Response to expression of concern regarding VIGOR study.
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Arthritis, Rheumatoid↗
Biomedical subjects
Richard Day
Publications and source records attributed to Richard Day.
Does cross-reactivity between mycobacterium avium paratuberculosis and human intestinal antigens characterize Crohn's disease?
BACKGROUND & AIMS: Most Crohn's disease (CD) patients show seroreactivity against Mycobacterium avium paratuberculosis (MAP), suggesting a pathogenic role for this organism. Our aim was to seek amino acid similarities between MAP and intestinal proteins that, through molecular mimicry, could serve as targets for cross-reactive immunity in CD. METHODS: Fifty-three peptides comprising 23 sets of MAP/human intestinal peptidyl mimics chosen for maximal homology were constructed and tested for immunologic cross-reactivity by enzyme-linked immunosorbent assay in 50 patients with CD, 50 with ulcerative colitis, and 38 healthy controls. RESULTS: Antibody reactivity was present in only 7 of 23 peptide sets. MAP/self-reactivity in at least 1 of the 7 reactive sets was present in 21 (42%) CD patients but was virtually absent in the controls. Significant double-reactivity was found against MAP glycosyl transferase d (gsd)(230-244)/human gastrointestinal glutathione peroxidase (GPg)(111-125) homologues in 15 of 50 (30%) CD patients; MAP alkylohydroperoxidase C (ahpC)(20-34)/human tumor overexpressed protein (TOG)(637-651) double-reactivity was present in 10 (20%) CD patients, but in none of the controls. Inhibition studies confirmed that simultaneous reactivity to mimics was caused by cross-reactivity. Three-dimensional modeling predicts GPg(111-125) will be exposed in a solvent-accessible surface region of the protein compatible with antibody recognition. Antibody affinity was greater for the MAP mimics than for the self-sequences, suggesting that reactivity to the mycobacterial sequences precedes that against self-sequences. CONCLUSIONS: We describe MAP/self-mimics as targets of cross-reactive antibody responses characterizing patients with CD. Our findings indicate gastrointestinal glutathione peroxidase as a novel autoantigen in CD.
Adolescent↗
Differential immunohistochemical expression of syndecan-1 and tumor necrosis factor alpha in colonic mucosa of patients with Crohn's disease.
Tumor necrosis factor alpha (TNFalpha) in intestinal mucosa plays a key role in the inflammation characterizing Crohn's disease (CD). Moreover, adhesion molecule syndecan-1 mediates the maintenance of mucosal integrity and supports tissue repair. Therefore, our aim in this study was to correlate simultaneous expression of TNFalpha and syndecan-1 in patients affected by CD. Biopsies from 10 patients with CD of large bowel and 10 subjects with irritable bowel syndrome (controls) were studied by immunohistochemical detection of both TNFalpha and syndecan-1 on successive serial sections. Overall labeling index (OLI) was indicated by the percentage of positive stromal (i.e., nonepithelial) cells/1000 counted in randomized fields, whereas selected labeling index (SLI) was represented by the simultaneous evaluation of both molecules in a same single selected field of each specimen. TNFalpha and syndecan-1 OLI were significantly higher in CD compared with controls, while SLI showed an inverse relationship between the molecules in CD which was not observed in controls. Epithelial syndecan-1 cytoplasmatic staining of superficial epithelium was associated with loss of basolateral staining in the crypts and high stromal TNFalpha in CD. In conclusion, TNFalpha and syndecan-1 expression is increased in the intestinal mucosa of patients with CD. However, the expression of the two molecules is inversely related when a single field is considered, these data supporting the possibility of a downregulation exerted by TNFalpha.
Adult↗
Predictors and correlates of high levels of depression and anxiety symptoms among children at age 10.
OBJECTIVE: To identify factors that predict or are correlated with symptoms of depression and anxiety in 10-year-olds. METHOD: Women and their offspring were followed from the fourth prenatal month through 10 years. There were 636 mother-child pairs at 10 years, a follow-up rate of 83% of the birth cohort. Cognitive, psychological, sociodemographic, and environmental factors were measured at each phase. High depression and anxiety were defined as having a number of symptoms >1 SD above the mean for each measure. These measures were combined to represent high depression and/or anxiety (D/A) at 10 years of age. RESULTS: Predictors from the prenatal period of D/A at 10 years were more maternal depression symptoms, African American race, less social support, greater household density, and prenatal marijuana exposure. From 18 months through 6 years, lower child IQ, child injuries at age 3, and attention problems predicted symptoms of D/A at age 10. Across all study phases, lower child IQ, household density during pregnancy, attention problems, early childhood injuries, and prenatal marijuana exposure predicted D/A. Maternal psychological and sociodemographic factors were not significant in the final model. CONCLUSIONS: Factors from gestation and early childhood predict high symptom levels of depression and anxiety at age 10. When gestational exposure, early environmental factors, and child characteristics were considered, maternal depression and socioeconomic status were not significantly associated with early onset D/A. Marijuana exposure during gestation marginally predicted depression/anxiety at age 10.
