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R Bullock

Publications and source records attributed to R Bullock.

At least 19 recordsLinked to original sources
PubMed2002

Risperidone in the treatment of psychoses in the elderly: a case report series.

Risperidone is one of the newer atypical antipsychotic agents, which combines potent serotonin and dopamine receptor antagonism. It shows efficacy against the positive and negative symptoms of schizophrenic psychoses and other psychotic conditions, and has a low propensity to cause extrapyramidal side effects. The aim of these case reports in elderly patients is to provide the benefit of personal experience with risperidone to the body of published literature and to demonstrate the types of patients that may benefit from treatment. These cases were compiled retrospectively from data collected on referral and during routine hospital appointments. This series covers four main areas of concern when treating the elderly: low-maintenance dosing minimising the likelihood of adverse events; successful treatment of patients previously uncontrolled and experiencing side effects with other antipsychotics; the possibility of intermittent rather than continuous treatment; and the benefits to patients, carers and the health services. At low doses, risperidone is an effective and well-tolerated treatment for psychoses in elderly patients that improves the quality of life for both patients and their caregivers.

Aged↗
PubMed2002

The clinical benefits of rivastigmine may reflect its dual inhibitory mode of action: an hypothesis.

Recent health technology assessments have given us the go-ahead to use cholinesterase inhibitors, which, in combination with community services, are currently the most appropriate treatment for patients with Alzheimer's disease (AD). Initial research focused upon acetylcholinesterase (AChE)-selective agents, but it is now thought that dual inhibitors of AChE and butyrylcholinesterase (BuChE) may provide more sustained efficacy over the course of AD and may help to slow disease progression. Rivastigmine is a potent inhibitor of AChE and BuChE and has demonstrated broad benefits across the severity of AD and across the cognitive, functional and behavioural domains of AD. In addition, rivastigmine has shown cognitive and behavioural benefits in patients with dementia with the Lewy body variant of AD. These benefits may reflect the inhibition of both AChE and BuChE, as demonstrated by significant correlations between cognitive improvements and cholinesterase inhibition in rivastigmine-treated patients with AD. Rivastigmine shows a clear dose-response relationship, and physicians should aim to maintain patients on doses of 6 mg/day or higher, to a maximum of 12 mg/day. As with all cholinesterase inhibitors, rapid forced dose escalation may increase the incidence of typical cholinergic side-effects, resulting in lower maintenance doses. In a chronic disease such as AD, there is time to implement slow dose escalation and higher final maintenance doses. If used appropriately, the benefits of rivastigmine seen in clinical practice may prove to be even greater than those reported in clinical trials.

Aged↗
PubMed2001

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease.

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.

Age of Onset↗
PubMed2001

Induced mitochondrial failure in the feline brain: implications for understanding acute post-traumatic metabolic events.

OBJECTIVE: Recently, evidence has become available implicating mitochondrial failure as a crucial factor in the pathogenesis of acute brain damage following severe traumatic brain injury (TBI). However, it remains unclear how mitochondrial dysfunction affects cerebral metabolism. Therefore the aim of the study was to evaluate the impact of 'isolated' mitochondrial failure on local cerebral metabolism. METHODS: Cerebral mitochondrial metabolism was blocked by local microdialysis perfusion with cyanide in seven cats. Local brain tissue oxygen tension (p(tiO(2))), carbon dioxide tension (p(tiCO(2))) and pH, as well as extracellular cerebral fluid, glucose, lactate, pyruvate and glutamate were monitored, using a Neurotrend sensor and microdialysis, respectively. Tissue oxygen consumption was measured in a microrespirometric system, and ultrastructural changes evaluated via electron microscopy. RESULTS: Brain tissue oxygen tension increased from a baseline of 31+/-9 mmHg to 84+/-30 mmHg after 60 min of cyanide perfusion (P<0.05), concomitant a decrease in oxygen consumption from 14.45+/-3.91 microl/h/mg to 10.83+/-1.74 microl/h/mg (P<0.05). Brain tissue pH was decreased after 60 min of cyanide perfusion (6.83+/-0.16) compared to baseline (7.07+/-0.39) (P<0.05), whereas p(tiCO(2)) did not show significant changes. Lactate massively increased from a baseline of 599+/-270 micromol/l to 2609+/-1188 micromol/l immediately after cyanide perfusion (P<0.05). The lactate:glucose ratio increased from 0.79+/-0.15 before cyanide perfusion to 6.40+/-1.44 at 40 min after cyanide perfusion (P<0.05), while no significant changes in the lactate:pyruvate ratio could be observed. Glutamate increased from a baseline of 11.6+/-7.2 micromol/l to 61.4+/-44.7 micromol/l after cyanide perfusion (P<0.05). CONCLUSION: The results of this study show that 'isolated' cerebral mitochondrial failure initiates changes in cerebral substrates and biochemistry, which are very similar to most of the changes seen after severe human head injury, except for the early fall in p(tiO(2)), further indicating a crucial involvement of mitochondrial impairment in the development of brain damage after TBI.

