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Biomedical subjects

S Roberts

Publications and source records attributed to S Roberts.

At least 37 records · Page 2Linked to original sources
PubMed2001

Timing and the control of variation.

Two rat experiments shed light on how variation in behavior is regulated. Experiment 1 used the peak procedure. On most trials, the 1st bar press more than 40 s after signal onset ended the signal and produced food. Other trials lasted much longer and ended without food. On those trials, the variability of bar-press duration increased greatly after the 1st response more than 40 s after signal onset. In Experiment 2, which asked whether the increase was due to the omission of expected reward or the decrease in reward expectation, reward expectation had a strong effect on response duration, whereas omission of expected reward had little effect. In both experiments, response rate and response duration changed independently, suggesting that they reflect different parts of the underlying mechanism. In Experiment 1, response durations implied that timing of the signal was more accurate than the rate-vs.-time function might suggest. Experiment 2 suggested that lowering reward expectation increases variation in response form.

Animals↗
PubMed2001

Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix.

Hypoxic tumors are known to be more malignant, to be more likely to metastasize, and to have a poor prognosis. They are also radio- and chemoresistant. For this reason, it is desirable that a clinically useful marker of hypoxia is found, so that treatment with radiotherapy and bioreductive chemotherapy can be rationally applied to individual patients. Glut-1 is a facilitative glucose transporter that is ubiquitously expressed in normal tissue and expressed at higher levels in a number of tumors. Its potential as an intrinsic hypoxia marker arises from its dual control in hypoxic conditions by reduced oxidative phosphorylation and the hypoxia-inducible factor (HIF-1) oxygen-sensing pathway. Eppendorf histography, by virtue of its proven predictive qualities, is a suitable gold standard used in our laboratory to validate new hypoxia markers. Using this technique, pretreatment pO(2) measurements were performed on 54 patients with locally advanced cervical carcinoma. Then, immunohistochemical staining was used to detect Glut-1 protein in individual tumor biopsy sections. Both measurements were made before initiation of treatment. By using a low-tech scoring system, pO(2) was found to correlate weakly with Glut-1 score (r = 0.28; P = 0.04). To extrapolate this correlation to the known adverse effects of tumor hypoxia on outcome, we examined the prognostic significance of Glut-1 staining in a retrospective series of 121 patients. An absence of Glut-1 significantly increased the likelihood of metastasis-free survival (P = 0.022) but did not significantly effect disease-free or recurrence-free survival. These findings suggest that Glut-1 be an intrinsic marker of hypoxia that can easily be applied in a clinical setting.

Biomarkers, Tumor↗
PubMed2001

RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid (RPR 119990). The compound displaced [3H]AMPA from rat cortex membranes with a K(i) of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a K(B) of 71 nM. The antagonist properties of this compound were confirmed on rat native AMPA receptors in cerebella granule neurons in culture and in hippocampal slices where it antagonized electrophysiological responses with IC50 values of 50 and 93 nM, respectively. RPR 119990 antagonized hippocampal evoked responses in vivo, demonstrating brain penetration at active concentrations. RPR 119990 is a potent anticonvulsant in the supramaximal electroshock in the mouse with an ED50 of 2.3 mg/kg 1 h post s.c. administration, giving it a workably long action. Pharmacokinetic studies show good passage into the plasma after subcutaneous administration, whereas brain penetration is low but with slow elimination. This compound was found active in a transgenic mouse model of familial amyotrophic lateral sclerosis (SOD1-G93A) where it was able to improve grip muscle strength and glutamate uptake from spinal synaptosomal preparations, and prolong survival with a daily dose of 3 mg/kg s.c.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Pathogenic mechanisms in rheumatic carditis: focus on valvular endothelium.

