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Biomedical subjects

M O'Shea

Publications and source records attributed to M O'Shea.

At least 19 recordsLinked to original sources
PubMed2006

The effect of 6 months supplementation with conjugated linoleic acid on insulin resistance in overweight and obese.

BACKGROUND: Contradicting results have been published regarding the effect of conjugated linoleic acid (CLA) on insulin resistance. However, only a few studies have used the euglycemic hyperinsulinemic clamp method, which is considered the standard for measuring insulin resistance. OBJECTIVE: To evaluate if CLA as a mixture of the main isomers trans-10 cis-12 and cis-9 trans-11 affects the insulin resistance in healthy overweight and obese male and female adults. DESIGN: The main study was a randomized, double-blind, placebo-controlled trial with change in body composition as primary end point comprising 118 subjects receiving supplementation with either placebo (olive oil) or CLA (Clarinol) for 6 months. A sub-population of 49 subjects agreed additionally to participate in an euglycemic hyperinsulinemic clamp study at baseline and after 6 months of supplementation with study drug. The primary outcome was the change in glucose uptake (M) as measured by the hyperinsulinemic euglycemic glucose clamp method. Secondary outcomes were the correlates between insulin resistance and changes in body composition or blood chemistry parameters. Forty-one subjects completed the clamp test at both time points. RESULTS: The median M of the CLA group was 11.0 mg min(-1) lean body mass (lbm)(-1) (n=24) at baseline, 10.3 mg min(-1) lbm(-1) (n=24) after 6 months, and the median difference was +0.21 mg min(-1) lbm(-1) (n=24). The median M of placebo group was 8.4 mg min(-1) lbm(-1) at baseline and 9.3 mg min(-1) lbm(-1) after 6 months and the median difference was -0.22 mg min(-1) lbm(-1) (n=17). No significant (P<0.05) differences were found within groups or between groups. Likewise, the glucose uptake insulin concentration ratio during clamp (M/I) was independent of treatment and time. Homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index derived from fasting glucose and insulin were also independent of treatment and time, and HOMA for the clamp population (n=49) corresponded well with HOMA for the per protocol population (n=83). Correlation analysis showed that changes in M were inversely correlated to changes in glucohemoglobin (P=0.002), but did not correlate with changes in either glucose, insulin, insulin c-peptide, leptin, adiponectin or percent body fat. CONCLUSIONS: CLA does not affect glucose metabolism or insulin sensitivity in a population of overweight or obese volunteers.

Adolescent↗
PubMed2005

Impaired learning in adulthood following neonatal delta9-THC exposure.

Cannabis is one of the most commonly used illicit drugs during pregnancy, but little is known about the lasting effects of early-life exposure to this drug. In this study, male Wistar rat pups were treated daily with (-)-delta9-tetrahydrocannabinol (THC; 5 mg/kg, s.c.) or its vehicle between postnatal days (PND) 4 and 14. Drug administration during this early postnatal period in rats is analogous to the third trimester of gestation in humans, which is a major period of synaptogenesis. Rats were subsequently tested drug-free during young adulthood (PND 56) using a two-component food-motivated double Y-maze test. Each trial included distinct spatial discrimination and delayed alternation components, which permitted the simultaneous assessment of reference memory and working memory. Rats were tested for 30 trials/day, 5 days/week for 5 weeks. Results revealed no significant differences between THC- and vehicle-treated rats in the spatial discrimination task. However, compared to vehicle-treated rats, THC-treated rats committed significantly more errors, and required significantly longer to obtain 80% correct over two consecutive days in the delayed alternation task. Results suggest that neonatal THC exposure leads to a specific and lasting deficit in learning in adulthood, which is likely due to impaired working memory function.

Analysis of Variance↗
PubMed2004

Safety profile of conjugated linoleic acid in a 12-month trial in obese humans.

Conjugated linoleic acid (CLA) is marketed in numerous commercially available dietary supplements, but few studies have looked at the long-term safety of this product. The current study evaluated the safety of one CLA product (Clarinol) over a one-year period in obese humans who were generally healthy. This was a randomized, double-blind study consisting of three phases in which subjects were given 6 g/day of CLA or placebo. Phase 1 was a low calorie diet (13 kcal/kg desirable weight) for 12 weeks or until 10-20% of initial body weight was lost. In phase 2, from weeks 12 to 28, subjects were re-fed a diet providing 25-30 kcal/kg of desirable body weight. Phase 3 was open label, with subjects from both groups taking CLA from weeks 28 to 52. At biweekly visits, subjects completed a questionnaire evaluating side effects and adverse events. Blood was taken for assay of liver function, glucose, insulin, serum lipids, blood counts, and general chemistry. Overall, body composition did not differ between groups. Laboratory tests showed no adverse effects of CLA. Adverse events and side effects were less in the CLA group compared to placebo. We conclude that CLA as Clarinol is safe for use in obese humans for at least one year.

