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PubMed1999

Model choice and influential cases for survival studies.

Deletion diagnostics are developed for identifying observations that influence the estimates of regression parameters and the mixture parameter in the families of relative risk functions for failure time data. The diagnostic for the regression parameters is a generalization of Cain and Lange's (1984, Biometrics 40, 493-499) measure of individual influence. The generalizations of martingale residuals, Schoenfeld's partial residuals (1982, Biometrika 69, 239-241), and score residuals by Therneau, Grambsch, and Fleming (1990, Biometrika 77, 147-160) are also obtained. The influence of some observations on regression parameters can be drastically modified as the mixture parameter changes, even for a very small change. In addition, adding or deleting some observations might result in choosing different models. The diagnostics are applied to a family proposed by Guerrero and Johnson (1982, Biometrika 69, 309-314). One illustrative example is presented.

Biometry↗

PubMed2006

Phenotype-genotype correlation in eight Chinese 17alpha-hydroxylase/17,20 lyase-deficiency patients with five novel mutations of CYP17A1 gene.

CONTEXT: P450c17 deficiency (17OHD), caused by mutation in CYP17A1 gene, is characterized by severe hypertension-hypokalemia, sexual infantilism in females, and pseudohermaphroditism in males. We investigated eight Chinese 17OHD patients with five novel mutations of CYP17A1 gene and analyzed phenotype-genotype correlation in a patient with regular menses and seven others with classic presentations by in vitro expression and computer modeling. OBJECTIVE: The objective of the study was to explore the phenotype-genotype correlation in patients with subtle and classic manifestations. SUBJECTS AND METHODS: Eight patients with 17OHD from seven families were diagnosed according to clinical manifestations and basal hormone assays. The CYP17A1 gene was amplified and sequenced. Haplotyping analysis was performed to determine a common ancestor for those subjects with a frequent mutation 1517_1525del. In vitro enzymatic activities assay and computer modeling were used to analyze the phenotype-genotype correlation. RESULTS: Five novel CYP17A1 mutations, homozygous D487_F489del (1517_1525del) and F453S, combined compound Y329K and 1047del, P434L and V310_W313del, and R416C and D487_F489del were identified. Haplotyping showed that 1517_1525del might be inherited from a common ancestor. Compared with the mutations in patients with classical manifestations, F453S in the patient with regular menses, occasional hypertension, and hypokalemia showed a partially reduced 17alpha-hydroxylase (29% of those of wild type) and a minor protein conformational change. CONCLUSION: The clinical manifestations in patients with 17OHD correlate with CYP17A1 mutations and enzymatic activities by in vitro enzyme assay and computer modeling. F453S mutation results in partially reduced enzymatic activities and a subtle phenotype. The prevalent mutation 1517_1525del in Chinese 17OHD patients might be a founder effect.

Adolescent↗

PubMed2004

Chronic cognitive effects of bilateral subdural haematomas in the rat.

Humans suffering from subdural haematomas often show long-term cognitive dysfunctions. For identifying putative, recovery-enhancing therapeutics, animal models need to be developed in which recovery of function can be measured. For investigating whether and which type of recovery, i.e. spontaneous or training-induced recovery, or continuous partial retardation, is present in the rat model for bilateral subdural haematomas, spatial navigation abilities were assessed in the Morris water escape task in independent groups of rats at 1, 2, 4, 8, or 18 weeks after surgery. Complete spontaneous recovery seemed to occur at 8 weeks after injury. However, at 18 weeks after injury, the subdural haematoma caused a renewed deterioration of water maze performance, which was of a lesser degree than the impairments observed immediately after injury. This second phase performance deterioration was accompanied by an increase in generalised astrocyte reactivity. The rat subdural haematoma model provides an interesting tool for investigating spontaneous recovery processes of spatial navigation (8 weeks after injury), but also for progressive brain dysfunctions, considering the second phase of behavioural impairments seen at 18 weeks after injury.

Animals↗

PubMed2000

Effective supervision in clinical practice settings: a literature review.

