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Biomedical subjects

R Walters

Publications and source records attributed to R Walters.

At least 19 recordsLinked to original sources
PubMed2006

Therapeutic use of cephazolin to prevent complications of spine surgery.

Discitis, caused by pyogenic organisms, is a potential complication of any procedure which involves entering the intervertebral disc during open or percutaneous procedures. While there are wide variations in the severity of symptoms, the characteristic feature of discitis is the development of increasingly severe back pain, which is not relieved by rest, or narcotic analgesics. While there is a tendency to spontaneous resolution over time, a self-limiting course does not always eventuate. Serious complications resulting from spread of the infective process can lead to vertebral osteomyelitis or to the formation of an epidural abscess with further risk of neural compression. Clinical and experimental evidence now supports the prophylactic use of a suitable antibiotic, but some uncertainties exist about the benefits of antibiotic therapy in treating established discitis. While cephazolin is a widely favoured choice of antibiotic, the timing of its administration to prevent or treat discitis has been complicated by the lack of suitable methods for detecting and measuring the concentration of cephazolin in the plasma and disc in experimental and clinical conditions. This paper describes a high-performance liquid chromatography technique for detecting the antibiotic cephazolin. The results conclude cephazolin can be detected in the plasma and disc after administering an intravenous bolus dose. However, concentration of cephazolin in the outer disc was 12 times greater than that of the inner disc.

Animals↗
PubMed2004

Salivary IgA response to prolonged exercise in a hot environment in trained cyclists.

UNLABELLED: The aim of this study was to determine the effects of prolonged exercise in hot conditions on saliva IgA (s-IgA) responses in trained cyclists. On two occasions, in random order and separated by 1 week, 12 male cyclists cycled for 2 h on a stationary ergometer at 62 (3)% V(.)O(2 max) [194 (4) W; mean (SEM)], on one occasion (HOT: 30.3 degrees C, 76% RH) and on another occasion ( CONTROL: 20.4 degrees C, 60% RH). Water was available ad-libitum. Venous blood samples and 2-min whole unstimulated saliva samples were collected at pre, post and 2 h post-exercise. The s-IgA concentration was determined using a sandwich-type ELISA. Exercising heart rate, rating of perceived exertion, rectal temperature, corrected body mass loss (P<0.01) and plasma cortisol (P<0.05) were greater during HOT. The decrease in plasma volume post-exercise was similar on both trials [HOT: -6.7 (1.1) and CONTROL: -6.6 (1.3)%; P<0.01]. Saliva flow rate decreased post-exercise by 43% returning to pre-exercise levels by 2 h post-exercise (P<0.05) with no difference between trials. Saliva IgA concentration increased post-exercise (P<0.05) with no difference between trials. Saliva IgA secretion rate decreased post-exercise by 34% returning to pre-exercise levels by 2 h post-exercise (P<0.05) with no difference between trials. These data show that a prolonged bout of exercise results in a reduction in s-IgA secretion rate. Additionally, these data demonstrate that performing prolonged exercise in the heat, with ad libitum water intake, does not influence s-IgA responses to prolonged exercise.

Adaptation, Physiological↗
PubMed2004

Provision of Epstein-Barr virus-transformed B-cell lines in a routine tissue typing laboratory: practicalities and applications.

A bank of Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell lines (BCLs) has been established in this laboratory over the last 7 years. Novel, rare and unusual HLA phenotypes were highlighted during routine clinical testing and during typing of volunteer haematopoietic stem cell donors for the Welsh Bone Marrow Donor Registry. The BCLs are routinely used as laboratory reagents, as a source of DNA for reference purposes and for research work. Consenting donors are tested for hepatitis B surface antigens (HBsAg), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) before their B-lymphocytes are transformed. Strict bio-identity checks are performed before and after transformation and after each BCL expansion. Each BCL is tested regularly for mycoplasma contamination. A total of 230 blood samples were transformed. One hundred and fifty-nine sterile samples produced 157 BCLs (98.7% success), while 71 non-sterile samples produced 50 BCLs (70.4% success), giving an overall success rate of 90.0%. Fifteen of the transformation failures have since been repeated successfully. Factors contributing to the high success rate and reasons for the 23 failed transformations are discussed. The successful development and use of pools of BCLs for HLA antibody screening by flow cytometry are described. Whilst certain training and health and safety issues require close attention, it is clear that EBV transformation of B lymphocytes and/or the use of BCLs is feasible in a routine tissue typing laboratory and that BCLs are a valuable resource. Careful adherence to the methods and procedures detailed here should virtually guarantee successful transformation (98.7%) from good quality, sterile whole blood samples.

B-Lymphocytes↗
PubMed2002

Detection of visual field defects in patients after anterior temporal lobectomy for mesial temporal sclerosis-establishing eligibility to drive.

