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Biomedical subjects

S J Thompson

Publications and source records attributed to S J Thompson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Relationship between disease severity and responses by blood mononuclear cells from patients with rheumatoid arthritis to human heat-shock protein 60.

The hypothesis that T-cell responses to the 60 000 MW family of heat-shock proteins (hsp) may be related to the severity of rheumatoid arthritis (RA) was examined. Peripheral blood mononuclear cells (PBMC) from most normal individuals and both early and established RA patients proliferated in vitro in response to human hsp 60 and mycobacterial hsp 65 as well as tetanus toxoid (TT) and mycobacterial purified protein derivative (PPD). PBMC from some patients with established RA gave responses to hsp 60 that were above the normal range and/or peaked earlier than PBMC from normal individuals. The responses of PBMC from established RA to hsp 65, but not PPD or TT, were also higher than those from normal individuals, but the peak responses to all three antigens appeared delayed. Thus a selective increase in responsiveness to hsp 60 develops with disease duration in many RA patients. Six assessments of disease activity and severity were made but apart from rheumatoid factor titre, they were unrelated to the proliferative response. Similarly, disease activity and severity did not differ between those RA patients whose hsp 60 stimulated cells produced interferon-gamma and those who did not, although patients whose hsp 60-stimulated T cells produced interleukin-4 (IL-4) and/or IL-10, appeared to have less disease activity and severity than those who did not. Significant negative correlations were found between IL-10 production by hsp 60-stimulated cells and disease assessments. It is considered that RA is less severe in those patients whose hsp 60-stimulated cells produce T-helper 2 type cytokines.

Adult↗
PubMed2000

The route of administration of an immunodominant peptide derived from heat-shock protein 65 dramatically affects disease outcome in pristane-induced arthritis.

Previous studies have shown that immunization of mice with an immunodominant epitope from heat-shock protein 65 (hsp 65) (amino acids 261-271) can protect from the development of pristane-induced arthritis (PIA) and this protection is mediated by an antigen-specific T helper type 2 (Th2) cytokine response. Here we confirm these findings and show that frequent intranasal administration of this peptide exacerbates disease. In naive mice given peptide intranasally an antigen-specific T-cell population is systemically activated similar to that induced by peptide immunization in incomplete Freund's adjuvant. Thus, a paradox exists whereby apparently similar peptide-specific populations are either associated with protection from, or exacerbation of, PIA. However, comparison of cytokine profiles reveals differences between these two cell populations. Peptide inhalation induces the production of Th1-type cytokines (interferon-gamma) whereas intraperitoneal immunization leads to the production of Th2-type cytokines (interleukin-4, interleukin-5 and interleukin-10) by splenic T cells upon stimulation with peptide. Thus, for the application of nasal 'tolerance' in clinical medicine, it is important to identify antigens and dosing regimes that counteract but do not activate adverse immune responses.

Animals↗
PubMed2000

Further analysis of the involvement of the envelope anion channel PIRAC in chloroplast protein import.

The ability of preferredoxin to inactivate a 50-pS anion channel of the chloroplast inner membrane in the presence of an energy source was investigated using single-channel recordings. It was found that preferredoxin cannot inactivate the channel when GTP is the only energy source present. From this it is concluded that the precursor has to interact with the, translocon of the inner membrane of chloroplasts (Tic) complex to be able to inactivate the 50-pS anion channel. The ability of two mutants of preferredoxin with deletions in their transit sequence to inactivate the channel was also tested. Both mutants have been shown to have a similar binding affinity for the chloroplast envelope, but only one is able to fully translocate. The mutants were both able to inactivate the channel in a similar manner. From this it is concluded that full translocation is not necessary for the inactivation of the channel. It is also shown that preferredoxin is capable of inactivating the 50-pS anion channel in the chloroplast-attached configuration as was previously found in the inside-out configuration. From this it is concluded that stromal factors do not influence the protein-import-induced inactivation of the 50-pS anion channel of the chloroplast inner membrane. Finally the effect of the anion channel blocker 4, 4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) on the channel activity and on protein import was investigated. It was found that DIDS blocked the channel. Furthermore the addition of the channel blocker reduces the efficiency of import to 52%. This leads to the conclusion that correct functioning of the channel is important for protein import.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein.