Animals↗
PubMed2001

Peri-operative risk factors for acute lung injury after elective oesophagectomy.

Acute lung injury after oesophagectomy is well recognized but the risk factors associated with its development are poorly defined. We analysed retrospectively the effect of a number of pre-, peri- and post-operative risk factors on the development of lung injury in 168 patients after elective oesophagectomy performed at a single centre. The acute respiratory distress syndrome (ARDS) developed in 14.5% of patients and acute lung injury in 23.8%. Mortality in patients developing ARDS was 50% compared with 3.5% in the remainder. Features associated with the development of ARDS included a low pre-operative body mass index, a history of cigarette smoking, the experience of the surgeon, the duration of both the operation and of one-lung ventilation, and the occurrence of a post-operative anastomotic leak. Peri-operative cardiorespiratory instability (measured by peri-operative hypoxaemia, hypotension, fluid and blood requirements and the need for inotropic support) was also associated with ARDS. Acute lung injury after elective oesophagectomy is associated with intraoperative cardiorespiratory instability.

Analysis of Variance↗
PubMed2001

Circulating endothelial cells in patients with septic shock.

The vascular endothelium has a central role in the control of microvascular tone, and it has been proposed that vascular endothelial damage occurs in septic shock, producing multiorgan failure. We have developed a method of detecting circulating endothelial cells (EC) that provides direct evidence of EC shedding in human sepsis. Human umbilical vein endothelial cells (HUVEC) were seeded in whole blood and recovered by isopycnic centrifugation to validate the technique. Blood samples were subsequently taken from 11 healthy volunteers, nine ventilated intensive care unit (ICU) control patients without sepsis, eight patients with sepsis but without shock, and 15 patients with septic shock. EC were identified by indirect immunofluorescence, using antibodies to von Willebrand factor (vWf) and the vascular endothelial growth factor receptor KDR. Mean HUVEC recovery was 86% for 20 to 100 seeded cells/ml of blood. vWf-positive EC counts per milliliter were significantly higher (analysis of variance [ANOVA], p < 0.0001) in patients with sepsis (16.1 +/- 2.7 [mean +/- SEM]) and septic shock (30.1 +/- 3.3) than in healthy (1.9 +/- 0.5) or ICU controls (2.6 +/- 0.6). KDR-positive EC counts per milliliter were also significantly higher (ANOVA, p < 0.0001) in patients with sepsis (4.2 +/- 1.1/ml) and septic shock (10.4 +/- 1.2/ml) than in healthy (0.7 +/- 0.3/ml) or ICU controls (0.5 +/- 0.2/ml). Cell counts made with anti-vWf antibody were consistently higher than those made with anti KDR antibody, but correlation between the two counts was high (r(2) = 0.93). The number of circulating KDR-positive EC was significantly higher in patients who died of septic shock than in survivors (12.0 +/- 1.6/ml versus 7.1 +/- 1.2/ml, p = 0.026). An increase in circulating EC can be identified during sepsis and septic shock. This supports the hypothesis that endothelial damage occurs in human sepsis.