Adult↗
PubMed2004

Infections in neurosurgical patients admitted to the intensive care unit at the University Hospital of the West Indies.

Patients admitted to the Intensive Care Unit (ICU) are at risk of developing life-threatening nosocomial infections, especially with organisms resistant to commonly used antibiotics. Neurosurgical patients are particularly vulnerable because of the serious nature of their illness, the frequency of associated trauma and the presence of invasive devices. Of 120 neurosurgical patients admitted to the ICU of the University Hospital of the West Indies (UHWI) between September 1995 and December 1999, the records of 73 patients were available for analysis. All had prophylactic antibiotics. Twenty-one of these 73 patients (28.8%) developed 22 infections after a mean of five days in the ICU: nine with chest infection, seven with urinary tract infection, four with central nervous system (CNS) infection and one each with wound and skin infection. This is an incidence of 11.6/1000 patient-days. The responsible organisms included Pseudomonas (7/21), Acinetobacter (3/21), E. coli 2/21, Enterobacter (2/21), and Klebsiella (2/21), and one each with Staphylococcus aureus, methicillin resistant Staphylococcus aureus, coagulase negative Staphylococcus, group D Streptococcus and bacteroides (1/21). Infection was significantly related to length of hospital stay, length of ICU stay, duration of intubation, duration of ventilation and the presence of diabetes mellitus. All patients who had surgery after ICU admission developed infection, seven with chest infection, two with urinary tract infection, two with CNS and one with skin infection. The three patients who were admitted with intracranial infections all developed other infections. Infected patients had a significantly longer hospital stay. Five patients died, none directly attributable to infection, while 55 (75.5%) made a good recovery. The problem of ICU infection may be expected to escalate with the increased use of intensive care, increasingly more complex surgical procedures and the growing problem of antibiotic resistance. Since infection is related to the length of ICU stay, earlier discharge of neurosurgical patients to an appropriately staffed high dependency unit is likely to result in reduction of the infection rate. Reinforcement of infection control strategies within the ICU may be expected to further minimize the infection rate.

Adolescent↗
PubMed2003

Repeated withdrawal from ethanol impairs acquisition but not expression of conditioned fear.

Repeated withdrawal from ethanol impairs acquisition of conditioned fear [Stephens, D.N., Brown, G., Duka, T. & Ripley, T.L. (2001) Eur. J. Neurosci., 14, 2023-2031]. This study further examined the effect of repeated withdrawal from ethanol on the expression and acquisition of fear conditioning. Following training, presentation of a cue associated with footshock (CS+) resulted in a suppression of operant responding for food reinforcement. In different groups, shock thresholds were manipulated to give weak or severe behavioural suppression. Rats were subsequently chronically treated with ethanol-containing liquid diet either continuously (single withdrawal) or with three withdrawal periods (repeated withdrawal). Ethanol treatment and withdrawal had no effect on conditioned suppression of responding tested 2 weeks after the final withdrawal, at either shock intensity. Nevertheless, extinction of conditioned fear was impaired in the repeated withdrawal group exposed to the higher shock intensity. In the high intensity group, the stimulus-shock association was then reversed, so that the previously neutral conditioned stimulus (CS-) became the CS+. Acquisition of suppression to the new CS+ was significantly less in the animals previously given repeated experience of withdrawal, confirming our previous finding. Thus, repeated withdrawal from ethanol lead to disruption in the acquisition of fear conditioning but had no effect on retrieval of an association formed prior to the ethanol-withdrawal experiences.

Animals↗
PubMed2001

Characterization of a putative nitric oxide synthase in the neuromuscular system of the parasitic nematode, Ascaris suum.

In this paper we report on the biochemical presence of nitric oxide synthase (NOS)-like activity in Ascaris suum tissue and examine the pharmacological effect of NO donors on A. suum muscle strip preparation. NOS activity was determined by monitoring the formation of [3H]citrulline from [3H]L-arginine and NO formation via the oxyhaemoglobin assay. Neuromuscular tissue from A. suum which stained positively for NADPH diaphorase, contained NOS activity. Neither NOS activity nor NADPH diaphorase staining was detected in intestinal tissue. The absence of Ca2+, NADPH and other co-factors normally required for mammalian neuronal NOS activity only partially reduced the formation of both citrulline and NO by A. suum neuromuscular homogenate. The results of the biochemical assays indicate the presence of an enzyme capable of producing NO and citrulline, but with a different profile from that of rat neuronal NOS. We also present preliminary evidence for the action of NO (NO donors) in the neuromuscular system of A. suum.

