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Biomedical subjects

P Brown

Publications and source records attributed to P Brown.

At least 55 records · Page 3Linked to original sources
PubMed2002

Intravenous immunoglobulin in neurological disease: a specialist review.

Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Drug Costs↗
PubMed2002

The cost-effectiveness of clozapine: a controlled, population-based, mirror-image study.

A retrospective cohort study, with a mirror-image design, was used to measure inpatient service utilization in 63 consecutive patients started on clozapine from a geographical catchment area compared to a control group matched for previous inpatient service use. An intent-to-treat analysis, including those patients (n = 28) who discontinued clozapine during the study period, showed a significant reduction in number of admissions and total time spent in hospital in the 2 years following clozapine initiation compared to the previous 2 years and to the follow-up period in the control group. This translated into a reduction of 7,300 pounds in hospitalization costs per patient started on clozapine, over the 2-year period. In those patients who continued clozapine treatment for the whole of the 2-year period, there was a two-thirds reduction in number of admissions and total time spent in hospital compared to no change in the clozapine discontinuers. These findings suggest that clozapine is a clinically and cost-effective intervention for severe schizophrenia in routine clinical settings.

Adult↗
PubMed2002

Hesx1 homeodomain protein represses transcription as a monomer and antagonises transactivation of specific sites as a homodimer.

The homeobox repressor Hesx1, expressed throughout Rathke's pouch and required for normal pituitary development, has been implicated in anterior pituitary pathogenesis in man. Prolonged expression of Hesx1 delays the appearance of anterior pituitary terminal differentiation markers in mice, particularly the gonadotroph hormones. We tested if Hesx1 could modulate gonadotrophin gene expression directly, and found that Hesx1 repressed both common alpha subunit (alpha GSU) and luteinising hormone beta-subunit (LH beta) gene promoters. Repression mapped to the Pitx1 homeodomain protein transactivation site in the proximal alpha GSU promoter, but did not map to the equivalent site on LH beta. Hesx1 repression of the alpha GSU Pitx1 site was overridden by co-transfection of Pitx1. In contrast, Hesx1 antagonised Pitx1 transactivation of LH beta in a dose-dependent manner. This was due to monomeric binding of Hesx1 on alpha GSU and homodimerisation on LH beta. The homodimerisation site comprises the Pitx1 DNA binding site and a proximal binding site, and mutation of either inhibited homodimer formation. Conversion of the LH beta Pitx1 DNA binding site to an alpha GSU-type did not promote homodimer formation, arguing that Hesx1 has pronounced site selectivity. Furthermore, mutation of the proximal half of the homodimerisation site blocked Hesx1 antagonisation of Pitx1 transactivation. We conclude that Hesx1 monomers repress gene expression, and homodimers block specific transactivation sites.

Animals↗
PubMed2001

A phase II trial of marimastat in advanced pancreatic cancer.

Pancreatic cancer has a poor response to conventional chemotherapy and radiotherapy. Inhibition of matrix metalloproteinase activity involved in tumour invasion and metastases is a novel biological approach for cancer treatment. This multicentre phase II clinical trial assessed marimastat, an oral matrix metalloproteinase inhibitor, in patients with advanced pancreatic cancer. A total of 113 patients received marimastat for 28 days at 100 mg b.d. (n = 9), 25 mg o.d. (n = 90) or 10 mg b.d. (n = 14). Patients with a response to treatment could continue marimastat beyond 28 days. Of 113 patients, 90 (80%) completed the 28-day study and 83 (73%) continued treatment. The principal side effect was arthralgia in 14 (12%) patients at 28 days and 33 (29%) patients over the whole study. There were 31 patients (27%) who required dose modification. Of 76 patients with evaluable CA19-9 levels, 23 (30%) showed no increase or fall in CA19-9. Of 83 patients with radiologically assessable disease, 41 (49%) had stable disease. The median survival was 245 days for those with a stable or falling CA19-9 level 128 days in those with rising CA19-9. The overall survival was 3.8 months. 5.9 months for stage II, 4.7 months for stage III and 3 months for stage IV disease. Of 90 patients, 46 (51%) had stabilization or reduction in pain, mobility and analgesia scores. Further development and clinical evaluation of matrix metalloproteinase inhibitors for the treatment of pancreatic cancer is warranted.

Adenocarcinoma↗
PubMed2001

The retinoic acid receptor antagonist, BMS453, inhibits normal breast cell growth by inducing active TGFbeta and causing cell cycle arrest.