To clarify immune-mediated mechanisms in rheumatic heart disease caused by group A streptococcal infection, valve tissues from rheumatic patients with valvular heart disease who required valve replacement were studied for reactivity with monoclonal anti-CD4 or anti-CD8 monoclonal antibodies or anti-vascular cell adhesion molecule-1 (VCAM-1). At the valve surface, CD4(+) and CD8(+) T lymphocytes were adherent to valve endothelium and penetrated through the subendothelial layer. T cell extravasation into the valve through the surface valvular endothelium appeared to be an important event in the development of rheumatic heart disease. VCAM-1 was expressed on the valvular endothelium in rheumatic valves. Evidence suggested that the pathogenesis of rheumatic heart disease involved the activation of surface valvular endothelium with the expression of VCAM-1 and the extravasation of CD4(+) and CD8(+) lymphocytes through the activated endothelium into the valve. Lymphocytic infiltration through the valve surface endothelium has not been appreciated as a potential initiating step in disease pathogenesis.

Adolescent↗
PubMed2000

Matrix metalloproteinases and aggrecanase: their role in disorders of the human intervertebral disc.

STUDY DESIGN: A comprehensive immunohistochemical study of matrix metalloproteinase activity in discs from patients with different disc diseases. OBJECTIVES: To identify individual matrix metalloproteinase enzymes that could contribute to the degeneration of the matrix of the intervertebral disc, to identify the cells that produce matrix metalloproteinases (for example, the endogenous disc cells or invading cells associated with vascularisation), and to determine if "aggrecanase" contributes to degradation of proteoglycans in disc disorders. SUMMARY OF BACKGROUND DATA: Matrix disorganization and loss of substance are the most common findings in degenerate discs, and proteinase enzyme activity is one means of causing these changes. METHODS: Forty-nine discs from 46 patients with degenerative disc disease, posterior anular tears, spondylolisthesis, or disc herniation were studied immunohistochemically to determine the presence of matrix metalloproteinases 1, 2, 3, 7, 8, 9 and 13, tissue metalloproteinases 1 and 2, and proteoglycan degradation products generated by either matrix metalloproteinases or aggrecanase activity. In addition, in situ zymography was used to confirm matrix metalloproteinase activity. RESULTS: The most extensive staining was seen for matrix metalloproteinases 1, 2, 3, and 9, with 91%, 71%, 65%, and 72% of samples having some immunopositivity for the respective antibodies. In contrast, staining for matrix metalloproteinases 7 and 8 was much less (38% for both). Tissue inhibitor of metalloproteinases 1 and 2 were expressed in 34% and 79% of specimens, respectively. Matrix metalloproteinases were found particularly in cell clusters and blood vessels of degenerate discs, with staining correlating positively with macroscopic degenerative grade. For all of the enzymes, there was most staining in the herniation specimens and least in the autopsy samples. The opposite was true of staining for the matrix metalloproteinases inhibitor, tissue inhibitor of metalloproteinases 2, with most found in the autopsy specimens. Enzyme activity was confirmed by in situ zymography and staining for matrix metalloproteinase degradation products of proteoglycans. In addition, there was staining with antibodies demonstrating aggrecanase degradation products. CONCLUSIONS: Matrix metalloproteinase activity is more prevalent in herniated discs than in other disc disorders studied, although matrix metalloproteinases may have been more common earlier in the disease progression. Matrix metalloproteinases can be produced by invading blood vessels and associated cells, as well as by indigenous disc cells. Aggrecanase activity, although present in some samples, was not as obvious as that of matrix metalloproteinases. In addition to altered matrix metalloproteinase production, there appears to be a change in the balance between enzymes and endogenous inhibitors, tissue inhibitors of metalloproteinases. This study highlights specific matrix metalloproteinases that might be most efficient to target in developing therapeutics for minimizing degradation of the extracellular matrix of the disc.

Adolescent↗
PubMed2000

Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia.