Animals↗
PubMed2000

Four-dimensional neuronal signaling by nitric oxide: a computational analysis.

Nitric oxide (NO) is now recognized as a transmitter of neurons that express the neuronal isoform of the enzyme nitric oxide synthase. NO, however, violates some of the key tenets of chemical transmission, which is classically regarded as occurring at points of close apposition between neurons. It is the ability of NO to diffuse isotropically in aqueous and lipid environments that has suggested a radically different form of signaling in which the transmitter acts four-dimensionally in space and time, affecting volumes of the brain containing many neurons and synapses. Although "volume signaling" clearly challenges simple connectionist models of neural processing, crucial to its understanding are the spatial and temporal dynamics of the spread of NO within the brain. Existing models of NO diffusion, however, have serious shortcomings because they represent solutions for "point-sources," which have no physical dimensions. Methods for overcoming these difficulties are presented here, and results are described that show how NO spreads from realistic neural architectures with both simple symmetrical and irregular shapes. By highlighting the important influence of the geometry of NO sources, our results provide insights into the four-dimensional spread of a diffusing messenger. We show for example that reservoirs of NO that accumulate in volumes of the nervous system where NO is not synthesized contribute significantly to the temporal and spatial dynamics of NO spread.

Cell Size↗
PubMed1999

Neuronal expression of neural nitric oxide synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an NOS pseudogene.

Here, we show that a nitric oxide synthase (NOS) pseudogene is expressed in the CNS of the snail Lymnaea stagnalis. The pseudo-NOS transcript includes a region of significant antisense homology to a previously reported neuronal NOS (nNOS)-encoding mRNA. This suggested that the pseudo-NOS transcript acts as a natural antisense regulator of nNOS protein synthesis. In support of this, we show that both the nNOS-encoding and the pseudo-NOS transcripts are coexpressed in giant identified neurons (the cerebral giant cells) in the cerebral ganglion. Moreover, reverse transcription-PCR experiments on RNA isolated from the CNS establish that stable RNA-RNA duplex molecules do form between the two transcripts in vivo. Using an in vitro translation assay, we further demonstrate that the antisense region of the pseudogene transcript prevents the translation of nNOS protein from the nNOS-encoding mRNA. By analyzing NOS RNA and nNOS protein expression in two different identified neurons, we find that when both the nNOS-encoding and the pseudo-NOS transcripts are present in the same neuron, nNOS enzyme activity is substantially suppressed. Importantly, these results show that a natural antisense mechanism can mediate the translational control of nNOS expression in the Lymnaea CNS. Our findings also suggest that transcribed pseudogenes are not entirely without purpose and are a potential source of a new class of regulatory gene in the nervous system.

Animals↗
PubMed1999

Long-term maintenance of therapeutic cyclosporine levels leads to optimal graft survival without evidence of chronic nephrotoxicity.

Since the introduction of cyclosporine into clinical use, a major area of concern within the transplant community has been the fear of chronic nephrotoxicity. Although progressive renal damage does appear to occur in native kidneys of heart and liver transplant patients receiving cyclosporine, it has been our contention that its use is not a major cause of deterioration in renal allografts. We therefore undertook a study of 91 consecutive renal transplants performed over a three-year period with a minimum graft survival of 1 year and a follow-up of 7-9 years. Serial serum creatinine values, iothalamate clearances and cyclosporine levels were obtained at 3 months after transplantation and yearly thereafter. Biopsies were performed on all grafts that had failed as well as on the majority of patients with deteriorating renal function, and were interpreted by two nephropathologists. As measured by iothalamate clearances, 65% of the patients in this series exhibited absolutely stable renal function despite the maintenance of cyclosporine levels of more than 200 ng/ml for 7-9 years. Since these stable patients did not reveal any decline in renal function, it therefore follows that they did not experience chronic cyclosporine nephrotoxicity. Furthermore, none of the patients with declining renal function or with failed grafts showed any evidence of nephrotoxicity on biopsy. Chronic cyclosporine nephrotoxicity may be a cause of declining function or graft loss with renal transplant recipients, but if so, it is exceedingly rare.

Creatine↗
PubMed1998

Anterograde signaling by nitric oxide: characterization and in vitro reconstitution of an identified nitrergic synapse.

