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Biomedical subjects

T Lewis

Publications and source records attributed to T Lewis.

At least 19 recordsLinked to original sources
PubMed2000

An African swine fever virus ERV1-ALR homologue, 9GL, affects virion maturation and viral growth in macrophages and viral virulence in swine.

The African swine fever virus (ASFV) genome contains a gene, 9GL, with similarity to yeast ERV1 and ALR genes. ERV1 has been shown to function in oxidative phosphorylation and in cell growth, while ALR has hepatotrophic activity. 9GL encodes a protein of 119 amino acids and was highly conserved at both nucleotide and amino acid levels among all ASFV field isolates examined. Monospecific rabbit polyclonal antibody produced to a glutathione S-transferase-9GL fusion protein specifically immunoprecipitated a 14-kDa protein from macrophage cell cultures infected with the ASFV isolate Malawi Lil-20/1 (MAL). Time course analysis and viral DNA synthesis inhibitor experiments indicated that p14 was a late viral protein. A 9GL gene deletion mutant of MAL (Delta9GL), exhibited a growth defect in macrophages of approximately 2 log(10) units and had a small-plaque phenotype compared to either a revertant (9GL-R) or the parental virus. 9GL affected normal virion maturation; virions containing acentric nucleoid structures comprised 90 to 99% of all virions observed in Delta9GL-infected macrophages. The Delta9GL virus was markedly attenuated in swine. In contrast to 9GL-R infection, where mortality was 100%, all Delta9GL-infected animals survived infection. With the exception of a transient fever response in some animals, Delta9GL-infected animals remained clinically normal and exhibited significant 100- to 10,000-fold reductions in viremia titers. All pigs previously infected with Delta9GL survived infection when subsequently challenged with a lethal dose of virulent parental MAL. Thus, ASFV 9GL gene deletion mutants may prove useful as live-attenuated ASF vaccines.

African Swine Fever↗
PubMed1999

Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution.

(-)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop (Galanthus nivalis), shows anticholinesterase activity. This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease. We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase (TcAChE) to 2.3 A resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290). The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring. The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 A) with Glu-199. The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor.

Acetylcholinesterase↗
PubMed1999

Developments with antarctic microorganisms: culture collections, bioactivity screening, taxonomy, PUFA production and cold-adapted enzymes

There have been recent research developments with Antarctic prokaryotes in the areas of isolations of novel bacterial, culture collections, bioactivity screening, taxonomy, production of polyunsaturated fatty acids (PUFAs), cold-adapted enzymes and bioremediation. Research to date confirms the novelty of bacteria isolated from this extreme environment. Opportunities now exist to exploit these and other findings to develop possible new biotechnological products from Antarctic microorganisms.

Journal Article↗
PubMed1999

A new cardiothoracic centre: 'how to do it?'.

All cardiac surgical patients, emergency and routine, from the South West peninsula of England had to travel long distances until 19 months ago, a stressful if not dangerous situation. This paper describes the planning, commissioning and start-up of a brand new cardiac surgical facility. The lessons learnt may help similar projects as provision of specialist health care decentralizes.

Cardiac Care Facilities↗
PubMed1999

Caring for the patient with Paget's disease of the bone.

Approximately 1 to 3 million Americans suffer from Paget's disease of the bone. This chronic disease often results in pain, deformity, and mobility impairments, and can dramatically impair a patient's quality of life. The primary care provider plays a pivotal role in diagnosing and managing the patient with Paget's disease. This article discusses Paget's disease diagnosis, management, pharmacologic therapy, referral, and follow-up.

Chronic Disease↗
PubMed1998

Mapping of a minimal AU-rich sequence required for lipopolysaccharide-induced binding of a 55-kDa protein on tumor necrosis factor-alpha mRNA.

