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P Brown

Publications and source records attributed to P Brown.

At least 19 recordsLinked to original sources
PubMed2006

The association of GRB 060218 with a supernova and the evolution of the shock wave.

Although the link between long gamma-ray bursts (GRBs) and supernovae has been established, hitherto there have been no observations of the beginning of a supernova explosion and its intimate link to a GRB. In particular, we do not know how the jet that defines a gamma-ray burst emerges from the star's surface, nor how a GRB progenitor explodes. Here we report observations of the relatively nearby GRB 060218 (ref. 5) and its connection to supernova SN 2006aj (ref. 6). In addition to the classical non-thermal emission, GRB 060218 shows a thermal component in its X-ray spectrum, which cools and shifts into the optical/ultraviolet band as time passes. We interpret these features as arising from the break-out of a shock wave driven by a mildly relativistic shell into the dense wind surrounding the progenitor. We have caught a supernova in the act of exploding, directly observing the shock break-out, which indicates that the GRB progenitor was a Wolf-Rayet star.

Journal Article↗
PubMed2006

Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents.

Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP(Sc), which is a misfolded isoform of the normal cellular prion protein PrP(C). Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP(C) and the suppression of PrP(Sc) accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC50s in the nanomolar range.

Acridines↗
PubMed2006

Hypospadias in rams.

In an abattoir survey conducted in south-west England, 15 of 6521 rams aged three to 12 months had hypospadias; in 27 others the scrotum was completely or partly divided, but they had no other abnormalities of the urinary or genital systems. The lesions observed in 11 of the rams in the abattoir survey, and in four young rams and one mature ram found during visits to farms, are described in detail. Five of them had periscrotal openings of the urethra and in the other 11 the openings were in a perineal position, close to the anus. In all of them the penis was underdeveloped, the prepuce had failed to fuse and the galea faced in a caudal direction. They all had completely or partially divided scrotums, and signs of urine scalding of the scrotum were visible.

Abattoirs↗
PubMed2006

Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner.

Mixed lineage leukemia (MLL) rearrangements occur in 80% of infants and 5% of older children with acute lymphoblastic leukemia (ALL). These cases have a poor prognosis with current therapy. The FLT3 kinase is overexpressed and constitutively activated in MLL-rearranged ALL cells. The FLT3 inhibitor CEP-701 selectively kills these cells, but is unlikely to be curative if used as monotherapy. To identify potentially synergistic combination strategies, we studied CEP-701 and six standard chemotherapeutic agents in three sequences of exposure (S1: chemotherapy followed by CEP-701, S2: simultaneous exposure to both; and S3: CEP-701 followed by chemotherapy) using MLL-rearranged ALL cell lines and patient bone marrow samples. MTT cytotoxicity and annexin V binding apoptosis assays were used to assess antileukemic effects. Combination indices (CI) were calculated for each combination (CI<0.9 - synergistic; CI 0.9-1.1 - additive; CI>1.1 - antagonistic). A striking pattern of sequence-dependent synergy was observed: S1 was markedly synergistic (mean CI=0.59+/-0.10), S2 was additive (mean CI=0.99+/-0.09) and S3 was antagonistic (mean CI=1.23+/-0.10). The sequence dependence is attributable to the effect of CEP-701 on cell cycle kinetics, and is mediated specifically by FLT3 inhibition, as these effects are not seen in control cells without activated FLT3.

Antineoplastic Agents↗
PubMed2006

Role of lymphangiogenesis in epithelial ovarian cancer.

We investigated the significance of lymphatic count, vascular count and angiogenic growth factors using immunohistochemistry in 108 tumour specimens of epithelial ovarian cancer with antibodies to lymphatic vessel endothelial hyaluronan receptor (LYVE-1), platelet endothelial cell adhesion molecule CD31, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) in epithelial ovarian cancer to understand the pathogenesis of metastasis in ovarian cancer. The effect of prognostic variables on progression-free and overall survival was assessed. On multivariate analysis, bulky residual disease after surgery was the best prognostic indicator (P<0.001) for progression-free and overall survival (P<0.001). Lymphatic count was statistically significant as a prognostic factor for progression-free (P=0.05) and overall survival (P=0.04). However, lymphatic count did not impact on survival curves. No correlation was found between lymphatic count and age, histological subtype, FIGO stage or residual disease. Vascular count, VEGF or TP expressions were not significant in either analysis. Lymphatic spread may be significant in aiding metastases in ovarian cancer but requires other biological factors to act in conjunction, as it does not have clearcut prognostic significance. Dissemination of ovarian cancer does not occur primarily through vascular or lymphatic routes but may occur through direct intraperitoneal spread of disease.

Adult↗
PubMed2006

Oscillatory pallidal local field potential activity correlates with involuntary EMG in dystonia.

