Biomedical subjects

K Davies

Publications and source records attributed to K Davies.

At least 37 records · Page 2Linked to original sources

PubMed2000

A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse.

As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.

Animals↗

PubMed2000

Germination-induced bioluminescence, a route to determine the inhibitory effect of a combination preservation treatment on bacterial spores.

In this work, we have used spores of Bacillus subtilis that specifically induce bioluminescence upon initiation of germination as a rapid, real-time monitor of the effects of preservative treatments on germination. Using this tool, we have demonstrated that the combination of mild acidity (pH 5.5 to 5.0), lactic acid (0. 5%), and a pasteurization step (90 degrees C for 5 min) results in enhanced inhibition of spore germination compared with the effects of the individual treatments alone. Inhibition by the combination treatment occurred as a result of both direct but reversible inhibition, entirely dependent on the physical presence of the preservative factors, and permanent, nonreversible damage to the L-alanine germination apparatus of the spore. However, we were able to restore germination of the preservative-damaged spores unable to germinate on L-alanine by supplementing the medium with the nonnutrient germinant calcium dipicolinic acid. The demonstration that simple combinations of preservative factors inhibit spore germination indicates that food preservation systems providing ambient stability could be designed which do not adhere to the strict limits set by commonly accepted processes and which are based on precise understanding of their inhibitory action.

Alanine↗

PubMed2000

VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain.

VEGF is a secreted mitogen associated with angiogenesis and is also a potent vascular permeability factor. The biological role of VEGF in the ischemic brain remains unknown. This study was undertaken to investigate whether VEGF enhances cerebral microvascular perfusion and increases blood-brain barrier (BBB) leakage in the ischemic brain. Using magnetic resonance imaging (MRI), three-dimensional laser-scanning confocal microscope, and functional neurological tests, we measured the effects of administrating recombinant human VEGF(165) (rhVEGF(165)) on angiogenesis, functional neurological outcome, and BBB leakage in a rat model of focal cerebral embolic ischemia. Late (48 hours) administration of rhVEGF(165) to the ischemic rats enhanced angiogenesis in the ischemic penumbra and significantly improved neurological recovery. However, early postischemic (1 hour) administration of rhVEGF(165) to ischemic rats significantly increased BBB leakage, hemorrhagic transformation, and ischemic lesions. Administration of rhVEGF(165) to ischemic rats did not change BBB leakage and cerebral plasma perfusion in the contralateral hemisphere. Our results indicate that VEGF can markedly enhance angiogenesis in the ischemic brain and reduce neurological deficits during stroke recovery and that inhibition of VEGF at the acute stage of stroke may reduce the BBB permeability and the risk of hemorrhagic transformation after focal cerebral ischemia.

Animals↗

PubMed2000

Characterization of perimenopausal bone loss: a prospective study.

This study characterized the change in bone mass, bone markers, pituitary/gonadal hormones, vitamin D, parathyroid hormone, and anthropometric variables in a cohort of healthy women as they passed through normal menopause. We recruited 75 women > 46 years old who had premenopausal estradiol (E2) and gonadotropin levels and regular menses. During 9.5 years of observation, 54 experienced normal menopause (PM group) and 21 remained estrogen replete (ER group). Before the beginning of the menopausal drop and after its completion, the slope of bone mass on time in the PM group was 0% for the spine, -0.61% per year for the total body, and -0.45 % per year for the femoral neck. Designating these losses as "age related," there were 0, 4.88, and 3.40% losses for spine, total body bone mineral (TBBM), and femoral neck, respectively, in the 8-year period for which the data were analyzed. Across menopause, we found a sigmoid pattern of bone loss in the PM group beginning about 2-3 years before the last menses and ending about 3-4 years after the last menses. The total estrogen-deprivation bone losses were 10.50, 7.73, and 5.30% for the spine, TBBM, and femoral neck, respectively. In the ER group, we found a 0, 0.59, and 0.93% per year loss in spine, TBBM, and femoral neck, respectively. Serum osteocalcin rose 77%, serum total alkaline phosphatase rose 34%, and urinary hydroxyproline/creatinine (Hypro/Cr) ratio rose 44% in the PM group, while remaining stable in the ER group. We conclude that menopausal bone loss is a composite of loss caused by estrogen deprivation and age per se for the hip and total body, but is caused by estrogen deprivation alone for the spine.