In monocyte/macrophage cells, the translation of tumor necrosis factor-alpha (TNF-alpha) mRNA is tightly controlled. In unstimulated cells, TNF-alpha mRNA is translationally repressed. However, upon stimulation of the cells with various agents (e.g. lipopolysaccharides (LPS) and viruses), this repression is overcome and translation occurs. The key element in this regulation is the AU-rich sequence present in the 3'-untranslated region of TNF-alpha mRNA. Several groups have described the binding of proteins on AU-rich elements (AREs). We have previously reported the binding of two cytosolic protein complexes (1 and 2) to the TNF-alpha mRNA ARE, one of which (complex 2) is observed only following induction of TNF-alpha production by LPS. In this report, we have demonstrated that complex 1 involves a long fragment of the ARE, whereas the formation of the LPS-inducible complex 2 requires a minimal sequence which corresponds to the nonanucleotide UUAUUUAUU. Furthermore, we show that the RNA-binding protein involved in complex 2 has an apparent molecular mass of 55 kDa. Finally, we tested other AREs for their ability to form complex 2. We observed that the ARE derived from granulocyte/macrophage colony-stimulating factor mRNA, which does contain the nonanucleotide, is able to sustain the LPS-induced binding of the 55-kDa protein. However, c-myc mRNA, which does not contain the nonanucleotide, is unable to promote the formation of any LPS-induced complex.

Animals↗
PubMed1998

Are genetic factors important in the aetiology of leukoaraiosis? Results from a memory clinic population.

OBJECTIVE: To discover whether polymorphism in either the apolipoprotein E (ApoE) or angiotensin-converting enzyme (ACE) genes is associated with leukoaraiosis, white matter lesions visible on neuroimaging of the brain, which is commonly seen in dementia as well as some normal elderly subjects. DESIGN: Prospective study of consecutive patients attending our memory disorders clinic, to examine the relationship between leukoaraiosis and polymorphism of the ApoE and ACE genes. SETTING: Memory disorders clinic in Bristol, UK. PATIENTS: 182 patients attending the memory disorders clinic for investigation of possible dementia of whom 75% were suffering from dementia, 20% from memory impairment but no dementia and in 5% of whom a dementing illness was thought to be unlikely; 38% of all patients had visible white matter lesions and 16% had cerebral infarcts. MEASURES: Patients and/or carers who agreed to participate in the study had their ACE and ApoE genotype determined and their brain CT/MRI scans were assessed by a neuroradiologist, blind to the result of the genotyping, for the presence or absence of white matter low attenuation. RESULTS: There was a significant association between white matter lesions and the DD genotype (p < 0.05), but not the ApoE genotype. However, this relationship with the DD genotype was only significant for patients with a previous infarct. CONCLUSION: Homozygosity of ACE gene deletion polymorphism is a risk factor for white matter lesions when it is associated with cerebral infarction. This suggests that it may be possible to identify subjects who are at greater risk of developing white matter lesions and are at risk of cognitive impairment and possibly dementia.

Aged↗
PubMed1998

The hospitalist: will inpatient specialists improve care?

The number of hospitalists--i.e., practitioners who specialize in the care of hospital inpatients--is growing rapidly in the United States. In part a response to managed care's push for better health outcomes with a minimum waste of time, effort, and money, this new specialty has its own national organization, affiliated with the American College of Physicians. Challenges to hospitalists include minimizing the use of consultations and unnecessary laboratory tests for inpatient care, and ensuring continuity of care once patients leave the hospital.

Continuity of Patient Care↗
PubMed1997

Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins.

Mitogens promote cell growth through integrated signal transduction networks that alter cellular metabolism, gene expression and cytoskeletal organization. Many such signals are propagated through activation of MAP kinase cascades partly regulated by upstream small GTP-binding proteins. Interactions among cascades are suspected but not defined. Here we show that Rho family small G proteins such as Rac1 and Cdc42hs, which activate the JNK/SAPK pathway, cooperate with Raf-1 to activate the ERK pathway. This causes activation of ternary complex factors (TCFs), which regulate c-fos gene expression through the serum response element. Examination of ERK pathway kinases shows that neither MEK1 nor Ras will synergize with Rho-type proteins, and that only MEK1 is fully activated, indicating that MEKs are a focal point for cross-cascade regulation. Rho family proteins utilize PAKs for this effect, as expression of an active PAK1 mutant can substitute for Rho family small G proteins, and expression of an interfering PAK1 mutant blocks Rho-type protein stimulation of ERKs. PAK1 phosphorylates MEK1 on Ser298, a site important for binding of Raf-1 to MEK1 in vivo. Expression of interfering PAK1 also reduces stimulation of TCF function by serum growth factors, while expression of active PAK1 enhances EGF-stimulated MEK1 activity. This demonstrates interaction among MAP kinase pathway elements not previously recognized and suggests an explanation for the cooperative effect of Raf-1 and Rho family proteins on cellular transformation.

