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Biomedical subjects

A J Bennett

Publications and source records attributed to A J Bennett.

At least 19 recordsLinked to original sources
PubMed2006

Cannabinoids and PPARalpha signalling.

Cannabinoids have been shown to possess anti-inflammatory and neuroprotective properties, which were proposed to occur mainly via activation of the G-protein-coupled receptor CB(1) (cannabinoid receptor 1). Recently, certain cannabinoids have been reported to be ligands for members of the nuclear receptor transcription factor superfamily known as PPARs (peroxisome-proliferator-activated receptors). This review summarizes the evidence for cannabinoid activation of PPARs and identifies a new intracellular target for cannabinoids as therapeutic agents for neuroprotective treatment.

Animals↗
PubMed2005

Bilateral congenital diaphragmatic hernia.

Bilateral congenital diaphragmatic hernia (CDH) is a rare condition, with the literature suggesting a bleak prognosis. We describe a case of bilateral CDH that, despite confirming the challenges of diagnosis, demonstrates that the condition can have a favourable outcome.

Diagnosis, Differential↗
PubMed2003

Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer.

BACKGROUND: Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors involved in genetic control of many cellular processes. PPAR and PPAR have been implicated in colonic malignancy. Here we provide three lines of evidence suggesting an inhibitory role for PPAR in colorectal cancer development. METHODS: Levels of PPAR mRNA and protein in human colorectal cancers were compared with matched non-malignant mucosa using RNAse protection and western blotting. APC(Min)/+ mice were randomised to receive the PPAR activator methylclofenapate 25 mg/kg or vehicle for up to 16 weeks, and small and large intestinal polyps were quantified by image analysis. The effect of methylclofenapate on serum stimulated mitogenesis (thymidine incorporation), linear cell growth, and annexin V and propidium iodide staining were assessed in human colonic epithelial cells. RESULTS: PPAR (mRNA and protein) expression levels were significantly depressed in colorectal cancer compared with matched non-malignant tissue. Methylclofenapate reduced polyp area in the small intestine from 18.7 mm(2) (median (interquartile range 11.1, 26.8)) to 9.90 (4.88, 13.21) mm(2) (p=0.003) and in the colon from 9.15 (6.31, 10.5) mm(2) to 3.71 (2.71, 5.99) mm(2) (p=0.009). Methylclofenapate significantly reduced thymidine incorporation and linear cell growth with no effect on annexin V or propidium iodide staining. CONCLUSIONS: PPAR may inhibit colorectal tumour progression, possibly via inhibition of proliferation, and may be an important therapeutic target.

Animals↗
PubMed2002

Early experience and serotonin transporter gene variation interact to influence primate CNS function.

Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

Alleles↗
PubMed2001

Initial ethanol exposure results in decreased heart rate variability in ethanol-naive rhesus monkeys.

Ethanol's effects on heart rate variability may contribute to the increased cardiac disease and mortality observed in alcoholics. We assessed cardiac response to ethanol in seven previously ethanol-naive monkeys given a standard dose of ethanol, or saline. Ethanol exposure reduced cardiac signal complexity [mean+/-S.D. (ethanol: Hurst parameter=0.39+/-0.02; saline: Hurst parameter=0.32+/-0.06)] and increased the spectral exponent (ethanol: beta=1.36+/-0.35; saline: beta=1.12+/-0.35) when compared to saline, while heart rate itself was unaffected (saline: interbeat interval=303.57+/-24.57; ethanol: interbeat interval=308.14+/-20.45). Taken together with data that show autonomic disregulation in alcoholics, these findings provide further evidence of deleterious ethanol effects on cardiac signal dynamics.

Animals↗
PubMed2001

A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2.

Cellular cholesterol homoeostasis is regulated through proteolysis of the membrane-bound precursor sterol-regulatory-element-binding protein (SREBP) that releases the mature transcription factor form, which regulates gene expression. Our aim was to identify the nature and intracellular site of the putative sterol-regulatory pool which regulates SREBP proteolysis in hamster liver. Cholesterol metabolism was modulated by feeding hamsters control chow, or a cholesterol-enriched diet, or by treatment with simvastatin or with the oral acyl-CoA:cholesterol acyltransferase inhibitor C1-1011 plus cholesterol. The effects of the different treatments on SREBP activation were confirmed by determination of the mRNAs for the low-density lipoprotein receptor and hydroxymethylglutaryl-CoA (HMG-CoA) reductase and by measurement of HMG-CoA reductase activity. The endoplasmic reticulum was isolated from livers and separated into subfractions by centrifugation in self-generating iodixanol gradients. Immunodetectable SREBP-2 accumulated in the smooth endoplasmic reticulum of cholesterol-fed animals. Cholesterol ester levels of the smooth endoplasmic reticulum membrane (but not the cholesterol levels) increased after cholesterol feeding and fell after treatment with simvastatin or C1-1011. The results suggest that an increased cellular cholesterol load causes accumulation of SREBP-2 in the smooth endoplasmic reticulum and, therefore, that membrane cholesterol ester may be one signal allowing exit of the SREBP-2/SREBP-cleavage-regulating protein complex to the Golgi.

