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Biomedical subjects

S Knight

Publications and source records attributed to S Knight.

At least 55 records · Page 3Linked to original sources
PubMed1998

Periplasmic chaperone recognition motif of subunits mediates quaternary interactions in the pilus.

The class of proteins collectively known as periplasmic immunoglobulin-like chaperones play an essential role in the assembly of a diverse set of adhesive organelles used by pathogenic strains of Gram-negative bacteria. Herein, we present a combination of genetic and structural data that sheds new light on chaperone-subunit and subunit-subunit interactions in the prototypical P pilus system, and provides new insights into how PapD controls pilus biogenesis. New crystallographic data of PapD with the C-terminal fragment of a subunit suggest a mechanism for how periplasmic chaperones mediate the extraction of pilus subunits from the inner membrane, a prerequisite step for subunit folding. In addition, the conserved N- and C-terminal regions of pilus subunits are shown to participate in the quaternary interactions of the mature pilus following their uncapping by the chaperone. By coupling the folding of subunit proteins to the capping of their nascent assembly surfaces, periplasmic chaperones are thereby able to protect pilus subunits from premature oligomerization until their delivery to the outer membrane assembly site.

Adhesins, Bacterial↗
PubMed1998

Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes.

Ruthenium red is a well known inhibitor of Ca2+ uptake into mitochondria in vitro. However, its utility as an inhibitor of Ca2+ uptake into mitochondria in vivo or in situ in intact cells is limited because of its inhibitory effects on sarcoplasmic reticulum Ca2+ release channel and other cellular processes. We have synthesized a ruthenium derivative and found it to be an oxygen-bridged dinuclear ruthenium amine complex. It has the same chemical structure as Ru360 reported previously (Emerson, J., Clarke, M. J., Ying, W-L., and Sanadi, D. R. (1993) J. Am. Chem. Soc. 115, 11799-11805). Ru360 has been shown to be a potent inhibitor of Ca2+-stimulated respiration of liver mitochondria in vitro. However, the specificity of Ru360 on Ca2+ uptake into mitochondria in vitro or in intact cells has not been determined. The present study reports in detail the potency, the effectiveness, and the mechanism of inhibition of mitochondrial Ca2+ uptake by Ru360 and its specificity in vitro in isolated mitochondria and in situ in isolated cardiac myocytes. Ru360 was more potent (IC50 = 0.184 nM) than ruthenium red (IC50 = 6.85 nM) in inhibiting Ca2+ uptake into mitochondria. 103Ru360 was found to bind to isolated mitochondria with high affinity (Kd = 0.34 nM, Bmax = 80 fmol/mg of mitochondrial protein). The IC50 of 103Ru360 for the inhibition of Ca2+ uptake into mitochondria was also 0.2 nM, indicating that saturation of a specific binding site is responsible for the inhibition of Ca2+ uptake. Ru360, as high as 10 microM, produced no effect on sarcoplasmic reticulum Ca2+ uptake or release, sarcolemmal Na+/Ca2+ exchange, actomyosin ATPase activity, L-type Ca2+ channel current, cytosolic Ca2+ transients, or cell shortening. 103Ru360 was taken up by isolated myocytes in a time-dependent biphasic manner. Ru360 (10 microM) applied outside intact voltage-clamped ventricular myocytes prevented Ca2+ uptake into mitochondria in situ where the cells were progressively loaded with Ca2+ via sarcolemmal Na+/Ca2+ exchange by depolarization to +110 mV. We conclude that Ru360 specifically blocks Ca2+ uptake into mitochondria and can be used in intact cells.

Animals↗
PubMed1998

Dyskeratosis Congenita (DC) Registry: identification of new features of DC.

Dyskeratosis congenita (DC) is an inherited disorder characterized by skin pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosis Congenita Registry was established at the Hammersmith Hospital. In the 46 families recruited, 76/83 patients were male, suggesting that the major form of DC is X-linked. As well as a variety of noncutaneous abnormalities, the majority (93%) of patients had bone marrow (BM) failure and this was the principal cause (71%) of early mortality. In addition to BM hypoplasia, some patients also developed myelodysplasia and acute myelod leukaemia. Pulmonary abnormalities were present in 19% of patients. In affected females the phenotype was less severe. Some female carriers of X-linked DC had clinical features. Carriers of X-linked DC showed skewed X-chromosome inactivation patterns (XCIPs), suggesting that cells expressing the normal DC allele have a growth/survival advantage over cells that express the mutant allele. Linkage analysis in multiplex families confirmed that the DKC1 gene, responsible for the X-linked form of DC, is located within Xq28 and facilitated its positional cloning. The high incidence of BM failure in association with a wide range of somatic abnormalities together with the ubiquitous expression of DKC1 suggest that, as well as having a critical role in normal haemopoiesis, this gene has a key role in normal cell biology.