CONTEXT: Clinical supervision has a vital role in postgraduate and, to some extent, undergraduate medical education. However it is probably the least investigated, discussed and developed aspect of clinical education. This large-scale, interdisciplinary review of literature addressing supervision is the first from a medical education perspective. PURPOSE: To review the literature on effective supervision in practice settings in order to identify what is known about effective supervision. CONTENT: The empirical basis of the literature is discussed and the literature reviewed to identify understandings and definitions of supervision and its purpose; theoretical models of supervision; availability, structure and content of supervision; effective supervision; skills and qualities of effective supervisors; and supervisor training and its effectiveness. CONCLUSIONS: The evidence only partially answers our original questions and suggests others. The supervision relationship is probably the single most important factor for the effectiveness of supervision, more important than the supervisory methods used. Feedback is essential and must be clear. It is important that the trainee has some control over and input into the supervisory process. Finding sufficient time for supervision can be a problem. Trainee behaviours and attitudes towards supervision require more investigation; some behaviours are detrimental both to patient care and learning. Current supervisory practice in medicine has very little empirical or theoretical basis. This review demonstrates the need for more structured and methodologically sound programmes of research into supervision in practice settings so that detailed models of effective supervision can be developed and thereby inform practice.

Clinical Clerkship↗

PubMed2004

Vocational rehabilitation of participants with severe substance use disorders in a VA veterans industries program.

There are approximately 100 Veterans Industries work therapy programs in the Veterans Health Administration (VHA) throughout the U.S. The majority of participants are veterans with severe substance use disorders and their length of stay ranges from 3 to 12 months. This study examines the Veterans Industries work therapy model at one site where veterans are referred from an addictions partial hospitalization treatment program. The study period was from 1996--97 and includes 80 patients. The characteristics of the participants are described. Barriers to employment are identified including unemployment rates, homelessness, drug of choice, age, and disability status. Outcome rates are reported including employment, abstinence, and housing support.

Adult↗

PubMed2005

Estimating marginal and incremental effects on health outcomes using flexible link and variance function models.

We propose an extension to the estimating equations in generalized linear models to estimate parameters in the link function and variance structure simultaneously with regression coefficients. Rather than focusing on the regression coefficients, the purpose of these models is inference about the mean of the outcome as a function of a set of covariates, and various functionals of the mean function used to measure the effects of the covariates. A commonly used functional in econometrics, referred to as the marginal effect, is the partial derivative of the mean function with respect to any covariate, averaged over the empirical distribution of covariates in the model. We define an analogous parameter for discrete covariates. The proposed estimation method not only helps to identify an appropriate link function and to suggest an underlying distribution for a specific application but also serves as a robust estimator when no specific distribution for the outcome measure can be identified. Using Monte Carlo simulations, we show that the resulting parameter estimators are consistent. The method is illustrated with an analysis of inpatient expenditure data from a study of hospitalists.

Adult↗

PubMed1994

Steroid receptors in human spermatozoa.

The presence of steroid binding sites in (or on) human spermatozoa was first suggested in the late 1970s, by studies showing that some steroids were able to influence sperm function. Subsequently, several effects exerted on spermatozoa by biological fluids, such as follicular fluid, were found to be probably linked to the action of steroids, and among them progesterone. Since the effects of progesterone on spermatozoa were rapid, dose-dependent and not affected by progesterone conjugation with high molecular weight proteins unable to cross the plasma membrane, the existence of a novel class of non-genomic progesterone receptors was strongly suspected. This hypothesis was further supported by the observation that some of the effects of progesterone on human spermatozoa were not abolished by inhibitors of the classical progesterone nuclear receptors, nor mimicked by progesterone genomic receptor agonists. Recently, surface progesterone binding sites were directly identified on the membranes of human spermatozoa, and their mechanism of action partially characterized.

Humans↗

PubMed1996

Inactivation of Th1 and Th2 cells by feeding ovalbumin.