AIMS: The aim of this study is to quantify visual field defects after temporal lobectomy for mesial temporal sclerosis and to establish eligibility for driving. METHODS: Automated static perimetry was performed on 14 patients who had undergone anterior temporal lobectomy for mesial temporal sclerosis. Perimetry consisted of monocular Humphrey Field Analyser (HFA) 30-2 test and a binocular Esterman 120 test. RESULTS: Of the 14 patients, three had no loss or non-specific loss, eight had partial homonymous quadrantanopia, one had complete homonymous quadrantanopia and two had concentric loss attributable to vigabatrin, which may have masked any loss occurring due to surgery. Of these, only seven passed the standardised DVLA visual fields. Of the seven who failed DVLA visual field, one had complete quadrantanopia, four had partial quadrantanopia and two had concentric loss (due to vigabatrin). CONCLUSIONS: Visual field defects contribute a great deal in the reduction of the quality of life in patients who have had surgery for mesial temporal sclerosis. Potential surgically induced visual field defects that could preclude driving need to be discussed with each patient preoperatively. In our study 50% of patients did not meet the required DVLA standards.

Adult↗
PubMed2002

Mapping the public health workforce I: a tool for classifying the public health workforce.

We aimed to develop a tool to identify members of the public health workforce and classify them using categories developed for the Chief Medical Officer's project to strengthen the public health function. The tool was developed to gain a picture of London's public health workforce, and needed to be reliable and easy to use in many settings inside and outside the health service. We needed to be able to classify posts from brief information without interrogation of postholders, so that the entire workforces of large organisations could be classified from information provided by only a few key informants. Key questions and decision rules were defined by presenting interviewees in public health with brief information on nine jobs and discussing with them the process by which they determined whether each post was in the public health workforce, and if so, in which category. The questions and decision rules were refined into a classification tool which was presented as a flow diagram and a questionnaire. Application of the tool revealed that it was understood by key informants and resulted in classifications which were accepted by the researchers. The tool has now been applied extensively in London and yielded useful results. Many other applications in public health workforce planning and development are anticipated.

Humans↗
PubMed2002

Driving after epilepsy surgery: effects of visual field defects and epilepsy control.

The aim of this study was to assess the eligibility to drive in patients with mesial temporal sclerosis who undergo anterior temporal lobectomy. The two major determinants in a patient's ability to drive after such surgery are visual field defects and their seizure frequency. Thirteen patients were selected. The postoperative seizure frequency was assessed using Engel's criteria. Automated static perimetry was performed which consisted of a Humphrey Field Analyser (HFA) 30-2 Test, one for each eye and a Binocular Esterman 120 Test. Seven out of the 13 (54%) selected patients had no seizures post-operatively (Engel's 1); three (23%) patients had less than two seizures per year (Engel's 2) and three (23%) had more than 90% improvement in the frequency of seizures (Engel's 3). The seven patients with no seizures postoperatively were eligible to apply for a driving licence. Automated static perimetry performed on the same patients revealed three (23%) had normal visual field or non-specific loss, seven (54%) had partial homonymous quadrantanopia, one (8%) had complete homonymous quadrantanopia and two (15%) had bilateral concentric loss attributable to vigabatrin, which may have masked any loss occurring due to surgery. Of the 13 patients, only seven (54%) passed the standardised DVLA Esterman visual field test. Of the six (46%) who failed DVLA Esterman visual field test, one had complete homonymous quadrantanopia, three had incomplete homonymous quadrantanopia and two had concentric loss (due to vigabatrin). Although seven (54%) patients passed the visual field test and seven (54%) patients were seizure free only five of the seven seizure-free patients (i.e. 38% of the total number of patients) had visual fields that would make them eligible to drive. As driving is now stated by patients' as a major factor that improves their quality of life, it is important to stress the significance of surgically induced or other iatrogenic visual field defects that may prevent them from driving prior to the operation to avoid disappointments afterwards.

Adult↗
PubMed2000

Phase II study of paclitaxel in patients with metastatic breast carcinoma refractory to standard chemotherapy.

