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Biomedical subjects

E Knight

Publications and source records attributed to E Knight.

At least 19 recordsLinked to original sources
PubMed2004

A Welch-type test for homogeneity of contrasts under heteroscedasticity with application to meta-analysis.

A common problem that arises in the meta-analysis of several studies, each with independent treatment and control groups, is to test for the homogeneity of effect sizes without the assumptions of equal variances of the treatment and the control groups and of equal variances among the separate studies. A commonly used test statistic, frequently denoted as Q, is the weighted sum of squares of the differences of the individual effect sizes from the mean effect size, with weights inversely proportional to the variances of the effect sizes. The primary contributions of this article are the presentation of improved and very accurate approximations to the distributions of the Q statistic when the effect size is a linear contrast such as the difference between the treatment and control means. Our improved approximation to the distribution of Q under the null hypothesis is based on a multiple of an F-distribution; its use yields a substantial reduction in the type I error rate of the homogeneity test. Our improved approximation to the distribution of Q under an alternative hypothesis is based on a shift of a chi-square distribution; its use allows for much greater accuracy in the computation of the power of the homogeneity test. These two improved approximate distributions are developed using the Welch methodology of approximating the moments of Q by the use of multivariate Taylor expansions. The quality of these approximations is studied by simulation. A secondary contribution of this article is a study of how best to combine the variances of the treatment and control groups (needed for the calculation of weights in the Q statistic). Our conclusion, based on simulations, is that use of pooled variances can result in substantially erroneous conclusions.

Biometry↗
PubMed2004

Orthopaedic intervention in early rheumatoid arthritis. Occurrence and predictive factors in an inception cohort of 1064 patients followed for 5 years.

OBJECTIVES: To assess the occurrence of and predictive factors for orthopaedic surgery in an inception cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 5 yr in nine regions in England. METHODS: Standard clinical, laboratory and radiological assessments and all interventions were recorded at baseline and yearly in RA patients (less than 2 yrs symptoms) prior to the use of disease-modifying drugs. RESULTS: One thousand and sixty-four patients completed 5 yr of follow-up. Two hundred and sixty-four orthopaedic procedures for RA were performed in 181 (17%) patients at a median of 36.5 months from baseline. Seventy-five (7%) had replacements of major joints. Risk factors at baseline for large joint replacement surgery were a low haemoglobin concentration [odds ratio scores (OR) 3.4, 95% confidence interval (CI) 2.1-5.8] and high scores for erythrocyte sedimentation rate (ESR) (OR 3.2, CI 1.8-5.3), disease activity (DAS) (OR 2.1, CI 1.2-3.5) and Larsen X-rays (OR 2.6, CI 1.4-4.8). For hand or foot joint surgery (4%), risk factors included female gender (OR 3.2, CI 1.3-7.6), joint score (OR 2.3, CI 1.2-4.3), erosions (OR 2.3, CI 1.1-4.8), DAS (OR 2.4, 1.3-4.5) and Health Assessment Questionnaire score (OR 1.9, CI 1.0-3.6). No significant associations were seen for tendon, soft tissue or other minor procedures (6%). The HLA-DRB1 RA shared epitope was associated with any type of orthopaedic surgery (OR 1.7, CI 1.1-2.7). CONCLUSIONS: Eleven per cent of RA patients treated with conventional drug therapy for 5 yr underwent large- or small-joint surgery, an outcome which could be compared against that for new disease-modifying drugs. Risk factors varied according to type of surgery, but included standard clinical and laboratory measures. In order to reduce the eventual need for surgery, a therapeutic target in the first year of RA is the suppression of disease activity, as measured by haemoglobin and ESR. These are useful details for clinicians, health professionals and patients.

Adult↗
PubMed2000

Neutrophilia and congestive heart failure after acute myocardial infarction.

