Biomedical subjects

H Shannon

Publications and source records attributed to H Shannon.

At least 19 recordsLinked to original sources

PubMed2005

Opportunities and challenges for collaboration in research and practice in injury prevention across work and other settings.

Even though injuries at work and in other settings (homes, roads, etc) commonly involve similar mechanisms, research and prevention are usually specific to each setting. The potential benefits of addressing common features of injury prevention are noted across setting, while some unique features of the work environment are acknowledged. Further integration is recommended using the following approaches: (i) organization of research questions by injury mechanisms and (ii) support of comparative research across settings by funding agencies.

Humans↗

PubMed2004

Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice.

RATIONALE: (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) is a potent and selective agonist for group II metabotropic glutamate (mGlu2 and mGlu3) receptors, with anxiolytic-like activity in animal and human models, and efficacy in anxiety patients. However, the lack of mGlu2 or mGlu3 receptor specific agonists has prevented in vivo characterization of individual functions of these two receptors in mediating the anxiolytic-like effects of LY354740. OBJECTIVE: To utilize mGlu2 receptor and mGlu3 receptor knockout animals and the mGlu2/3 selective antagonist (2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl)glycine (LY341495) to further investigate the roles of mGlu2 and mGlu3 receptors in mediating the anxiolytic-like actions of LY354740 in a mouse model of anxiety [elevated plus maze (EPM) test]. METHODS: To confirm that mGlu2/3 receptors are responsible for anxiolytic-like activity in the EPM under these test conditions, mice were pretreated with LY341495 at 30 min prior to s.c. administered LY354740. Subsequently, saline vehicle or LY354740 was administered (s.c.) 30 min before the EPM testing in wild-type, mGlu2 receptor knockout, and mGlu3 receptor knockout mice. RESULTS: LY354740 reduced in a dose-dependent manner anxiety-related behavior on the EPM in wild-type mice with a maximally effective dose of 10--20 mg/kg s.c. Pretreatment with LY341495 potently prevented the anxiolytic-like effects of LY354740 (20 mg/kg, s.c.) in mice. Although the mGlu2 receptor knockout and mGlu3 receptor knockout mice were grossly normal, the anxiolytic-like activity of LY354740 (20 mg/kg, s.c.) was not evident in either mGlu2 or mGlu3 receptor knockout mice, when compared to their wild-type controls. CONCLUSIONS: The activation of both mGlu2 and mGlu3 receptors by LY354740 appears to be required for anxiolytic-like activity in the EPM test in mice. These studies serve as a foundation for additional studies on underlying circuits, brain structures, and receptor subtypes involved in the anxiolytic-like actions of mGlu receptor active agents, and the design of future drugs for anxiety disorders in humans.

Amino Acids↗

PubMed2004

A novel approach to a patient with Crohn disease and a high stoma output: a missed opportunity?

The development of stricturing or penetrating behaviour in Crohn disease is influenced by disease location, clinical activity of the disease and smoking habit. The management of inflammatory bowel disease remains unsatisfactory, and the influence of current therapies--immunosuppressants, and especially the novel biological treatment now commonly used in Crohn disease--remains largely unknown. A relatively smaller number of patients receive dietary treatment as well. Physicians' scepticism, under-resourced dietetic departments and patient compliance are the main concerns in considering enteral nutrition. The management of high stomal output in Crohn disease is even more challenging. We report a case of active Crohn disease with high stoma output treated successfully solely with enteral feeding without the need for surgical intervention or administration of potent pharmacotherapy.

Adult↗

PubMed2001

Generation and pharmacological analysis of M2 and M4 muscarinic receptor knockout mice.

Muscarinic acetylcholine receptors (M1-M5) play important roles in the modulation of many key functions of the central and peripheral nervous system. To explore the physiological roles of the two Gi-coupled muscarinic receptors, we disrupted the M2 and M4 receptor genes in mice by using a gene targeting strategy. Pharmacological and behavioral analysis of the resulting mutant mice showed that the M2 receptor subtype is critically involved in mediating three of the most striking central muscarinic effects, tremor, hypothermia, and analgesia. These studies also indicated that M4 receptors are not critically involved in these central muscarinic responses. However, M4 receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses following drug-induced activation of D1 dopamine receptors. This observation is consistent with the concept that M4 receptors exert inhibitory control over D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are known to be coexpressed. These findings emphasize the usefulness of gene targeting approaches to shed light on the physiological and pathophysiological roles of the individual muscarinic receptor subtypes.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2000

Central muscarinic inhibition of lower urinary tract nociception.