Acetamides↗
PubMed2001

Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Alleles↗
PubMed2001

A behavioral characterization of the effects of food deprivation on food and nonfood object interaction: an investigation of the information-gathering functions of exploratory behavior.

Previous research has shown that exploratory behavior serves not only to procure food, but also as a means of general information gathering. The purpose of this experiment was to investigate the function of exploratory behavior in rats by measuring behavior as they interacted with food and nonfood stimuli under different levels of food deprivation. Rats were food-deprived (0, 24, and 48 h), given free access to an open-field arena, and videotaped for a 20-min test session. The rats' behavior was assessed in a manner that isolated locomotor-, object-, and nonobject-related components. Deprivation did not affect locomotor activity levels; however, a decrease in rearing and propping against the test arena was shown. Rats distinguished between the food and nonfood objects because they attempted to ingest the food but not the nonfood object. Deprivation did result in increased contact with food objects; however, nonfood object interactions were maintained throughout the test session. These results suggest that exploratory behavior is separable from food seeking and functions in acquisition of information relating to multiple aspects of the environment.

Animals↗
PubMed2001

Use of formalin-fixed, propidium iodide-stained human leukocytes as a standard for enumerating CD4+ T lymphocytes in a single-platform assay.

A new, inexpensive method is described that enables lymphocytes to be enumerated very precisely. Normal leukocytes were simultaneously stained and fixed with a propidium iodide-paraformaldehyde solution. The preparation obtained (CellBeads) was used as an internal standard for cell enumeration by flow cytometry and was stable at 4 degrees C for at least 60 days. Unlike synthetic beads, the CellBeads behaved similarly to normal cells during red blood cell lysis and cell washing procedures. When known numbers of CellBeads were added to whole-blood samples and the numbers of CellBeads and lymphocytes were determined, highly reproducible and accurate enumerations were obtained-far more so than when synthetic beads were used. This inexpensive method is suitable for routine use.

CD3 Complex↗
PubMed2001

Direct-to-consumer drug marketing: public service or disservice?

Pharmaceutical industry spending on direct-to-consumer advertising has been increasing rapidly. While the primary goal of direct-to-consumer advertising is to sell drugs, supposed secondary goals include patient education and improved health. However, these benefits of direct-to-consumer advertising are unproved. Moreover, such advertising may create unnecessary tension between the patient and the patient's physician and insurer, and may divert physicians' efforts away from important patient concerns, and toward marketing-generated discussions. On the other hand, direct-to-consumer advertising may lead to patient-doctor encounters that would not have occurred otherwise. Direct-to-consumer advertising should be modified to unambiguously benefit the health-care interests of consumers and patients.

Advertising↗
PubMed2001

Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide.

UNLABELLED: Inhaled nitric oxide (iNO) is used to treat preterm infants with hypoxaemic respiratory failure. In this study we describe the long-term survival and neurodevelopmental status of high-risk preterm infants enrolled into a randomized controlled trial of iNO therapy. Information regarding long-term outcome was available for all 25 children enrolled in the original trial who survived until discharge from hospital. Formal, blinded, developmental assessment and neurological examinations were performed in 21 out of 22 children still alive at 30 mo of age, corrected for prematurity. No significant differences were found in long-term mortality (12/20 vs 8/22, RR 1.65, 95% CI 0.87-3.3), neurodevelopmental delay (4/7 vs 9/14, RR 0.89, 95% CI 0.37-1.75), severe neurodisability (0/7 vs 5/14, p = 0.12) or cerebral palsy (0/7 vs 2/14, p = 0.53) between iNO-treated and control infants. CONCLUSION: In this study there was no evidence of a significant effect on either survival or long-term neurodevelopmental status in infants treated with iNO.

Administration, Inhalation↗
PubMed2001

Postnatal development of hepatocellular apolipoprotein B assembly and secretion in the rat.

In this study, we explored the paradox that in suckling rats the serum concentration of LDL is high although the liver secretes only minimal quantities of VLDL, the presumed precursor of LDL. Freshly isolated hepatocytes and hepatocytes in primary culture obtained from adult (90 days old) and suckling (17 days old) rats were used to investigate the synthesis and secretion of apolipoprotein B (apoB) and lipids as well as the density profile of secreted apoB-containing lipoproteins. Furthermore, the effects of dexamethasone and oleate on apoB biogenesis were investigated in primary cultures of hepatocytes from adult and suckling rats. Hepatocytes from suckling rats were unable to assemble mature VLDL but secreted apoB as primordial lipoprotein particles in the LDL-HDL density range. Intracellular degradation of apoB was also reduced in hepatocytes from suckling rats compared with that in hepatocytes from adults. The immaturity in VLDL assembly and apoB degradation of hepatocytes from suckling rats could be overcome by treating the cultures with dexamethasone plus oleate or dexamethasone alone. The lower microsomal triacylglycerol transfer protein (MTP) mRNA concentrations in hepatocytes from suckling rats in comparison with hepatocytes from adult rats were not reflected in lower MTP activity levels. Furthermore, dexamethasone plus oleate treatment had no effect on MTP activity although VLDL assembly and secretion were clearly stimulated. We conclude that, during the suckling period of the rat, serum LDL is directly produced by the liver. This is a result of impaired hepatic VLDL assembly, which is a consequence of low triglyceride synthesis and an inefficient mobilization of bulk lipids in the second step of VLDL assembly.