Several different mechanisms have been implicated in oral tolerance to protein antigens, depending on the nature and dose of antigen used and the species under study. Here, we have investigated the basis of unresponsiveness in a well-established model of oral tolerance in mice fed 25 mg ovalbumin (OVA). Our results show that CD8+ T-cell activity is suppressed by feeding OVA and that these cells are not required for the induction of tolerance. CD4+ T cells are essential for tolerance to occur, but both Th1 and Th2 cell-dependent functions are tolerized equally in OVA-fed mice. Peripheral lymph node cells from tolerized mice rapidly undergo apoptosis when cultured in vitro but produce substantial amounts of transforming growth factor beta (TGFbeta) in response to OVA. The appearance of tolerance in vivo is preceded by a transient phase of T-cell priming, and we propose that this model of oral tolerance reflects partial activation of T cells by fed antigen, leading to selective production of TGFbeta and consequent inactivation of all effector T cells. These findings indicate that the active suppression and clonal anergy identified previously in mice with oral tolerance may not be mutually exclusive phenomena.

Administration, Oral↗

PubMed1999

pH-dependent changes in photoaffinity labeling patterns of the H1 influenza virus hemagglutinin by using an inhibitor of viral fusion.

The hemagglutinin (HA) protein undergoes a low-pH-induced conformational change in the acidic milieu of the endosome, resulting in fusion of viral and cellular membranes. A class of compounds that specifically interact with the HA protein of H1 and H2 subtype viruses and inhibit this conformational change was recently described (G. X. Luo et al., Virology 226:66-76, 1996, and J. Virol. 71:4062-4070, 1997). In this study, purified HA trimers (bromelain-cleaved HA [BHA]) are used to examine the properties and binding characteristics of these inhibitors. Compounds were able to inhibit the low-pH-induced change of isolated trimers, as detected by resistance to digestion with trypsin. Protection from digestion was extremely stable, as BHA-inhibitor complexes could be incubated for 24 h in low pH with almost no change in BHA structure. One inhibitor was prepared as a radiolabeled photoaffinity analog and used to probe for specific drug interactions with the HA protein. Analysis of BHA after photoaffinity analog binding and UV cross-linking revealed that the HA2 subunit of the HA was specifically radiolabeled. Cross-linking of the photoaffinity analog to BHA under neutral (native) pH conditions identified a stretch of amino acids within the alpha-helix of HA2 that interact with the inhibitor. Interestingly, cross-linking of the analog under acidic conditions identified a different region within the HA2 N terminus which interacts with the photoaffinity compound. These attachment sites help to delineate a potential binding pocket and suggest a model whereby the BHA is able to undergo a partial, reversible structural change in the presence of inhibitor compound.

Amino Acid Sequence↗

PubMed2002

Costs and benefits of carotid endarterectomy and associated preoperative arterial imaging: a systematic review of health economic literature.

BACKGROUND AND PURPOSE: Carotid endarterectomy (CEA) reduces the risk of stroke in patients with severe stenosis of the internal carotid artery. However, the cost implications of this procedure have not yet been satisfactorily addressed. The objective of this systematic review was to critically appraise the studies addressing the economic implications of CEA and the associated preoperative arterial imaging. METHODS: A systematic search strategy was developed to identify research articles related to the economic evaluation of CEA and the associated preoperative imaging. MEDLINE, EMBASE, and BIOSIS were electronically searched, and reference lists from identified studies were searched manually. Methods used to critically appraise these studies followed proposed guidelines for an economic evaluation that addresses 10 distinct aspects under 3 separate headings. RESULTS: Studies identified were either partial economic or full economic evaluations, with the majority coming from the United States. The methodological quality seems to have improved over time. The studies that assessed cost-effectiveness of CEA were all modeling studies; although the same baseline parameters were used, divergent conclusions were reached. Variation in the cost estimates of CEA ($9500 to $11 500) in the same health care system was also observed in the studies reporting only on the cost of carotid surgery. For a symptomatic patient, the benefit of CEA ranged from 0.35 quality adjusted life years (QALYs) (4.2 months) at a cost of $4100 per QALY to 0.93 QALYs (11.2 months) at a cost of $434 per QALY. For an asymptomatic patient, the cost-effectiveness of CEA varied from 0.15 QALYs (1.8 months) at a cost of $52 700 per QALY to 0.25 QALYs (3 months) at a cost of $8004 per QALY. CONCLUSIONS: Divergent conclusions of the cost-effectiveness of CEA were reported from studies that addressed the same questions and using similar parameters in their models. The cost estimates of the procedure and the different time periods used in the studies might explain these inconsistencies. Modeling studies in hypothetical cohorts might also be to blame. The cost-effectiveness of CEA will only definitively be assessed when real patient data are used.

