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Biomedical subjects

C Myers

Publications and source records attributed to C Myers.

At least 19 recordsLinked to original sources
PubMed2005

[Pediatrics. Conjugate anti-pneumoccoccal vaccine: what are the results four years after introduction?].

Considerable morbidity and mortality are related to pneumococcal disease predominantly in high risk populations: infants and young children, the elderly and the immunocompromised. A recent heptavalent conjugate anti-pneumococcal vaccine, introduced in the routine immunization program in the United States in 2001, has been shown to be spectacularly effective in the prevention of invasive disease in the very young in contrast to the pre-existing polysaccharide vaccine. As a consequence, horizontal transmission throughout the community is decreased with a reduction in disease rates in non-vaccinated adults. Finally the conjugate vaccine also provides an effective tool for reduction of drug-resistant pneumococcal strains. A review of the existing anti-pneumococcal vaccines, their direct and indirect effects and their recommended use in Switzerland.

Child, Preschool↗
PubMed2004

Human midbrain sensitivity to cognitive feedback and uncertainty during classification learning.

Mesencephalic dopaminergic system (MDS) neurons may participate in learning by providing a prediction error signal to their targets, which include ventral striatal, orbital, and medial frontal regions, as well as by showing sensitivity to the degree of uncertainty associated with individual stimuli. We investigated the mechanisms of probabilistic classification learning in humans using functional magnetic resonance imaging to examine the effects of feedback and uncertainty. The design was optimized for separating neural responses to stimulus, delay, and negative and positive feedback components. Compared with fixation, stimulus and feedback activated brain regions consistent with the MDS, whereas the delay period did not. Midbrain activity was significantly different for negative versus positive feedback (consistent with coding of the "prediction error") and was reliably correlated with the degree of uncertainty as well as with activity in MDS target regions. Purely cognitive feedback apparently engages the same regions as rewarding stimuli, consistent with a broader characterization of this network.

Adult↗
PubMed2001

Interactive memory systems in the human brain.

Learning and memory in humans rely upon several memory systems, which appear to have dissociable brain substrates. A fundamental question concerns whether, and how, these memory systems interact. Here we show using functional magnetic resonance imaging (FMRI) that these memory systems may compete with each other during classification learning in humans. The medial temporal lobe and basal ganglia were differently engaged across subjects during classification learning depending upon whether the task emphasized declarative or nondeclarative memory, even when the to-be-learned material and the level of performance did not differ. Consistent with competition between memory systems suggested by animal studies and neuroimaging, activity in these regions was negatively correlated across individuals. Further examination of classification learning using event-related FMRI showed rapid modulation of activity in these regions at the beginning of learning, suggesting that subjects relied upon the medial temporal lobe early in learning. However, this dependence rapidly declined with training, as predicted by previous computational models of associative learning.

Adult↗
PubMed2001

Proapoptotic anti-inflammatory drugs.

The very fact that apoptosis and nonsteroidal anti-inflammatory drugs (NSAIDs) can be linked in the same title should tell you that something unusual is happening. The image of NSAIDs among physicians is certainly discordant with that associated with cancer treatment, which usually involves administration of drugs with serious or even life-threatening toxicity. In contrast, the drugs discussed in this review, including selective cyclooxygenase-2 inhibitors, lipoxygenase inhibitors, and novel NSAID derivatives (eg, sulindac sulfone and R-flurbiprofen), offer the promise of oral, nontoxic agents able to control the progression of established prostate cancer and possibly to prevent the development of prostate cancer de novo. NSAIDs were initially developed to suppress inflammation and pain by inhibiting the production of prostaglandin E2 and its metabolites. At first glance, the fact that NSAIDs are active against prostate cancer in laboratory and clinical studies might suggest that prostaglandins play a pivotal role in prostate cancer biology. However, the story is much more complex than that. Although cyclooxygenase-mediated production of prostaglandins appears to play an important role in the biology of prostate cancer, the NSAIDs and derivatives with promising activity against prostate cancer manifest several mechanisms of action that can include direct inhibition of eicosanoid formation, indirect inhibition of eicosanoid formation by inhibiting expression of enzymes involved in eicosanoid synthesis, or by interfering with the function of cyclic guanosine monophosphate.

Angiogenesis Inhibitors↗
PubMed2001

Amphipathic variable region heavy chain peptides derived from monoclonal human Wegener's anti-PR3 antibodies stimulate lymphocytes from patients with Wegener's granulomatosis and microscopic polyangiitis.