BACKGROUND: Inflammation associated with acute myocardial infarction (AMI) is frequently marked by a peripheral leukocytosis and relative neutrophilia. Whether this process may contribute to the development of postinfarction congestive heart failure (CHF) is not established. The objective of this study was to examine the association between hospital admission peripheral total leukocyte count and the neutrophil percentage and the subsequent development of CHF in patients with AMI. The study was designed as a retrospective cohort study in the setting of a tertiary referral hospital. Participants included 185 patients discharged with a diagnosis of AMI between May 1 and Sept 30, 1996. METHODS AND RESULTS: Outcome measures included clinical episodes of CHF with confirmatory chest roentgenogram findings and/or echocardiographic evidence of contractile dysfunction. Multivariable logistic regression analyses were performed to examine the relation between the total leukocyte count, neutrophil percentage, and the development of CHF in the first 4 days after AMI while controlling for baseline characteristics and early therapeutic interventions. Thirty-one percent of the cohort had a leukocyte count >11.0 x10(9)/L on admission to the hospital; 65% had a neutrophil percentage >65%, and 61% had a lymphocyte percentage </=25%. CHF developed in 43% of the cohort. Of these, 92. 5% had relative neutrophilia (neutrophil percentage >65%) compared with 45% of those in whom CHF did not develop. Multivariable analysis revealed a highly significant association between relative neutrophilia and the subsequent development of CHF (odds ratio 14.3; 95% confidence interval 5.2 to 39.3). CONCLUSIONS: Relative neutrophilia on admission to the hospital in patients with AMI is significantly associated with the early development of CHF. This association may help in the identification of individuals at high risk who might benefit from more aggressive interventions to prevent or reduce the risk of CHF.

Adult↗
PubMed2000

Recovery challenges among dually diagnosed individuals.

Although there is a high prevalence of co-occurring mental and substance abuse disorders, and empirical evidence shows the need to integrate multiple treatment services for dually diagnosed persons, service integration is relatively recent and often poorly implemented. Moreover, service providers and clients often hold divergent views of what constitute appropriate and feasible treatment goals. This paper presents interview data from an urban sample of dually diagnosed members of self-help groups (N = 310) concerning the challenges confronting them in their recovery, and discusses the interrelations of these issues. The findings indicate that most clients struggle with emotional and socioeconomic issues, which bear significantly on their ability to handle adequately other aspects of recovery.

Adult↗
PubMed2000

Support, mutual aid and recovery from dual diagnosis.

Recovery from substance abuse and mental health disorders (dual-diagnosis) requires time, hard work and a broad array of coping skills. Empirical evidence has demonstrated the buffering role of social support in stressful situations. This paper investigates the associations among social support (including dual-recovery mutual aid), recovery status and personal well-being in dually-diagnosed individuals (N = 310) using cross-sectional self-report data. Persons with higher levels of support and greater participation in dual-recovery mutual aid reported less substance use and mental health distress and higher levels of well-being. Participation in mutual aid was indirectly associated with recovery through perceived levels of support. The association between mutual aid and recovery held for dual-recovery groups but not for traditional, single-focus self-help groups. The important role of specialized mutual aid groups in the dual recovery process is discussed.

Adult↗
PubMed1998

Motoneuron apoptosis is blocked by CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling pathway.

Neurons undergoing apoptosis can be rescued by trophic factors that simultaneously increase the activity of extracellular signal-regulated kinase (ERK) and decrease c-Jun N-terminal kinase (JNK) and p38. We identified a molecule, CEP-1347 (KT7515), that rescues motoneurons undergoing apoptosis and investigated its effect on ERK1 and JNK1 activity. Cultured rat embryonic motoneurons, in the absence of trophic factor, began to die 24-48 hr after plating. During the first 24 hr ERK1 activity was unchanged, whereas JNK1 activity increased fourfold. CEP-1347 completely rescued motoneurons for at least 72 hr with an EC50 of 20 +/- 2 nM. CEP-1347 did not alter ERK1 activity but rapidly inhibited JNK1 activation. The IC50 of CEP-1347 for JNK1 activation was the same as the EC50 for motoneuron survival. Inhibition of JNK1 activation by CEP-1347 was not selective to motoneurons. CEP-1347 also inhibited JNK1 activity in Cos7 cells under conditions of ultraviolet irradiation, osmotic shock, and inhibition of glycosylation. Inhibition by CEP-1347 of the JNK1 signaling pathway appeared to be selective, because CEP-1347 did not inhibit p38-regulated mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP2) activity in Cos7 cells subjected to osmotic shock. The direct molecular target of CEP-1347 was not JNK1, because CEP-1347 did not inhibit JNK1 activity in Cos7 cells cotransfected with MEKK1 and JNK1 cDNA constructs. This is the first demonstration of a small organic molecule that promotes motoneuron survival and that simultaneously inhibits the JNK1 signaling cascade.

