Transfusion medicine and spongiform encephalopathy.
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Blood Transfusion↗
Biomedical subjects
P Brown
Publications and source records attributed to P Brown.
Blood infectivity and the prospects for a diagnostic screening test in Creutzfeldt-Jakob disease.
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Animals↗
Residential and nursing home care of elderly people with cognitive impairment: prevalence, mortality and costs.
Cognitive impairment among residents has considerable resource implications for both individuals and those responsible for publicly funded care. Two linked surveys were carried out in England: (1) a longitudinal study followed 2500 admissions to publicly funded care up to 42 months after admission; and (2) a cross-sectional survey of 618 homes collected information about 11,900 residents. Information was collected about cognitive impairment using the Minimum Data Set Cognitive Performance Scale. Cognitive impairment was associated with source of funding and type of home. Although level of cognitive impairment has some effect, fees and costs were most influenced by type of home. At the same level of impairment, self-funded residents were more likely to be located in relatively low-cost settings than publicly funded residents. In independent homes fees were lower for publicly funded than for self-funded residents. Overall median length of stay of publicly funded admissions was 18 months. For the most part length of stay was not associated with level of cognitive impairment on admission. It is concluded that more information is needed about the effect of quality of care on people with cognitive impairment in different settings. If the same quality of care can be achieved in residential and nursing homes, the evidence would suggest that changes in placement policies could result in potential savings to the public purse.
Activities of Daily Living↗
Missing value estimation methods for DNA microarrays.
MOTIVATION: Gene expression microarray experiments can generate data sets with multiple missing expression values. Unfortunately, many algorithms for gene expression analysis require a complete matrix of gene array values as input. For example, methods such as hierarchical clustering and K-means clustering are not robust to missing data, and may lose effectiveness even with a few missing values. Methods for imputing missing data are needed, therefore, to minimize the effect of incomplete data sets on analyses, and to increase the range of data sets to which these algorithms can be applied. In this report, we investigate automated methods for estimating missing data. RESULTS: We present a comparative study of several methods for the estimation of missing values in gene microarray data. We implemented and evaluated three methods: a Singular Value Decomposition (SVD) based method (SVDimpute), weighted K-nearest neighbors (KNNimpute), and row average. We evaluated the methods using a variety of parameter settings and over different real data sets, and assessed the robustness of the imputation methods to the amount of missing data over the range of 1--20% missing values. We show that KNNimpute appears to provide a more robust and sensitive method for missing value estimation than SVDimpute, and both SVDimpute and KNNimpute surpass the commonly used row average method (as well as filling missing values with zeros). We report results of the comparative experiments and provide recommendations and tools for accurate estimation of missing microarray data under a variety of conditions.
Algorithms↗
Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial and generalized seizures: A newly recognized epilepsy syndrome with linkage to chromosome 2p11.1-q12.2.
We describe a pedigree in which eight individuals presented with a non-progressive disorder with onset between the ages of 12 and 50 years. It was characterized by predominantly distal, semi-continuous rhythmic myoclonus (all patients), generalized tonic-clonic seizures (all patients) and complex partial seizures (three patients). Most individuals had rarely suffered seizures and had a normal cognitive level, but three individuals with intractable seizures had mild mental retardation. The pattern of inheritance was autosomal dominant with high penetrance. We defined this disorder as autosomal dominant cortical myoclonus and epilepsy (ADCME). All patients had frontotemporal as well as generalized interictal EEG abnormalities. A neurophysiological study of the myoclonus suggested a cortical origin. Back-averaging of the data generated a series of waves with a frequency that mirrored the frequency of EMG bursts. Frequency analysis identified significant peaks with coherence between EMG and EEG, which were recorded over the contralateral rolandic area in five patients. The frequency of coherence was 8-25 Hz and phase spectra confirmed that EEG activity preceded EMG activity by 8-15 ms. In two individuals there was also significant coherence between the ipsilateral EEG and EMG, consistent with the transcallosal spread of myoclonic activity. The C-reflex at rest was enhanced and somatosensory and visual evoked potentials were of high amplitude. The resting motor threshold intensity to transcranial magnetic stimulation was significantly reduced (38%; SD +/- 7; P = 0.01) and the post-motor evoked potential silent period (101 ms; SEM +/- 10) was significantly shortened compared with the controls (137 ms; SEM +/- 18). These clinical and neuro- physiological characteristics suggest diffuse cortical hyperexcitability and high propensity for intra-hemispheric and inter-hemispheric cortical spread, as well as rhythmic myoclonic activity. Genome-wide linkage analysis identified a critical region spanning 12.4 cM between markers D2S2161 and D2S1897 in 2p11.1-q12.2, with a maximum two-point LOD score of 3.46 at Theta 0.0 for marker D2S2175. Multipoint LOD score values, reaching 3.74 around D2S2175, localize the ADCME gene to the centromeric region of chromosome 2. The exclusion of the locus for familial adult myoclonic epilepsy on chromosome 8q23.3-q24 from linkage to our family and the new localization of the responsible gene to chromosome 2cen, together with the different phenotype, define a new epilepsy syndrome. We hypothesize that the responsible gene causes cortical hyperexcitability that is widespread but particularly involves the frontotemporal circuits.
