PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (153)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity 
Translational Psychiatry  2014;4(3):e369-.
Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.
doi:10.1038/tp.2013.131
PMCID: PMC3966037  PMID: 24618688
attentional bias; cocaine; cue reactivity; 5-HT2C receptor; prefrontal cortex; serotonin
2.  Blockade of the serotonin 5-HT2A receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model 
Behavioral neuroscience  2009;123(2):10.1037/a0014592.
The serotonin 5-HT2A receptor (5-HT2AR) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT2A receptor (5-HT2AR) antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in naïve, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT2AR antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001 – 0.8 mg/kg, i.p.) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (“high extinction” responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT2AR attenuates the incentive-motivational effects of cocaine-paired cues, particularly in “high extinction” responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse.
doi:10.1037/a0014592
PMCID: PMC3830454  PMID: 19331461
Cocaine self-administration; Cue-induced reinstatement; Extinction; M100907; 5-HT2AR antagonist
4.  Fatal PML associated with efalizumab therapy 
Neurology  2012;78(7):458-467.
Objectives:
Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders.
Methods:
We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLβ2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients.
Results:
Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE.
Conclusions:
From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.
doi:10.1212/WNL.0b013e3182478d4b
PMCID: PMC3280052  PMID: 22302546
5.  Investigation of Occult Hip Fractures: The Use of CT and MRI 
The Scientific World Journal  2013;2013:830319.
Aim. At present there is no data looking at modern multislice computerised tomography (CT) in the investigation of occult hip fracture. The aim of this study was to retrospectively compare the reports of patients sent for magnetic resonance imaging (MRI) or CT with negative radiographs and a clinical suspicion of a fractured neck of femur. Methods. All patients presenting to the hospital with a clinical suspicion of a hip fracture but initial negative radiographs over a three-year period were included. Patients were either investigated with an MRI scan or CT scan. The presence of a fracture, the requirement for surgery, and any further requirement for imaging were recorded. Results. Over three years 92 patients were included of which 61 were referred for a CT and 31 for an MRI. Thirty-four patients were found to have a fracture. Of these, MRI picked up a fracture in 36% and CT in 38% of referrals. Discussion. Up to 10% of proximal femur fractures may be missed on initial radiographs. Current guidelines state patients should be offered MRI if hip fracture is suspected despite negative hip radiographs. Our findings show that modern multislice CT may be comparable with MRI for detecting occult fracture.
doi:10.1155/2013/830319
PMCID: PMC3582164  PMID: 23476147
6.  Hip precautions after hemiarthroplasty: what is happening in the UK and at what cost? 
INTRODUCTION
The aim of this study was to observe current practice of the use of hip precautions following hemiarthroplasty for hip fractures in England and to audit the cost of hip precautions in this patient group.
METHODS
A telephone review was undertaken of all units identified by the National Hip Fracture Database as receiving centres for hip fractures across England to ascertain current practice in the use of hip precautions. A prospective audit of occupational therapy (OT) practice including the cost of equipment provision and OT time was carried out locally.
RESULTS
All 174 units in England were successfully contacted. Practice varied between centres but hip precautions were in use at 78% of centres. Prior to stopping hip precautions at the local hospital, we audited the costs associated with their use. Mean equipment costs per patient decreased by £12 (from £49 to £37, range: £0–£83) and mean OT time per patient decreased by 1.5 hours (from 8 hours to 6.5 hours, range: 1–22 hours) following removal of hip precaution guidelines. A mean of 0.25 days' discharge delay (range: 0–4 days) due to equipment provision was identified prior to removing hip precautions with no discharge delay following.
CONCLUSIONS
This study has highlighted the variation in practice across the country and inconsistency with the advice published by the British Orthopaedic Association and British Geriatrics Society in the ‘Blue Book’ (The Care of Patients with Fragility Fracture). Hip precautions are unnecessary after hemiarthroplasty, cost money both in therapist time and equipment provision and increase the length of hospital stay. Nevertheless, they continue to be used by three-quarters of trauma hospitals in England.