Aging↗
PubMed2000

Disclosure and prevention of medical errors. Committee on Bioethical Issues of the Medical Society of the State of New York.

Medical errors occur and are sometimes unavoidable. Physicians generally, but not always, have ethical and moral obligations to disclose their errors to the patient. Because common medical errors can be expected, physicians are obligated to work within health systems toward reducing systems flaws that promote errors. However, the obligations of physicians to disclose errors made by others are less clear. This article discusses the professional ethics involved in disclosing and preventing medical errors.

Ethics, Medical↗
PubMed2000

Ondansetron modulates pharmacodynamic effects of ketamine on electrocardiographic signals in rhesus monkeys.

Electrocardiographic signal dynamics were examined in rhesus monkeys (Macaca mulatta) before and after treatment with ketamine and/or ondansetron. Ketamine exerts differential pharmacodynamic effects on behavior in animals stratified according to a measure of central serotonergic turnover. We hypothesized that measures of serotonergic turnover might explain some of the variance in the electrocardiographic (ECG) response to ketamine. Electrocardiographic recordings of animals were obtained at baseline, after administration of either saline or ondansetron (0.125 mg/kg), and after administration of ketamine (15 mg/kg). Electrocardiographic signal dynamics were measured using an algorithm that extracts the Hurst parameter (H) of the interbeat interval (IBI) time-series. H decreased after ketamine administration, (mean+/-S.E.M.), 0.33+/-0.04 vs. 0.12+/-0.02, P</=0. 001, n=10. Cerebrospinal fluid 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations, a measure of serotonergic turnover, predicted the monkeys' response to ketamine, H=0.001 (5-HIAA, pmol/ml)-0.130, R=0.66, P</=0.003, n=18. Ondansetron attenuated the response to ketamine, 0.14+/-0.02 vs. 0.08+/-0.02, P</=0.05, n=8, ondansetron vs. saline. These data provide evidence that naturally occurring differences in serotonin function alter the ECG response of the animals to ketamine and that activation of the serotonin type-3 receptor by ketamine is involved.

Animals↗
PubMed2000

Interactive effects of dietary cholesterol and different saturated fatty acids on lipoprotein metabolism in the hamster.

The present study examines the interactive effects of three fatty acids: myristic, palmitic and stearic acids, with dietary cholesterol, on lipoprotein metabolism in the hamster. Each saturated fatty acid was fed at a concentration of 100 g pure synthetic triacylglycerol/kg in the presence of 100 g triolein/kg and was fed in the presence of 0.05, 1.2 or 2.4 g dietary cholesterol/kg. Dietary cholesterol increased the concentration of cholesterol in each of the major plasma lipoprotein fractions. The largest effects on VLDL and LDL were seen in the presence of tripalmitin where the increase between the lowest and highest dietary cholesterol groups were 129% and 38% respectively. In contrast, HDL showed the greatest change in the tristearin group when the equivalent increase was 59%. No interactive effects of dietary cholesterol and fat were seen on hepatic mRNA concentrations for the LDL receptor, hydroxymethylglutaryl-CoA reductase or the microsomal triacylglycerol transfer protein. As the amount of cholesterol in the diet increased, large differences were seen in the storage of hepatic cholesterol ester. At the highest dietary cholesterol intake the amount of hepatic cholesterol ester was 1.7-fold higher in the animals fed trimyristin compared with those fed tripalmitin. These results suggest that, as the amount of cholesterol in the diet is increased, palmitic acid becomes more hypercholesterolaemic. This is associated with a reduced ability to store cholesterol ester in the liver.

Analysis of Variance↗
PubMed2000

Reporting by physicians of impaired drivers and potentially impaired drivers. The Committee on Bioethical Issues of the Medical Society of the State of New York.

Physicians routinely care for patients whose ability to operate a motor vehicle is compromised by a physical or cognitive condition. Physician management of this health information has ethical and legal implications. These concerns have been insufficiently addressed by professional organizations and public agencies. The legal status in the United States and Canada of reporting of impaired drivers is reviewed. The American Medical Association's position is detailed. Finally, the Bioethics Committee of the Medical Society of the State of New York proposes elements for an ethically defensible public response to this problem.

Age Factors↗
PubMed2000

Communication in caring for terminally ill patients.

Good care for dying patients has always been an obligation in medicine. To fulfill this obligation, physicians must embrace the integralness of dying in life, must recognize when to submit to death and dying with equanimity, and must develop attentive and individualized plans of care for each patient. Approaches to care should have, at their core, a reinvigorated commitment to communication between health professionals and patients and their intimates.

Journal Article↗