein-triacylglycerol. Forearm muscle, in contrast, appears to play a much smaller role in the extraction of plasma triacylglycerol, especially that in the very-low-density lipoprotein fraction.

Adipose Tissue↗