Animals↗
PubMed1997

A bioluminescent assay for agonist activity at potentially any G-protein-coupled receptor.

Transient expression of apoaequorin in Chinese hamster ovary (CHO) cells and reconstitution with the co-factor coelenterazine resulted in a large, concentration-dependent agonist-mediated luminescent response following cotransfection with the endothelin ETA, angiotensin ATII, thyrotropin-releasing hormone (TRH), and neurokinin NK1 receptors, all of which interact pre-dominantly with the G alpha q-like phosphoinositidase-linked G-proteins. A substantially greater luminescence was obtained with mitochondrially targeted apoaequorin compared to cytoplasmically expressed apoaequorin. To generate a system amenable for the study of agonist activity at virtually any G-protein-coupled receptor the alpha subunit of the receptor promiscuous G-protein G alpha 16 was either transiently or stably expressed in CHO cells together with apoaequorin. In cells expressing G alpha 16, but not in its absence, agonists at a series of receptors which normally interact with either G alpha s or G alpha i were now able to cause a luminescent response from mitochondrially targeted apoaequorin. In the case of the A1 adenosine receptor, this response was clearly a result of activation of G alpha 16 and not a consequence of the release of the G alpha i-associated beta/gamma complex, as the luminescent response was unaffected by pertussis toxin treatment of the cells, whereas agonist-mediated inhibition of adenylyl cyclase activity was attenuated. These studies describe the use of coexpressed apoaequorin as a reporter for G-protein-coupled receptor-mediated calcium signaling. Furthermore, coexpression of G alpha 16 and apoaequorin provides a basis for a generic mammalian cell microplate assay for the assessment of agonist action at virtually any G-protein-coupled receptor, including orphan receptors for which the physiological signal transduction mechanism may be unknown.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed1997

A radioactive binding assay for inhibitors of trkA kinase.

The high-affinity receptor for nerve growth factor (NGF), trkA, is a receptor-linked tyrosine kinase. The binding of NGF to trkA, depending on the context of its environment, can cause beneficial or deleterious responses in the target cells. For example, the activation of trkA in sympathetic and sensory neurons causes the subsequent survival and differentiation of these cells. On the other hand, the activation of trkA by NGF in other cells has been implicated in several pathologies including inflammation-induced hyperalgesia and several cancers. A radioactive binding assay to evaluate inhibitors of the kinase domain of trkA has been developed and validated. The assay monitors the specific binding of an inhibitor of trkA kinase activity, the indolocarbazole K-252a, to the trkA receptor. [3H]K-252a binds with high affinity to one site on the cytoplasmic kinase domain of the trkA receptor. Binding is saturable and reversible with a dissociation constant (Kd) of 1.5 nM. The binding assay has been used in competition binding experiments to determine the inhibition constants for other indolocarbazole compounds. The IC50 values for compounds obtained in the binding assay correlate very well with the IC50 values obtained in an enzyme-linked immunosorbent assay for trkA tyrosine kinase activity.

Adenosine Triphosphate↗
PubMed1997

Transurethral resection of the prostate: still the gold standard.