BACKGROUND: P-glycoprotein is a transmembrane protein expressed by multiple mammalian cell types, including the endothelial cells that comprise the blood-brain-barrier. P-glycoprotein functions to actively pump a diverse array of xenobiotics out of the cells in which it is expressed. The purpose of this study was to determine if P-glycoprotein alters the analgesic efficacy of clinically useful opioids. METHODS: Using a standard hot-plate method, the magnitude and duration of analgesia from morphine, morphine-6-glucuronide, methadone, meperidine, and fentanyl were assessed in wild-type Friends virus B (FVB) mice and in FVB mice lacking P-glycoprotein [mdr1a/b(-/-)]. Analgesia was expressed as the percent maximal possible effect (%MPE) over time, and these data were used to calculate the area under the analgesia versus time curves (AUC) for all opioids studied. In addition, the effect of a P-glycoprotein inhibitor (cyclosporine, 100 mg/kg) on morphine analgesia in both wild-type and mdr knockout mice was also determined. RESULTS: Morphine induced greater analgesia in knockout mice compared with wild-type mice (AUC 6,450 %MPE min vs. 1,610 %MPE min at 3 mg/kg), and morphine brain concentrations were greater in knockout mice. Analgesia was also greater in knockout mice treated with methadone and fentanyl but not meperidine or morphine-6-glucuronide. Cyclosporine pretreatment markedly increased morphine analgesia in wild-type mice but had no effect in knockout mice. CONCLUSIONS: These results suggest that P-glycoprotein acts to limit the entry of some opiates into the brain and that acute administration of P-glycoprotein inhibitors can increase the sensitivity to these opiates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Pediatric low-grade and ependymal spinal cord tumors.

Our institutional experience with pediatric spinal cord tumors includes 25 patients with the diagnosis of ependymoma (EP; n = 4), myxopapillary ependymoma (MPEP; n = 4), juvenile pilocytic astrocytoma (JPA; n = 5), nonpilocytic astrocytoma (WHO grade I or II, n = 6), and other nonastrocytic spinal cord tumors (n = 6) treated during the period 1974-1999. Nineteen patients required radiation therapy (RT). The median progression-free survival following RT was 65 months (range 1-206 months). Seven patients recurred at an average of 22 months. The EP patients recurred at an average of 8.5 months, while the patients with low-grade astrocytoma recurred at an average of 42 months. Including the 6 nonsurviving patients, the median overall survival was 96 months. Two EP patients died with a progression-free survival of 9 months. One patient with MPEP died of other causes at 7 months. The treatment of pediatric spinal cord tumors should be individualized based on the histologic type. Radical surgery is indicated for nonmyxopapillary EP and low-grade astrocytic tumors. The need for adjuvant therapy most often depends on the extent of resection as well as the tumor type. Patients with disseminated EP, MPEP, JPA and nonpilocytic astrocytoma may achieve long-term progression-free survival with craniospinal irradiation.

Adolescent↗
PubMed2000

The social and cultural context of risk and prevention: food and physical activity in an urban Aboriginal community.

One of the key public health challenges facing indigenous and other minority communities is how to develop and implement effective, acceptable, and sustainable strategies for the prevention of non-insulin-dependent diabetes mellitus (NIDDM). In this article, the authors describe how an ethnographic approach was used to contextualize the behavioral risk factors for NIDDM and applied to the development of a more meaningful and appropriate epidemiological risk factor survey instrument for an urban Aboriginal population in Australia. The overall research design comprised a mixture of qualitative and quantitative methods. The ethnographic study showed that the complex web of meanings that tie people to their family and community can and should be taken into account in any social epidemiology of health and illness if the findings are to have any effective and long-term potential to contribute to successful public health interventions targeting these behavioral risk factors.

Adult↗
PubMed1999

Dual signal peptides mediate the signal recognition particle/Sec-independent insertion of a thylakoid membrane polyprotein, PsbY.

The nuclear psbY gene (formerly ycf32) encodes two distinct single-spanning chloroplast thylakoid membrane proteins in Arabidopsis thaliana. After import into the chloroplast, the precursor protein is processed to a polyprotein in which each "mature" protein is preceded by an additional hydrophobic region; we show that these regions function as signal peptides that are cleaved after insertion into the thylakoid membrane. Inhibition of the first or second signal cleavage reaction by enlargement of the -1 residues leads in each case to the accumulation of a thylakoid-integrated intermediate containing three hydrophobic regions after import into chloroplasts; a double mutant is converted to a protein containing all four hydrophobic regions. We propose that the overall insertion process involves (i) insertion as a double-loop structure, (ii) two cleavages by the thylakoidal processing peptidase on the lumenal face of the membrane, and (iii) cleavage by an unknown peptidase on the stromal face on the membrane between the first mature protein and the second signal peptide. We also show that this polyprotein can insert into the thylakoid membrane in the absence of stromal factors, nucleoside triphosphates, or a functional Sec apparatus; this effectively shows for the first time that a multispanning protein can insert posttranslationally without the aid of signal recognition particle, SecA, or the membrane-bound Sec machinery.