Adolescent↗
PubMed1998

A study of the 'lived' experience of change during a period of curriculum and organizational reform in a department of nurse education.

In this paper an attempt is made to illustrate the experience of lecturers in a department of nursing preparing to implement the adult branch component of the pre-registration Higher Education Diploma in Nursing Studies. The study was conducted in a college of health in England at a time when the college was only beginning to discuss the possibility of closer links with universities. It highlights the grief responses associated with change exhibited by nursing lecturers during a period of organizational upheaval and curriculum change and maps the transition through stages of adaptation over a 2-year period. The analysis of the effects of change and the coping strategies adopted by nursing lecturers presented here is most relevant to educational managers who are charged with integrating nurse education into higher education.

Adaptation, Psychological↗
PubMed1998

Clinical trials of antibacterial agents: a practical guide to design and analysis. Statisticians in the Pharmaceutical Industry Working Party.

Guidelines on the conduct of clinical trials of antibacterial agents produced by the US Food and Drug Administration, the British Society for Antimicrobial Chemotherapy, the Infectious Diseases Society of America and a European Working Party have been reviewed. Although very informative, these guidelines provide limited practical guidance on the design and statistical aspects of phase III studies of antimicrobial agents. This paper describes the differences between antibacterial trials and clinical studies in other therapeutic areas with regard to subjective endpoints, dual clinical and bacteriological endpoints, frequent protocol violations and difficulty of using placebo controls. The importance of a detailed protocol and planned analysis strategy is emphasized. The choice of comparator agents, practical issues with the blinding of trial materials and the documentation of patients excluded from study entry are discussed. The use of different patient groups and different endpoints in analyses are described. The principles of equivalence and their application to trials of antibacterial agents are discussed, together with an approach to calculating sample size. A variety of statistical analyses of results are compared for different situations indicating some of the problems that can arise. Different methods of presentation of study data are included with emphasis on regulatory submissions rather than scientific publications. Some graphical presentations are recommended and issues regarding data across different studies are discussed.

Anti-Infective Agents↗
PubMed1998

Beneficial impact of the homelands movement on health outcomes in central Australian aborigines.

OBJECTIVE: This study compares prevalence of obesity, hypertension and diabetes in two groups of Aboriginal adults: those living in homelands versus centralised communities in central Australia. It also compares weight gain, incidence of diabetes, mortality and hospitalisation rates between the groups over a seven-year period. METHODS: Baseline survey of 826 Aboriginal adults in rural central Australian communities in 1987-88 with a follow-up survey of 416 (56% response rate, excluding deaths). Each time, they had a 75 g oral glucose tolerance test (OGTT), and blood pressure and anthropometry measurement. Deaths and hospitalisations for all of the original cohort were recorded for the seven-year period. RESULTS: Homelands residents had a lower baseline prevalence of diabetes (risk ratio [RR] = 0.77, 0.59-1.00), hypertension (RR = 0.66, 0.54-0.80) and overweight/obesity (RR = 0.70, 0.59-0.83). The incidence of diabetes was lower among homelands residents (RR = 0.70, 0.46-1.06). They were less likely to die than those living in centralised communities (RR = 0.56, 0.37-0.85) and less likely to be hospitalised for any cause (RR = 0.79, 0.71-0.87), particularly infections (RR = 0.70, 0.61-0.80), injury involving alcohol (RR = 0.61, 0.47-0.79) and other injury (RR = 0.75, 0.60-0.93). Mean age at death was 58 and 48 years for residents of homelands and centralised communities respectively. CONCLUSION: Aboriginal people who live in homelands communities appear to have more favourable health outcomes with respect to mortality, hospitalisation, hypertension, diabetes and injury, than those living in more centralised settlements in Central Australia. These effects are most marked among younger adults.

Adult↗
PubMed1998

Phase II study of dexverapamil plus anthracycline in patients with metastatic breast cancer who have progressed on the same anthracycline regimen.