Absorptiometry, Photon↗

PubMed2000

Igf2 imprinting in development and disease.

Igf2 is one of the first imprinted genes discovered and occupies a centre stage in the study of imprinting. This is because it has dramatic effects on the control of fetal growth, it is involved in growth disorders and in cancer, it interacts with products of other imprinted genes, and its imprinting status is under complex regulation in a cluster of tightly linked imprinted genes. Here we review briefly the key features of Igf2 imprinting in normal development and in disease, and hope to show what a fascinating subject of study this gene and its biology provides.

Animals↗

PubMed1999

Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain.

Recent in vitro studies have shown that the periventricular subependymal zone (SEZ) of the rodent brain is capable of de novo generation of neurons and glia. There is less information available on neurogenesis in the adult human brain, and no study has shown the clonal generation of neurons and glia from in vitro-generated "neurospheres." Here we describe the isolation of proliferative stem/progenitor cells within neurospheres from two different regions, the SEZ and the hippocampus, from surgical biopsy specimens of adult (24-57 years) human brain. Using light and electron microscopy; immunocytochemistry for a variety of neuronal, glial, and developmental (including extracellular matrix; ECM) markers; and the reverse transcriptase polymerase chain reaction to demonstrate different gene transcripts found in neurospheres, it is shown that the adult human brain harbors a complex population of stem/progenitor cells that can generate neuronal and glial progeny under particular in vitro growth conditions. These methods also show that these neurospheres contain both neurons and glia and demonstrate regional similarities at the mRNA level, indicating common stem/progenitor cell types within two different neurogenic regions of the adult human brain. In addition to the synthesis of developmentally regulated molecules such as the ECM protein tenascin-C, a variety of other genes (e.g., Pax 6) and proteins (e.g. , Bcl-2) involved in cell survival and differentiation are expressed by adult human brain neurospheres.

Adolescent↗

PubMed1999

Applicability of the Health Utilities Index to a population of childhood survivors of central nervous system tumours in the U.K.

This paper describes the application of a multi-attribute, preference-linked health status and health-related quality of life measurement system--the Health Utilities Index (developed in Canada)--to a group of subjects in the U.K. Children who had survived tumours of the central nervous system (n = 30, age 6-16 years) formed the study group. Respondents (children, parents, physicians and physiotherapists) found the activity (completion of a 15-item questionnaire) to be acceptable and not burdensome (it was accomplished easily by all children > or = 10 years of age). Instrumental reliability was established by acceptable intra- and interobserver agreement and construct validity was supported by strong similarities between the results obtained in this study and those reported from a similar group of children in Canada. The greatest burden of morbidity was reported for the attributes of emotion and cognition (each affected in > 50% of the children). Pain was surprisingly prevalent (affected in approximately one-third of children). The finding of a large number of unique health states emphasises the complex morbidity burden experienced by these children who self-reported poorer overall health (as reflected in utility scores) than did the proxy respondents. The information obtained from this study is readily interpretable and clinically useful. The results of this study also illustrate that extreme caution must be exercised in undertaking linguistic modifications to established instruments for, in this instance, these resulted in a loss of the ability to detect the most severe emotional morbidity and reduced the comparability of results between studies. With this provision, the Health Utilities Index is evidently applicable in the U.K. and the original version has been recommended for use in brain tumour studies by the U.K. CCSG (the U.K. Children's Cancer Study Group).

Adolescent↗

PubMed1999

Domestic violence: a challenge to accident and emergency nurses.

A wide range of victims of assault are admitted to our Accident and Emergency (A&E) departments. Their injuries vary from minor to severe trauma and multiple injuries. Lloyd (1991) recognized that the victims of domestic violence are usually female and that the aggressor is almost always known to them. Indeed, the person who administers the assault is often the spouse or partner in a relationship in which there is a regular cycle of abuse. While it is sometimes difficult for A&E nurses to remain impartial it is vital that they do so. It is also essential that the A&E nurse is aware of the support networks that are available and how to access them. Patients arriving at the A&E department following an incident of domestic violence often need protection as well as physical and psychological care. This article aims to explore issues of domestic violence that involve the admission of abused females to A&E departments.