Amphipathic variable-region heavy chain 11-mer peptides from monoclonal human IgM antiproteinase-3 antibodies were studied for peripheral blood lymphocyte stimulation in 21 patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), connective tissue disease controls and normal control subjects. Positive T-cell activation was observed in most experiments with WG patients' lymphocytes using amphipathic VH-region peptides from four different human monoclonal anti-PR3 antibodies. Control peptides of the same length but without amphipathic characteristics along with other amphipathic peptides not derived from monoclonal anti-PR3 sequence were employed as controls. No significant lymphocyte stimulation was observed with normal controls, but positive stimulation with amphipathic VH peptides was also recorded in other connective tissue disease controls mainly patients with rheumatoid arthritis. Amphipathic peptides not derived from anti-PR3 sequence did not stimulate WG lymphocytes. Our findings indicate that lymphocyte reactivity as an element of cell-mediated immunity may be activated by amphipathic VH-region amino acid sequences of autoantibodies which are themselves associated with diseases such as WG.

Adult↗
PubMed2001

Genomics: implications for health systems.

In anticipation of and following the announcement of the completion of the mapping of the human genome, numerous articles have appeared in scientific, industry, and consumer journals and magazines on the topic of genomics. Building off the excitement surrounding this scientific milestone, many of these articles--irrespective of the audience--look to the future and anticipate how this knowledge breakthrough will change the way classes of diseases are diagnosed, treated, and even prevented over the next several generations. However, literature that explores the potential effect of genomics on health system care delivery is virtually nonexistent. As such, this article begins to prepare health system executives for the future by speculating how genomics may affect their organizations and suggesting strategies for future success.

Delivery of Health Care↗
PubMed2001

Model reactions of Cr (VI) with DNA mediated by thiol species.

Model reactions were devised to investigate the capacity of physiologically interesting thiol compounds to mediate reactions between CrO4(2-) (Cr (VI)) and DNA. The sulfhydryl containing reagents included cysteine, glutathione, apo-metallothionein (apoMT). Zinc finger 3 of transcription factor IIIA (Zn-F3) of Xenopus laevis was investigated as a potential redox active site of reaction of Cr (VI) and thiol compounds. The DNA samples were calf thymus DNA and two oligomers, one of them specific for binding Zn-F3. Results showed that in the presence of Cr (VI) apoMT readily participated in damaging DNA in a reaction that appeared to be hydroxyl radical dependent. It also became cross-linked to oligomer and native DNA samples. In comparison, the other two thiol donors were largely inactive in these assays even though they, like apoMT, were able to reduce Cr (VI) to Cr (III) under the conditions of the experiments. Direct attempts to cross link thiols with DNA in the presence of Cr3+ were unsuccessful at pH 7.4. Together, the results indicate that apoMT can effectively collaborate with Cr (VI) in reactions that are deleterious to DNA.

Animals↗
PubMed2000

Maf transcriptionally activates the mouse p53 promoter and causes a p53-dependent cell death.

An increase in the level of the tumor suppressor protein p53 can induce cell cycle arrest or cell death. Although mechanisms for regulating the life span of p53 have been described, there is growing evidence that transcriptional regulation of the p53 gene contributes significantly to controlling p53 protein levels and therefore the fate of a cell. However, the signal transduction pathways that lead to transcriptional activation of the p53 gene are poorly understood. The oncoprotein v-Maf and its cellular counterparts belong to the large combinatorially complex basic leucine zipper family of transcription factors, which include the AP1 family. To date few cellular targets of c-Maf have been identified. It is demonstrated here that v-Maf can bind as a homodimer to a variant Maf recognition element located between -66 and -54 upstream in the mouse p53 promoter. V-Maf and its cellular counterparts are shown to activate p53 expression through this site. The ability of v-Maf to activate p53 expression is modulated by AP1 family members. In addition, overexpression of v-Maf in primary cells leads to a p53-dependent cell death. Thus, Maf and members of the AP1 family are able to regulate p53 expression through this site in the p53 promoter.

Animals↗
PubMed2000

Homeobox B3 promotes capillary morphogenesis and angiogenesis.