Amino Acid Sequence↗
PubMed1999

Association between exercise and HIV disease progression in a cohort of homosexual men.

PURPOSE: To study the relationship between exercise and human immunodeficiency virus (HIV) disease progression. METHODS: 415 individuals (156 HIV positive, 259 HIV negative), from a cohort study of 851 homosexual men from New York City, 1985-1991. By 1991, 68 of the 156 persons developed Acquired Immune Deficiency Syndrome (AIDS) and 49 died with AIDS. Exercise was defined as self-report of exercising 3-4 times/week or daily at entry; less was considered nonexercise. CD4 lymphocyte decline was constructed for each subject by modeling log CD4 count against time in days. The association between exercise and progression to AIDS and death with AIDS, adjusting for baseline CD4 count, was determined using Cox model. Linear regression was used to model CD4 decline with exercise for HIV positive and HIV negative groups separately, adjusting for initial CD4 count. RESULTS: Having exercised was associated with slower progression to AIDS at 1 year (HR = 0.68, 90% confidence interval (CI): 0.4-1.17); hazard ratios (HR) at 2, 3, and 4 years were 0.96, 1.18, and 1.36, respectively. Having exercised was also associated with slower progression to death with AIDS at 1 year (HR = 0.37, 90% CI: 0.14-0.94) with hazard ratios at 2, 3, and 4 years of 0.68, 0.98, and 1.27, respectively, suggesting a protective effect close to the time exercise was assessed, but an increased risk after 2 years. Exercising 3-4 times/week had a more protective effect than daily exercise. Exercisers in the HIV positive group showed an increase in CD4 count during a year by a factor of 1.07. CONCLUSION: Moderate physical activity may slow HIV disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Accumulation of mercury and its effect on antioxidant enzymes in brain, liver, and kidneys of mice.

The effect of mercuric chloride (HgCl2) on the activities of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and its effect on glutathione (GSH) content were evaluated in different organs (liver, kidneys, and brain) of mice after administration at 0, 0.25, 0.5 and 1.0 mg/kg/day for 14 days. The uptake of mercury shows that the kidneys accumulated the highest levels of mercury compare to brain and liver. The enzyme levels varied in mercury treated organs compare to control. A dose dependent increase of antioxidant enzymes occurred in the liver and kidneys. The increase in enzyme activities correlated with highest mercury accumulation in the kidneys and liver. Mercury is known to generate reactive oxygen species (ROS) in vivo and in vitro, therefore, it is likely that enzyme activities increased to scavenge ROS levels produced as a result of mercury accumulation. Glutathione content increased in liver and kidneys of mercury treated mice compare to control. The results showed that the highest oral dose of mercury significantly increased antioxidant enzymes in kidneys and liver. The increased antioxidant enzymes enhance the antioxidant potential of the organs to reduce oxidative stress.

Animals↗
PubMed1999

High-grade pediatric spinal cord tumors.

Our institutional experience with high-grade pediatric spinal cord tumors includes 11 children treated during the period of 1981-1997. All patients underwent a biopsy or an attempt at resection and received postoperative radiation therapy. Three patients had a gross-total resection of their primary tumor, 6 patients had a subtotal resection and the remaining 2 were biopsied. Histologically, these tumors were characterized as anaplastic astrocytoma (n = 6), glioblastoma multiforme (n = 3) or anaplastic oligodendroglioma (n = 2). Three patients were treated with craniospinal irradiation (38-48 Gy) in addition to a boost to the residual tumor. The median dose to the primary site for all patients was 48.6 Gy (range 38-55 Gy). The median overall survival was 13 months (range 8-149 months). Only 2 patients were alive at 138 and 149 months following radiation therapy. The median progression-free survival following radiation therapy was 10 months (range 2-80 months). There was no difference in progression-free or overall survival for those diagnosed with glioblastoma multiforme when compared to patients diagnosed with anaplastic astrocytoma or anaplastic oligodendroglioma. The pattern of failure was either diffuse or local. For the patients who failed diffusely (n = 6), the median progression-free survival was 2 months compared to 23 months for those whose failure was entirely local (p < 0.01). The median overall survival was significantly shorter for those who failed diffusely compared to those who failed locally (10 vs. 37 months, p < 0.01). High-grade spinal cord tumors in children have a poor prognosis based on this report. It is important to document the extent of disease accurately prior to the initiation of radiation therapy, since a subset of these patients progress rapidly outside of the field of irradiation.