The purpose of this study is to evaluate whether metastatic breast cancer that has progressed on an anthracycline-containing drug regimen will subsequently respond to that identical regimen if dexverapamil, a modulator of P-glycoprotein-mediated drug resistance, is given concomitantly. Eligible patients received 180 mg/m2 dexverapamil every 6 h for 15 doses with the anthracycline administered 30 min after the seventh dose. Blood for dexverapamil levels was drawn before and 30 min after this dose. When possible, biopsies were obtained to measure mdr-1 expression by reverse transcription-PCR and by image cytometry. Of the 21 patients entered onto the trial, 20 were evaluable for response. There were two partial responses (10%) that both lasted for 6 months, and two additional patients had stable disease. Seven patients had asymptomatic cardiotoxicity consisting of hypotension (24%), bradycardia (5%), or prolongation of the P-R interval (14%). Two patients developed acute congestive heart failure, one on dexverapamil and one 10 days after stopping it. Dexverapamil did not seem to increase anthracycline toxicity. The median trough dexverapamil plus norverapamil level on day 3 was 1110 ng/ml (range, 186-3385 ng/ml), and the median peak level was 2164 ng/ml (range, 964-8382 ng/ml). There was poor correlation between reverse transcription-PCR and image cytometry for the level of mdr-1 expression. Because dexverapamil has been shown to affect doxorubicin pharmacokinetics subsequent to the initiation of this trial, it cannot be concluded that the responses seen were necessarily due to P-glycoprotein inhibition. Additional studies are necessary to determine whether mdr-1 modulators can reverse clinical drug resistance in breast cancer patients. The intrinsic cardiotoxicity of dexverapamil makes it less suitable for such studies than several other available agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Crystallization and preliminary X-ray diffraction studies of the FimC-FimH chaperone-adhesin complex from Escherichia coli.

A complex of the periplasmic chaperone FimC and the mannose-binding adhesin FimH from the Escherichia coli type 1 pilus system has been crystallized from ammonium sulfate solution using the hanging-drop vapour-diffusion method. The crystals diffract to a minimum Bragg spacing of 2.7 A and belong to the space group P4(1)2(1)2 or P4(3)2(1)2 with cell dimensions a = b = 97.7, c = 215.9 A at room temperature. Data to 3.0 A have been collected from a single-crystal frozen to T = 100 K.

Journal Article↗
PubMed1997

Practice-led education and development project: developing styles in clinical supervision.

This paper is the second installment which reports a study conducted by the authors following successful application to the Yorkshire Regional Health Authority in response to a call for proposals for studies into practice-led education and development. The aim of the project is to pilot and evaluate an approach to leadership development based upon a conceptual model of reflectivity within a learning organization whilst developing and evaluating a model of supervised practice.

Education, Nursing, Baccalaureate↗
PubMed1997

Hemodynamic evaluation of foot venous compression devices.

PURPOSE: Venous compression devices effectively prevent deep venous thrombosis. Recently, because traumatic injury of the limb often precludes application of calf devices, newer methods have been developed that are only applied to the foot. This study was designed to evaluate the venous hemodynamic effects produced by four different compressive devices compared with calf-only intermittent pneumatic compression (IPC). METHODS: Twenty-seven healthy volunteers had application of each device followed by duplex scanning determination of the venous hemodynamics at the popliteal vein (PV) and the common femoral vein (CFV). Endpoints included (1) resting (peak) systolic velocity (RSV); (2) maximum venous velocity (MVV) during device activation; (3) acceleration, the slope of the line from RSV to MVV; and (4) return time (RT) from MVV back to RSV. The devices evaluated included two commercially available mechanical foot devices, (1) foot compressive device (FCD1), and (2) FCD2; (3) an experimental mechanical foot device (FCD3); (4) an experimental pneumatic foot device (FCD4); and (5) a calf-only IPC device (IPC). RESULTS: The RSV was higher in the CFV than the PV. The initial RSV was not statistically significant between the five experimental groups (p = 0.37) at either the PV or CFV, although the RSV was higher in the CFV than in the calf (CFV, 24.3 +/- 6.7 cm/sec; PV, 12.5 +/- 3.7 cm/sec; p < 0.0001). MVV was significantly higher with FCD2 and the IPC (p = 0.0002) at the PV level, but this difference decreased at the CFV. Acceleration was greatest with the two available foot devices, FCD1 and FCD2, compared with the other three devices (p < 0.0001) at both levels. On the other hand, the RT was significantly longer only with the IPC; RT was four to 10 times slower at the PV and three to five times slower at the CFV compared with the other four devices. CONCLUSIONS: The two commercially available foot devices, FCD1 and FCD2, and the IPC produced significant alterations in venous hemodynamics. Changes produced at the PV level by both foot and calf devices were seen proximally at the CFV, although the changes were usually less. The mechanical devices produced rapid acceleration of venous flow to an elevated MVV, whereas the IPC produced an elevated peak with a sustained period of flow above baseline (RT). Further clinical comparison should be completed before widespread adaptation of these devices as an equivalent to existing IPC devices.

