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Biomedical subjects

S Dolan

Publications and source records attributed to S Dolan.

At least 19 recordsLinked to original sources
PubMed2002

Behavioral evidence supporting a differential role for spinal group I and II metabotropic glutamate receptors in inflammatory hyperalgesia in sheep.

A differential role for metabotropic glutamate receptors (mGluRs) in spinal nociception in normal animals has previously been identified. The present study examined the contribution of group I and group II mGluRs to the development and maintenance of inflammatory hyperalgesia produced by unilateral intradermal injection of carrageenan into the lower forelimb in sheep. Carrageenan (7.5 mg in 500 micro l) produced a significant bilateral reduction in forelimb mechanical withdrawal thresholds. Intrathecal administration of saline-vehicle or the group II mGluR antagonist (2S)-alpha-ethylglutamate (EGLU; 570 nmol) had no effect on either the development or maintenance of hyperalgesia. However, intrathecal administration of the group I mGluR antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 450 nmol) before carrageenan blocked the development of ipsilateral hyperalgesia, and when given 2 h after carrageenan, reversed both ipsilateral and contralateral hyperalgesia. Intrathecal administration of the group II mGluR agonist (2S,1S,2S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 620 nmol) given either before or after carrageenan treatment produced analgesia and anti-hyperalgesia, an effect abolished by co-administration of EGLU (570 nmol). The magnitude of the analgesic response, assessed by the area under the response curve, was significantly greater than that produced by LCCG-I in normal animals. These data demonstrate that the development and maintenance of inflammatory hyperalgesia is dependent on activation of group I mGluRs in spinal cord. In addition, the analgesic and anti-hyperalgesic actions of group II mGluRs suggest that these receptors play a crucial role in modulating acute inflammatory hyperalgesia.

Amino Acids, Dicarboxylic↗
PubMed2001

Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy.

PURPOSE: To evaluate efficacy, safety, and quality of life (QOL) changes with epoetin alfa therapy for anemia in patients with nonmyeloid malignancies. PATIENTS AND METHODS: Anemic cancer patients were enrolled onto this prospective, open-label study from 34 centers across Canada. The trial had two cohorts: patients who were and were not receiving chemotherapy during the 16-week study. All patients initially received epoetin alfa 150 IU/kg subcutaneously three times per week. The dose was doubled after 4 weeks for patients who did not experience sufficient response. RESULTS: Of the 183 patients enrolled in the nonchemotherapy cohort, statistically significant and clinically relevant improvements in QOL were observed with epoetin alfa therapy using both the FACT-An questionnaire and linear analog scale assessment. Hemoglobin levels increased significantly (P <.001; mean increase 2.5 g/dL from baseline to end of study) and these increases were positively correlated with improved QOL and change in Eastern Cooperative Oncology Group (ECOG) scores. There was a significant reduction in the percentage of patients who required blood transfusions. The 218 patients in the chemotherapy cohort also experienced significant improvements in QOL, decreased transfusion use, and increased hemoglobin levels that correlated with QOL improvements and change in ECOG scores. Epoetin alfa was well-tolerated in both cohorts. CONCLUSION: Epoetin alfa administered to patients with cancer-related anemia for up to 16 weeks resulted in significantly improved QOL, increased hemoglobin levels, and decreased transfusion use. These benefits were observed in cancer patients who were not receiving chemotherapy as well as those who were.

Aged↗
PubMed2001

Biphasic modulation of nociceptive processing by the cyclic AMP-protein kinase A signalling pathway in sheep spinal cord.

A role for the cyclic AMP (cAMP)-protein kinase A (PKA) transduction cascade in nociceptive processing has been identified. This study examined the effects of intrathecal treatment with the cAMP analogue 8-Bromo-cAMP and the PKA inhibitor H-89 dihydrochloride on nociceptive thresholds to mechanical stimulation in six adult sheep to define further the role of cAMP in spinal nociception. Treatment with 420 nmol 8-Br-cAMP induced significant hypoalgesia to noxious stimulation, while a 10-fold higher dose (4.2 micromol) induced mechanical hyperalgesia. Both of these behaviours were blocked by H-89 (38-380 nmol). Treatment with high dose H-89 (380 nmol) alone significantly increased nociceptive thresholds. These results demonstrate that activation of the cAMP-PKA signalling pathway modulates acute nociceptive events in spinal cord in a biphasic manner, and suggest that significant tonic activity exists in this pathway.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Decision-making deficits, linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers.