BACKGROUND: In recent times there has been a number of newer methods advocated as treatment for bladder outlet obstruction. Prior to embracing these newer technologies, the authors' experiences with conventional transurethral resection of the prostate should be evaluated and compared with those experienced in the newer modalities. The objective was to determine whether a standard transurethral resection of the prostate (TURP) still compared favourably with the newer modalities in terms of duration of stay, duration of catheterization, re-admission rate, re-catheterization rate, cost and long-term results. The results are compared with those of workers whose level of expertise was the best that could be achieved with transurethral needle ablation (TUNA) and laser prostatectomy. METHODS: During the 3-year period from September 1992 to September 1995, 575 TURP were carried out in a regional hospital. The total duration of stay, the postoperative duration of stay, the re-catheterization and re-admission rates were assessed and the costs estimated. RESULTS: Transurethral resection of the prostate was shown to compare favourably in terms of the duration of hospital admission and the duration of catheterization, and to have a significantly lower re-catheterization rate and a significantly lower re-admission rate than the newer modalities. CONCLUSION: Transurethral resection of the prostate is still the method of choice for surgical management of bladder outlet obstruction, and it remains as the gold standard. Having reviewed the results of the newer modalities as carried out by the experts in those fields, it was found that TURP compares favourably with those procedures. From the point of view of duration of stay, duration of catheterization, re-admission rate and re-catheterization rate, as well as cost and long-term results, TURP remains as the gold standard and the newer modalities are not believed to be advantageous at this stage.

Aged↗
PubMed1996

In vitro and in vivo secretion of human ISG15, an IFN-induced immunomodulatory cytokine.

ISG15, a 15-kDa protein of unique primary amino acid sequence, functions intracellularly as a ubiquitin homologue and a cytokine that induces production of IFN-gamma and augments NK/lymphokine-activated killer cell proliferation and function. ISG15 is secreted from monocytes and lymphocytes, and in this study we have characterized in vitro and in vivo production of ISG15 in response to IFN-alphabeta. Low levels of ISG15 were present constitutively in PBMCs; dose-dependent ISG15 synthesis was observed in response to IFN-alpha or IFN-beta, but not IFN-gamma. High m.w. conjugates, present in PBMC extracts constitutively, were enhanced after IFN-alpha or IFN-beta treatment. Metabolic labeling experiments demonstrated that IFN-beta-induced ISG15 was released from primary cultures of peripheral blood CD3+ (including both CD4+ and CD8+ subpopulations). Furthermore, ISG15 was released from viable cell lines of monocyte, T lymphocyte, B lymphocyte, and epithelial origins. Since ISG15 was secreted in response to IFN treatment in vitro, its levels in the serum of healthy human volunteers treated with IFN-beta(ser) were quantitated by asymmetric sandwich ELISA. Both single and multiple doses of IFN-beta(ser) increased serum ISG15 levels significantly (p < 0.01) over baseline. A maximum 7.3-fold enhancement of serum ISG15 was obtained after multiple injections of 8 million units of IFN-beta(ser). Significant change was observed at 24 and 48 h of multiple 0.02-million-unit injections, yielding 1.2- and 1.7-fold increases over basal levels, respectively. These studies suggest that ISG15 is a novel member of the cytokine cascade that is synthesized and released in response to IFN-beta both in vitro and in vivo.

Adenocarcinoma↗
PubMed1996

Immunoregulatory properties of ISG15, an interferon-induced cytokine.