The pathophysiology of dystonia is unclear. The authors recorded local field potentials (LFPs) from deep brain stimulation electrodes implanted in the pallidum of 13 dystonic patients. LFP power correlated with the level of dystonic EMG in the sternocleidomastoid, with maximal positive correlations at the lower contacts of pallidal electrodes. The data suggest that the neuronal synchronization indexed by LFP oscillations in the globus pallidus may be mechanistically linked to dystonic EMG activity.

Action Potentials↗
PubMed2006

Bad oscillations in Parkinson's disease.

Recordings in humans as a result of functional neurosurgery have revealed a tendency for basal ganglia neurons to oscillate and synchronise their activity, giving rise to a rhythmic population activity, manifest as oscillatory local field potentials. The most important activity is synchronised oscillation in the beta band (13-30 Hz), which has been picked up at various sites within the basal ganglia-cortical loop in PD. Dopaminergic medication and movement suppress this activity, with the timing and degree of suppression closely correlating with behavioural performance. Accordingly synchronisation in the beta band has been hypothesised to be essentially antikinetic in nature and pathophysiologically relevant to bradykinesia.

Animals↗
PubMed2006

A randomised trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding.

OBJECTIVE: To compare the levonorgestrel intrauterine system (LNG-IUS) (Mirena); Schering Co., Turku, Finland) and thermal balloon ablation (Thermachoice; Gynecare Inc., Menlo Park, CA, USA) for the treatment of heavy menstrual bleeding. DESIGN: An open, pragmatic, prospective randomised trial. SETTING: A menstrual disorders clinic at National Women's Hospital, Auckland, New Zealand. POPULATION: Seventy-nine women with heavy menstrual bleeding randomised to the LNG-IUS (40 women) or the thermal balloon ablation (39 women). METHODS: Women were randomised to treatment with the LNG-IUS or thermal balloon ablation and followed up by a postal and telephone questionnaire. MAIN OUTCOME MEASURES: Menstrual loss measured by a pictorial bleeding assessment chart (PBAC) at 3, 6, 12 and 24 months. Patient satisfaction, quality of life and menstrual symptoms were assessed by questionnaire administered at 3, 6, 12 and 24 months. Treatment side effects and treatment failures were also recorded. RESULTS: Both the treatments resulted in a significant reduction in PBAC scores. At 12 and 24 months, median PBAC scores were significantly lower in women treated with the LNG-IUS compared with women treated by thermal balloon ablation (11.5 versus 60.0 at 12 months [P= 0.002]; 12.0 versus 56.5 [P= 0.002] at 24 months). At 24 months, nine (35%) women still using the LNG-IUS had amenorrhoea compared with one (5%) woman successfully treated by thermal balloon ablation (P = 0.025). There were no significant differences in patient satisfaction between two treatments during follow up. Treatment failed in 11 (28%) women using the LNG-IUS and in 10 (26%) women treated with thermal balloon ablation. Overall, women in both groups showed an increased quality of life as a result of the treatment, with Short Form-36 scores increasing from 63.7 at randomisation to 76.1 at 24 months. CONCLUSIONS: At 12 and 24 months of follow up, women with heavy menstrual bleeding treated with the LNG-IUS have significantly lower PBAC scores than women treated with thermal balloon ablation. Both the treatments resulted in a significant increase in overall quality of life, but there were no significant differences between either treatment in quality of life, patient satisfaction or the number of women requesting an alternative treatment during 24 months of follow up.

Adult↗
PubMed2006

The national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis.

OBJECTIVES: This study summarises the results of a National Audit of sino-nasal surgery carried out in England and Wales. It describes patient and operative characteristics as well as patient outcomes up to 36 months after surgery. DESIGN: Prospective cohort study. SETTING: NHS hospitals in England and Wales. PARTICIPANTS: Consecutive patients undergoing surgery for nasal polyposis and/or chronic rhinosinusitis. MAIN OUTCOME MEASURE: The total score derived from a 22-item version of the Sino-Nasal Outcome Test (SNOT-22). Lower scores represent better health-related quality of life. RESULTS: A total of 3128 consecutive patients at 87 NHS hospitals were enrolled. There is a large improvement in SNOT-22 scores from the pre-operative period (mean = 42.0) to 3 months after surgery (mean = 25.5). The scores for patients undergoing nasal polypectomy improved from 41.0 before surgery to 23.1 at 3 months after surgery, while the scores for patients undergoing surgery for chronic rhinosinusitis alone improved from 44.2 to 31.2. The SNOT-22 scores reported at 12 and 36 months after surgery were similar to those reported at 3 months. Excessive bleeding occurred in 5% of patients during the operation and in 1% of patients after the operation. Intra-orbital complications were reported in 0.2%. Of those patients undergoing primary surgery for bilateral grade I or II polyposis, 18% had not received a pre-operative course of steroid treatment. At the 36-month follow-up, 11.4% of patients had undergone revision surgery. CONCLUSIONS: The audit confirms that sino-nasal surgery is generally safe and effective. There is some evidence that patient selection for surgery could be improved.