Emergency Nursing↗

PubMed1999

High resolution quantitation of microvascular plasma perfusion in non-ischemic and ischemic rat brain by laser-scanning confocal microscopy.

Laser-scanning confocal microscopy (LSCM) was used to measure at high resolution cerebral plasma volumes (perfusion) using two fluorescent plasma markers in a rat model of embolic stroke. This application of LSCM to study the microvascular circulation in embolic stroke was developed as an alternative to autoradiography to measure cerebral perfusion. An additional benefit of LSCM is that it quantitates with great accuracy the structural relationships of the microcirculation to cells and the pathological alterations of the ischemic brain. Autoradiography allows only a quantitative analysis of cerebral perfusion. For example, in order to study the microcirculation and its relationship to blood brain barrier damage, the volume of perfused cerebral capillaries was measured by administering two fluorescent plasma markers (FITC-dextran and Evans blue) intravenously to a rat. Evans blue was administered before cerebral ischemia and FITC-dextran administered post-ischemia 1 min before sacrifice. Volumes of plasma perfusion were analyzed by means of a system developed for 3D analysis of fixed and stained serial brain histologies. Plasma volumes for the non-ischemic cerebral cortex were 1.00%+/-0.38% while plasma volumes in the caudate/putamen were 0.69%+/-0.17% in good agreement with the previously published values using the autoradiography method. The architecture of the capillaries in the ischemic core showed perfusion of Evans blue but there was no flow of FITC dextran. Our work represents a novel application of this technology to investigation of cerebral vascular disease and identifies its potential to become an important tool for investigation of cerebral pathology.

Animals↗

PubMed1999

The extended role of the nurse: the United Kingdom perspective.

There has been considerable discussion and debate in the United Kingdom regarding the role and function of the nurse. This article outlines the main tenets of the debate, namely the extended/expanded role and function, and gives a brief overview of the situation to date. Professional guidance from the United Kingdom Central Council for Nurses, Midwives and Health Visitors is explored and the implications this has for the nurse in the exercise of accountability. The legal implications of the nursing function in an expanded role capacity is discussed, in particular in relation to legal accountability, with reference to existing case law. Recommendations are made for the development of the expanded role.

Forecasting↗

PubMed1999

Quantitation of microvascular plasma perfusion and neuronal microtubule-associated protein in ischemic mouse brain by laser-scanning confocal microscopy.

In an exposition of the technique of calculating distribution volumes from laser-scanning confocal microscopic (LSCM) data, three-dimensional images of the distribution of one or two fluorescent markers in mouse brain specimens were generated by LSCM and processed by a system developed for morphometric analysis of fixed and stained serial brain histologic samples. To determine the volume of perfused cerebral capillaries, one of two fluorescent plasma markers, either fluorescein isothiocyanate (FITC)-dextran or Evans blue, was intravenously administered to mice subjected to 1 hour of embolic middle cerebral artery (MCA) occlusion (n = 9) and to mice that were not operated on (n = 3); after 1 minute of circulation, brains were removed, immersion-fixed, and processed for LSCM. In some of these animals (n = 5), the volume of endogenous microtubule-associated protein-2 (MAP2) fluorescence was also determined using immunohistochemical staining. For mice that were not operated on, this methodology yielded highly localized volumes of (1) microvascular plasma, which agree with those determined for rodents by other techniques, and (2) MAP2 expression, which appears physiologically and morphologically reasonable. After 1 hour of MCA occlusion, the MAP2 volumes of distribution were less than 10% of normal in the ipsilateral hemisphere in which plasma perfusion essentially ceased. In conclusion, precise colocalization and quantitation of early ischemic neuronal damage and cerebral plasma perfusion deficit can be done with this three-dimensional, microphysiologic and microanatomic methodology.

Animals↗

PubMed1999

Visual confrontation naming outcome after standard left anterior temporal lobectomy with sparing versus resection of the superior temporal gyrus: a randomized prospective clinical trial.

