Quantitative assessment of the nociceptive withdrawal reflex in healthy, non-medicated experimental sheep

This study aimed to characterize the nociceptive withdrawal reflex (NWR) and to define the nociceptive threshold in 25 healthy, non-medicated experimental sheep in standing posture. Electrical stimulation of the dorsal lateral digital nerves of the right thoracic and the pelvic limb was performed and surface-electromyography (EMG) from the deltoid (all animals) and the femoral biceps (18 animals) or the peroneus tertius muscles (7 animals) was recorded. The behavioural reaction following each stimulation was scored on a scale from 0 (no reaction) to 5 (strong whole body reaction). A train-of-five 1 ms constant-current pulse was used and current intensity was stepwise increased until NWR threshold intensity was reached. The NWR threshold intensity (It) was defined as the minimal stimulus intensity able to evoke a reflex with a minimal Root-Mean-Square amplitude (RMSA) of 20 μV, a minimal duration of 10 ms and a minimal reaction score of 1 (slight muscle contraction of the stimulated limb) within the time window of 20 to 130 ms post-stimulation. Based on this value, further stimulations were performed below (0.9It) and above threshold (1.5It and 2It). The stimulus-response curve was described. Data are reported as medians and interquartile ranges. At the deltoid muscle It was 4.4 mA (2.9–5.7) with an RMSA of 62 μV (30–102). At the biceps femoris muscle It was 7.0 mA (4.0–10.0) with an RMSA of 43 μV (34–50) and at the peroneus tertius muscle It was 3.4 mA (3.1–4.4) with an RMSA of 38 μV (32–46). Above threshold, RMSA was significantly increased at all muscles. Below threshold, RMSA was only significantly smaller than at It for the peroneus tertius muscle but not for the other muscles.

Behavioural and histopathological alterations in mice with cerebral malaria.

Different features of sensorimotor function and behaviour were studied in murine cerebral malaria (CM) and malaria without cerebral involvement (non-CM) applying the primary screen of the SHIRPA protocol. Histopathological analysis of distinct brain regions was performed and the relative size of haemorrhages and plugging of blood cells to brain vasculature was analysed. Animals suffering from CM develop a wide range of behavioural and functional alterations in the progressive course of the disease with a statistically significant impairment in all functional categories assessed 36 h prior to death when compared with control animals. Early functional indicators of cerebral phenotype are impairments in reflex and sensory system and in neuropsychiatric state. Deterioration in function is paralleled by the degree of histopathological changes with a statistically significant correlation between the SHIRPA score of CM animals and the mean size of brain haemorrhage. Furthermore, image analysis yielded that the relative area of the brain lesions was significantly larger in the forebrain and brainstem compared with the other regions of interest. Our results indicate that assessment of sensory and motor tasks by the SHIRPA primary screen is appropriate for the early in vivo discrimination of cerebral involvement in experimental murine malaria. Our findings also suggest a correlation between the degree of functional impairment and the size of the brain lesions as indicated by parenchymal haemorrhage. Applying the SHIRPA protocol in the functional characterization of animals suffering from CM might prove useful in the preclinical assessment of new antimalarial and potential neuroprotective therapies.

The effects of assessment type on verbal ratings of conditional stimulus valence and contingency judgments: Implications for the extinction of evaluative learning

Recent research on causal learning found (a) that causal judgments reflect either the current predictive value of a conditional stimulus (CS) or an integration across the experimental contingencies used in the entire experiment and (b) that postexperimental judgments, rather than the CS's current predictive value, are likely to reflect this integration. In the current study, the authors examined whether verbal valence ratings were subject to similar integration. Assessments of stimulus valence and contingencies responded similarly to variations of reporting requirements, contingency reversal, and extinction, reflecting either current or integrated values. However, affective learning required more trials to reflect a contingency change than did contingency judgments. The integration of valence assessments across training and the fact that affective learning is slow to reflect contingency changes can provide an alternative interpretation for researchers' previous failures to find an effect of extinction training on verbal reports of CS valence.