BACKGROUND: Previous studies have yielded conflicting results and substantial uncertainty about any independent association of Helicobacter pylori infection with dyspepsia, and about any benefits of antibiotic treatments for nonulcer or uninvestigated dyspepsia. OBJECTIVES: To perform a systematic review of the literature to determine whether chronic infection with H pylori is relevant to nonulcer or uninvestigated dyspepsia. METHODS: Observational studies of associations between H pylori and dyspepsia published before April 1999 and randomized trials of the effects of H pylori eradication on dyspepsia published before January 2000 were identified by computer-assisted literature searches of relevant journals, reference lists, and discussions with authors. Relevant data were abstracted from the published reports by 2 investigators according to a fixed protocol. RESULTS: Thirty relevant observational studies were identified involving approximately 3392 patients with nonulcer dyspepsia, and 11 separate observational studies were identified, involving 6426 patients with uninvestigated dyspepsia. Reports of strong associations in small observational studies without appropriate adjustment for potential confounding factors were not generally confirmed by larger and better-designed studies. No studies have been reported, however, that can reliably confirm or exclude the existence of any weak associations. Twenty-two randomized trials of treatments against H pylori were found involving a total of 2340 patients with nonulcer dyspepsia, almost all with positive H pylori test results. Only a few of these trials involved effective antibacterial regimens with prolonged follow-up, and even these studies were too small to assess the possibility of moderate benefits. CONCLUSION: The available evidence indicates that there is no strong association between H pylori and dyspepsia, but there is insufficient evidence to confirm or refute the existence of a modest association.

Chronic Disease↗
PubMed2000

The zinc ribbon domains of the general transcription factors TFIIB and Brf: conserved functional surfaces but different roles in transcription initiation.

The function of the conserved zinc-binding domains in the related Pol II- and Pol III-specific factors TFIIB and Brf was investigated. Three-dimensional structure modeling and mutagenesis studies indicated that for both factors, the functional surface of the zinc ribbon fold consists of a small conserved patch of residues located on one face of the domain comprised mainly of the second and third antiparallel beta strands. Previous studies have shown that the TFIIB zinc ribbon is essential for recruitment of Pol II into the preinitiation complex. In contrast, Pol III recruitment assays and in vitro transcription demonstrate that the disruption of the Brf zinc ribbon does not lead to a defect in Pol III recruitment but, rather, a defect in open complex formation. Therefore, the same conserved surface of the zinc ribbon domain has been adapted to serve distinct roles in the Pol II and Pol III transcription machinery.

Amino Acid Sequence↗
PubMed2000

X-Ray Absorption Spectroscopy of Strontium(II) Coordination.

Sorption of dissolved strontium on kaolinite, amorphous silica, and goethite was studied as a function of pH, aqueous strontium concentration, the presence or absence of atmospheric CO(2) or dissolved phosphate, and aging over a 57-day period. Selected sorption samples ([Sr(aq)](i) approximately 0.5-1x10(-3) m) were examined with synchrotron X-ray absorption spectroscopy (XAS) at low (13-23 K) and room temperatures to determine the local molecular coordination around strontium. Quantitative analyses of the extended X-ray absorption fine structure (EXAFS) of kaolinite, amorphous silica, and most goethite sorption samples showed a single first shell of 9-10 (+/-1) oxygen atoms around strontium at an average Sr-O bond-distance of 2.61 (+/-0.02) Å, indicating hydrated surface complexes. The EXAFS spectra were unchanged after reaction for up to 57 days. Likewise, in kaolinite sorption samples prepared in 100% nitrogen atmosphere, the presence of dissolved phosphate (0.5x10(-3) m) in addition to strontium did not change the local coordination around strontium. In two goethite sorption samples reacted in air at pH approximately 8.5, the EXAFS spectra (collected at low and room temperature) clearly showed that the local structure around strontium is that of strontianite (SrCO(3)(s)). We also noted an increase in strontium uptake on goethite in the presence of atmospheric CO(2) in batch experiments, relative to CO(2)-free experiments. These observations suggest that sorption of carbonate may nucleate the precipitation of SrCO(3) in the pH range in which carbonate sorption on goethite is near a maximum. At higher pH, carbonate surface sorption decreases as dissolved CO(2) decreases. For goethite sorption samples above pH 8.6, hydrated surface complexes, rather than a precipitate, were observed in the EXAFS spectra. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

Nine independent F9 mutations in the Mexican hemophilia B population: nonrandom recurrences of point mutation events in the human germline.

