Biomedical subjects
Publications and source records attributed to P Brown.
Novel inhibitors of bacterial tyrosyl tRNA synthetase have been synthesised in which the cyclic hydroxylamine moiety of SB-219383 is replaced by C-pyranosyl derivatives. Potent and selective inhibition of bacterial tyrosyl tRNA synthetase was obtained.
Novel pyranosyl analogues of SB-219383 have been synthesised to elucidate the structure-activity relationships around the pyran ring. Analogues with highly potent stereoselective and bacterioselective inhibition of bacterial tyrosyl tRNA synthetase have been identified. A major reduction in the overall polarity of the molecule can be tolerated without loss of the nanomolar level of inhibition.
The extent of synchronization within and between the nuclei of the basal ganglia is unknown in Parkinson's disease. The question is an important one because synchronization will increase postsynaptic efficacy at subsequent projection targets. We simultaneously recorded local potentials (LPs) from the globus pallidus interna (GPi) and subthalamic nucleus (STN) in four awake patients after neurosurgery for Parkinson's disease. Nuclei from both sides were recorded in two patients so that a total of six ipsilateral GPi-STN LP recordings were made. Without medication, the power within and the coherence between the GPi and STN was dominated by activity with a frequency <30 Hz. Treatment with the dopamine precursor levodopa reduced the low-frequency activity and resulted in a new peak at approximately 70 Hz. This was evident in the power spectrum from STN and GPi and in the coherence between these nuclei. The phase relationship between the nuclei varied in a complex manner according to frequency band and the presence of exogenous dopaminergic stimulation. Synchronization of activity does occur between pallidum and STN, and its pattern is critically dependent on the level of dopaminergic activity.
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BACKGROUND: We propose a new method for supervised learning from gene expression data. We call it 'tree harvesting'. This technique starts with a hierarchical clustering of genes, then models the outcome variable as a sum of the average expression profiles of chosen clusters and their products. It can be applied to many different kinds of outcome measures such as censored survival times, or a response falling in two or more classes (for example, cancer classes). The method can discover genes that have strong effects on their own, and genes that interact with other genes. RESULTS: We illustrate the method on data from a lymphoma study, and on a dataset containing samples from eight different cancers. It identified some potentially interesting gene clusters. In simulation studies we found that the procedure may require a large number of experimental samples to successfully discover interactions. CONCLUSIONS: Tree harvesting is a potentially useful tool for exploration of gene expression data and identification of interesting clusters of genes worthy of further investigation.
BACKGROUND: Gerstmann-Sträussler-Scheinker disease is a rare form of prion disease. OBJECTIVE: To determine the prion mutation in a 51-year-old man without a family history of neurologic disease who died from Gerstmann-Sträussler-Scheinker disease. PATIENT AND METHODS: The patient was a 51-year-old man who died after a 9-year illness characterized by dementia and eventually ataxia. Neuropathologic studies were performed, the results of which revealed abundant prion protein-immunopositive amyloid plaques in the cerebellum without spongiform degeneration. RESULTS: Genetic analysis of the prion protein gene showed a novel mutation at codon 131 that caused a valine-for-glycine substitution (G131V) and homozygosity at codon 129 (129M). Proteinase K-resistant prion protein was detected by Western blot analysis. CONCLUSIONS: This is the first mutation described in the short, antiparallel beta-sheet domain of the prion protein. This report highlights the importance of genetic analysis of patients with atypical dementia even in the absence of a family history.
OBJECTIVES: To quantify the risk of Creutzfeldt-Jakob disease (CJD) among cornea donors, evaluate supplemental screening strategies, and address concerns about the adequacy of current methods of screening tissue donors in the United States. METHODS: Reported data on deaths due to CJD and from all causes were used to estimate the rate of CJD among cornea donors. The impact of increased screening on risk of CJD and donor supply was evaluated. RESULTS: Only 1.3 of the approximately 45 000 cornea donors in the United States each year might be expected to have CJD. Most of the estimated risk (91%) is due to preclinical (asymptomatic) disease and therefore could not be eliminated by screening for signs or symptoms. If only the highest-risk age group (60 to 69 years) were screened and specificity were 90%, more than 21 000 otherwise acceptable donors would incorrectly be excluded over a period of 17.5 years to correctly exclude a single donor with symptomatic CJD. CONCLUSIONS: Currently, the risk of CJD transmission following cornea transplantation is remarkably low. Screening for symptoms of CJD would have minimal impact on safety, but would reduce donor supply and likely result in many patients not receiving needed treatment.