BACKGROUND: The authors conducted a single institution Phase II clinical trial to determine whether paclitaxel had antitumor activity in patients with metastatic breast carcinoma that was refractory to standard chemotherapy. METHODS: Patients with metastatic breast carcinoma were eligible for the study if they had disease progression after at least 2 prior chemotherapy regimens. Patients who had received three prior regimens were treated in a separate cohort. All patients were required to have received doxorubicin in the past and were not eligible if they had received prior therapy with paclitaxel. The starting dose of paclitaxel for low risk patients was 175 mg/m2, administered as a 24-hour continuous infusion; the starting dose of paclitaxel was 150 mg/m2 for patients who had received > or = 3 prior regimens. Therapy was given every 3 weeks and continued for at least 2 courses unless there was evidence of rapidly progressing disease, for at least 3 courses if there was no change in disease and Grade 3 or 4 (based on National Cancer Institute toxicity criteria) toxicity was not noted, and for 6 courses beyond the maximum response in patients who demonstrated complete or partial responses and showed no evidence of disease progression. RESULTS: Sixty-eight of 69 patients entered in the study were evaluable for response: 35 patients who had received 2 prior chemotherapy regimens for Stage IV disease and 33 patients who had received > or =3 prior regimens. A partial response was observed in 7 patients who had received 2 prior regimens, for an objective response rate of 20% (95% confidence interval [95% CI], 14-26%). In the group who had received > or = 3 prior regimens, a total of 6 partial responses were observed, for an objective response rate of 18% (95% CI, 12-23%). The median response duration was 8.2 months (range, 2.7-10.1 months) for the group who had received 2 prior regimens and 5.8 months (range, 2.1-9.5 months) for patients who received > or = 3 prior regimens. Responses were noted in patients with anthracycline-resistant tumors. CONCLUSIONS: Paclitaxel was active in heavily pretreated patients with metastatic breast carcinoma, including anthracycline-resistant breast carcinoma.

Adult↗
PubMed2000

Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer.

In the genetic disease cystic fibrosis, recombinant adeno-associated virus type 2 (AAV2) is being investigated as a vector to transfer CFTR cDNA to airway epithelia. However, earlier work has shown that the apical surface of human airway epithelia is resistant to infection by AAV2, presumably as a result of a lack of heparan sulfate proteoglycans on the apical surface. This inefficiency can be overcome by increasing the amount of vector or by increasing the incubation time. However, these interventions are not very practical for translation into a therapeutic airway-directed vector. Therefore, we examined the efficiency of other AAV serotypes at infecting human airway epithelia. When applied at low multiplicity of infection to the apical surface of differentiated airway epithelia we found that a recombinant AAV5 bound and mediated gene transfer 50-fold more efficiently than AAV2. Furthermore, in contrast to AAV2, AAV5-mediated gene transfer was not inhibited by soluble heparin. Recombinant AAV5 was also more efficient than AAV2 in transferring beta-galactosidase cDNA to murine airway and alveolar epithelia in vivo. These data suggest that AAV5-derived vectors bind and mediate gene transfer to human and murine airway epithelia, and the tropism of AAV5 may be useful to target cells that are not permissive for AAV2.

Animals↗
PubMed1999

Mechanism by which calcium phosphate coprecipitation enhances adenovirus-mediated gene transfer.

Delivery of a normal copy of CFTR cDNA to airway epithelia may provide a novel treatment for cystic fibrosis lung disease. Unfortunately, current vectors are inefficient because of limited binding to the apical surface of airway epithelia. We recently reported that incorporation of adenovirus in a calcium phosphate coprecipitate (Ad:CaPi) improves adenovirus-mediated gene transfer to airway epithelia in vitro and in vivo. To understand better how coprecipitation improves gene transfer, we tested the hypothesis that incorporation in a CaPi coprecipitate increases the binding of adenovirus to the apical surface of differentiated human airway epithelia. When a Cy3-labelled adenovirus was delivered in a coprecipitate, binding increased 54-fold as compared with adenovirus alone. Moreover, infection by Ad:CaPi was independent of fiber knob-CAR and penton base-integrin interactions. After binding to the cell surface, the virus must enter the cell in order to infect. We hypothesized that Ad:CaPi may stimulate fluid phase endocytosis, thereby facilitating entry. However, we found that neither adenovirus nor Ad:CaPi coprecipitates altered fluid phase endocytosis. Nevertheless, Ad:CaPi preferentially infected cells showing endocytosis. Thus, CaPi coprecipitation improves adenovirus-mediated gene transfer by coating the epithelial surface with a layer of virus which enters cells during the normal process of endocytosis.

Adenoviridae↗
PubMed1998

Medical workforce planning. Spreading the load.

Medical workforce planning is a difficult and neglected area, but ignoring it will cost the NHS dear. Setting up collaborative mechanisms to deal with medical training and workforce issues is not easy, but has been shown by one health authority to be worthwhile. Plans for an 8 per cent increase in consultant posts will, if implemented, cost the HA 700,000 Pounds a year in salaries and on-costs alone, but better information has enabled the most beneficial to be prioritised.

Health Planning↗
PubMed1995

PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase.