Carotid Artery Diseases↗

PubMed2004

Relationships between stem cells and cancer stem cells.

Stem cells have been shown to exist in a variety of tissues. Recent studies have characterized stem cell gene expression patterns, phenotypes, and potential therapeutic uses. One of the most important properties of stem cells is that of self renewal. This raises the possibility that some of the clinical properties of human tumors may be due to transformed stem cells. Similar signaling pathways may regulate self renewal in normal and transformed stem cells. These rare transformed stem cells may drive the process of tumorigenesis due to their potential for self renewal. There are important ramifications for clinical cancer treatment if the growth of solid tumors is at least partially dependent on a cancer stem cell population. In the cancer stem cell model, tumor recurrence may be due to the non-targeted stem cell compartment repopulating the tumor. If cancer stem cells can be prospectively identified and isolated, it should be possible to identify therapies that will selectively target these cells.

Animals↗

PubMed2000

An assessment of levetiracetam as an anti-epileptic drug.

A brief review of epilepsy as a disease, anti-epileptic drugs (AEDs) and methods of evaluation of AEDs are presented as a background for the assessment of levetiracetam which has been approved by the FDA as add-on therapy for the treatment of partial seizures with or without secondary generalisation in adults. The exact mechanism of action of levetiracetam is not known but its action differs from that of other anti-epileptic drugs. A specific binding site for levetiracetam has been identified and is possibly related to anticonvulsant activity. Levetiracetam offers an effective and broad spectrum treatment of epileptic seizures, partial as well as generalised epilepsy. Levetiracetam has been shown to be effective in genetic and kindled animal models of epilepsy and against chemoconvulsant-induced partial epileptic seizures. Levetiracetam has a near perfect pharmacokinetic profile, with rapid absorption following oral administration, excellent bioavailability, quick attainment of steady-state concentrations, linear kinetics and minimal plasma protein binding. Levetiracetam does not interact with commonly used drugs and other AEDs. In recent Phase III clinical trials, the responder rate was 39.4 - 42.1% on 3000 mg dose, compared with placebo rates of 10.9 - 16.7%. Levetiracetam has a favourable safety profile and the most frequently reported adverse events were somnolence, asthenia and dizziness. Overall, levetiracetam is considered to have several advantages over current AEDs.

Animals↗

PubMed2004

Cell cycle regulation and hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) develops on a background of chronic hepatitis or cirrhosis. The slow progression of this disease has facilitated the identification of discrete pathologic stages. Increased rates of hepatocyte proliferation in preneoplastic nodules is an early event in the progression of HCC. Increased cell turnover results in the selection of monoclonal hepatocyte populations that subsequently undergo genomic alterations that lead to the development of HCC. The heterogeneous nature of genomic alterations identified in tumors from patients with HCC has impeded the identification of regulatory pathways whose disruption are critical for tumor initiation. However, several regulatory networks important for liver cell proliferation have been characterized using the partial hepatectomy model, an in vivo model of liver cell cycle progression, and are likely relevant to the pathogenesis of hepatocellular carcinoma.

Animals↗

PubMed1998

Correction for partial volume effects in PET: principle and validation.