Endothelial cells (EC) express several members of the Homeobox (Hox) gene family, suggesting a role for these morphoregulatory mediators during angiogenesis. We have previously established that Hox D3 is required for expression of integrin alphavbeta3 and urokinase plasminogen activator (uPA), which contribute to EC adhesion, invasion, and migration during angiogenesis. We now report that the paralogous gene, Hox B3, influences angiogenic behavior in a manner that is distinct from Hox D3. Antisense against Hox B3 impaired capillary morphogenesis of dermal microvascular EC cultured on basement membrane extracellular matrices. Although levels of Hox D3-dependent genes were maintained in these cells, levels of the ephrin A1 ligand were markedly attenuated. Capillary morphogenesis could be restored, however, by addition of recombinant ephrin A1/Fc fusion proteins. To test the impact of Hox B3 on angiogenesis in vivo, we constitutively expressed Hox B3 in the chick chorioallantoic membrane using avian retroviruses that resulted in an increase in vascular density and angiogenesis. Thus, while Hox D3 promotes the invasive or migratory behavior of EC, Hox B3 is required for the subsequent capillary morphogenesis of these new vascular sprouts and, together, these results support the hypothesis that paralogous Hox genes perform complementary functions within a particular tissue type.

Animals↗
PubMed2000

Effects of repeated withdrawal from continuous amphetamine administration on brain reward function in rats.

RATIONALE: The study of the effects of repeated amphetamine administration and withdrawal on brain reward function has relevance to both amphetamine dependence and non-drug-induced depressions. OBJECTIVES: The purpose of this study was to investigate the effects of continuous amphetamine administration and withdrawal on brain stimulation reward thresholds, and the changes that occur with repeated amphetamine exposures. METHODS: Rats were prepared with bipolar electrodes in the lateral hypothalamus and trained in a discrete-trial reward threshold procedure. Then, rats underwent two separate periods of amphetamine administration via subcutaneous osmotic mini-pumps. RESULTS: Continuous amphetamine administration was associated with lowering in brain reward thresholds and decreases in response latencies, while withdrawal was associated with threshold elevations. These effects changed with subsequent amphetamine administration and withdrawal. CONCLUSIONS: The results of this study indicated that with the amphetamine administration regime used here, rats developed increased sensitivity to the effects of acute amphetamine administration and tolerance to the effects of amphetamine withdrawal.

Amphetamine↗
PubMed1999

Comparison of Euroqol EQ-5D and SF-36 in patients with chronic fatigue syndrome.

The objective of the study was to compare the Euroqol EQ-5D (Euroqol) and short-form 36 (SF-36) health questionnaires in patients with chronic fatigue syndrome (CFS). One hundred and twenty-seven outpatients referred to a hospital-based infectious disease clinic with a diagnosis of CFS were contacted by post and asked to complete both questionnaires. Additional data were determined from hospital casenotes. Eighty-five patients returned correctly completed questionnaires. Euroqol health values and visual analogue scale (VAS) scores were strongly and significantly correlated with all dimensions of the SF-36, with the exception of physical limitation of role. SF-36 dimensions were in turn strongly and significantly correlated with each other, with the same exception. Patients reported a high degree of physical disability and a moderate degree of emotional or psychological ill-health. The Euroqol elements dealing with mobility and self-care referred to inappropriately severe degrees of disability for these patients with CFS. Similarly some dimensions in the SF-36 were oversensitive and did not discriminate between patients with moderate or severe disability. It was concluded that Euroqol scores correlated strongly with SF-36 scores and provided useful information about patients with CFS and that Euroqol would be a useful tool for the rapid assessment of health status in CFS. The current Euroqol instrument refers to inappropriately severe degrees of disability for patients with CFS and would need to be modified to be maximally useful in this situation.

Activities of Daily Living↗
PubMed1999

Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats.

Melatonin (MEL) is a widely used, over-the-counter sleep aid, and it has putative contraceptive, antioxidant, antiaging, and anticancer effects. The developmental toxicity potential for repeated oral doses of MEL had not previously been evaluated. In the present studies, time-mated, Sprague-Dawley-derived (CD) rats were administered MEL or vehicle by gavage on gestation days (gd) 6-19. MEL-treated groups received 1-, 10-, 100-, 150-, or 200-mg/kg body weight/day in the screening study (15 rats/group), and 50, 100, or 200 mg/kg/day in the definitive study (25 rats/group). In both studies, maternal food/water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20, both studies), maternal liver and gravid uterine weights, number of ovarian corpora lutea, conceptus survival, fetal sex, and fetal body weight were evaluated. Fetal morphological examination included external structures (both studies) as well as visceral and skeletal structures (definitive study). In the screening study, maternal serum levels of 17beta-estradiol, progesterone, prolactin, and luteinizing hormone were determined by radioimmunoassay, and mammary tissue was fixed, stained, and evaluated for percent glandular area within the fat pad. No maternal morbidity/mortality was found in either study. In the screening study, aversion to treatment (> or =100 mg/kg/day) and reduced maternal weight gain (> or =150 mg/kg/day) were noted, but reproductive/endocrine parameters and fetal development were not affected. In the definitive study, aversion to treatment was noted at > or =50 mg/kg/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg/day. MEL had no effect on prenatal survival, fetal body weight, or incidences of fetal malformations/variations. Thus, in the definitive study, the maternal toxicity NOAEL and LOAEL were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was > or =200 mg/kg/day.