PURPOSE: Intraoperative mapping of eloquent cortex during left (speech dominant) anterior temporal lobectomy has shown a significant proportion of patients to have sites on the anterior superior temporal gyrus at which visual confrontation naming can be disrupted by electrical stimulation. The purpose of this investigation was to conduct a randomized clinical trial to determine whether sparing versus resection of the superior temporal gyrus affected visual confrontation naming outcome after standard left anterior temporal lobectomy. Also examined was the degree to which inherent patient characteristics were associated with language outcome regardless of surgical technique. METHODS: Thirty patients with intractable left temporal lobe epilepsy undergoing standard anterior temporal lobectomy were randomized in regard to whether the superior temporal gyrus was resected or spared. Patients were tested preoperatively and 6-8 months postoperatively by using two conventional tests of visual confrontation naming ability. RESULTS: No significant differences were found between the groups in either confrontation naming or surgical outcome. Postoperative decline in nominal speech was most closely associated with later age at onset of epilepsy/absence of hippocampal sclerosis. CONCLUSIONS: It appears that specific types of localization-related temporal lobe epilepsy are more closely associated with the risk of adverse language outcome after anterior temporal lobectomy than with the surgical variations investigated in this study.

Adult↗

PubMed1999

Multicenter evaluation of the Abbott LCx Mycobacterium tuberculosis ligase chain reaction assay.

Four Australian hospital laboratories evaluated the performance of the Abbott LCx Mycobacterium tuberculosis assay with 2,347 specimens (2,083 respiratory and 264 nonrespiratory specimens) obtained from 1, 411 patients. A total of 152 specimens (6.5%) were culture positive for Mycobacterium tuberculosis complex (MTBC); of these, 79 (52%) were smear positive. After resolution of discrepant data, the overall sensitivity, specificity, and positive and negative predictive values for the LCx assay were 69.7, 99.9, 99.1, and 97.7% respectively. For smear-positive respiratory specimens that were culture positive for MTBC, the values were 98.5, 100, 100, and 98.4%, respectively, while the values for smear-negative respiratory specimens were 41.5, 99.9, 96.4, and 98%, respectively. Relative operating characteristic curves were constructed to demonstrate the relationship between sensitivity and specificity for a range of possible cutoff values in the LCx assay. These graphs suggested that the assay sensitivity for respiratory samples could be increased from 70.2 to 78.6%, while the specificity would be reduced from 99.9 to 99.4% by inclusion of a grey zone (i.e., LCx assay values of between 0.2 and 0.99). An algorithm is presented for the handling of specimens with LCx assay values within this grey zone.

DNA Ligases↗

PubMed1998

The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity.

We have reported recently that the dual specificity mitogen-activated protein kinase phosphatase-3 (MKP-3) elicits highly selective inactivation of the extracellular signal-regulated kinase (ERK) class of mitogen-activated protein (MAP) kinases (Muda, M., Theodosiou, A., Rodrigues, N., Boschert, U., Camps, M., Gillieron, C., Davies, K., Ashworth, A., and Arkinstall, S. (1996) J. Biol. Chem. 271, 27205-27208). We now show that MKP-3 enzymatic specificity is paralleled by tight binding to both ERK1 and ERK2 while, in contrast, little or no interaction with either c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) or p38 MAP kinases was detected. Further study revealed that the N-terminal noncatalytic domain of MKP-3 (MKP-3DeltaC) binds both ERK1 and ERK2, while the C-terminal MKP-3 catalytic core (MKP-3DeltaN) fails to precipitate either of these MAP kinases. A chimera consisting of the N-terminal half of MKP-3 with the C-terminal catalytic core of M3-6 also bound tightly to ERK1 but not to JNK3/SAPKbeta. Consistent with a role for N-terminal binding in determining MKP-3 specificity, at least 10-fold higher concentrations of purified MKP-3DeltaN than full-length MKP-3 is required to inhibit ERK2 activity. In contrast, both MKP-3DeltaN and full-length MKP-3 inactivate JNK/SAPK and p38 MAP kinases at similarly high concentrations. Also, a chimera of the M3-6 N terminus with the MKP-3 catalytic core which fails to bind ERK elicits non selective inactivation of ERK1 and JNK3/SAPKbeta. Together, these observations suggest that the physiological specificity of MKP-3 for inactivation of ERK family MAP kinases reflects tight substrate binding by its N-terminal domain.