Previous studies indicate cholinergic systems suppress somatic nociception. The present studies determined if cholinergic muscarinic systems suppress visceral nociception, specifically, chemical irritation of the lower urinary tract. Bladders of urethane-anesthetized rats were cannulated through the dome for continuous-infusion cystometrogram recordings. EMG electrodes recorded anal sphincter activity. Infusion of 0.5% acetic acid into the bladder to produce irritation increased bladder activity and anal sphincter activity (i.e. activation of a nociceptive vesicoanal reflex). Oxotremorine (a muscarinic agonist) and (-)butylthio[2.2.2] (a mixed muscarinic agonist/antagonist) dose-dependently inhibited vesicoanal reflex activity. This inhibition was antagonized by atropine (a centrally active muscarinic antagonist) but not by scopolamine methylbromide (a peripherally restricted muscarinic antagonist). Physostigmine (a centrally active cholinesterase inhibitor) also dose-dependently inhibited vesicoanal reflex activity in an atropine-sensitive manner, while neostigmine (a peripherally restricted cholinesterase inhibitor) did not. Atropine alone (i.e. administered without prior administration of muscarinic agonist or cholinesterase inhibitor) produced robust but transient (15 min) increases in vesicoanal activity and bladder activity under conditions of acetic acid infusion into the bladder. Under conditions of saline infusion into the bladder, atropine had the opposite effect on bladder activity (i.e. inhibition). These studies indicate that an endogenous cholinergic muscarinic system can be activated by lower urinary tract irritation to suppress visceral nociception through central nervous system mechanisms.

Acetylcholine↗

PubMed2000

An examination of the role of clinical psychology in meeting the needs of young disabled clients and their families/carers.

This paper examines the views of clients with a physical disability, general practitioners and staff working in health and social work physical disability services about the needs of young disabled people. The most common area of disability seen by GPs was respiratory, followed by cardiac problems and stroke. With the exception of cardiac patients a third to over half of GPs felt that the needs of the identified groups were not being adequately met, in particular the needs of individuals with progressive neuromuscular problems. Over a quarter of clients felt that their needs were not being adequately met. Ninety-five percent of GPs and 100% of staff identified psychological needs of clients. For clients themselves, physical needs are ranked highest, with over 33 percent identifying psychological problems, 50 percent neuropsychological problems and 25 percent psychosexual difficulties as priority needs. In relation to carers, over 90 percent of GPs, 100% of staff and 50 percent of clients highlighted psychological needs. The majority of participants felt that clinical psychology had an important role to play in physical disability services. There was broad agreement on the areas of need which psychology would be seen to address. These were psychological needs, behavioural problems, neuropsychological problems and relationship/psychosexual difficulties. A high percentage of both staff and GPs also saw a role for clinical psychology in meeting the psychological, relationship and psychosexual needs of carers.

Attitude of Health Personnel↗

PubMed1999

Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice.

Muscarinic acetylcholine receptors (M(1)-M(5)) regulate many key functions of the central and peripheral nervous system. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of the individual muscarinic receptor subtypes remain to be elucidated. Interestingly, the M(4) receptor subtype is expressed abundantly in the striatum and various other forebrain regions. To study its potential role in the regulation of locomotor activity and other central functions, we used gene-targeting technology to create mice that lack functional M(4) receptors. Pharmacologic analysis of M(4) receptor-deficient mice indicated that M(4) receptors are not required for muscarinic receptor-mediated analgesia, tremor, hypothermia, and salivation. Strikingly, M(4) receptor-deficient mice showed an increase in basal locomotor activity and greatly enhanced locomotor responses (as compared with their wild-type littermates) after activation of D1 dopamine receptors. These results indicate that M(4) receptors exert inhibitory control on D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are coexpressed at high levels. Our findings offer new perspectives for the treatment of Parkinson's disease and other movement disorders that are characterized by an imbalance between muscarinic cholinergic and dopaminergic neurotransmission.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1999

Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice.