We have previously shown that a retinoic acid receptor (RAR) antagonist BMS453, which does not activate RAR-dependent gene transcription in breast cells, inhibits normal breast cell growth. In this study we have investigated the mechanisms by which this retinoid receptor antagonist inhibits cell growth. Both all trans retinoic acid (atRA) and BMS453 inhibited the proliferation of normal breast cell growth without significantly inducing apoptosis. Both retinoids caused a G1 block in the cell cycle with an increase in the proportion of cells in G0/G1 and a decrease in the proportion of cells in S phase. We then investigated the effects of the retinoids on molecules that regulate the G1 to S transition. These studies demonstrated that both atRA and BMS453 induce Rb hypophosphorylation and decrease CDK2 kinase activity. We then studied the effect of the retinoids on the expression of CDK inhibitors. atRA and BMS453 increased total p21 protein levels and CDK2-bound p21 protein, but did not change CDK4-bound p21. These results suggest that atRA and BMS453 increase p21, decrease CDK2 kinase activity, which in turn leads to hypophosphorylation of Rb and G1 arrest. Because transforming growth factor beta (TGFbeta) has been proposed as a mediator of retinoid-induced growth inhibition, we next investigated whether TGFbeta mediates the anti-proliferative effect of atRA and BMS453 in normal breast cells. These studies showed that atRA and BMS453 increased total TGFbeta activity by 3-5-fold. However, BMS453 increased active TGFbeta activity by 33-fold while atRA increased active TGFbeta activity by only threefold. These results suggest that BMS453 treatment induces conversion of latent TGFbeta to active TGFbeta. To investigate whether this increase in active TGFbeta mediates the anti-proliferative effects of these retinoids, a TGFbeta-blocking antibody was used in an attempt to prevent retinoid-induced growth inhibition. Results from these experiments showed that the anti-TGFbeta antibody prevented the inhibition of cell proliferation induced by BMS453, but did not prevent the inhibition of cell proliferation induced by atRA. These results demonstrate that BMS453 inhibits breast cell growth predominantly through the induction of active TGFbeta, while atRA inhibits growth through other mechanisms. These results suggest that retinoid analogs that increase active TGFbeta may be promising agents for the prevention of breast cancer.

Blotting, Western↗
PubMed2001

Illusory perceptions of space and time preserve cross-saccadic perceptual continuity.

When voluntary saccadic eye movements are made to a silently ticking clock, observers sometimes think that the second hand takes longer than normal to move to its next position. For a short period, the clock appears to have stopped (chronostasis). Here we show that the illusion occurs because the brain extends the percept of the saccadic target backwards in time to just before the onset of the saccade. This occurs every time we move the eyes but it is only perceived when an external time reference alerts us to the phenomenon. The illusion does not seem to depend on the shift of spatial attention that accompanies the saccade. However, if the target is moved unpredictably during the saccade, breaking perception of the target's spatial continuity, then the illusion disappears. We suggest that temporal extension of the target's percept is one of the mechanisms that 'fill in' the perceptual 'gap' during saccadic suppression. The effect is critically linked to perceptual mechanisms that identify a target's spatial stability.

Adult↗
PubMed2001

Reproductive changes in fluctuating house mouse populations in southeastern Australia.

House mice (Mus domesticus) in the Victorian mallee region of southeastern Australia show irregular outbreaks. Changes in reproductive output that could potentially drive changes in mouse numbers were assessed from 1982 to 2000. Litter size in females is positively correlated with body size. When standardized to an average size female, litter size changes seasonally from highest in spring to lowest in autumn and winter. Litter size is depressed throughout breeding seasons that begin when the abundance of mice is high, but is similar in breeding seasons over which the abundance of mice increases rapidly or remains low. Breeding begins early and is extended on average by about five weeks during seasons when mouse abundance increases rapidly. The size at which females begin to reproduce is larger during breeding seasons that begin when mouse abundance is high. An extended breeding season that begins early in spring is necessary for the generation of a house mouse plague, but it is not in itself sufficient. Reproductive changes in outbreaks of house mice in Australia are similar but not identical to reproductive changes that accompany rodent population increases in the Northern Hemisphere. We conclude that food quality, particularly protein, is a probable mechanism driving these reproductive changes, but experimental evidence for field populations is conflicting.

Animals↗
PubMed2001

Intermuscular coherence in Parkinson's disease: relationship to bradykinesia.