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Classical and modern studies of the pathogenesis of transmissible spongiform encephalopathy are reviewed, with particular attention paid to recent investigations of the routes of neuroinvasion. In various experimental models, a heirarchy of paths to the brain includes direct neural transit from the site of infection, replication in the spleen and neural entry through the spinal cord, and hematogenous spread. Possible modes and sites of therapeutic intervention are suggested.
The authors review the literature from the last year examining the benefits of cholinesterase inhibitors in the treatment of behavioral disturbance in Alzheimer's disease (AD) and other dementias. Previous review has indicated that cholinesterase inhibitors have psychotropic properties. We found more evidence to support both the benefits of cholinesterase inhibitors in behavioral disturbance, and that specific behaviors may be selectively responsive to treatment.
Blood infectivity data from rodent models of transmissible spongiform encephalopathies (TSEs), and infectivity-prion protein (PrP) equivalence data from scrapie-infected hamster brain suggest a minimum requirement for PrP detection in blood buffy coat of < or = 10 pg/mL. This estimate could either be more or less stringent than calculated-more, if infectivity levels in human blood are lower than in experimental rodent models; less, if the infectivity-PrP ratio is lower in blood than in brain tissue, or if there is a large as yet undetected pool of abnormal but proteinase-sensitive PrP. None of several testing methods under development has yet achieved the calculated sensitivity requirement, but a few are within range, and it should be possible within the coming year to determine whether PrP occurs at a practically detectable level in the blood of patients with TSE.
Primary orthostatic tremor (OT) consists of rhythmical muscle contractions at a frequency of around 16 Hz, causing discomfort and/or unsteadiness while standing. Diagnosis has hitherto relied on recording Electromyography (EMG) from affected muscles. The main aim of this study was to see if the characteristic postural tremor in OT can be identified with force platforms. We also quantified postural sway in OT patients to assess their degree of objective unsteadiness. Finally, we investigated the time relations between bursts of activity in the various affected muscle groups. Subjects stood on a force platform with concurrent multichannel surface EMG recordings from the lower limbs. Seven patients with clinical and EMG diagnosis of OT were examined and the force platform data compared with those of 21 other neurological patients with postural tremor and eight normal controls. All OT patients had high frequency peaks in power spectra of posturography and EMG recordings (12--16 Hz). No such high frequency activity was evident in patients with Parkinson's disease, cerebellar degenerations, essential tremor or in healthy controls. Additionally, OT patients showed increased sway at low frequencies relative to normal controls, suggesting that the unsteadiness reported by OT patients is at least partly due to increased postural sway. Examination of EMG timing showed fixed patterns of muscle activation when maintaining a quiet stance within but not across OT patients. These data show a high correlation between EMG and posturography and confirm that OT may be diagnosed using short epochs of force platform recordings.
OBJECTIVES: To investigate the mechanisms responsible for suppressing the amplitude of electromyogram (EMG) responses to a standard transcranial magnetic stimulus (TMS) after prior conditioning of the motor cortex with repetitive subthreshold TMS (rTMS) at a frequency of 1 Hz. METHODS: EMG responses from the first dorsal interosseous, abductor pollicis brevis and flexor carpi radialis (FCR) muscles were recorded after suprathreshold TMS of the motor cortex. In some experiments, H-reflexes were also obtained in the FCR. The amplitude of these responses was compared before and after applying from 150 to 1500 rTMS pulses to motor cortex at an intensity of 95% resting motor threshold through the same figure-of-8 coil. RESULTS: When tested with subjects relaxed, rTMS conditioning reduced the amplitude of motor evoked potentials (MEPs) to approximately 60% of pre-conditioning values for 2-10 min after the end of the conditioning train, depending on the number of pulses in the train. There was more suppression with 1500 rTMS pulses than with 150 pulses. There was no effect on H-reflexes. There was no effect on MEPs if the test stimuli were given during active contraction of the target muscle. CONCLUSIONS: The findings confirm previous observations that low-frequency, low-intensity rTMS to motor cortex can produce transient depression of MEP excitability. Since there was no effect on spinal H-reflexes, this is consistent with the idea that some of the suppression occurs because of an effect on the motor cortex itself. The lack of any conditioning effect on MEPs evoked in actively contracting muscle is not readily consistent with the idea that rTMS depresses transmission in synaptic connections to pyramidal cells activated by the test TMS pulse. An alternative explanation is that rTMS reduces the excitability of cortical neurones in relaxed subjects, so that responses to a given input are smaller than before conditioning. Voluntary contraction normalises excitability levels so that the effect is no longer seen.