Members of the muscarinic acetylcholine receptor family (M1-M5) are known to be involved in a great number of important central and peripheral physiological and pathophysiological processes. Because of the overlapping expression patterns of the M1-M5 muscarinic receptor subtypes and the lack of ligands endowed with sufficient subtype selectivity, the precise physiological functions of the individual receptor subtypes remain to be elucidated. To explore the physiological roles of the M2 muscarinic receptor, we have generated mice lacking functional M2 receptors by using targeted mutagenesis in mouse embryonic stem cells. The resulting mutant mice were analyzed in several behavioral and pharmacologic tests. These studies showed that the M2 muscarinic receptor subtype, besides its well documented involvement in the regulation of heart rate, plays a key role in mediating muscarinic receptor-dependent movement and temperature control as well as antinociceptive responses, three of the most prominent central muscarinic effects. These results offer a rational basis for the development of novel muscarinic drugs.

Analgesia↗

PubMed1999

Performance of open-fronted microbiological safety cabinets: the value of operator protection tests during routine servicing.

The performance of class I and II microbiological safety cabinets over 7 years, employed in a force-ventilated containment level 3 (CL-3) laboratory, is described. Operator Protection (OP) provided by the cabinets, assessed by still and latterly limited 'in-use' KI-Discus tests, showed no overall deterioration during the review period. Comparisons show that a selected class II unit, but not a second, and a new class II MSC in a recently commissioned, similar CL-3 facility, provide the same order of OP as a class I cabinet. From the experiences described, it is strongly recommended that OP tests (OPTs) should be part of the routine servicing regime to ensure that cabinets meet required performance levels, and additionally to allow detection and rectification of poor containment, particularly where induced by environmental factors. The value of OPTs is discussed with reference to certain national standards.

Containment of Biohazards↗

PubMed1999

Are risk factors for atherothrombotic disease associated with back pain sickness absence? The Whitehall II Study.

STUDY OBJECTIVE: To explore the previously stated hypothesis that risk factors for atherothrombotic disease are associated with back pain. DESIGN: Prospective (mean of four years of follow up) and retrospective analyses using two main outcome measures: (a) short (< or = 7 days) and long (> 7 days) spells of sickness absence because of back pain reported separately in men and women; (b) consistency of effect across the resulting four duration of spell and sex cells. SETTING: 14 civil service departments in London. PARTICIPANTS: 3506 male and 1380 female white office-based civil servants, aged 35-55 years at baseline. MAIN RESULTS: In age adjusted models, low apo AI was associated with back pain across all four duration-sex cells and smoking was associated across three cells. Six factors were associated with back pain in two cells: low exercise and high BMI, waist-hip ratio, triglycerides, insulin and Lp(a). On full adjustment (for age, BMI, employment grade and back pain at baseline), each of these factors retained a statistically significant effect in at least one duration-sex cell. Triglycerides were associated with short and long spells of sickness absence because of back pain in men in fully adjusted models with rate ratios (95% confidence intervals) of 1.53 (1.1, 2.1) and 1.75 (1.0, 3.2) respectively. There was little or no evidence of association in age adjusted models with: fibrinogen, glucose tolerance, total cholesterol, apoB, hypertension, factor VII, von Willebrand factor, electrocardiographic evidence of coronary heart disease and reported angina. CONCLUSIONS: In this population of office workers, only modest support was found for an atherothrombotic component to back pain sickness absence. However, the young age of participants at baseline and the lack of distinction between different types of back pain are likely to bias the findings toward null. Further research is required to ascertain whether a population sub-group of atherothrombotic back pain can be identified.

Absenteeism↗

PubMed1998

Preventing disability from work-related low-back pain. New evidence gives new hope--if we can just get all the players onside.

Despite the publication in the mid-1990s of comprehensive practice guidelines for the management of acute low-back pain, both in the United States and elsewhere, this ubiquitous health problem continues to be the main cause of workers' compensation claims in much of the Western world. This paper represents a synthesis of the intervention studies published in the last 4 years and is based on a new approach to categorizing these studies that emphasizes the stage or phase of back pain at the time of intervention and the site or agent of the intervention. Current thinking suggests that medical management in the first 3-4 weeks after the onset of pain should be generally conservative. Several studies of rather heterogeneous interventions focusing on return to work and implemented in the subacute stage (3-4 to 12 weeks after the onset of pain) have shown important reductions in time lost from work (by 30% to 50%). There is substantial evidence indicating that employers who promptly offer appropriately modified duties can reduce time lost per episode of back pain by at least 30%, with frequent spin-off effects on the incidence of new back-pain claims as well. Finally, newer studies of guidelines-based approaches to back pain in the workplace suggest that a combination of all these approaches, in a coordinated workplace-linked care system, can achieve a reduction of 50% in time lost due to back pain, at no extra cost and, in some settings, with significant savings.