Animals↗
PubMed1999

Paroxetine pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of paroxetine in children and adolescents and to explore the role of genetic polymorphisms in paroxetine pharmacokinetics. METHOD: Thirty depressed youths were enrolled. Samples for phenotyping with respect to cytochrome P450 2D6 (CYP2D6) and catechol-O-methyltransferase were collected. A single 10-mg dose of paroxetine was then administered followed by 5 days of blood and urine collection for pharmacokinetic analyses. Subjects subsequently received open treatment for 8 weeks, and weekly blood samples were obtained for plasma concentration measurements. RESULTS: There was tremendous interindividual variability in paroxetine disposition. The mean half-life of paroxetine was 11.1 +/- 5.2 (SD) hours. The average clearance was 88.7 +/- 66.4 mL/min/kg. The mean area under the plasma drug concentration curve was 0.09 +/- 0.10 microgram/mL.hr. Within-subject variability of plasma paroxetine concentrations was generally not significant. Clearance and fractional urinary excretion of paroxetine were found to correlate with CYP2D6 activity. Two subjects developed hypomania necessitating drug discontinuation. No clinically significant changes in any safety assessments were noted. CONCLUSIONS: Paroxetine is more rapidly cleared in youths than adults and may be given once daily in this population. Short-term treatment with paroxetine appears safe and well tolerated in this relatively small sample of pediatric patients.

Adolescent↗
PubMed1999

Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.

PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Androgens↗
PubMed1999

Neural dynamics of perceptual order and context effects for variable-rate speech syllables.

How does the brain extract invariant properties of variable-rate speech? A neural model, called PHONET, is developed to explain aspects of this process and, along the way, data about perceptual context effects. For example, in consonant-vowel (CV) syllables, such as /ba/ and /wa/, an increase in the duration of the vowel can cause a switch in the percept of the preceding consonant from /w/ to /b/ (J.L. Miller & Liberman, 1979). The frequency extent of the initial formant transitions of fixed duration also influences the percept (Schwab, Sawusch, & Nusbaum, 1981). PHONET quantitatively simulates over 98% of the variance in these data, using a single set of parameters. The model also qualitatively explains many data about other perceptual context effects. In the model, C and V inputs are filtered by parallel auditory streams that respond preferentially to the transient and sustained properties of the acoustic signal before being stored in parallel working memories. A lateral inhibitory network of onset- and rate-sensitive cells in the transient channel extracts measures of frequency transition rate and extent. Greater activation of the transient stream can increase the processing rate in the sustained stream via a cross-stream automatic gain control interaction. The stored activities across these gain-controlled working memories provide a basis for rate-invariant perception, since the transient-to-sustained gain control tends to preserve the relative activities across the transient and sustained working memories as speech rate changes. Comparisons with alternative models tested suggest that the fit cannot be attributed to the simplicity of the data. Brain analogues of model cell types are described.

Attention↗
PubMed1998

Dynamic expression of L-selectin in cell-to-cell interactions between neutrophils and endothelial cells in vitro.

Neutrophil-endothelial cell interactions are regulated by cell adhesion molecules and their cognate ligands. It has been proposed that L-selectin and Mac-1 (CD11b/CD18), two neutrophil adhesion receptors, have sequential roles in neutrophil extravasation during inflammation. In this model, L-selectin mediates rolling and initial adherence of neutrophils to endothelial cells, while Mac-1 strengthens this initial adherence and also facilitates migration of neutrophils through endothelial cells. L-selectin and Mac-1 expression are known to be inversely regulated. Here an in vitro culture system has been developed to investigate in situ expression of L-selectin during cell-to-cell interactions between neutrophils and endothelial cell monolayers by confocal immunofluorescence analysis. Neutrophils underwent profound cell shape change from round to polarized cell morphology with pseudopod formation after 5 to 15 min coculture with IL-1-stimulated human endothelial cells. L-selectin was redistributed to the pseudopod of the polarized neutrophils in correlation with such cellular changes. During initial cell attachment, neutrophils bound to IL-1-stimulated endothelial cells expressed a high level of L-selectin in a polarized pattern. L-selectin expression decreased over time during neutrophil-endothelial cell interactions.

Adult↗