BACKGROUND: Phosphoinositide 3-kinases (PI 3-kinases) are thought to play an important role in coordinating the responses elicited by a variety of growth factors, oncogene products and inflammatory stimuli. These responses include activation of membrane ruffling, chemotaxis, glucose transport, superoxide production, neurite outgrowth and pp70 S6 kinase. Some of these responses are also known to be regulated by Rac, a small GTP-binding protein related to Ras. Neither the transducing elements upstream of Rac, nor those downstream of PI 3-kinase, have been defined. RESULTS: We show here that platelet-derived growth factor (PDGF) can stimulate an increase in the level of GTP-Rac by at least two distinct mechanisms: firstly, by increased guanine nucleotide exchange; and secondly, by inhibition of a Rac GTPase activity. The first of these mechanisms is essential for the activation of Rac, and we show that it is dependent upon PDGR-stimulated synthesis of phosphatidylinositol (3,4,5)-trisphosphate. CONCLUSIONS: These results suggest that Rac activation lies downstream of PI 3-kinase activation on a PDGF-stimulated signalling pathway. Furthermore, as Rac has been implicated in at least two diverse cellular responses that are also though to require activation of PI 3-kinase--a reorganization of the actin cytoskeleton known as membrane ruffling and the neutrophil oxidative burst--these results suggest that Rac may be a major effector protein for the PI 3-kinase signalling pathway in many cell types.

Cell Line↗
PubMed1995

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer.

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.

Adult↗
PubMed1994

Characterization of a phosphatidylinositol-specific phosphoinositide 3-kinase from mammalian cells.

BACKGROUND: As phosphoinositides can serve as signalling molecules within cells, the enzymes responsible for their synthesis and cleavage are likely to be involved in the transduction of signals from the cell surface through the cytoplasm. The precise role of the phosphoinositide 3-kinase that has been cloned from mammalian cells is not known, but it has been implicated in receptor-stimulated mitogenesis, glucose uptake and membrane ruffling. The enzyme can use phosphatidylinositol (PtdIns), PtdIns 4-phosphate and PtdIns (4,5)-bisphosphate as substrates in vitro, but it seems to phosphorylate PtdIns (4,5)-bisphosphate preferentially in vivo. The VPS34 gene product of yeast, by contrast, is a phosphoinositide 3-kinase homologue implicated in vacuolar protein sorting that apparently utilizes only PtdIns as a substrate. The significance of this difference in lipid-substrate preference and its relationship to the functions of the two phosphoinositide kinases is unknown. RESULTS: We have characterized a distinct PtdIns-specific phosphoinositide 3-kinase activity in mammalian cells. Unlike the previously identified, broad-specificity mammalian phosphoinositide kinase, this enzyme is resistant to the drug wortmannin and uses only PtdIns as a substrate in vitro; it therefore has the capacity to generate PtdIns 3-phosphate specifically. The newly characterized enzyme, which was purified by chromatography from cytosol, has biochemical and pharmacological characteristics distinct from those of the broad-specificity enzyme. CONCLUSIONS: The enzyme we have characterized may serve to generate PtdIns 3-phosphate for fundamentally different roles in the cell from those of PtdIns (3,4)-bisphosphate and/or PtdIns (3,4,5)-trisphosphate. Furthermore, the functions of the VSP34 gene product, which may not be relevant to the broad-specificity mammalian phosphoinositide 3-kinase, may be related to those of the enzyme we describe.

Amino Acid Sequence↗
PubMed1994

Phase I trial of droloxifene in patients with metastatic breast cancer.

Droloxifene (3-hydroxytamoxifen) is a new, nonsteroidal antiestrogen. In comparison with tamoxifen, it has a 10- to 64-fold higher affinity for the estrogen receptor and has shown a lower estrogenic and higher antiestrogenic effect in experimental studies. The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy. In this study, 30 patients were treated in groups of 6 at 5 different doses (20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic effects included hot flashes, nausea, and fatigue and were not dose-related. Toxicity did not require any dose reduction or discontinuation of therapy. There was one episode of deep venous thrombosis and pulmonary embolism. There was no complete or partial response in this study, but four patients showed a minor response (13%). These data illustrate that this drug is well tolerated and needs to be further evaluated in phase II and III studies.

Adult↗
PubMed1994

Growth effects of instantaneous change in mandibular position: experimental study.

PURPOSE: To investigate the mandibular growth pattern in rats during adolescence after altering the position of the mandible in the frontal plane instanteously by two surgical procedures. METHODS: Mandibular morphology during growth was recorded by cephalometric methods during the 3-week experimental period. RESULTS: All procedures tested caused an altered mandibular morphology. An overall change was found in the shape of the mandible in the experimental groups, with the jaw being more square compared with the rectangular form found for the mandible in the control group. Condylar growth was abnormal and the cartilage of the experimental groups showed a reduced thickness and distorted morphology, indicating disturbed cellular activity. CONCLUSION: In view of the findings, it was concluded that considerations to instantaneously alter the mandibular position during adolescence may not be advisable.

Age Factors↗