Adult↗
Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson's disease.
Ten patients with Parkinson's disease were seen following bilateral or unilateral implantation of macroelectrodes into the subthalamic nucleus. Local field potentials (LFPs) were recorded from adjacent subthalamic nucleus macroelectrode (STNME) contacts simultaneously with EEG activity over the supplementary motor (Cz-FCz) and sensorimotor (C3/4-FC3/4) areas and EMG activity from the contralateral wrist extensors during isometric and phasic wrist movements. Significant coherence was seen between STNME LFPs and Cz-FCz, STNME LFPs and C3/4-FC3/4, and STNME LFPs and EMG over the range 7-45 Hz. EEG phase-led STNME LFPs by 24.4 ms (95% confidence interval 19.8 to 29.0 ms). EMG also led STNME LFPs, but time differences tended to cluster around one of two values: 6.3 ms (-0.7 to 13.3 ms) and 46.5 ms (26.2 to 66.8 ms). Recordings from the STNME contact that demonstrated the most consistent coherence with Cz-FCz in the 15-30 Hz band coincided with the contact which, when electrically stimulated at high frequencies, produced the most effective clinical response in eight out of nine (89%) subjects (P < 0.01). Oscillatory activity at 15-30 Hz may therefore prove of use in localizing the subthalamic nucleus target that provides the best clinical effect on stimulation. These results extend the hypothesis that coherent activity may be useful in binding together related activities in simultaneously active motor centres. The presence of coherence between EEG and STNME LFPs in both the beta and the gamma band (as opposed to only the beta band between EEG and cerebellar thalamus) suggests that there may be some relative frequency selectivity in the communication between different motor structures.
Aged↗
Evidence for subcortical involvement in the visual control of human reaching.
To test whether the most rapid visually evoked reach adjustments are cortically organized in humans, we have measured their latency in a healthy subject with complete agenesis of the corpus callosum. This condition precludes direct communication between left and right cerebral cortices and so, in this subject, a purely cortical visuomotor process would be expected to produce longer-latency responses to a target that appears in the visual hemifield contralateral to the responding limb (crossed) compared with the ipsilateral hemifield (uncrossed). As predicted, when performing simple reaction time tasks that involved lifting a finger or an arm in response to a visual stimulus presented to either hemifield, this acallosal subject showed a significant crossed-uncrossed latency difference (mean 35.8 ms) that was not present in control subjects (group mean 2.2 ms). In contrast, when she reached for a target that unexpectedly jumped into either visual hemifield, the latencies of mid-flight adjustment were the same (approximately 120 ms) irrespective of either the target jump direction or which hand was used. This was not due to an early movement of the eyes bringing the target back on to the fovea since this subject's finger always deviated towards the new target position in advance of her eyes. Neither could it be explained by the use of ipsilateral corticospinal projections since transcranial magnetic stimulation over the motor cortex failed to evoke ipsilateral responses in arm or hand muscles. These results suggest that, even in humans, subcortical structures are involved in the fastest adjustments of the reaching arm made in response to fresh visual information. An additional finding in this subject was that, when reaching, the eye saccadic latency was greater by 36 ms on average when the target jumped right compared with left, irrespective of which hand was being used. This is the same value as the mean interhemispheric transfer time obtained in the simple reaction time tasks and may indicate right-hemispheric dominance for saccadic eye movement control.
Adolescent↗
Sperm swim-up techniques and DNA fragmentation.
BACKGROUND: Swim-up techniques for sperm separation may have detrimental effects on sperm DNA. We wished to determine whether the normal swim-up method with centrifugation used in our laboratory, which involves a centrifugation step, was harmful to sperm compared with swim-up without centrifugation. METHODS: Semen samples were obtained from patients undergoing IVF or andrology assessment. An aliquot was removed for fixation and subsequent DNA fragmentation determination. The remaining sample was divided into two equal parts, which were subjected to swim-up either with (normal swim-up) or without (direct-swim-up) centrifugation. Semen analysis was performed both before and after swim-up. DNA fragmentation, in spermatozoa previously fixed in 4% paraformaldehyde, was assessed by the terminal transferase-mediated DNA end-labelling procedure (TUNEL). The percentage of spermatozoa with DNA damage after each swim-up technique was compared with that in the original semen sample. RESULTS: DNA damage was <5% in most samples. No significant change in DNA fragmentation was observed between the two swim-up procedures, although the 'normal' swim-up sample had significantly less DNA fragmentation than the pre-swim-up sample. CONCLUSIONS: We conclude that our normal swim-up technique caused no more DNA damage to spermatozoa from normal semen samples than a direct swim-up technique that involved no centrifugation step.