Nitric oxide (NO) is recognized as a signaling molecule in the CNS where it is a candidate retrograde neurotransmitter. Here we provide direct evidence that NO mediates slow excitatory anterograde transmission between the NO synthase (NOS)-expressing B2 neuron and an NO-responsive follower neuron named B7nor. Both are motoneurons located in the buccal ganglia of the snail Lymnaea stagnalis where they participate in feeding behavior. Transmission between B2 and B7nor is blocked by inhibiting NOS and is suppressed by extracellular scavenging of NO. Furthermore, focal application of NO to the cell body of the B7nor neuron causes a depolarization that mimics the effect of B2 activity. The slow interaction between the B2 and B7nor neurons can be re-established when the two neurons are cocultured, and it shows the same susceptibility to NOS inhibition and NO scavenging. In cell culture we have also examined spatial aspects of NO signaling. We show that before the formation of an anatomical connection, the presynaptic neuron can cause depolarizing potentials in the follower neuron at distances up to 50 micro(m). The strength of the interaction increases when the distance between the cells is reduced. Our results suggest that NO can function as both a synaptic and a nonsynaptic signaling molecule.

Animals↗
PubMed1998

Nitric oxide compartments in the mushroom bodies of the locust brain.

All insect brains contain mushroom-shaped neural bodies which are implicated in associative learning. Here we show that the mushroom bodies of the locust brain have a remarkable and hitherto undescribed neural organisation consisting of six tubular structures in which bundles of axons are enclosed by cylindrical walls of nitric oxide synthase (NOS) expressing processes. A dynamic temporo-spatial simulation shows that the tubular organization allows NO to attain and maintain locally elevated concentrations within highly structured domains in the CNS. A diffusible gaseous signalling molecule such as NO can therefore selectively affect computational processes occurring in discrete parallel channels of information flow in the brain. The implications of this are discussed in relation to the role of NO in a compartmental model of the mushroom bodies and more generally in the context of the targetting of diffusible messenger molecules in the brain.

Animals↗
PubMed1998

Magnetic resonance spectroscopy: use in monitoring MELAS treatment.

BACKGROUND: Sodium dichloroacetate has been used to treat patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Magnetic resonance spectroscopy (MRS) has been used to assess cerebral metabolism in MELAS, but to our knowledge, the findings of serial MRS studies performed after therapeutic intervention of strokelike episodes have not been reported. METHODS: Proton MRS was serially used to measure brain metabolites in strokelike regions and in clinically uninvolved brain regions in a patient with MELAS. PATIENT: A patient with MELAS and a strokelike episode clinically improved after treatment with sodium dichloroacetate. An elevated lactate-creatine ratio in the "stroke" region decreased on MRS studies after treatment. After a second episode, the lactate-creatine ratio increased from baseline in a region of the brain that was normal on magnetic resonance imaging scans. CONCLUSIONS: To our knowledge, this is the first study to assess the response to treatment of a MELAS strokelike episode and the first to show an increase in the lactate-creatine ratio in a brain region that was associated with a clinical abnormality, even though it appeared normal on magnetic resonance imaging. We conclude that MRS may help to monitor therapeutic efficacy in mitochondrial encephalomyopathies.

Adult↗
PubMed1998

Molecular characterization of NOS in a mollusc: expression in a giant modulatory neuron.

Here we report on the molecular characterization of the first molluscan NOS in the CNS of the pond snail Lymnaea stagnalis. This Lymnaea NOS (Lym-nNOS) which is expressed preferentially in the CNS is most similar to mammalian neuronal NOS but contains tandem repeats of a seven amino acid motif not found in any other known NOS. We have localized Lym-nNOS to the serotonergic cerebral giant cells (CGCs) which modulate synaptic transmission within a neural network that generates feeding behavior. Our results suggest that the CGCs employ both NO and serotonin in the modulation of the central neural network underlying feeding.

Amino Acid Sequence↗
PubMed1998

Extravasation injury associated with low-dose dopamine.