Absenteeism↗

PubMed1998

Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells.

Complementary DNA (cDNA) encoding human beta-amyloid precursor protein familial Alzheimer's disease (FAD) Swedish mutant (beta APPSM) form was cloned into a mammalian expression vector (PK255) containing the CMV promoter. The vector was transfected into Chinese hamster ovary cells containing human muscarinic m1 receptors (CHO-m1), and clonal cells stably expressing beta APPSM were isolated. The effects of m1-receptor activation by the selective m1 agonist xanomeline and the non-selective muscarinic agonist carbachol on processing of beta APPSM to release soluble APP (APPs) and beta-amyloid peptide (A beta) were compared. Xanomeline stimulated APP release with a potency 1000-fold greater than that observed for carbachol. Concentrations of carbachol and xanomeline producing maximal effects on APPs release reduced the secretion of A beta by 28 and 46%, respectively. These results extend previous studies with xanomeline and suggest that cholinergic replacement therapy for Alzheimer's disease may reduce amyloid deposition.

Alzheimer Disease↗

PubMed1998

Determinants of disability after a work related musculetal injury.

OBJECTIVE: Musculoskeletal soft tissue injuries consume considerable resources in personal suffering, medical care, work absenteeism, and compensation benefits. Our aim was to determine specific clinical and behavioral factors that prognostically influence return to work following musculoskeletal work related injuries. METHODS: A longitudinal cohort study was conducted on 148 randomly selected workers who had not returned to work in 3 months following musculoskeletal soft tissue injury. The cohort was identified from the files of the Workers' Compensation Board of Ontario, Canada. The workers were interviewed and assessed at 3, 9, 15, and 21 months after injury. The WHO Classification of Impairment, Disabilities and Handicap was used as the conceptual framework. The analysis employed a proportional hazards regression model with allowance for time dependent covariates. RESULTS: The rate of return to work for men was 1.5 times that for women, and 20% less for every 10 year increase in age. Controlling for sex and age, psychological distress and functional disability were associated with a slower rate of return to work. The rate of return to work for workers who were provided with modified jobs was 2 times higher than for those with no such accommodation in employment. CONCLUSION: The negative effect of psychological distress and functional disability on return to work rates must be considered in the design and delivery of rehabilitation programming for workers with musculoskeletal soft tissue injuries. The employer's provision of a "modified job" is important in the prevention of continued disability.

Adult↗

PubMed1997

Assessment of physical work load in epidemiologic studies: common measurement metrics for exposure assessment.

There are many possible means of determining exposure ranging from self-reports of physical exposure to measures of muscle activations and estimated spinal loads. In epidemiologic studies, issues of validity make instrumented measures preferable, however issues of cost and practicability tend to force investigators to less costly but less valid and less reliable measures of exposure, such as self-report questionnaires. This paper presents a method by which estimates of exposure from self-report questionnaires, expert observers, work sampling, video analysis and electromyograms can be reported in a common metric, Newtons of force on a tissue, and show, as an example of its application, estimation of spinal compression on auto workers. A common metric allows a flexible approach to selection of measurement methods in occupational settings: no matter which instrument is used the results can be combined to provide an overall picture of exposure. This approach to exposure assessment for the low back allows for comparability across studies and settings.

Automobiles↗

PubMed1997

Behavioral pharmacology of olanzapine: a novel antipsychotic drug.