The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.

Factor IX↗
PubMed2000

The human factor IX gene as germline mutagen test: samples from Mainland China have the putatively endogenous pattern of mutation.

Germline mutations are the major source of genetic variation that allows a species to evolve over time but at the cost of Mendelian disease and genetic predisposition to multifactorial diseases. Previous analyses have revealed that the pattern of germline mutations in the factor IX gene (F9) is similar among a variety of ethnically and geographically diverse populations and compatible with the ancient pattern that has shaped the mammalian genome. Here, we compare the pattern of germline mutation in a population of hemophilia B patients from Mainland China (n=66) to that in U.S. Caucasians, Blacks, and Mexican Hispanics and stratify by disease severity and ethnicity. The similar pattern of germline mutation in all ethnic groups studied to date provides additional data compatible with the inference that endogenous processes predominate in germline mutations.

China↗
PubMed2000

Factor IX mutations in South Africans and African Americans are compatible with primarily endogenous influences upon recent germline mutations.

Similar patterns of germline mutations in the factor IX gene (F9) have been observed in certain geographically and racially diverse populations. Germline mutation data have not been available from any region of Africa or from the Black race. Analysis of mutation data for Blacks is of interest, since this race has a high frequency of polymorphism compared to other races. This high frequency has been interpreted as evidence for the "out of Africa" hypothesis for the origin of humans, but it is possible that Blacks have a higher mutation rate due to genetic differences or environmental exposures. We report 26 independent mutations that were detected in patients of mixed races with hemophilia B from South Africa. The pattern of mutation in patients from this African country was similar to that of U.S. Caucasians. In addition, 22 independent mutation were detected in African American patients. The patterns of independent germline mutation in 22 African Americans (and in a combination 34 North American and African Blacks) is similar to that of U.S. Caucasians. Neither genetic differences between the Black and Caucasian races nor environmental and cultural differences between South Africa and the U.S. alter the germline pattern of mutation observed in F9. Hum Mutat 16:372, 2000.

Black People↗
PubMed2000

Intentions to quit smoking in substance-abusing teens exposed to a tobacco program.

In 1993-94, fifty-five clients at an adolescent residential drug treatment facility with an innovative tobacco prevention, education and cessation program reported their tobacco attitudes, intentions, and behavior at admission and discharge. Of entering clients, 93% were current smokers and 93% felt the facility should help clients quit smoking. Clients interested in quitting increased from 61% at admission to 87% at discharge, as measured by the precontemplation/contemplation ladder of Rustin and Tate (1993). Clients who wanted to immediately quit smoking increased from 15% to 29%. Sixty-five percent of the teens studied said the tobacco-free activities were extremely helpful. At discharge, 16% of the smokers reported having quit tobacco and all four nonsmokers remained smoke-free. During the preceding year there was a naturally occurring quit rate of 1%. As a result of this work, the facility required residential clients to be nicotine-free as of July 1996.

Adolescent↗
PubMed2000

How persuasive is a good fit? A comment on theory testing.

Quantitative theories with free parameters often gain credence when they closely fit data. This is a mistake. A good fit reveals nothing about the flexibility of the theory (how much it cannot fit), the variability of the data (how firmly the data rule out what the theory cannot fit), or the likelihood of other outcomes (perhaps the theory could have fit any plausible result), and a reader needs all 3 pieces of information to decide how much the fit should increase belief in the theory. The use of good fits as evidence is not supported by philosophers of science nor by the history of psychology; there seem to be no examples of a theory supported mainly by good fits that has led to demonstrable progress. A better way to test a theory with free parameters is to determine how the theory constrains possible outcomes (i.e., what it predicts), assess how firmly actual outcomes agree with those constraints, and determine if plausible alternative outcomes would have been inconsistent with the theory, allowing for the variability of the data.