Adult↗
PubMed1997

Molecular-cytogenetic detection of a deletion of 1p36.3.

We report a deletion of 1p36.3 in a child with microcephaly, mental retardation, broad forehead, deep set eyes, depressed nasal bridge, flat midface, relative prognathism, and abnormal ears. The phenotype is consistent with that described for partial monosomy for 1p36.3. Reverse chromosome painting and microsatellite and Southern blot analyses were used to map the extent of the deletion. Fluorescence in situ hybridisation (FISH) analysis using probes from every telomere indicates that the rearrangement is likely to be a chromosomal truncation or rearrangement involving subtelomeric repetitive DNA. The deletion was identified by screening a sample of children and adults with idiopathic mental retardation. In conjunction with previous work on this sample, we estimate that 7.4% of the group have subtelomeric rearrangements.

Adolescent↗
PubMed1997

Psychiatric complications of homozygous sickle cell disease among young adults in the Jamaican Cohort Study.

BACKGROUND: This study aimed to determine the prevalence of psychiatric disorder in young adults with homzygous sickle cell (SS) disease and in controls with normal haemoglobin, and to examine factors associated with psychiatric disorder. METHOD: The study design was cross-sectional. Subjects were aged 18-20 years: 63 with SS disease and 89 controls. The Psychiatric Assessment Schedule was used to determine psychiatric disorder at index of Definition level 5. RESULTS: Psychiatric disorder was identified in 18 (29%) SS disease patients and in 22 (25%) controls. In SS patients, psychiatric disorder was not related to illness severity but was associated with leaving school early, difficulties in social adjustment, impaired cognitive function and having previous psychiatric difficulties. Male SS patients with psychiatric disorder all had low body mass index (BMI < 17.60). In controls, psychiatric disorder was associated with female gender, unemployment and difficulties in social adjustment. CONCLUSIONS: The prevalence of psychiatric disorder was similar in patients and controls, although associated factors tended to be different. The association with low BMI in SS men merits further study.

Adolescent↗
PubMed1996

Defining a model for team leader development.

This paper will provide details of a study conducted jointly by the authors following successful application to the Yorkshire Regional Health Authority in response to a call for proposals for studies into 'Practice-Led Education and Development'. The aim of the project was to pilot and evaluate an approach to leadership development based upon a conceptual model of reflectivity within a learning organization whilst developing and evaluating a model of supervised practice.

Education, Nursing, Continuing↗
PubMed1996

Fostering multidisciplinary research and approaches to rural health issues: the concept of an International Summer Institute.

The challenge of how best to provide equitable, accessible and affordable health care in rural and remote settings is an international concern. It has been acknowledged that a multidisciplinary approach to current rural health issues involving social scientists and health practitioners may be crucial in developing appropriate responses. One initiative designed to facilitate multidisciplinary research and greater collaboration between researchers and practitioners was an International Summer Institute sponsored by the Social Science and Humanities Research Council of Canada. This article outlines an Australian perspective on the rationale for, background to, and structure of this initiative, and evaluates it as one option for promoting multidisciplinary approaches to rural health research.

Allied Health Personnel↗
PubMed1996

Effect of an immunisation campaign in Natal and KwaZulu on vaccinaton coverage rates, 1990-1991.

In 1990 the Department of National Health and Population Development of South Africa launched a nationwide immunisation campaign targeted mainly at measles. In order to measure the effect of the campaign on vaccination coverage rates for children, pre- and post- campaign vaccination coverage surveys were undertaken using a modified Expanded Programme for Immunisation technique, stratified for race and urban/rural residence. The results in KwaZulu-Natal showed no significant increase in measles vaccination coverage for any race rates after the campaign (as documented by Road-to-Health cards). There was a decrease in coverage of the black population. However, when a history of measles vaccination was accepted, the results showed an increase in coverage. The results call into question the effectiveness of immunisation campaigns as a strategy for raising vaccination coverage levels, as well as their having a sustained impact on the incidence of measles. Alternative strategies, such as the strengthening and expansion of existing primary health care services, should be considered.

Child, Preschool↗