3T3 Cells↗
PubMed1997

The presence of leuko-araiosis in patients with Alzheimer's disease predicts poor tolerance to tacrine, but does not discriminate responders from non-responders.

BACKGROUND: approximately one-third of patients with Alzheimer's disease (AD) respond favourably to the anticholinesterase tacrine, but the drug's usefulness is marred by a high incidence of side-effects. OBJECTIVE: to discover if AD patients with white matter low attenuation (WMLA) represents a subgroup that responds differently to tacrine from those with no WMLA. DESIGN: the results come from a combination of double-blind and open studies. Seventy-two AD patients prescribed tacrine in our centre were divided into two groups according to the presence or absence of WMLA on brain CT scans. We compared the rate of response to and withdrawal from tacrine between the groups. Response was defined as an improvement in the Mini-Mental State Examination score of three or more points at 3 months. RESULTS: 18 of the 72 patients were found to have WMLA. There was no significant difference in the proportion of patients responding to tacrine in each group (28.5% in those with WMLA and 31% in those without), but the rate of withdrawal from tacrine did differ: 11 patients with WMLA (61%) had to be withdrawn prematurely, compared with 14 patients (26%) in the group without evidence of WMLA (P = 0.015). CONCLUSION: AD patients with WMLA can still respond to tacrine, although the rate of withdrawal from treatment is much higher in such patients.

Alzheimer Disease↗
PubMed1997

Eosinophilia-myalgia syndrome: selective cognitive impairment, longitudinal effects, and neuroimaging findings.

OBJECTIVE: To identify the specific nature of the neurocognitive impairments of eosinophilia-myalgia syndrome (EMS) in an unselected population, and to present longitudinal patterns. METHODS: A consecutive sample of 23 patients with EMS and 18 age and education matched control subjects were assessed on a comprehensive neuropsychological battery. Longitudinal results were gathered from six patients. RESULTS: Neurocognitive impairments were found which represent a subset of deficits reported in previous group and case study reports. Deficits were limited to complex visual memory, conceptual set shifting, and attention, which suggest a selective dysexecutive syndrome. The motor slowing and verbal memory deficits previously reported were not found. Although depression, fatigue, sleep deprivation, and pain were significant symptoms, they were unassociated with deficits with the exception of an association of depression with one deficit. There was no pattern of overall decline over time in a subset of the group, although considerable heterogeneity in the longitudinal patterns of neurocognitive tests was found. Abnormalities of white matter appeared in the MRI of eight of 12 patients. CONCLUSIONS: The neurocognitive and neuroimaging findings contribute to the evidence which indicates that the neural substrate of EMS is white matter damage.

Adult↗
PubMed1996

Passive immunization of Ebola virus-infected cynomolgus monkeys with immunoglobulin from hyperimmune horses.

A commercially available immunoglobulin G (IgG) from horses, hyperimmunized to Ebola virus, was evaluated for its ability to protect cynomolgus monkeys against disease following i.m. inoculation with 1 000 PFU Ebola virus (Zaire '95 strain). Six monkeys were treated immediately after infection by i.m. infection of 6.0 ml IgG; these animals developed passive ELISA titers of 1:160 to 1:320 to Ebola, two days afer inoculation. However, the beneficial effects of IgG treatment were limited to a delay in onset of viremia and clinical signs, in comparison with untreated controls. The six IgG recipients had no detectable viremia day 5, in contrast with three virus infected controls whose viremias exceeded 7.0 log10 PFU/ml that day. The controls died on days 6, 6, and 7, while two IgG recipients died day 7 and the remaining 4 died day 8, all with high viremias. These results document that passively acquired antibody can have a beneficial effect in reducing the viral burden in Ebola-infected primates; however, effective treatment of human patients may require antibodies with higher specific activities and more favorable pharmacokinetic properties than the presently available equine IgG.

Animals↗
PubMed1996

Hereditary spinal osteochondromas in diaphyseal aclasia.