In this paper, we attempt to determine whether delays in scheduling operation affect waiting time in a queue for elective surgery. We analyze the waiting-list management system in a Canadian hospital. We estimate the impact of scheduling delays by modeling access to treatment as a multistate process. We found that patients with any delay in scheduling surgery had longer waiting times than patients without delays. For certain sources of delays, the admission rate was 50-60% lower compared with the rate for admissions without a delay independent of urgency of surgical intervention. Our findings support a concern that waiting time for elective surgery is not simply determined by how many patients are on the waiting list, or by how urgently they need treatment, but also by the waiting list management practice.
OBJECTIVE: To determine the incidence, severity and reporting of adverse drug reactions occurring to newly marketed drug (all drugs annotated with a black triangle symbol) in the Division of Psychiatry. METHOD: All patient commenced on a black triangle drug in the previous month and satisfying all inclusion criteria were interviewed by a pre-registration pharmacist. The investigator collected details regarding drug prescribed, side effects reported and non-compliance. Reports sent to the CSM were noted. RESULTS: Twenty-two patients received 25 black triangle drugs. Sixteen (60%) suffered an adverse drug reaction. Eight reported these to their doctor with 7 (28%) discontinuing treatment due to the severity of the side effects. Two adverse drugs reactions were classified as serious according to CSM criteria (jerking movements, rash), 3 further reactions led to a deterioration in the patients mental state. No yellow cards were completed. CONCLUSION: Both patient and health care professionals underreport adverse drug reactions. All reactions to a black triangle drug should be reported. A medicines and healthy living group attended by patients and professionals involved in their case has allowed an increased awareness, monitoring and reporting of adverse drug reactions.
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The beta-subunits of luteinizing hormone (LH beta) and follicle-stimulating hormone (FSH beta) are differentially expressed, and this may contribute to the unique expression and storage patterns of LH and FSH. Therefore, to determine if the in vivo expression profile of FSH beta could be altered to that of LH beta, a truncated ovine FSH beta (oFSH beta) gene, which would encode a mRNA lacking the putative destabilizing 3' untranslated region, was fused downstream of the ovine LH beta (oLH beta) promoter and expressed in transgenic mice. In two independent lines, line 16 and 17, we measured oFSH beta, mouse LH beta (mLHbeta) and mouse FSH beta (mFSH beta) mRNA levels: (i) after castration in males; (ii) after administering inhibin to ovariectomized mice; and (iii) during the oestrous cycle. In each experiment, the expression profile of oFSH beta mRNA mimicked mLH beta and not mFSH beta mRNA. In addition, after actinomycin D treatment of pituitary cultures, while mFSH beta mRNA did decay, there was no measurable decay of the oFSH beta mRNA transcript. These differences increased total FSH beta steady-state mRNA expression levels in male transgenics. However, there was no detectable increase in pituitary FSH by either radioimmunoassay or western blotting analysis of pituitary extracts. Subsequent analysis revealed that pituitary FSH beta in line 16 was heavily glycosylated; in contrast, pituitary FSH beta in line 17 was largely unmodified. These differences in post-translational modification of the beta-subunit, and the lack of intracellular storage, contributed to increased plasma FSH levels and ovulation rate in line 16, but not line 17. In conclusion, the expression profile of oFSH beta mRNA was manipulated to mimic mLH beta mRNA and this increased FSH beta mRNA expression levels, but did not increase storage of FSH. This suggests that, regardless of the levels of synthesis, post-translational sorting preferentially promotes FSH secretion from the pituitary.