Humans↗
PubMed2000

The procedural validity of retrospective case note diagnosis.

OBJECTIVE: Deriving diagnoses from retrospective case note examination is a common practice in psychiatric research. The Operational Criteria (OPCRIT) diagnostic checklist is essentially a checklist built up of operational criteria defined by a comprehensive glossary and is designed to assign reliable diagnoses from case notes. However, the validity of such a procedure compared with procedures involving prospective assessment has never been tested. We examined the procedural validity of the OPCRIT diagnostic system in relation to four other diagnostic procedures mostly employing prospectively gathered information. METHOD: Three experienced psychopathology raters rated the case notes and clinical abstracts, using the OPCRIT method of diagnostic assignment, of 50 subjects who had participated in an early procedural validity study as an adjunct to the DSM-IV Field Trial for psychotic disorders. The setting was the Early Psychosis Prevention and Intervention Centre (EPPIC), which focuses on first episode psychosis. RESULTS: The pairwise concordance with the other procedures for DSM-III-R diagnoses assigned by OPCRIT using ratings derived from either the clinical abstracts or the case notes was found to be only poor to moderate when compared with the pairwise concordance of the four other procedures. The per cent agreement between OPCRIT clinical abstracts diagnoses and the other procedures ranged from 49% to 60% with kappa values between 0.30 and 0.45, and for OPCRIT case note diagnoses and the other procedures the per cent agreement range was between 44% and 57% and the kappa values were between 0.35 and 0.49. CONCLUSIONS: The procedural validity of diagnoses assigned via the application of checklists of operational criteria to case notes and clinical abstracts alone is unacceptably poor. Such sources need to be buttressed by other data, particularly direct patient interview and informant material.

Adolescent↗
PubMed2000

Assessment of long-term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975.

The aim of this study was to examine the long-term effects of hepatitis C virus (HCV) infection on a cohort of patients admitted with acute viral hepatitis from 1971 through 1975. The availability of stored sera from this time enabled testing to identify those who were anti-HCV-positive on admission. Sixteen percent (n = 238) of the cohort tested anti-HCV-positive. The unexposed group was selected from those who were anti-HCV-negative. Systematic approaches were used to locate the cohort and health outcomes assessed by a study-specific questionnaire and clinical, serological, virological, and biochemical assessment. Complete follow-up was achieved on 98 anti-HCV-positive individuals and 201 negatives. Injecting drug use (IDU) was the presumed route of infection. At a mean of 25 years' follow-up, 54% of the anti-HCV-positive group had evidence of chronic HCV infection (both anti-HCV- and HCV-RNA-positive); the remainder were HCV-RNA-negative. Sixty-nine percent of those chronically infected had elevated serum alanine transaminase (ALT) levels, but only 8% had progressed to overt cirrhosis, and no cases of hepatocellular carcinoma (HCC) were identified. In summary, anti-HCV-positive subjects were 8 times more likely to have died from suicide or drug overdose than from HCV-related disease. Anti-HCV-positive study subjects were at increased risk of liver-related pathology after 25 years' follow-up, but few had progressed to overt cirrhotic liver disease. Excess mortality in this group was not the result of liver disease. This suggests that the natural history of community-acquired HCV may be more benign than previously thought.

Adult↗
PubMed2000

Transactional conflict between psychobiology and culture in the etiology of postpartum depression.

In vulnerable individuals, postpartum depression may be triggered by the disruption of neuropsychological processes during pregnancy and parturition. It is proposed that in Western societies pre- and postnatal psychological and instrumental needs are poorly met and this crisis may interact with neurophysiological factors in compromising maternal psychological functioning. The influence of developmental factors and psychological and physical stressors are discussed in relation to women's neuropsychological health during the peripartal transition. It is hypothesized that the environmental milieu may support, neglect or derail the mother's psychobiological transition from pregnancy to effective postnatal parenting and resumption of family and work roles.

Conflict, Psychological↗