Amino Acid Sequence↗

PubMed1998

Human genetics. Hair apparent.

Explore the source record for details and available documents.

Alopecia↗

PubMed1998

Neuropsychological outcome following anterior temporal lobectomy in patients with and without the syndrome of mesial temporal lobe epilepsy.

The nature, pattern, and degree of neuropsychological change following anterior temporal lobectomy (ATL) were examined as a function of the presence or absence of the syndrome of mesial temporal lobe epilepsy (MTLE). Fifty-four patients exhibited the syndrome of MTLE, while 34 patients were without the syndrome (non-MTLE). The test-retest performance of a group of 40 epilepsy patients who did not undergo surgery was used to derive regression-based estimates of test-retest change. Overall, the MTLE group did not show significant cognitive decline following ATL. In contrast, the left non-MTLE group showed significant declines on verbal memory, confrontation naming, and verbal conceptual ability. Further, verbal memory was the most substantial area of decline, and was independent of seizure outcome. Clinical and theoretical implications of these findings are discussed.

Adult↗

PubMed1998

Expression of full-length utrophin prevents muscular dystrophy in mdx mice.

Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fiber leading to the gradual depletion of skeletal muscle. The molecular structure of dystrophin is very similar to that of the related protein utrophin. Utrophin is found in all tissues and is confined to the neuromuscular and myotendinous junctions in mature muscle. Sarcolemmal localization of a truncated utrophin transgene in the dystrophin-deficient mdx mouse significantly improves the dystrophic muscle phenotype. Therefore, up-regulation of utrophin by drug therapy is a plausible therapeutic approach in the treatment of DMD. Here we demonstrate that expression of full-length utrophin in mdx mice prevents the development of muscular dystrophy. We assessed muscle morphology, fiber regeneration and mechanical properties (force development and resistance to stretch) of mdx and transgenic mdx skeletal and diaphragm muscle. The utrophin levels required in muscle are significantly less than the normal endogenous utrophin levels seen in lung and kidney, and we provide evidence that the pathology depends on the amount of utrophin expression. These results also have important implications for DMD therapies in which utrophin replacement is achieved by delivery using exogenous vectors.

Animals↗

PubMed1998

Psychiatric outcome of temporal lobectomy for epilepsy: incidence and treatment of psychiatric complications.

PURPOSE: To determine the incidence of psychiatric disorders before and after surgical treatment for partial epilepsy and to document the effectiveness of their treatment. METHODS: Fifty consecutive patients treated surgically for focal epilepsy (44 temporal and six frontal) were evaluated by established neuropsychiatric methods before surgery and over a mean period of 2 years after surgery. The patients with interictal dysphoric disorders, with or without psychotic episodes, were treated with tricyclic antidepressant medication alone or combined with serotonin selective reuptake inhibitors and, if necessary, with the addition of risperidone. RESULTS: Before surgery, 25 (57%) of the 44 patients with temporal lobe epilepsy had dysphoric disorders. After surgery, 17 (39%) of the 44 patients experienced either de novo psychiatric complications (six psychotic episodes, six dysphoric disorders, and two depressive episodes) or exacerbation of preoperative dysphoric disorder (three patients). Eight previously intact patients of the 19 (42%) developed dysphoric disorders after surgery that were significantly related to recurrence of seizures. All psychiatric complications occurred in the first 2 months after surgery, except for the six patients intact before surgery, who had a recurrence of seizures. A significant predictor of ultimate excellent psychiatric outcome was complete absence of seizures after surgery. All postoperative psychiatric complications remitted on treatment with psychotropic medication in the compliant patients. CONCLUSIONS: An exceptional psychiatric morbidity is associated with the months after temporal lobectomy. Possible pathogenetic mechanisms are discussed. Antidepressant drugs are very effective in treating the psychiatric disorders of chronic epilepsy; their use in conjunction with the surgical treatment of epilepsy appears to be crucial for the overall positive outcome of a significant number of patients.

Adolescent↗