Adolescent↗
PubMed2005

Further evidence for small-bodied hominins from the Late Pleistocene of Flores, Indonesia.

Homo floresiensis was recovered from Late Pleistocene deposits on the island of Flores in eastern Indonesia, but has the stature, limb proportions and endocranial volume of African Pliocene Australopithecus. The holotype of the species (LB1), excavated in 2003 from Liang Bua, consisted of a partial skeleton minus the arms. Here we describe additional H. floresiensis remains excavated from the cave in 2004. These include arm bones belonging to the holotype skeleton, a second adult mandible, and postcranial material from other individuals. We can now reconstruct the body proportions of H. floresiensis with some certainty. The finds further demonstrate that LB1 is not just an aberrant or pathological individual, but is representative of a long-term population that was present during the interval 95-74 to 12 thousand years ago. The excavation also yielded more evidence for the depositional history of the cave and for the behavioural capabilities of H. floresiensis, including the butchery of Stegodon and use of fire.

Aging↗
PubMed2005

Activation of the subthalamic region during emotional processing in Parkinson disease.

OBJECTIVE: To elucidate the involvement of the human subthalamic nucleus (STN) region in the processing or transmission of emotional information. METHODS: Local field potentials (LFPs) were recorded from this region in 10 patients with Parkinson disease (PD) undergoing bilateral implantation of the STN for high-frequency stimulation. LFP recordings were made while patients viewed pleasant and unpleasant emotionally arousing and neutral pictures. RESULTS: A significant decrease (event-related desynchronization [ERD]) in the local alpha power (8 to 12 Hz) was found for all stimulus categories starting at about 0.5 seconds after stimulus presentation. However, 1 to 2 seconds poststimulus, the ERD was larger in trials of pleasant (mean ERD: 21.6 +/- 2.8%; p < 0.009) and unpleasant (mean ERD: 15.0 +/- 4.2%; p = 0.018) stimuli compared with neutral stimuli (mean ERD: 4.4 +/- 4.2%). CONCLUSION: The delayed modulation of alpha activity recorded from the area of the subthalamic nucleus in PD may reflect the processing or transmission of information related to emotional stimuli. "Limbic" activation in the region of the subthalamic nucleus may explain why high-frequency stimulation of the subthalamic nucleus alters affect in some patients with PD.

Affect↗
PubMed2005

A comparison of fibre counting across three European national proficiency testing schemes.

Proficiency testing (PT) schemes seek to improve and maintain consistency in asbestos fibre counting by circulating mounted samples to laboratories, which return counts for comparison with consensus reference values. This study compares the level of these consensus values in three (Spanish, Belgian and UK) national PT schemes. It also assesses the effect of the imminent change in the European standard rules for counting asbestos fibres, to the new rules from the World Health Organisation (WHO), which will include more fibres. Forty samples from the three schemes were circulated to six laboratories, two in each national scheme. The UK and Spanish laboratories counted using both the ERM and the WHO method. Belgian laboratories already use the WHO method, and they counted only by this method. Densities from counts in this sample exchange served as a common basis against which we compared the national reference values (R). This produced a geometric overall mean ratio of R to exchange mean density of 0.94 for the UK scheme, 1.01 for the Spanish and 0.97 for the Belgian scheme, and thus indicated remarkably similar levels. Nevertheless, non-trivial systematic inter-laboratory differences confirmed the need for regular PT and international inter-laboratory comparisons. Examination of previous data from the national PT schemes and from an international scheme (AFRICA) provided further comparisons for the same laboratories (either comparing the laboratory's data with R values or making direct comparisons between laboratories) that are consistent with those from this special exchange. The change in fibre counting rule (to include fibres apparently touching particles with diameter >3 microm) produced mean increases in reported densities that ranged among samples from 0 to 70% (highest individual estimate 170%); the effect was broadly similar for the three schemes. The laboratories gave mostly similar estimates of percentage increase; however, one laboratory occasionally produced high estimates indicating a possible need for training for using the new method.

Air Pollutants, Occupational↗
PubMed2005

Coherent spike-wave oscillations in the cortex and subthalamic nucleus of the freely moving rat.