A decision-making instrument known as the "gambling task" was used, which has been shown to be sensitive to the decision-making impairment of patients with bilateral lesions of the ventromedial prefrontal cortex (VM). Three groups of subjects were tested, substance dependent individuals (SD) (n=41), normal controls (n=40), and VM patients (n=5). All SD met the DSM-IV criteria for dependence, with either alcohol or stimulants (metamphetamine or cocaine) as the primary substance of choice. The results revealed a significant impairment in the performance of SD relative to normal controls. A significantly high proportion of SD (61 vs. only 32.5% of normal controls) performed within the range of the VM patients, while the rest performed within the range of normal controls. General demographic factors such as age, sex, and level of education could not explain these differences in performance. As well, differences in performance were not explained by intelligence (IQ), memory, or performance on standard executive function/frontal lobe tests. Performance on the gambling task was best predicted by a combination of factors, including duration of abstinence, years of abuse, relapses and times in treatment, and the ability to hold gainful employment. The results support the hypothesis that impairment in decision-making linked to a dysfunctional VM cortex is associated with at least a sub-group of SD.

Adult↗
PubMed2000

Behavioural evidence supporting a differential role for group I and II metabotropic glutamate receptors in spinal nociceptive transmission.

Metabotropic glutamate receptors (mGluRs) have been shown to contribute to nociceptive processing in spinal cord. This study examined the effects of intrathecal treatment with group I and II mGluR compounds on withdrawal thresholds to noxious mechanical stimuli, in the absence of tissue damage or inflammation, in adult female sheep. Both the group I/II mGluR agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 5.2-520 nmol) and the group II agonist (2S,1S, 2S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 620 nmol) significantly increased mechanical withdrawal thresholds between 5-15 min post-injection. These anti-nociceptive effects were blocked by co-administration of the mGluR antagonist (2S)-alpha-ethylglutamate (EGLU; 570 nmol; group II), but not (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 450 nmol; group I). Intrathecal administration of the group I-specific agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG; 50 nmol) produced a significant reduction in mechanical thresholds, which was blocked by co-administration of the group I antagonist AIDA. In contrast, the highest dose of (S)-3,5-DHPG tested, 5 micromol, significantly elevated response thresholds. These results demonstrate that both group I and II mGluRs play crucial, but contrasting roles in mediating acute mechanical nociceptive events in spinal cord.

Amino Acids, Dicarboxylic↗
PubMed2000

Lipopolysaccharide binding protein in acute pancreatitis.

OBJECTIVE: To assess the expression of plasma lipopolysaccharide binding protein (LBP) concentrations and its relationship to markers of the systemic inflammatory response syndrome during acute pancreatitis. DESIGN: A prospective study. SETTING: General surgical units of university teaching hospitals in the Belfast area. PATIENTS: The study included 18 patients admitted with established diagnosis of acute pancreatitis on the basis of elevated serum amylase or by contrast radiology. Patients were retrospectively stratified using the Modified Glasgow Criteria into severe (n = 7) and mild (n = 11) disease. INTERVENTIONS AND MEASUREMENTS: Blood samples were obtained at admission (day 1) and for a further 3 days for the measurement of LBP, C-reactive protein (CRP), tumor necrosis factor, and interleukin (IL)-6. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated on day 1 and day 2. MAIN RESULTS: LBP and CRP concentrations were significantly increased from healthy control values in acute pancreatitis patients at presentation. In the mild group LBP, CRP and IL-6 concentrations remained relatively constant throughout the study period. By comparison, severe acute pancreatitis was associated with significantly higher LBP concentrations and a marked systemic inflammatory response as evidenced by increased CRP, IL-6, and APACHE II scores. The rise in LBP occurred after the observed increase of these markers. Significant correlations were found among CRP and LBP, IL-6 and LBP, and IL-6 and APACHE II scores. There were no fatalities in the mild group, whereas four of the seven patients with severe disease died. CONCLUSIONS: LBP was significantly raised in patients with severe acute pancreatitis but would seem to be of limited use in predicting disease severity. This acute phase protein may have a role in the progression of systemic complications associated with acute pancreatitis.

APACHE↗
PubMed2000

Low cortisol and risk for PTSD in adult offspring of holocaust survivors.