BACKGROUND: In this paper, we review the behavioral pharmacology of olanzapine and compare it to its in vitro profile and to clozapine and a number of other antipsychotic agents, and we estimate the likelihood that olanzapine will be an effective and safe antipsychotic with fewer side effects. METHOD: Since there is no model of schizophrenia, per se, a battery of behavioral assays was used. RESULTS: Behavioral assays confirmed the in vitro results that olanzapine interacts with dopamine, serotonin, and muscarinic receptor subtypes. Moreover, olanzapine appears to have a clozapine-like atypical profile based on (1) mesolimbic selectivity, (2) blocking 5-HT receptors at a lower dose than dopamine receptors, and (3) inhibiting the conditioned avoidance response (indicative of antipsychotic efficacy) at doses that are lower than those required to induce catalepsy (indicative of extrapyramidal side effects). No only is this profile similar to that of clozapine, but olanzapine has other similarities: olanzapine substitutes for clozapine in a drug discrimination assay; like clozapine and unlike "typical" antipsychotics, olanzapine increases responding in a conflict procedure; and olanzapine, like clozapine, reverses changes induced by antagonists of the NMDA receptor. CONCLUSION: On the basis of these findings, we predict that olanzapine will be an efficacious antipsychotic, active against both positive and negative symptoms, while producing fewer extrapyramidal symptoms than existing treatments.

Animals↗

PubMed1996

Effects of electroconvulsive therapy on peripheral adrenoceptors, plasma, noradrenaline, MHPG and cortisol in depressed patients.

BACKGROUND: The mechanism of the antidepressant action of electroconvulsive therapy (ECT) remains unknown. Based on previous work with antidepressant drugs and their effects on the noradrenergic system, we undertook this study to further determine the effects of ECT on selected indices of peripheral adrenoceptor function in depressed patients. METHODS: Binding parameters (Bmax and Kd) of platelet alpha 2- and leukocyte beta 2-adrenoceptors, plasma noradrenaline (NA), 3-methoxy-4-hydroxy-phenylglycol (MHPG) and cortisol levels were determined in 18 patients, prior to treatment and 14 days after the last of a series of ECTs, and compared with samples obtained from 18 matched control subjects. RESULTS: Platelet alpha 2-adrenoceptor sites were significantly elevated in untreated patients compared with controls (P < 0.03), but leukocyte beta 2-adrenoceptor numbers did not differ. Treatment with ECT led to a significant reduction in platelet alpha 2-adrenoceptor numbers, whereas leukocyte beta 2-adrenoceptor densities increased. Pre-ECT plasma NA, MHPG, and cortisol levels were elevated in patients, compared with controls, and decreased following ECT, but these differences were not statistically significant. Post-ECT plasma NA and beta 2-adrenoceptor numbers were significantly, negatively correlated (P < 0.05). CONCLUSIONS: These results suggest that platelet alpha 2-adrenoceptors are supersensitive in depressed patients and treatment with ECT results in down-regulation of these receptors, which may be interpreted as a primary therapeutic, "normalising' effect. The post-ECT changes in leukocyte beta 2-adrenoceptors are probably only secondary to the lower circulating plasma NA levels.

Adult↗

PubMed1995

Basic statistics for clinicians: 4. Correlation and regression.

Correlation and regression help us to understand the relation between variables and to predict patients' status in regard to a particular variable of interest. Correlation examines the strength of the relation between two variables, neither of which is considered the variable one is trying to predict (the target variable). Regression analysis examines the ability of one or more factors, called independent variables, to predict a patient's status in regard to the target or dependent variable. Independent and dependent variables may be continuous (taking a wide range of values) or binary (dichotomous, yielding yes-or-no results). Regression models can be used to construct clinical prediction rules that help to guide clinical decisions. In considering regression and correlation, clinicians should pay more attention to the magnitude of the correlation or the predictive power of the regression than to whether the relation is statistically significant.

Data Interpretation, Statistical↗

PubMed1995

Basic statistics for clinicians: 3. Assessing the effects of treatment: measures of association.

In the third of a series of four articles the authors show the calculation of measures of association and discuss their usefulness in clinical decision making. From the rates of death or other "events" in experimental and control groups in a clinical trial, we can calculate the relative risk (RR) of the event after the experimental treatment, expressed as a percentage of the risk without such treatment. The absolute risk reduction (ARR) is the difference in the risk of an event between the groups. The relative risk reduction is the percentage of the baseline risk (the risk of an event in the control patients) removed as a result of therapy. The odds ratio (OR), which is the measure of choice in case-control studies, gives the ratio of the odds of an event in the experimental group to those in the control group. The OR and the RR provide limited information in reporting the results of prospective trials because they do not reflect changes in the baseline risk. The ARR and the number needed to treat, which tells the clinician how many patients need to be treated to prevent one event, reflect both the baseline risk and the relative risk reduction. If the timing of events is important--to determine whether treatment extends life, for example--survival curves are used to show when events occur over time.

Case-Control Studies↗