Neuropsychological assessment of an eighty-nine year old man

A case of first onset of the symptoms of mania in an eighty-nine year old man is reported. Organic contributions appear to be particularly important in cases of mania in older adults. In cases of first onset of mania in older adults the major differential diagnosis is between primary mania and a wide range of possible secondary etiological factors. This man had no known history of affective disorder and at the time of initial examination no organic explanation for his symptoms could be identified. While lateonset bipolar disorder has been reported in the literature, such cases are rare and are usually proceeded by a history of major depressive disorder or dysthymia. A range of neuropsychological assessment instruments were administered as part of a comprehensive inpatient examination of this man, commenting on his cognitive functioning and competence to manage his affairs. This assessment indicated that while his functioning was intact in some areas, there were areas of significant difficulty. The case illustrates the difficulties in interpreting neuropsychological assessment results obtained during a manic phase, and highlights some of the difficulties of conducting research with older adults.

Quantitative assessment of the pharmacotherapy of biopolar disorder and schizophrenia

The work present in this thesis was aimed at assessing the efficacy of lithium in the acute treatment of mania and for the prophylaxis of bipolar disorder, and investigating the value of plasma haloperidol concentration for predicting response to treatment in schizophrenia. The pharmacogenetics of psychotropic drugs is critically appraised to provide insights into interindividual variability in response to pharmacotherapy, In clinical trials of acute mania, a number of measures have been used to assess the severity of illness and its response to treatment. Rating instruments need to be validated in order for a clinical study to provide reliable and meaningful estimates of treatment effects, Eight symptom-rating scales were identified and critically assessed, The Mania Rating Scale (MRS) was the most commonly used for assessing treatment response, The advantage of the MRS is that there is a relatively extensive database of studies based on it and this will no doubt ensure that it remains a gold standard for the foreseeable future. Other useful rating scales are available for measuring mania but further cross-validation and validation against clinically meaningful global changes are required. A total of 658 patients from 12 trials were included in an evaluation of the efficacy of lithium in the treatment of acute mania. Treatment periods ranged from 3 to 4 weeks. Efficacy was estimated using (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates. The response rate ratio for lithium against placebo was 1.95 (95% CI 1.17 to 3.23). The mean number needed to treat was 5 (95% CI 3 to 20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1.96, 95% CI 1.02 to 3.77). The mean number needed to treat (NNT) was 4 (95% CI 3 to 9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1.01 (95% CI 0.54 to 1.88) for lithium compared to carbarnazepine and 1.22 (95% CI 0.91 to 1.64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were -2.79 (95% CI -4.22 to -1.36) in favour of risperidone with respect to symptom severity improvement and -0.76 (95% CI -1.11 to -0,41) on the basis of reduction in global severity of disease. Symptom and global severity was at least as well controlIed with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate. A total of 554 patients from 13 trials were included in the statistical analysis of lithium's efficacy in the prophylaxis of bipolar disorder. The mean follow-up period was 5-34 months. The relapse risk ratio for lithium versus placebo was 0.47 (95% CI 0.26 to 0.86) and the NNT was 3 (95% CI 2 to 7). The relapse risk ratio for lithium versus imipramine was 0.62 (95% CI 0.46 to 0.84) and the NNT was 4 (951% Cl 3 to 7), The combination of lithium and imipramine was no more effective than lithium alone. The risk of relapse was greater with lithium alone than with the lithium-divalproate combination. A risk difference of 0.60 (95% CI 0.21 to 0.99) and an NNT of 2 (95% CI 1 to 5) were obtained. Lithium was as effective as carbamazepine. Based on individual data concerning plasma haloperidol concentration and percent improvement in psychotic symptoms, our results suggest an acceptable concentration range of 11.20-30.30 ng/mL A minimum of 2 weeks should be allowed before evaluating therapeutic response. Monitoring of drug plasma levels seems not to be necessary unless behavioural toxicity or noncompliance is suspected. Pharmacokinetics and pharmacodynamics, which are mainly determined by genetic factors, contribute to interindividual and interethnic variations in clinical response to drugs. These variations are primarily due to differences in drug metabolism. Variability in pharmacokinetics of a number of drugs is associated with oxidation polymorphism. Debrisoquine/sparteine hydroxylase (CYP2D6) and the S-mephenytoin hydroxylase (CYP2C19) are polymorphic P450 enzymes with particular importance in psychopharmacotherapy. The enzymes are responsible for the metabolism of many commonly used antipsychotic and antidepressant drugs. The incidence of poor metabolisers of debrisoquine and S-mephenytoin varies widely among populations. Ethnic variations in polymorphic isoenzymes may, at least in part, explain ethnic differences in response to pharmacotherapy of antipsychotics and antidepressant drugs.