Adult↗
PubMed2001

Medical treatment and neuroprotection in traumatic brain injury.

The goal of this article is to give an overview about the established current treatment concepts of traumatic brain injury, as well as an outlook on possible future developments in pharmacological neuroprotection. Modern medical treatment modalities of traumatic brain injury (TBI), including the preclinical management of severely head-injured patients, are reviewed. Since an increased intracranial pressure represents the most common complication of severe traumatic brain injury, frequently associated with the development of secondary brain damage, special emphasis was given to an updated treatment algorithm for this important condition. New insight into the pathophysiology of severe traumatic brain injury, especially the realization that brain damage develops sequentially, initiated several new treatment approaches aiming at the interruption of pathophysiological mechanisms leading to secondary brain injury. A high number of pharmacological substances have been tested for their ability to ameliorate secondary damage after TBI, or are currently under clinical trial. Although no drug has achieved this goal so far, the most promising of these therapeutical approaches, glutamate receptor antagonists, calcium channel antagonists, free radical scavengers, and cyclosporin A will be discussed in this review. Although a "magical bullet" for the treatment of traumatic brain injury has not been developed yet, several of the currently investigated neuroprotective strategies seem to be encouraging. A promising future approach might be to evaluate treatment strategies that combine several pharmacological agents, and possibly other treatment modalities, such as mild hypothermia, "tailored" according to the special pathology of patient subgroups, or even to every single patient in order to achieve an improvement in outcome after TBI.

Brain Injuries↗
PubMed2000

Elderly care. Armchair theatre.

The government's plan to free beds in the acute sector by discharging elderly people from hospital into private nursing homes are ill-thought out and a poor response to a complex problem. Older people may come to fear admission to hospital, seeing it as a prelude to being put in a home. Greater investment in community services would be the best hope of appropriate care for many older people. The government should have the need for hospital-based services for older people in the next three years and aim for a corresponding increase in good community services.

Acute Disease↗
PubMed2000

Brain lactate uptake increases at the site of impact after traumatic brain injury.

Although glucose is the main carbohydrate energy substrate for the normal brain, several studies published over the last 10 years now challenge this assumption. The activated brain increases its metabolism to meet increased energy demands by glycolysis after injury. In vitro studies now show that lactate alone can serve as an energy source to maintain synaptic function. In this study, we used 14C-lactate to test the hypothesis that blood lactate is acutely taken up by the injured brain, after fluid percussion injury (FPI) in the rat. 50 microCi radioactive lactate was injected i.v. immediately after FPI, in injured and sham rats. After 30 min, the brain was removed, frozen, and cut into 20 microm sections for autoradiography. Uptake of 14C-label was mainly concentrated at the injury site (2.5 times greater) although uninjured brain also took up the 14C-label. This increased concentration of radioactive lactate at the injury site suggests that the injured brain may use the lactate as an energy source.

Animals↗
PubMed2000

rCBF in hemorrhagic, non-hemorrhagic and mixed contusions after severe head injury and its effect on perilesional cerebral blood flow.