UNLABELLED: The accuracy of PET for measuring regional radiotracer concentrations in the human brain is limited by the finite resolution capability of the scanner and the resulting partial volume effects (PVEs). We designed a new algorithm to correct for PVEs by characterizing the geometric interaction between the PET system and the brain activity distribution. METHODS: The partial volume correction (PVC) algorithm uses high-resolution volumetric MR images correlated with the PET volume. We used a PET simulator to calculate recovery and cross-contamination factors of identified tissue components in the brain model. These geometry-dependent transfer coefficients form a matrix representing the fraction of true activity from each distinct brain region observed in any given set of regions of interest. This matrix can be inverted to correct for PVEs, independent of the tracer concentrations in each tissue component. A sphere phantom was used to validate the simulated point-spread function of the PET scanner. Accuracy and precision of the PVC method were assessed using a human basal ganglia phantom. A constant contrast experiment was performed to explore the recovery capability and statistic error propagation of PVC in various noise conditions. In addition, a dual-isotope experiment was used to evaluate the ability of the PVC algorithm to recover activity concentrations in small structures surrounded by background activity with a different radioactive half-life. This models the time-variable contrast between regions that is often seen in neuroreceptor studies. RESULTS: Data from the three-dimensional brain phantom demonstrated a full recovery capability of PVC with less than 10% root mean-square error in terms of absolute values, which decreased to less than 2% when results from four PET slices were averaged. Inaccuracy in the estimation of 18F tracer half-life in the presence of 11C background activity was in the range of 25%-50% before PVC and 0%-6% after PVC, for resolution varying from 6 to 14 mm FWHM. In terms of noise propagation, the degradation of the coefficient of variation after PVC was found to be easily predictable and typically on the order of 25%. CONCLUSION: The PVC algorithm allows the correction for PVEs simultaneously in all identified brain regions, independent of tracer levels.

Algorithms↗

PubMed2006

Methylmercury induces activation of Notch signaling.

Methylmercury (MeHg) toxicity in humans manifests deficits in neurological function. Cases of prenatal exposure to mercury have established that the developing nervous system is most highly susceptible to perturbation by MeHg. At a cellular level, MeHg-induced defects result from altered neuronal proliferation, migration and pathfinding. However, the molecular targets of MeHg that give rise to these outcomes are not fully understood. In an overall effort to identify the fundamental molecular targets of MeHg in neural development, we have explored the effects of MeHg on cell surface receptor function using the simplified Drosophila model. In this study, we investigated the potential role of MeHg to alter activity of the Notch receptor pathway, a highly conserved cell-cell signaling mechanism that controls cell fate decisions, proliferation, migration and neurite outgrowth in neural development. Notch receptor activation requires proteolysis by a cell surface ADAM metalloprotease. ADAM proteases are required for normal neural development and are activated by organomercurials, thus presenting a possible mechanism for MeHg neurotoxicity. Here, we demonstrate a concentration- and time-dependent increase in Notch receptor activity with MeHg exposure in three distinct Drosophila cell lines. Ten micromolar MeHg results in a 4-5.5-fold increase in Notch signaling as measured by the upregulation of two enhancer of split (E(spl)) target genes. MeHg-induced Notch activity also correlates with receptor proteolysis. Targeted knockdown of Notch protein expression demonstrates that MeHg induced E(spl) activation specifically requires the Notch receptor. Furthermore, MeHg-induced Notch activity is partially attenuated by the metalloprotease inhibitor, GM6001, consistent with a model in which MeHg promotes activation of ADAM metalloproteases. Finally, we demonstrate that inorganic HgCl(2) is significantly less active in inducing Notch activity, suggesting a mechanism specific to organic species of mercury. Overall, these data identify Notch as a potential target for MeHg toxicity in the developing nervous system.

Animals↗

PubMed2000

Investigation into the role of the serine protease HtrA in Yersinia pestis pathogenesis.

The HtrA stress response protein has been shown to play a role in the virulence of a number of pathogens. For some organisms, htrA mutants are attenuated in the animal model and can be used as live vaccines. A Yersinia pestis htrA orthologue was identified, cloned and sequenced, showing 86% and 87% similarity to Escherichia coli and Salmonella typhimurium HtrAs. An isogenic Y. pestis htrA mutant was constructed using a reverse genetics approach. In contrast to the wild-type strain, the mutant failed to grow at an elevated temperature of 39 degrees C, but showed only a small increase in sensitivity to oxidative stress and was only partially attenuated in the animal model. However, the mutant exhibited a different protein expression profile to that of the wild-type strain when grown at 28 degrees C to simulate growth in the flea.