ISG15 is a 15-kDa protein of unique primary amino acid sequence, which is transcriptionally regulated by interferon (IFN) alpha and IFN-beta. Because it is synthesized in many cell types and secreted from human monocytes and lymphocytes, we postulated that ISG15 might act to modulate immune cell function. ISG15 stimulated B-depleted lymphocyte proliferation in a dose-dependent manner with significant proliferation induced by amounts of ISG15 as low as 1 ng/ml (58 pM). Maximal stimulation of [3H]thymidine incorporation by B-depleted lymphocytes occurred at 6-7 days. Immunophenotyping of ISG15-treated B-depleted lymphocyte cultures indicated a 26-fold expansion of natural killer (NK) cells (CD56+). In cytotoxicity assays, ISG15 was a potent inducer of cytolytic activity directed against both K562 (100 lytic units per 10(6) cells) and Daudi (80 lytic units per 10(6) cells) tumor cell targets, indicating that ISG15 enhanced lymphokine-activated killer-like activity. ISG15-induced NK cell proliferation required coculturing of T and NK cells, suggesting that soluble factor(s) were required. Measurement of ISG15-treated cell culture supernatants for cytokines indicated production of IFN-gamma (> 700 units/ml). No interleukin 2 or interleukin 12 was detected. IFN-gamma itself failed to stimulate lymphocyte proliferation and lymphokine-activated killer cell activation. Further, induced expression of IFN-gamma mRNA was detected by reverse transcription-PCR in T lymphocytes after ISG15 treatment but not in NK cells. Enhancement of NK cell proliferation, augmentation of non-major histocompatibility complex-restricted cytotoxicity, and induction of IFN-gamma from T cells identify ISG15 as a member of the cytokine cascade and suggest that it may be responsible for amplifying and directing some of the immunomodulatory effects of IFN-alpha or IFN-beta.

Adjuvants, Immunologic↗
PubMed1995

Membranes of human neuroblastoma SH-SY5Y cells contain specific binding sites for [3H]K-252A.

K-252a and the structurally similar compound staurosporine promote neurotrophic responses in several cell lines (PC12, SH-SY5Y human neuroblastoma) and in cultures of primary neurons. The molecular mechanisms involved in the induction of these neurotrophic activities are unknown. It is demonstrated in this report that [3H]K-252a binds to SH-SY5Y membranes and that the binding is specific and saturable with a Kd of 2.7 nM and a Bmax of 100,000 sites per cell. The association of [3H]K-252a with its binding site is rapid and reversible, and the binding was inhibited by unlabeled K-252a and by staurosporine. Binding of [3H]K-252a was not inhibited by the potent protein kinase C (PKC) inhibitor GF109203X. Down regulation of PKC by treating SH-SY5Y cells with a phorbol ester did not cause a reduction in the specific binding of [3H]K-252a to membranes, suggesting that the binding is not to PKC. Treatment of the SH-SY5Y membranes with trypsin and by boiling destroyed all specific binding of [3H]K-252a. These results suggest that the [3H]K-252a binds to a specific protein site that is associated with membranes of SH-SY5Y cells.

Alkaloids↗
PubMed1995

Consumers as peer specialists on intensive case management teams: impact on client outcomes.

OBJECTIVE: The study examined whether employing mental health consumers as peer specialists in an intensive case management program can enhance outcomes for clients with serious mental illness. METHODS: A quasiexperimental, longitudinal, nonequivalent control group design was used to compare outcomes of clients assigned to three case management conditions: teams of case managers plus peer specialists, teams of case managers plus nonconsumer assistants, and case managers only. Outcomes were measured at baseline and at three six-month intervals. Repeated-measures analysis of variance was used to assess between-group differences. RESULTS: Complete data were available for 104 clients. Compared with clients in the other two groups, clients served by teams with peer specialists demonstrated greater gains in several areas of quality of life and overall reduction in the number of major life problems experienced. They also reported more frequent contact with their case managers and the largest gains of all three groups in the areas of self-image and outlook and social support. No differences in outcomes were found between clients served by teams with nonconsumer assistants and those served by case managers only. CONCLUSIONS: Integration of peer specialists into intensive case management programs appears to lead to enhanced quality of life for clients and more effective case management.

Adult↗
PubMed1994

Postcardiac catheterization time-in-bed study: enhancing patient comfort through nursing research.

Cardiac catheterization has become a routine diagnostic procedure. Little has been written about standards for nursing care related to bed rest postcatheterization. The purpose of this experimental study was to determine whether there was a significant difference in incidence of bleeding from catheter insertion site between those patients who remained in bed for 12 hours and those who remained in bed for 6 hours post-procedure. There was no significant difference between the two groups. Postprocedure bed rest was reduced from 12 to 6 hours in this tertiary care medical center. Decreasing time in bed reduced cost and patient discomfort.

Adult↗