We hypothesised that bradykinesia may be partly due to the failure of the corticomuscular system to engage in high frequency oscillatory activity in Parkinson's disease (PD). In healthy subjects such oscillations are evident in coherence between active muscles at 15--30 Hz. We therefore investigated the effects of therapeutic stimulation of the basal ganglia on this coherence and related it to changes in bradykinesia in the contralateral arm. Increases in coherence at 15--30 Hz and improvements in bradykinesia upon stimulation were correlated (r = 0.564, p < 0.001). This suggests that the basal ganglia modulate oscillatory activity in the corticomuscular system and that impairment of the motor system's ability to engage in synchronised oscillations at high frequency may contribute to bradykinesia in PD.

Electric Stimulation Therapy↗
PubMed2001

Involvement of the sensorimotor cortex in physiological force and action tremor.

Whole scalp magnetoencephalography (MEG) signals were recorded in 10 healthy subjects simultaneously with the surface electromyogram (EMG) of the contralateral forearm extensor muscles during isometric contraction and phasic movement of the wrist. In eight subjects, coherence and time domain analyses demonstrated correspondence between the MEG signal, originating near or in the hand region of the motor cortex, and the 6-12 Hz EMG recorded during isometric postural contractions. In contrast, we found little evidence for correspondence between the contralateral EMG and the MEG recorded over the Rolandic region during phasic movements. We conclude that the sensorimotor cortex is differentially involved in physiological force and action tremor at the wrist.

Adolescent↗
PubMed2001

Specific detection of DNA and RNA targets using a novel isothermal nucleic acid amplification assay based on the formation of a three-way junction structure.

The formation of DNA three-way junction (3WJ) structures has been utilised to develop a novel isothermal nucleic acid amplification assay (SMART) for the detection of specific DNA or RNA targets. The assay consists of two oligonucleotide probes that hybridise to a specific target sequence and, only then, to each other forming a 3WJ structure. One probe (template for the RNA signal) contains a non-functional single-stranded T7 RNA polymerase promoter sequence. This promoter sequence is made double-stranded (hence functional) by DNA polymerase, allowing T7 RNA polymerase to generate a target-dependent RNA signal which is measured by an enzyme-linked oligosorbent assay (ELOSA). The sequence of the RNA signal is always the same, regardless of the original target sequence. The SMART assay was successfully tested in model systems with several single-stranded synthetic targets, both DNA and RNA. The assay could also detect specific target sequences in both genomic DNA and total RNA from Escherichia coli. It was also possible to generate signal from E.coli samples without prior extraction of nucleic acid, showing that for some targets, sample purification may not be required. The assay is simple to perform and easily adaptable to different targets.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed2001

Intermuscular coherence in Parkinson's disease: effects of subthalamic nucleus stimulation.

It remains unclear how high frequency stimulation of the subthalamic nucleus (STN) improves parkinsonism. We hypothesized that stimulation may affect the organization of the cortical drive to voluntarily activated muscle. Normally this is characterized by oscillations at 15-30 Hz, manifest in coherence between muscles in the same frequency band. We therefore investigated the effects of STN stimulation on electromyographic (EMG) activity in co-contracting distal arm muscles in nine subjects with Parkinson's disease off drugs. Without stimulation, coherence between EMG signals was diminished at 15-30 Hz compared with nine controls. STN stimulation increased coherence in the 15-30 Hz band, so that it approached that in healthy subjects. The results suggest that STN stimulation facilitates the normal cortical drive to muscles.

Analysis of Variance↗
PubMed2001

Avascular necrosis of bone in patients with human immunodeficiency virus infection: report of 6 cases and review of the literature.

In 1998 and 1999, we diagnosed avascular necrosis of bone in 6 patients in our human immunodeficiency virus clinic practice, an incidence of 0.45%, which is 45 times greater than would be expected in the general population. Antiphospholipid antibodies and hyperlipidemia secondary to protease inhibitor therapy have been implicated as possible etiologies; however, these abnormalities cannot explain all cases of avascular necrosis of bone reported in patients with human immunodeficiency virus infection.

Adult↗
PubMed2001

Task-related EEG-EEG coherence depends on dopaminergic activity in Parkinson's disease.

We investigated whether functional coupling between different cortical areas is impaired in Parkinson's disease, using corticocortical coherence as a surrogate measure of coupling. We recorded scalp EEG from different sites in seven parkinsonian patients while they tracked a visual target using their wrist, or copied the same movement from memory. Differences in EEG-EEG coherence between the tracking and copying tasks and their respective controls, visual tracking alone and fixation of a stationary target, were determined on and off levodopa. After levodopa we found extensive task-specific and broad band cortico-cortical coherence. Off levodopa cortico-cortical coherence was much reduced. Ascending dopaminergic projections from the ventral mesencephalon may therefore be important in determining the pattern and extent of corticocortical coupling during executive tasks.

Aged↗