OBJECTIVE: To describe the occurrence of extravasation in two patients receiving low-dose dopamine infusions. CASE SUMMARY: Intravenous dopamine was infused peripherally (in the antecubital fossa) to two patients in the cardiac intensive care unit in an attempt to enhance renal blood perfusion and urine output. Dopamine extravasation occurred in both patients while the low dose (< 3 micrograms/kg/min) was infused. Significant local tissue injury was observed in both patients. DISCUSSION: Dopamine infusion can cause tissue ischemia or necrosis secondary to vasospasm and extravasation. Most of the case reports in the literature have occurred when relatively high doses of dopamine were infused. Only one reported extravasation-induced injury with low-dose dopamine. Although low-dose dopamine has a vasodilatory effect in selected tissues, high concentrations achieved locally as a result of extravasation can still cause severe vasoconstriction and ischemic tissue injury. CONCLUSIONS: Low-dose dopamine therapy should be administered with similar precautions as high-dose dopamine. A central intravenous access should be placed for dopamine infusion whenever possible. If this approach is not feasible, dopamine should be infused only peripherally through a long intravenous catheter into a large vein. A 5-cm angiocatheter that is 20 gauge or larger is recommended for peripheral dopamine infusion in our institution. The infusion site should be inspected frequently for early detection of extravasation, and changed to a central or a peripherally inserted central catheter as soon as possible, especially in patients at high risk for extravasation.

Aged↗
PubMed1997

The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction.

Recombinant human procollagenase-3 and a C-terminal truncated form (Delta249-451 procollagenase-3) have been stably expressed in myeloma cells and purified. The truncated proenzyme could be processed by aminophenylmercuric acetate via a short-lived intermediate form (N-terminal Leu58) to the final active form (N-terminal Tyr85). The kinetics of activation were not affected by removal of the hemopexin-like C-terminal domain. The specific activities of both collagenase-3 and Delta249-451 collagenase-3 were found to be similar using two quenched fluorescent substrates, but Delta249-451 collagenase-3 failed to cleave native triple helical collagens (types I and II) into characteristic one- and three-quarter fragments. It was noted, however, that the beta1,2(I) chains of type I collagen were susceptible to Delta249-451 collagenase-3, which indicates that the catalytic domain displays telopeptidase activity, thereby generating alpha1,2(I) chains that are slightly shorter than those in native type I collagen. It can be concluded that the C-terminal domain is only essential for the triple helicase activity of collagenase-3. Binding of procollagenase-3 and active collagenase-3 to type I collagen is mediated by the C-terminal domain. Both collagenase-3 and Delta249-451 collagenase-3 hydrolyzed the large tenascin C isoform, fibronectin, recombinant fibronectin fragments, and type IV, IX, X, and XIV collagens; thus, these events were independent from C-terminal domain interactions. In contrast, the minor cartilage type XI collagen was resistant to cleavage. Kinetic analysis of the mechanism of inhibition of wild-type and Delta249-451 collagenase-3 by wild-type and mutant tissue inhibitors of metalloproteinase (TIMPs) revealed that the association rates for complex formation were influenced by both N- and C-terminal domain interactions. The C-terminal domain of wild-type collagenase-3 promoted increased association rates with the full-length inhibitors TIMP-1 and TIMP-3 and the hybrid N.TIMP-2/C.TIMP-1 by a factor of up to 33. In contrast, the association rates for complex formation with TIMP-2 and N.TIMP-1/C.TIMP-2 were only marginally affected by C-terminal domain interactions.

Amino Acid Sequence↗
PubMed1997

Lung volume reduction surgery at a community hospital: program development and outcomes.

STUDY OBJECTIVES: Description of the development and results of a program in lung volume reduction surgery (LVRS) at a community hospital. DESIGN: Prospective data collection. SETTING: A 320-bed community hospital. PATIENTS: Fifty-five patients consecutively discharged from the hospital following LVRS. The mean preoperative FEV1 averaged 28% (+/-8%) of predicted values, while the preoperative PaCO2 averaged 49 mm Hg (+/-11.5 mm Hg). Forty-eight patients completed a preoperative conditioning regimen and underwent the procedure on an elective basis. Seven patients underwent the procedure during a hospital admission for a COPD exacerbation. Eight patients required mechanical ventilation preoperatively, including three who had required long-term mechanical ventilatory support. RESULTS: Three patients (5%) died in the hospital following surgery. One patient developed chronic ventilator dependence. All three of the patients who required long-term mechanical ventilation preoperatively were weaned from the ventilator and returned home. Follow-up pulmonary function testing is available for 42 patients 3 months after surgery, and for 20 patients 6 months after the operation. At 3 months, the mean FEV1 improved 0.19 L (p=0.0002), the mean improvement for FVC was 0.37 L (p=0.0001), and the mean drop in residual volume was 0.97 L (p=0.0001). Similar changes are seen at 6 months. Highly significant improvements were also seen in quality of life measurements and exercise performance. The benefits of surgical treatment of emphysema seemed similar in both elective and urgent groups. CONCLUSIONS: LVRS can be done safely and effectively at a community hospital, with significant improvement in pulmonary function and quality of life.

Adult↗