The basal ganglia play a critical role in controlling seizures in animal models of idiopathic non-convulsive (absence) epilepsy. Inappropriate output from the substantia nigra pars reticulata (SNr) is known to exacerbate seizures, but the precise neuronal mechanisms underlying abnormal activity in SNr remain unclear. To test the hypothesis that cortical spike-wave oscillations, often considered indicative of absence seizures, propagate to the subthalamic nucleus, an important afferent of SNr, we simultaneously recorded local field potentials from the frontal cortex and subthalamic nucleus of freely moving rats. Spontaneous spike-wave oscillations in cortex (mean dominant frequency of 7.4 Hz) were associated with similar oscillations in the subthalamic nucleus (mean of 7.9 Hz). The power of oscillations at 5-9 Hz was significantly higher during spike-wave activity as compared with rest periods without this activity. Importantly, spike-wave oscillations in cortex and subthalamic nucleus were significantly coherent across a range of frequencies (3-40 Hz), and the dominant (7-8 Hz) oscillatory activity in the subthalamic nucleus typically followed that in cortex with a small time lag (mean of 2.7 ms). In conclusion, these data suggest that ensembles of subthalamic nucleus neurons are rapidly recruited into oscillations during cortical spike-wave activity, thus adding further weight to the importance of the subthalamic nucleus in absence epilepsy. An increase in synchronous oscillatory input from the subthalamic nucleus could thus partly underlie the expression of pathological activity in SNr that could, in turn, aggravate seizures. Finally, these findings also reiterate the importance of oscillations in these circuits in normal behaviour.

Action Potentials↗
PubMed2005

Blood infectivity, processing and screening tests in transmissible spongiform encephalopathy.

Surprising advances have been made in the areas of blood infectivity, infectivity removal and, especially, blood screening tests for transmissible spongiform encephalopathy (TSE) in the past few years. In fact, if anyone as recently as last year had suggested that a screening test for preclinical human infection might be available before the end of 2005, the statement would have been met with smiling disbelief. Nevertheless, it can be confidently predicted that the diagnostic misfolded 'prion' protein (PrP(TSE)) will soon be reliably detectable in blood during the symptomatic phase of disease, and it is highly probable that it will also be detectable in blood from at least a proportion of infected individuals during the preclinical phase of disease.

Aged↗
PubMed2005

Levodopa-induced modulation of subthalamic beta oscillations during self-paced movements in patients with Parkinson's disease.

Excessive synchronization of neural activity in the beta frequency band ( approximately 20 Hz) within basal ganglia circuits might contribute to the paucity and slowness of movement in Parkinson's disease (PD). Treatment with dopaminergic drugs reduces the background level of beta frequency band synchronization in the subthalamic nucleus (STN), but has not been shown to increase the proportion of beta activity that is suppressed before voluntary movement in PD. We assessed changes in the event-related desynchronization (ERD) in the beta frequency band of local field potential signals from the region of the STN in 14 patients with PD as they performed self-paced movements of a joystick before and after levodopa administration. The dopamine precursor, levodopa, increased the duration and magnitude of the premovement beta ERD, but did not alter postmovement synchronization in the beta band. Both the latency and magnitude of the beta ERD inversely correlated with the degree of motor impairment. These findings suggest that the beta ERD recorded in the STN area reflects motor-preparative processes that are at least partly dependent on dopaminergic activity within the basal ganglia.

Adult↗
PubMed2005

Coarse and reliable geometric alignment for protein docking.

We present an efficient algorithm for generating a small set of coarse alignments between interacting proteins using meaningful features on their surfaces. The proteins are treated as rigid bodies, but the results are more generally useful as the produced configurations can serve as input to local improvement algorithms that allow for protein flexibility. We apply our algorithm to a diverse set of protein complexes from the Protein Data Bank, demonstrating the effectivity of our algorithm, both for bound and for unbound protein docking problems.

Algorithms↗
PubMed2005

A clinical audit of the quality of care of hypertension in general practice.

Clinical audits monitor the use of particular interventions, or the care received by patients, against agreed standards. Any departures from "best practice" can then be examined, and causes can be determined and acted upon. The Ministry of Health (MOH), Jamaica, has recently published standards of care for hypertension. The medical records of a convenience sample of 125 hypertensive patients being managed by five current family medicine residents in their respective primary care practices were audited Initial results showed limited adherence to the MOH recommended hypertension management guidelines. The same practices were re-audited after an interval of six months, during which time the physicians were sensitized to the results of the preliminary audit. Marked improvements were noted in the second audit. Assessment for co-risk factors for hypertension-related diseases improved: nutritional advice (33% to 74%), smoking and alcohol intake history (40% to 65%) and history taking of physical activity (30% to 47%). Assessment for target organ damage also improved: fundoscopy done (11% to 54%), foot examination done (30% to 58%) and yearly electrolytes done (28% to 62%). There are clear gaps between current practice and standards that exist internationally and locally for management of hypertension. The MOH needs to disseminate and educate general practitioners about the standards of care guidelines.

Adult↗