doi:10.1308/003588411X581376
PMCID: PMC3365459
Femoral neck fractures; Hip fractures; Dislocations; Occupational therapy; Physical therapy; Rehabilitation
7.  Using an Automated Recruitment Process to Generate an Unbiased Study Sample of Multiple Sclerosis Patients 
Abstract
The objective of this study was to test the efficiency of an automated recruitment methodology developed as a component of a practical controlled trial to assess the benefits of a Web-based personal health site to guide self-management of multiple sclerosis symptoms called Mellen Center Care On-line. We describe the study's automated recruitment methodology using clinical and administrative databases and assess the comparability between subjects who completed informed consent (IC) forms, and individuals who were invited to participate but did not reply, designated as patient nonresponders (PNR). The IC and PNR groups were compared on demographics, number of physician or advanced practice nurse/physician assistant visits during the 12 months prior to the initial invitation, and level of disability as measured by the Charlson Comorbidity Index (CCI). Out of a total dynamic potential pool of 2,421 patients, 2,041 had been invited to participate, 309 had become ineligible to participate during the study, and 71 individuals remained in the pool at the end of recruitment. The IC group had a slightly greater proportion of females. Both groups were predominantly white with comparable marital status. The groups had comparable mean household income, education level, and commercial insurance. The computed mean CCI was similar between the groups. The only significant difference was that the PNR group had fewer clinic visits in the preceding 12 months. The subjects were highly representative of the target population, indicating that there was little bias in our selection process despite a constantly changing pool of eligible individuals.
doi:10.1089/tmj.2009.0078
PMCID: PMC2998972  PMID: 20064056
e-health; telehealth; multiple sclerosis; self-management; Mellen Center Care On-line
10.  Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function 
Neurology  2009;72(5):402-409.
Background:
Accelerating the clearance of therapeutic monoclonal antibodies (mAbs) from the body may be useful to address uncommon but serious complications from treatment, such as progressive multifocal leukoencephalopathy (PML). Treatment of PML requires immune reconstitution. Plasma exchange (PLEX) may accelerate mAb clearance, restoring the function of inhibited proteins and increasing the number or function of leukocytes entering the CNS. We evaluated the efficacy of PLEX in accelerating natalizumab (a therapy for multiple sclerosis [MS] and Crohn disease) clearance and α4-integrin desaturation. Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood–brain barrier (ivBBB).
Methods:
Twelve patients with MS receiving natalizumab underwent three 1.5-volume PLEX sessions over 5 or 8 days. Natalizumab concentrations and α4-integrin saturation were assessed daily throughout PLEX and three times over the subsequent 2 weeks, comparing results with the same patients the previous month. Peripheral blood mononuclear cell (PBMC) migration (induced by the chemokine CCL2) across an ivBBB was assessed in a subset of six patients with and without PLEX.
Results:
Serum natalizumab concentrations were reduced by a mean of 92% from baseline to 1 week after three PLEX sessions (p < 0.001). Although average α4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 μg/mL. PBMC transmigratory capacity increased 2.2-fold after PLEX (p < 0.006).
Conclusions:
Plasma exchange (PLEX) accelerated clearance of natalizumab, and at natalizumab concentrations below 1 μg/mL, desaturation of α4-integrin was observed. Also, CCL2-induced leukocyte transmigration across an in vitro blood–brain barrier was increased after PLEX. Therefore, PLEX may be effective in restoring immune effector function in natalizumab-treated patients.
GLOSSARY
= adverse event;
= blood–brain barrier;
= body weight;
= Expanded Disability Status Scale;
= human IgG4 monoclonal antibody conjugated with phycoerythrin;
= immunoglobulin;
= in vitro blood–brain barrier;
= monoclonal antibody;
= mean fluorescence intensity;
= multiple sclerosis;
= peripheral blood mononuclear cell;
= plasma exchange;
= progressive multifocal leukoencephalopathy;
= total drug load;
= volume of distribution of the central compartment;
= volume of distribution.
doi:10.1212/01.wnl.0000341766.59028.9d
PMCID: PMC2677532  PMID: 19188571
11.  Reliability and validity of measures taken during the Chester step test to predict aerobic power and to prescribe aerobic exercise 
Objectives: To evaluate the reliability and validity of measures taken during the Chester step test (CST) used to predict VO2max and prescribe subsequent exercise.
Methods: The CST was performed twice on separate days by 7 males and 6 females aged 22.4 (SD 4.6) years. Heart rate (HR), ratings of perceived exertion (RPE), and oxygen uptake (VO2) were measured at each stage of the CST.