Animals↗

PubMed2006

Homologous desensitization of signalling by the beta (beta) isoform of the human thromboxane A2 receptor.

Thromboxane (TX) A(2) is a potent stimulator of platelet activation/aggregation and smooth muscle contraction and contributes to a variety of pathologies within the vasculature. In this study, we investigated the mechanism whereby the cellular responses to TXA(2) mediated through the TPbeta isoform of the human TXA(2) receptor (TP) are dynamically regulated by examining the mechanism of agonist-induced desensitization of intracellular signalling and second messenger generation by TPbeta. It was established that TPbeta is subject to profound agonist-induced homologous desensitization of signalling (intracellular calcium mobilization and inositol 1,3,5 trisphosphate generation) in response to stimulation with the TXA(2) mimetic U46619 and this occurs through two key mechanisms: TPbeta undergoes partial agonist-induced desensitization that occurs through a GF 109203X-sensitive, protein kinase (PK)C mechanism whereby Ser(145) within intracellular domain (IC)(2) has been identified as the key phospho-target. In addition, TPbeta also undergoes more profound and sustained agonist-induced desensitization involving G protein-coupled receptor kinase (GRK)2/3-phosphorylation of both Ser(239) and Ser(357) within its IC(3) and carboxyl-terminal C-tail domains, respectively. Inhibition of phosphorylation of either Ser(239) or Ser(357), through site directed mutagenesis, impaired desensitization while mutation of both Ser(239) and Ser(357) almost completely abolished desensitization of signalling, GRK phosphorylation and beta-arrestin association, thereby blocking TPbeta internalization. These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs. TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization. Thromboxane (TX) A(2) is a potent stimulator of platelet aggregation and smooth muscle contraction and contributes to a variety of vascular pathologies. Herein the mechanism whereby the cellular responses to TXA(2) mediated through the TPbeta isoform of the human TXA(2) receptor (TP) are dynamically regulated was investigated by examining the mechanism of its agonist-induced desensitization of intracellular signalling and second messenger generation. TPbeta is subject to profound agonist-induced homologous desensitization of signalling (intracellular calcium mobilization and inositol 1,3,5 trisphosphate generation) in response to stimulation with the TXA(2) mimetic U46619 and this occurs through two key mechanisms: TPbeta undergoes partial agonist-induced desensitization that occurs through a GF 109203X-sensitive, protein kinase (PK)C mechanism whereby Ser(145) within intracellular domain (IC)(2) was identified as the key phospho-target. In addition, TPbeta also undergoes more profound and sustained agonist-induced desensitization involving G protein-coupled receptor kinase (GRK)2/3-phosphorylation of both Ser(239) and Ser(357) within its IC(3) and carboxyl-terminal C-tail domains, respectively. Inhibition of phosphorylation of either Ser(239) or Ser(357), through site directed mutagenesis, impaired desensitization while mutation of both Ser(239) and Ser(357) almost completely abolished desensitization of signalling, GRK phosphorylation and beta-arrestin association, thereby blocking TPbeta internalization. These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1996

Coupling of cortical and thalamic ictal activity in human partial epilepsy: demonstration by functional magnetic resonance imaging.

PURPOSE: To localize metabolic coupling between a cortical seizure focus and other brain regions by using functional magnetic resonance imaging (fMRI) data of ictal events obtained in a patient with frequent partial seizures involving his right face. METHODS: Cross-correlation analysis was used to examine time-dependent alterations in regional signal intensity that correlated with signal-intensity changes from a well-characterized cortical seizure focus in a patient with frequent partial seizures. RESULTS: Signal changes in the left ventrolateral thalamus showed a high degree of temporal correlation with signal changes in the left frontal cortical seizure focus, demonstrating close corticothalamic coupling of metabolism. CONCLUSIONS: A significant role for thalamocortical interactions in the pathophysiology of epilepsy has been suggested by studies in animal models and human patients. This finding provides further support for the integral involvement of the thalamus in human focal epilepsy and underscores the potential for identifying neuronal networks by using cross-correlation analysis of fMRI data.

Adult↗