OBJECTIVE: The study examined the association between cortisol and putative risk factors for posttraumatic stress disorder (PTSD) in a sample of subjects at increased risk for the development of PTSD. METHOD: Twenty-four-hour urinary cortisol excretion was measured in 35 adult offspring of Holocaust survivors and 15 healthy comparison subjects who were not offspring of Holocaust survivors. Subjects were also characterized with regard to clinical symptoms, presence or absence of psychiatric diagnoses including PTSD, and presence or absence of PTSD in their parents. RESULTS: Low cortisol levels were significantly associated with both PTSD in parents and lifetime PTSD in subjects, whereas having a current psychiatric diagnosis other than PTSD was relatively, but nonsignificantly, associated with higher cortisol levels. Offspring with both parental PTSD and lifetime PTSD had the lowest cortisol levels of all study groups. CONCLUSIONS: Parental PTSD, a putative risk factor for PTSD, appears to be associated with low cortisol levels in offspring, even in the absence of lifetime PTSD in the offspring. The findings suggest that low cortisol levels in PTSD may constitute a vulnerability marker related to parental PTSD as well as a state-related characteristic associated with acute or chronic PTSD symptoms.

Adult↗
PubMed1999

Explaining differences in English hospital death rates using routinely collected data.

OBJECTIVES: To ascertain hospital inpatient mortality in England and to determine which factors best explain variation in standardised hospital death ratios. DESIGN: Weighted linear regression analysis of routinely collected data over four years, with hospital standardised mortality ratios as the dependent variable. SETTING: England. SUBJECTS: Eight million discharges from NHS hospitals when the primary diagnosis was one of the diagnoses accounting for 80% of inpatient deaths. MAIN OUTCOME MEASURES: Hospital standardised mortality ratios and predictors of variations in these ratios. RESULTS: The four year crude death rates varied across hospitals from 3.4% to 13.6% (average for England 8.5%), and standardised hospital mortality ratios ranged from 53 to 137 (average for England 100). The percentage of cases that were emergency admissions (60% of total hospital admissions) was the best predictor of this variation in mortality, with the ratio of hospital doctors to beds and general practitioners to head of population the next best predictors. When analyses were restricted to emergency admissions (which covered 93% of all patient deaths analysed) number of doctors per bed was the best predictor. CONCLUSION: Analysis of hospital episode statistics reveals wide variation in standardised hospital mortality ratios in England. The percentage of total admissions classified as emergencies is the most powerful predictor of variation in mortality. The ratios of doctors to head of population served, both in hospital and in general practice, seem to be critical determinants of standardised hospital death rates; the higher these ratios, the lower the death rates in both cases.

Data Collection↗
PubMed1999

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.

BACKGROUND: The aim of this study was to compare the efficacy and safety of Thymoglobulin (a rabbit-derived polyclonal antibody) to Atgam (a horse-derived polyclonal antibody) for induction in adult renal transplant recipients. METHODS: Transplant recipients (n=72) were randomized 2:1 in a double-blinded fashion to receive Thymoglobulin (n=48) at 1.5 mg/kg intravenously or Atgam (n=24) at 15 mg/kg intravenously, intraoperatively, then daily for at least 6 days. Recipients were observed for at least 1 year of follow-up. RESULTS: By 1 year after transplantation, 4% of Thymoglobulin-treated patients experienced acute rejection compared with 25% of Atgam-treated patients (P=0.014). The rate of acute rejection was lower with Thymoglobulin than Atgam (relative risk=0.09; P=0.009). Rejection was less severe with Thymoglobulin than Atgam (P=0.02). No recurrent rejection occurred with Thymoglobulin compared with 33% with Atgam (P=NS). Patient survival was not different, but the composite end point of freedom from death, graft loss, or rejection, the "event-free survival," was superior with Thymoglobulin (94%) compared with Atgam (63%; P=0.0005). Fewer adverse events occurred with Thymoglobulin (P=0.013). Leukopenia was more common with Thymoglobulin than Atgam (56% vs. 4%; P<0.0001) during induction. The mean absolute lymphocyte count remained below baseline with Thymoglobulin throughout the study (P<0.007), but with Atgam, significant lymphocyte reductions occurred only at day 7. The incidence of cytomegalovirus disease was less with Thymoglobulin than Atgam at 6 months (10% vs. 33%; P=0.025). CONCLUSIONS: Brief (7-day) induction with Thymoglobulin resulted in less frequent and less severe rejection, a better event-free survival, less cytomegalovirus disease, fewer serious adverse events, but more frequent early leukopenia than induction with Atgam. These results may in fact be explained by a more profound and durable beneficial lymphopenia.