Results: RPE, HR, and actual VO2 were the same at each stage for both trials but each of these measures was significantly different between CST stages (p<0.0005). Intertrial bias ±95% limits of agreement (95% LoA) of HR reached acceptable limits at CST stage IV (-2±10 beats/min) and for RPE at stages III (0.2±1.4) and IV (0.5±1.9). Age estimated HRmax significantly overestimated actual HRmax of 5 beats/min (p = 0.016) and the 95% LoA showed that this error could range from an underestimation of 17 beats/min to an overestimation of 7 beats/min. Estimated versus actual VO2 at each CST stage during both trials showed errors ranging between 11% and 19%. Trial 1 underestimated actual VO2max by 2.8 ml/kg/min (p = 0.006) and trial 2 by 1.6 ml/kg/min (not significant). The intertrial agreement in predicted VO2max was relatively narrow with a bias ±95% LoA of -0.8±3.7 ml/kg/min. The RPE and %HRmax (actual) correlation improved with a second trial. At all CST stages in trial 2 RPE:%HRmax coefficients were significant with the highest correlations at CST stages III (r = 0.78) and IV (r = 0.84).
Conclusion: CST VO2max prediction validity is questioned but the CST is reliable on a test-retest basis. VO2max prediction error is due more to VO2 estimation error at each CST stage compared with error in age estimated HRmax. The HR/RPE relation at >50% VO2max reliably represents the recommended intensity for developing cardiorespiratory fitness, but only when a practice trial of the CST is first performed.
doi:10.1136/bjsm.2003.005389
PMCID: PMC1724781  PMID: 15039259
13.  The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C 
Gut  2002;50(2):248-252.
Background: Chronic hepatitis C virus (HCV) infection is frequently associated with elevated markers of iron stores. Recessively inherited mutations in the HFE gene are responsible for iron accumulation in most cases of hereditary haemochromatosis and may have a role in HCV infection. They may also be associated with progressive liver fibrosis although this remains controversial.
Aims: To assess the prevalence of HFE mutations in Scottish HCV infected patients and to explore the effect of the carrier state on serum and liver iron stores, and the severity of liver disease.
Patients: A total of 164 patients with antibodies to HCV who underwent liver biopsy were assessed prospectively.
Methods: Each patient was screened for HFE mutations (Cys282Tyr and His63Asp). Iron markers were assessed in serum (ferritin, transferrin saturation) and on liver biopsy (stainable iron, liver iron concentration (LIC) and hepatic iron index).
Results: There were 67 (41%, 26 Cys282Tyr, 33 His63Asp, eight compound) heterozygotes. Forty four (28%) patients had elevated serum iron markers, 24 (15%) had stainable liver iron, and five (3%) had elevated LICs. Carriage of HFE mutations was not associated with any clinical, biochemical, virological, or pathological features, including accumulation of liver iron. Elevated serum iron markers were associated with male sex, increased alcohol consumption, and increased liver inflammation and fibrosis. Patients with elevated LICs were older, acquired HCV infection earlier, and had more liver inflammation.
Conclusions: Patients with chronic HCV infection frequently have elevated serum iron markers although elevated LICs are uncommon. Elevated serum iron studies and LICs occur in patients with more severe liver disease. Carriage of HFE mutations, although frequently observed in these HCV infected patients, does not have a role in the accumulation of iron or the progression of liver disease in HCV infection.
PMCID: PMC1773101  PMID: 11788568
hepatitis C virus; HFE mutations; iron; hepatic iron index
14.  Responses of butterflies to twentieth century climate warming: implications for future ranges. 
We analyse distribution records for 51 British butterfly species to investigate altitudinal and latitudinal responses to twentieth century climate warming. Species with northern and/or montane distributions have disappeared from low elevation sites and colonized sites at higher elevations during the twentieth century, consistent with a climate explanation. We found no evidence for a systematic shift northwards across all species, even though 11 out of 46 southerly distributed species have expanded in the northern part of their distributions. For a subset of 35 species, we model the role of climate in limiting current European distributions and predict potential future distributions for the period 2070-2099. Most northerly distributed species will have little opportunity to expand northwards and will disappear from areas in the south, resulting in reduced range sizes. Southerly distributed species will have the potential to shift northwards, resulting in similar or increased range sizes. However, 30 out of 35 study species have failed to track recent climate changes because of lack of suitable habitat, so we revised our estimates accordingly for these species and predicted 65% and 24% declines in range sizes for northern and southern species, respectively. These revised estimates are likely to be more realistic predictions of future butterfly range sizes.
doi:10.1098/rspb.2002.2134
PMCID: PMC1691143  PMID: 12396492
16.  Impact on medical students of incorporating GALS screen teaching into the medical school curriculum 
Annals of the Rheumatic Diseases  2000;59(9):668-671.
OBJECTIVE—To assess the impact of GALS locomotor screen teaching to all 3rd year medical students, at a British medical school.