We present cases of cervical cord compression in father and son with diaphyseal aclasia. Both patients were investigated with plain radiography, CT and MRI. We believe this to be the first report of spinal cord compression in first-degree relatives with diaphyseal aclasia.

Adolescent↗
PubMed1996

Event-related potentials--neurophysiological tools for predicting emergence and early outcome from traumatic coma.

OBJECTIVE: To determine the prognostic value of multimodal evoked potentials (EPs) and event-related (ERPs) potentials in coma (Glasgow Coma Score <8), after severe traumatic brain injury (TBI). DESIGN: Prospective, longitudinal study of neurophysiological responses recorded during traumatic coma. SETTING: Intensive Care Unit, Frenchay Hospital, Bristol, UK. PARTICIPANTS: Fifty-four comatose TBI patients (age range 1-80 years, mean 36.4). METHODS: Neurophysiological responses were recorded from 11 scalp electrodes with earlobe reference. Conduction times were measured for brainstem auditory, flash visual and somatosensory, short-latency EPs. Peak latencies and amplitudes were determined for long-latency components of visual and auditory ERPs, generated by passive "oddball" paradigms. These neurophysiological and various clinical parameters were correlated with patient outcome using Pearson's coefficient. MAIN OUTCOME MEASURE: Three month Glasgow Outcome Scale (GOS). RESULTS AND CONCLUSION: Highly significant (P <0.001) correlations exist between long-latency ERP components and 3-month outcome. Short-latency EPs, brainstem (wave I-V) and somatosensory conduction times also correlate significantly with the GOS (P <0.01). Of the clinical measurements, pupillary response patterns, APACHE II and Glasgow Coma Scores (GCS) correlate significantly with outcome, as do the retrospective measures of duration of coma and post-traumatic amnesia (PTA) in survivors. Unfortunately, due to variance of long-latency responses, even in controls, absolute values cannot be relied upon as prognosticators. The presence of "mismatch negativity" predicted the return of consciousness (89.7% sensitivity and 100% specificity) and preceded changes in GCS. Its latency was the single best indicator of 90-day outcome from coma (r = -0.641).

Acoustic Stimulation↗
PubMed1996

Field intubation of trauma patients: complications, indications, and outcomes.

Neither the success nor the complication rate for field intubation of trauma patients is known with any certainty. A retrospective audit of 94 severely injured patients who required field intubation was undertaken. Fifty percent (13 of 26) of survivors and 67% (37 of 71) of nonsurvivors were successfully intubated in the field (not significant). Mechanism of injury was similar in both groups, but survivors were younger (27 v 60 years, P= .049) and less critically injured, as reflected by their Injury Severity Scale scores, their Trauma Scores, and their field Glasgow Coma Scale scores (22.1 v 30.8, P = .0035; 7.7 v 4.2, P < .0002; and 6.3 v 3.3, P < .0001). When compared with previously published studies of medical patients with cardiac arrest, the success rate was lower in our trauma patients. When compared with patients having similar injuries intubated at the trauma center, field intubation was three times more likely to be associated with the development of nosocomial pneumonia than was hospital intubation.

Emergency Medical Services↗
PubMed1996

The effect of white matter low attenuation on cognitive performance in dementia of the Alzheimer type.

The effect of leukoaraiosis or white matter low attenuation (WMLA) on cognitive function is not fully understood. We compared the neuropsychological performance of 37 Alzheimer's disease patients with WMLA on CT brain scans with a similar group of 31 Alzheimer's disease patients with no evidence of white matter lesions. Patients with WMLA performed significantly worse on tests of visuospatial function (Cube Analysis test, p = 0.004), and cognitive speed (Kenrick Digit Copying test, p = 0.05) compared to those with no visible white matter lesions. Patients with widespread WMLA performed generally worse in tests of cognitive function than those with frontal or a mixture of frontal and occipital WMLA. This was most significant in the areas of attention (forward digit span, p = 0.003), visual recognition (p = 0.004), and cognitive speed (p = 0.03). There is an association between impaired cognitive performance and the presence of WMLA in Alzheimer's disease patients, with WMLA probably contributing to the cognitive impairment. This is most evident in patients with widespread white matter lesions.

Aged↗