Adult↗
Differentiation of glucose transport in human brain gray and white matter.
Localized 1H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible Michaelis-Menten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, V(max), to the cerebral metabolic utilization rate of glucose, CMR(Glc), was 3.2 +/- 0.10 and 3.9 +/- 0.15 for gray matter and white matter using the standard transport model and 1.8 +/- 0.10 and 2.2 +/- 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant K(m) was 6.2 +/- 0.85 and 7.3 +/- 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 +/- 0.66 and 1.7 +/- 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMR(Glc) in white matter, this finding suggests that blood--brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood--brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.
Adult↗
Designing and delivering neonatal care in single rooms.
This article will outline the phases of the design process and describe the outcomes as related to a specific neonatal intensive care design project. The single-room concept allows for increased privacy and confidentiality, as well as decreased stress of family, staff, and especially patients. The improvement in family space facilitates improved opportunities for encouraging parent and sibling participation in care. Specific developmental and technological improvements have also been gained and are outlined throughout the article.
Health Facility Environment↗
Genetic control of natural variation in Arabidopsis glucosinolate accumulation.
Glucosinolates are biologically active secondary metabolites of the Brassicaceae and related plant families that influence plant/insect interactions. Specific glucosinolates can act as feeding deterrents or stimulants, depending upon the insect species. Hence, natural selection might favor the presence of diverse glucosinolate profiles within a given species. We determined quantitative and qualitative variation in glucosinolates in the leaves and seeds of 39 Arabidopsis ecotypes. We identified 34 different glucosinolates, of which the majority are chain-elongated compounds derived from methionine. Polymorphism at only five loci was sufficient to generate 14 qualitatitvely different leaf glucosinolate profiles. Thus, there appears to be a modular genetic system regulating glucosinolate profiles in Arabidopsis. This system allows the rapid generation of new glucosinolate combinations in response to changing herbivory or other selective pressures. In addition to the qualitative variation in glucosinolate profiles, we found a nearly 20-fold difference in the quantity of total aliphatic glucosinolates and were able to identify a single locus that controls nearly three-quarters of this variation.
Arabidopsis↗
Crystal structure of Staphylococcus aureus tyrosyl-tRNA synthetase in complex with a class of potent and specific inhibitors.
SB-219383 and its analogues are a class of potent and specific inhibitors of bacterial tyrosyl-tRNA synthetases. Crystal structures of these inhibitors have been solved in complex with the tyrosyl-tRNA synthetase from Staphylococcus aureus, the bacterium that is largely responsible for hospital-acquired infections. The full-length enzyme yielded crystals that diffracted to 2.8 A resolution, but a truncated version of the enzyme allowed the resolution to be extended to 2.2 A. These inhibitors not only occupy the known substrate binding sites in unique ways, but also reveal a butyl binding pocket. It was reported that the Bacillus stearothermophilus TyrRS T51P mutant has much increased catalytic activity. The S. aureus enzyme happens to have a proline at position 51. Therefore, our structures may contribute to the understanding of the catalytic mechanism and provide the structural basis for designing novel antimicrobial agents.
Amino Acid Sequence↗
Functional characterisation of the volume-sensitive anion channel in rat pancreatic beta-cells.
The whole-cell and perforated patch configurations of the patch-clamp technique were used to characterise the volume-sensitive anion channel in rat pancreatic beta-cells. The channel showed high permeability (P ) relative to Cl(-) to extracellular monovalent organic anions (P(SCN)/P(Cll) = 1.73, P(acetate)/P(Cll) = 0.39, P(lactate)/P(Cll) = 0.38, P(acetoacetate)/P(Cll) = 0.32, P(glutamate)/P(Cll) = 0.28) but was less permeable to the divalent anion malate (P(malate)/P(Cll) = 0.14). Channel activity was inhibited by a number of putative anion channel inhibitors, including extracellular ATP (10 mM), 1,9-dideoxyforskolin (100 microM) and 4-OH tamoxifen (10 microM). Inclusion of the catalytic subunit of protein kinase A in the pipette solution did not activate the volume-sensitive anion channel in non-swollen cells. Furthermore, addition of 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) or forskolin failed to activate the channel in intact cells under perforated patch conditions. Addition of phorbol 12,13-dibutyrate (200 nM), either before or after cell swelling, also failed to affect channel activation. Our findings do not support the suggestion that the volume-sensitive anion channel in pancreatic beta-cells can be activated by protein kinase A. Furthermore, the beta-cell channel does not appear to be subject to regulation via protein kinase C. Experimental Physiology (2001) 86.2, 145-150.