METHOD—In 1998, during their 3rd year, all students were taught the GALS screen in a one hour small group session. At the end of this year, 242 medical students undertook a 16 station Objective Structured Clinical Examination (OSCE). One station assessed the locomotor screening examination, while six stations assessed the examination of other systems. The students completed a five point likert scale, self rating their confidence in each of the skills assessed at this time. Pre-registration house officers (PRHOs) at two London hospitals were invited to undertake the same OSCE and self rating.
RESULTS—The students performed the locomotor screen well (mean station score 80%). Three body systems were examined better and one significantly worse (p<0.05). 22/40 PRHOs undertook the assessment. Compared with the students they examined the locomotor system (mean score 20%, p<0.001), but not other systems, less well. The PRHOs felt less confident (p<0.05) examining the locomotor system (mean rating 3.6/5) than the other systems (mean rating 4.6/5), while no significant difference in confidence ratings was seen for the students.
CONCLUSION—Students who are taught the GALS screen as part of the curriculum, perform it well in an end of year OSCE, as confidently as other systems, and to a higher standard than PRHOs. Further study is required to determine whether this benefit persists, overcoming the poor skills and confidence in locomotor examination of existing PRHOs, not previously taught a GALS screen.


doi:10.1136/ard.59.9.668
PMCID: PMC1753279  PMID: 10976078
17.  How should we be teaching our undergraduates? 
Annals of the Rheumatic Diseases  2000;59(9):662-667.
doi:10.1136/ard.59.9.662
PMCID: PMC1753256  PMID: 10976077
18.  Environmental sensitivities: prevalence of major symptoms in a referral center: the Nova Scotia Environmental Sensitivities Research Center Study. 
Environmental Health Perspectives  2001;109(2):161-165.
Although the phenomenon of environmental sensitivities (ES) has no clear etiology nor well-accepted pathophysiology, affected individuals experience symptoms that cause varying levels of dysfunction. Through a dedicated, government-funded research and treatment center, a detailed questionnaire covering 217 symptoms in 13 systems was mailed in 1997-1998 to 812 individuals referred to the center by physicians. A total of 385 (47%) questionnaires were returned, and data were analyzed on 351 individuals. Participants tended to be women (80%), middle-aged individuals (37% age 40-49 years), and those in higher educational groups (28% completed university), but there was wide variation in demographic variables. General symptoms such as difficulty concentrating, fatigue, forgetfulness, and irritability dominated the overall prevalence of symptoms since the start of their illness. Those related to irritation such as sneezing, itchy or burning eyes, and hoarseness or loss of voice were more common after exposure to environmental irritants. Ranking of symptoms using severity scores was consistent between men and women. Overall scores were higher in women, in participants who were separated or divorced, and in low-income groups. The type and consistency of symptoms experienced after exposure to triggering substances may not fit a purely psychogenic theory.
PMCID: PMC1240637  PMID: 11266327
19.  Of knowledge and deception. 
PMCID: PMC1297968  PMID: 10844877
20.  A knowledge-based patient assessment system: conceptual and technical design. 
This paper describes the design of an inpatient patient assessment application that captures nursing assessment data using a wireless laptop computer. The primary aim of this system is to capture structured information for facilitating decision support and quality monitoring. The system also aims to improve efficiency of recording patient assessments, reduce costs, and improve discharge planning and early identification of patient learning needs. Object-oriented methods were used to elicit functional requirements and to model the proposed system. A tools-based development approach is being used to facilitate rapid development and easy modification of assessment items and rules for decision support. Criteria for evaluation include perceived utility by clinician users, validity of decision support rules, time spent recording assessments, and perceived utility of aggregate reports for quality monitoring.
PMCID: PMC2243964  PMID: 11079970
21.  Medicine in the Millennium. 
PMCID: PMC1288054  PMID: 10700849
22.  Expandable metal stents for non-malignant bronchial obstruction. 
Thorax  1996;51(9):963-964.
An expandable metal stent was inserted to relieve bronchial obstruction following lobectomy for localised squamous carcinoma which had not been relieved by bronchoplasty with a Goretex flap. This resulted in substantial improvement in lung function and exercise tolerance for nine months, following which severe inflammation around the stents required residual pneumonectomy.
Images
PMCID: PMC472627  PMID: 8984715
23.  E-biomed. 
PMCID: PMC1297351  PMID: 10645289
25.  Healing powers. 
PMCID: PMC1296634  PMID: 9659300

Results 1-25 (153)