Child↗
PubMed1999

Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor.

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET. PATIENTS AND METHODS: As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD. RESULTS: Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively. CONCLUSION: With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET.

Adolescent↗
PubMed1999

Comparison of lumbar and shunt cerebrospinal fluid specimens for cytologic detection of leptomeningeal disease in pediatric patients with brain tumors.

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps. PATIENTS AND METHODS: As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells. RESULTS: The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n = 10), ependymoma (n = 5), germinoma (n = 3), atypical teratoid rhabdoid tumor (n = 2), choroid plexus carcinoma (n = 2), and pineoblastoma (n = 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P =.0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P =.011). Analysis of the subset of patients with embryonal tumors showed similar results (P =.0008). CONCLUSION: Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors.

Adolescent↗
PubMed1999

Infectious meningitis mimicking recurrent medulloblastoma on magnetic resonance imaging. Case report.

This report and the accompanying review of the literature address the challenges, when using surveillance magnetic resonance (MR) imaging, of establishing the origin of newly detected central nervous system lesions. Routine surveillance MR imaging in a 16-year-old boy, whose medulloblastoma had been successfully treated, demonstrated asymptomatic nodular leptomeningeal enhancement of the brain and spinal cord, which was consistent with recurrent disease. Examination of the cerebrospinal fluid, however, led to the diagnosis of bacterial meningitis. Two weeks after completion of antibiotic therapy, the original MR imaging findings were seen to have resolved. This case illustrates the importance of considering clinical and laboratory data, including results from a complete examination of the cerebrospinal fluid, when interpreting the origin of new lesions revealed by MR imaging.

Adolescent↗
PubMed1998

P450-catalyzed in-chain desaturation of valproic acid: isoform selectivity and mechanism of formation of Delta 3-valproic acid generated by baculovirus-expressed CYP3A1.

The mechanism of formation of the in-chain, unsaturated fatty acid metabolite, Delta3-valproic acid (Delta3-VPA) by rat liver microsomes was examined. Microsomal rates of formation of Delta3-VPA were below quantifiable limits in reactions catalyzed by control female rat liver microsomes, but were induced more than 20-fold following pretreatment with triacetyloleandomycin and pregnenolone-16alpha-carbonitrile. Microsomal incubations conducted with 3-hydroxy-VPA or [2-2H1]VPA demonstrated that Delta3-VPA did not arise by dehydration of preformed alcohol nor was it reversibly isomerized to Delta2-VPA. CYP3A1 expression was optimized in the baculovirus expression vector system, and infected insect cell membranes which were supplemented with P450 reductase catalyzed formation of 3-OH-, 4-OH-, 5-OH-, Delta3-, and Delta4-VPA in ratios of 160:35:6:3:1. Intramolecular deuterium isotope effects on metabolite formation, determined with cDNA-expressed CYP3A1 and either [3,3-2H2]VPA or [4,4-2H2]VPA, yielded kH/kD values for Delta3-VPA of 2.00 +/- 0.06 and 2.36 +/- 0.08, respectively. These values were significantly lower than the isotope effects observed in the same incubations for 3-OH-VPA formation from 3,3-D2-VPA (kH/kD = 6.04 +/- 0.08), or for 4-OH- and Delta4-VPA formation from 4, 4-D2-VPA (kH/kD > 5). Collectively, these data demonstrate the existence of a microsomal P450-dependent in-chain fatty acid desaturase system distinct from the well-documented cytochrome b5-linked CoA desaturases and suggest further that CYP3A1-dependent formation of Delta3-VPA arises via nonselective, initial hydrogen atom abstraction from either the C-3 or the C-4 position.

Animals↗
PubMed1998

Sec-independent insertion of thylakoid membrane proteins. Analysis of insertion forces and identification of a loop intermediate involving the signal peptide.