Adolescent↗
PubMed1999

N-methyl D-aspartate induced mechanical allodynia is blocked by nitric oxide synthase and cyclooxygenase-2 inhibitors.

The role of spinal NMDA receptors in mechanical nociceptive processing was assessed in sheep. Intrathecal NMDA (2 nmol-1 micromol) produced a significant reduction in mechanical withdrawal thresholds. This effect was attenuated by pretreatment with the NMDA receptor antagonist MK801 (100 nmol), the cyclooxygenase-2 (COX-2) inhibitor 5,5-dimethyl-3-(3-flourophenyl)-4-(4-methylsulphonyl)phenyl-2(5H) furanone DFU; 200 nmol) and the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 2 micromol), but not by the metabotropic glutamate receptor antagonist (S)-alpha-methyl-4-carboxyphenylglycine (MCPG; 200 nmol-2 micromol) or the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX; 200 nmol-1 micromol). This first report of NMDA-induced mechanical allodynia suggests that spinal NMDA receptors are involved in mediating acute mechanical nociceptive processing through activation of NOS and COX-2 enzymes.

Animals↗
PubMed1999

Do social factors affect where patients die: an analysis of 10 years of cancer deaths in England.

BACKGROUND: This study investigated whether indices of social deprivation were related to the proportion of cancer patients who died at home. METHODS: Data were derived from death registrations for all cancer deaths 1985-1994 in England. Two indices of deprivation (Underprivileged Area Score (UPA), or Jarman, and Townsend scores) were calculated for each electoral ward; 1991 Census data were used. The scores use combinations of variables, including the percentage in overcrowded homes, the percentage of elderly people living alone, the percentage of one-parent families, etc. A high score indicates more deprivation. The main outcome measures were the proportion (in five and ten year averages) of cancer deaths which occurred at home, calculated for every electoral ward (with populations usually ranging from 5000 to 11,000). Spearman rho was used to test for correlations between the proportion of cancer deaths at home and deprivation score. Electoral wards were categorized by deprivation score into three groups of equal size and analysed over 10 years. Multivariate analysis was used to determine the relative association of different patient based and electoral ward variables with cancer death at home. p < 0.05 (two-tailed) was taken as significant. RESULTS: There were over 1.3 million death registrations from cancer in the 10 years. The proportion who died at home was 0.27, in hospital 0.47, and other setting 0.26. There were wide variations (0.05-0.75) in the proportion of people who died at home in different electoral wards. Small inverse correlations were found between the percentage who died at home and the UPA (-0.35; p < 0.001) and Townsend (-0.26; p < 0.001) scores. The correlations were greatest in North Thames (-0.63, UPA) and smallest in West Midlands (-0.20, UPA). The proportion of home deaths for the different bands of deprivation were: 0.30 (low deprivation), 0.27 (middle deprivation) and 0.24 (high deprivation). Plotting the trends over 10 years suggests no change in this relationship. Multiple regression analysis predicted several ward and patient characteristics and accounted for 30 per cent of the variation. Increased age (patient variable), Jarman score and ethnic minorities (both ward variables) were associated with fewer patients dying at home. Being male and having cancer of the digestive organs were associated with home death. CONCLUSION: There are wide variations in the percentage of cancer deaths at home in different electoral wards. Social factors are inversely correlated with home cancer death, and may explain part of this variation. Home care in deprived areas may be especially difficult to achieve.

Adolescent↗
PubMed1999

Impact of the introduction of a daily trauma list on out-of-hours operating.

The British Orthopaedic Association have recommended that all hospitals should have daily, consultant-led, trauma lists. We have prospectively examined the introduction of a daily trauma list on the out-of-hours operating and the management of trauma in one district hospital. The data collected were compared with a corresponding 6-month period in 1996. It was found that the mean usage of the list was 2 h 38 min; 10% of lists were not used. There has been a significant reduction in the number of operations performed out-of-hours, and also a significant reduction in the amount of out-of-hours operating after midnight. More complex cases have also been operated on in normal working hours. The initial introduction of a daily trauma list has had a significant impact on the total amount of out-of-hours operating and has increased consultant supervision of the management of trauma, thereby increasing the quality of care for these patients.

Emergency Treatment↗