Intracerebral contusions can lead to regional ischemia caused by extensive release of excitotoxic aminoacids leading to increased cytotoxic brain edema and raised intracranial pressure. rCBF measurements might provide further information about the risk of ischemia within and around contusions. Therefore, the aim of the presented study was to compare the intra- and perilesional rCBF of hemorrhagic, non-hemorrhagic and mixed intracerebral contusions. In 44 patients, 60 stable Xenon-enhanced CT CBF-studies were performed (EtCO2 30 +/- 4 mmHg SD), initially 29 hours (39 studies) and subsequent 95 hours after injury (21 studies). All lesions were classified according to localization and lesion type using CT/MRI scans. The rCBF was calculated within and 1-cm adjacent to each lesion in CT-isodens brain. The rCBF within all contusions (n = 100) of 29 +/- 11 ml/100 g/min was significantly lower (p < 0.0001, Mann-Whitney U) compared to perilesional rCBF of 44 +/- 12 ml/100 g/min and intra/perilesional correlation was 0.4 (p < 0.0005). Hemorrhagic contusions showed an intra/perilesional rCBF of 31 +/- 11/44 +/- 13 ml/100 g/min (p < 0.005), non-hemorrhagic contusions 35 +/- 13/46 +/- 10 ml/100 g/min (p < 0.01). rCBF in mixed contusions (25 +/- 9/44 +/- 12 ml/100 g/min, p < 0.0001) was significantly lower compared to hemorrhagic and non-hemorrhagic contusions (p < 0.02). Intracontusional rCBF is significantly reduced to 29 +/- 11 ml/100 g/min but reduced below ischemic levels of 18 ml/100 g/min in only 16% of all contusions. Perilesional CBF in CT normal appearing brain closed to contusions is not critically reduced. Further differentiation of contusions demonstrates significantly lower rCBF in mixed contusions (defined by both hyper- and hypodense areas in the CT-scan) compared to hemorrhagic and non-hemorrhagic contusions. Mixed contusions may evolve from hemorrhagic contusions with secondary increased perilesional cytotoxic brain edema leading to reduced cerebral blood flow and altered brain metabolism. Therefore, the treatment of ICP might be individually modified by the measurement of intra- and pericontusional cerebral blood.

Adolescent↗
PubMed2000

Comparison of NAA measures by MRS and HPLC.

This work investigates the accuracy of an in vivo estimation of absolute N-acetyl aspartate (NAA) concentrations by magnetic resonance spectroscopy (MRS) using cerebral water as an internal reference standard. Single-voxel, proton spectroscopy was carried out in two groups of rats (normal and diffuse head injury), using a PRESS sequence with TR = 3 s, TE = 135 ms. Fully relaxed water spectra and water-suppressed proton spectra were obtained from a 7 x 5 x 5 mm3 volume of tissue. MRI-based brain water content measurements were also performed. Following MRS, HPLC determinations of NAA were carried out. In the normal rats the MRS yielded 10.98 +/- 0.83 mmol/kg w.w. vs 10.76 +/- 0.76 for HPLC with a mean absolute difference of 0.8. In the injured rats the corresponding results were 9.41 +/- 1.78 (MRS) and 8.16 +/- 0.77 (HPLC) with a mean absolute difference of 1.66. The in vivo absolute method accurately documented the temporal NAA changes compared to the NAA/Cr approach.

Animals↗
PubMed2000

Distinguishing between cellular and vasogenic edema in head injured patients with focal lesions using magnetic resonance imaging.

Having determined that edema and not vascular engorgement is the major factor leading to traumatic brain swelling, the objective of this study was to determine which type of edema, cellular or vasogenic, is responsible for increased tissue water in patients with focal lesions. Severely head injured patients (GCS 8 or less) were transported to imaging suites for measurement of brain water and apparent diffusion coefficient (ADC) using magnetic resonance technique. Cerebral blood flow by stable Xenon method was also measured in the regions of interest. Brain water was increased significantly in the hemisphere with lesion. The increase in water was associated with reduced ADC signifying a predominant cellular edema. The ADC in the contralateral hemisphere was near normal value. Cerebral blood flow values in the regions of interest were above ischemic levels suggesting that factors other than ischemia are responsible for the cytotoxic swelling in patients with focal injury.

Blood-Brain Barrier↗
PubMed2000

Evidence for lactate uptake after rat fluid percussion brain injury.