A group of membrane proteins are synthesized with cleavable signal sequences but inserted into the thylakoid membrane by an unusual Sec/SRP-independent mechanism. In this report we describe a key intermediate in the insertion of one such protein, photosystem II subunit W (PSII-W). A single mutation in the terminal cleavage site partially blocks processing and leads to the formation of an intermediate-size protein in the thylakoid membrane during chloroplast import assays. This protein is in the form of a loop structure: the N and C termini are exposed on the stromal face, whereas the cleavage site has been translocated into the lumen. In this respect the insertion of this protein resembles that of M13 procoat, which also adopts a loop structure during insertion, and we present preliminary evidence that a similar mechanism is used by another thylakoid protein, PSII-X. However, whereas the negatively charged region of procoat is translocated by an apparently electrophoretic mechanism using the DeltamuH+, the corresponding region of PSII-W is equally acidic but insertion is DeltamuH+ independent. We furthermore show that neutralization of this region has no apparent effect on the insertion process. We propose that a central element in this insertion mechanism is a loop structure whose formation is driven by hydrophobic interactions.

Amino Acid Sequence↗
PubMed1998

An immunodominant epitope from mycobacterial 65-kDa heat shock protein protects against pristane-induced arthritis.

Previous studies showed that mice with pristane-induced arthritis (PIA) and those protected from the disease by preimmunization with mycobacterial 65-kDa heat shock protein (hsp65) possess raised immune responses to hsp65. Additionally, T cells from hsp65-protected mice, but not from pristane-injected or normal mice, produced the Th2-associated cytokines IL-4, IL-5, and IL-10 in response to stimulation with hsp65. Here we demonstrate that the specificity of the immune response to hsp65 and related heat shock protein (hsps) differs between protected and PIA mice. T cells from hsp65-protected mice respond to the bacterial hsps tested but not to the mammalian homologue, hsp58. Similarly, they exhibit high serum titers of anti-hsp65 Abs, yet they have virtually undetectable levels of anti-hsp58 IgG. By contrast, both cellular and humoral immune responses are detectable to bacterial and mammalian hsps in mice with PIA. An immunodominant T cell epitope has been identified in hsp65-protected mice corresponding to amino acids 261-271 from hsp65. Immunization of mice, either before or after the induction of arthritis, with this bacterial peptide, but not its mammalian homologue, protects mice from the development of PIA, and protection is associated with the production of Th2-type cytokines. Other experiments revealed that T cells primed with bacterial 261-271 or the mammalian homologue do not cross-react at the proliferative or cytokine level. These results demonstrate that an hsp65 peptide-specific Th2 response confers protection from PIA but do not support the idea that protection is mediated by a cross-reaction with self hsp58 in the joints.

Animals↗
PubMed1998

The association of psychiatric diagnosis with weather conditions in a large urban homeless sample.

Assessment of psychiatric disorders encounters unique complexities in homeless populations. Although the use of structured diagnostic instruments has significantly improved research methodology in this area, questions remain about the validity of using cross-sectional diagnostic methods derived from studies of more general populations. In particular, the validity of structured diagnostic instruments in the assessment of schizophrenia, depression, drug use disorder, and antisocial personality disorder (ASPD) in homeless populations has been questioned. The purpose of this study was to examine the association of psychiatric diagnoses with the weather. It was hypothesized that self-report of psychiatric illness may be affected by prevailing weather conditions. Nine hundred homeless subjects randomly sampled from St. Louis shelters, day centers, and unsheltered locations were interviewed over a 1-year period. Official average daily temperature and amount of precipitation on the day of each subject's interview were compared with lifetime and current psychiatric diagnoses ascertained by the Diagnostic Interview Schedule. Similar analyses were performed in general population data from the Epidemiologic Catchment Area study. The study found that among homeless men, inclement weather on the day of interview was associated with lifetime and current diagnoses of major depression, lifetime drug use disorder, lifetime diagnosis of ASPD, and current alcohol use disorder. These findings, however, were not present in homeless women and not reflected in the general population. The results, although limited, suggest that weather may confound cross-sectional, standardized methods of psychiatric diagnosis in homeless men. Weather-related factors among homeless men are associated with ascertainment of both lifetime and current diagnosis of major depression, as well as lifetime drug use disorder and ASPD and current alcohol use disorder. Possible interpretations of these findings are discussed, with implications for intervention strategies for psychiatric disorders in the larger context of homelessness and social problems.

Adult↗