Animals↗
Potential for bias in waiting time studies: events between enrolment and admission.
STUDY OBJECTIVE: To demonstrate the effect of exclusion of data on delays in scheduling operations in calculating difference in admission rates between two enrolment periods. DESIGN: A prospective cohort study; outcome measure-waiting time for elective admission; study variables-enrolment periods, before 31 March 1997 and after that date; the time of scheduling delay; gender; age; urgency, and type of surgery. SETTING: An acute care hospital in Ontario, Canada. PARTICIPANTS: 1173 consecutive cases accepted for elective vascular surgery between 1 July 1994 and 31 March 1999. MAIN RESULTS: Before adjustment for scheduling delays, a 20% lower admission rate was associated with period 2, rate ratio (RR) = 0.8 (95% confidence intervals (CI)= 0.7, 0.9). The difference between the periods became only marginally significant after the adjustment, RR = 0.9 (95% CI=0.8, 1.0). No difference between the periods was found when admission rates were compared before a delay occurred, RR = 0.9 (95% CI=0.8, 1.1). In delayed patients, those enrolled in period 1 and 2 had, respectively, a 40% and a 60% lower admission rate than the period 1 patients admitted without scheduling delays, RR = 0.6 (95% CI=0.4, 0.8) for period 1 and RR = 0.4 (95%CI=0.3, 0.5) for period 2. CONCLUSIONS: The results provide evidence that patients experiencing a delay in scheduling operation have a lower admission rate after the event. Thus, potential for bias exists when between group comparison of waiting time is done without adjustment for an intermediate event that may occur before elective admission.
Adult↗
Transverse myelopathy and radiculomyelopathy associated with pulmonary atypical Mycobacterium infections.
Myelopathy is a well recognised but rare association with Mycobacterium tuberculosis infection, but has not been described with atypical mycobacteria. We report two cases of disabling myelopathy in association with pulmonary infection by Mycobacterium kansasii and Mycobacterium malmoense; the myelopathy is presumed to be a para-infectious phenomenon.
Adult↗
Thy1 glomerulonephritis induced in young lewis rats accelerates age-related glomerulosclerosis.
Age-related and disease-induced glomerulosclerosis (GS) in rats have both been well defined in a number of strains and experimental models, but the inter-relationship between the two is not clear. The present study was undertaken to compare the pattern of glomerular injury in these two types of GS. One- and two-shot Thy1 glomerulonephritis (GN) was induced at 2 months of age and followed for 12 months. At 12 months histological injury in proteinuric rats was characterized by segmental hyaline lesions. Two-shot Thy1 GN resulted in accelerated, but morphologically identical injury at 8 months. Histological lesions predictive of subsequent accelerated GS were evaluated at 1, 2, 4 and 6 months. In this regard, glomerular hypercellularity, rather than hypertrophy or matrix increase, was the most consistent histological index of later accelerated disease. The profibrotic cytokines transforming growth factor (TGF)-beta(1) and -beta(3) were localized distinctly to segmental hyaline lesions, but not to areas of matrix increase within the glomerular tuft. This study reveals that GS after Thy1 GN represents acceleration of an age-related disease, presents evidence for use of prolonged glomerular hypercellularity as the best histological index of future disease progression, and correlates the key lesion of GS in these animals, the segmental hyaline lesion, with the presence of TGF-beta peptides.
Aging↗
Cortical network resonance and motor activity in humans.
Large areas of the human motor cortex are devoted to the control of the contralateral hand and forearm. Just how activities scattered across these motor areas may be brought together in the execution of a given movement remains unclear. There is increasing evidence, largely from animal studies, suggesting that sensory integration involves the synchronization of activity between spatially distributed cortical sites. Here we review recent evidence that cortical activity becomes oscillatory and synchronized between spatially distributed sites during performance of a movement in humans. Cortico-cortical synchronization may occur with a precision in the millisecond range, is essentially limited to those cortical elements active in a given task, and changes in both its distribution and frequency in a task-related manner. Synchronization at specific frequencies may therefore link disparate cortical activities into the functional ensembles underlying voluntary movement in humans.
Animals↗
Community cancer control in a rural, underserved population: the Appalachian Leadership Initiative on Cancer Project.
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Appalachian Region↗