UNLABELLED: Traumatic brain injury (TBI) places enormous early energy demand on brain tissue to reinstate normal ionic balance. Glucose declines and lactate increases after TBI as demonstrated in clinical and lab studies, suggesting increased glycolysis. This led us to hypothesize that high extracellular fluid (ECF) lactate may be beneficial after TBI. We measured cerebral dialysate lactate and glucose, and arterial lactate and glucose, before & after rat Fluid Percussion Injury (FPI) (2.06 +/- 0.13 atm) with and without i.v. lactate infusion (100 mM x 4.5 hours) to test the hypotheses that arterial lactate determines ECF lactate. 14C-lactate autoradiography was also performed, to demonstrate whether lactate is taken up by traumatized brain. RESULTS: Dialysate lactate was always significantly higher than arterial. After lactate infusion, both the dialysate and the arterial lactate were significantly increased (P < 0.0001). Dialysate lactate increased within 10 min. following FPI, with significantly higher values in the lactate infusion group (82% higher with lactate infusion after FPI). Dialysate glucose fell following FPI, with a more severe decline in the saline group (129% lower), suggesting lactate infusion preserves or "spares" glucose in ECF. In our autoradiographic study, i.v. 14C-lactate accumulated at the injury site, with levels 2-4 times higher than in contralateral cortex. In conclusion, arterial lactate augmentation thus increases brain dialysate lactate and results in less reduction in ECF glucose, after FPI. Infused lactate accumulates at the injury site, where metabolism is probably the greatest.

Animals↗
PubMed2000

Mechanical injury alters volume activated ion channels in cortical astrocytes.

UNLABELLED: Although astrocytic swelling is likely to mediate brain edema and high ICP after traumatic brain injury, the mechanism is not understood. We employed whole cell patch clamp electrophysiology and a stretch injury model to understand whether volume regulating ion currents are altered following cell injury. Mixed rat astrocytes and neurons were co-cultured on deformable silastic membranes. Mild-moderate cell injury was produced using a timed pulse of pressurized air to deform the silastic substrates by 6.5 mm. Then, ion currents were recorded with patch clamp methods. Cells were held at -65 mV and were stepped to +10 mV to monitor current changes. RESULTS: In unstretched astrocytes, small amplitude currents were obtained under isotonic conditions. Hypotonic solution activated an outwardly-rectifying current which reversed near -40 mV. This current resembled a previously reported anion current whose activation may restore cell volume by mediating a net solute efflux. In contrast, stretch injured cells exhibited a large amplitude, nonrectifying current. This current was not due to non-specific ionic leakage, since it was fully suppressed by the cation channel blocker gadolinium. Activation of novel stretch-activated cation currents may exacerbate cell swelling in injured astrocytes. Stretch injured astrocytes thus express a dysfunctional cation current as opposed to an osmoregulatory anion current. This mechanism, if present in vivo, may contribute to the cytotoxic swelling seen after traumatic brain injury.

Animals↗
PubMed2000

Low extracellular (ECF) glucose affects the neurochemical profile in severe head-injured patients.

Glucose (Gluc) is the main energy source for the brain. After severe head-injury energy demand is massively increased and supply is often decreased. In pilot microdialysis studies, many patients with severe head-injury had undetectable glucose concentrations, probably reflecting changes in metabolism and/or reduced supply. We therefore investigated whether patients with low ECF glucose (criterion: < 50 microM for > or = 5 hrs), LOWgluc, differ from patients with higher glucose levels (NORMALgluc) We also tested the interrelationships between other parameters such as lactate, glutamate, K+, brain O2 and CO2, ICP, CPP, and CBF in these two groups. We found that patients with low ECF glucose, LOWgluc, have significantly lower lactate concentrations than patients with "normal" glucose, NORMALgluc, levels do. Spearman correlations between glucose and most other parameters were similar in both patient groups. However, glutamate correlated positively with glucose, lactate, brain CO2 and negatively with brain O2 in the NORMALgluc patient group, whereas glutamate did not significantly correlate with any of these parameters in the LOWgluc group. There was also no correlation between outcome and the dialysate glucose. The results indicate that low ECF glucose is almost always present in severe head-injury. Moreover, the lack of correlation between low glucose and outcome, however, suggests that other energy substrates, such as lactate, are important after TBI.

Blood Glucose↗