Adolescent↗
Ties that bind: multiple relationships between clinical researchers and the pharmaceutical industry.
BACKGROUND: It is believed that pharmaceutical industry sponsorship of clinical research leads to the development of multiple ties between clinicians and the pharmaceutical industry. To quantify this relationship we conducted a survey of medical specialists listed in the Medical Directory of Australia in 2002 and 2003. METHODS: A questionnaire was mailed that elicited information about all aspects of research relationships between clinicians and pharmaceutical companies. The odds of reporting multiple additional ties (financial and professional) with pharmaceutical companies by clinicians who had an active research relationship were compared with those who did not. All clinicians who returned a completed questionnaire about their research activities were included in the study. RESULTS: A questionnaire was mailed to 2120 medical specialists; 823 (39%) responded. Of these, 338 (41%) reported involvement in industry-sponsored research in the previous year. They were more likely than others to have been offered industry-sponsored items or activities valued at more than 500 AU dollars (>382 US dollars; odds ratio [OR], 3.5; 95% confidence interval [CI], 2.6-4.7) and support for attending international conferences (OR, 5.4; 95% CI, 3.9-7.4). The strongest associations were seen for acting as a paid consultant to industry (OR, 9.0; 95% CI, 3.9-20.4) and for membership on advisory boards (OR, 6.9; 95% CI, 5.1-9.6). There was a strong relationship between research collaboration and accumulation of industry ties. For 1 additional tie the OR was 2.2 (95% CI, 1.2-3.8) and rose to 6.3 (95% CI, 3.5-11.1) with 3 ties and 41.8 (95% CI, 14.5-143.4) with 6 or more ties. CONCLUSIONS: Medical specialists who have research relationships with the pharmaceutical industry are much more likely to have multiple additional ties than those who do not have research relationships. Institutional review should discourage clinical researchers from developing multiple ties.
Australia↗
Characterization of epididymal epithelial cell-specific gene promoters by in vivo electroporation.
The mammalian epididymis plays a critical role in sperm maturation, a function dependent on testicular androgens. However, the function of the initial segment, the most proximal part of the epididymis, is also dependent on luminal factors of testicular origin. Efferent duct ligation (EDL), which prevents luminal testicular fluid from reaching the epididymis, results in changes in gene expression within this region. Cystatin-related epididymal spermatogenic (cres) gene and gamma-glutamyl transpeptidase (GGT) mRNA IV are highly expressed in the initial segment and are regulated by luminal testicular factors. EDL results in decreased expression of both genes. To evaluate these promoters in the context of their native physiological state, an in vivo electroporation procedure was used. Significant differences were observed in vivo compared to previous in vitro results. Whereas two C/EBP sites were necessary for transcriptional activity from a 135-base-pair (bp) cres promoter in vitro, only the 5' site displayed functional activity in the in vivo system. A 135-bp GGT promoter IV construct was sufficient for reporter gene expression in vitro. However, in vivo, substantial expression was not observed until the construct was extended to 530 bp. Three polyoma enhancer activator 3 (PEA3) sites were found to be necessary for in vivo reporter gene expression from this construct. A cis-acting negative regulatory element between -530 and -681 bp was also identified that was not previously recognized in the in vitro studies. These studies demonstrate the utility of in vivo electroporation for elucidating promoter elements that may not be identified when traditional in vitro methods are used.
Animals↗
Evaluation of familial influences on the course and severity of schizophrenia among US and Indian cases.
BACKGROUND: Prior studies suggest familial (possibly genetic) influences on the course of schizophrenia. AIMS: The aim of this study was to compare familial influences on the course and severity of schizophrenia in two independent samples. METHOD: Thirteen selected measures were compared among affected sibling pairs (ASPs) from Pittsburgh, USA and New Delhi, India (48 US pairs, 53 Indian pairs). For each ASP proband, an unrelated patient was selected randomly from a suitable pool of cases ascertained in the same study (Sibpair proband-comparison case or S-C pairs). Correlations between these pairs were compared. RESULTS: The correlations varied by item and by site. Significant correlations for longitudinal course and pattern of severity were noted among the ASPs from USA, but did not remain significant following corrections for multiple comparisons. Comparisons between the correlations for ASPs and the S-C pairs, used to estimate familial effects, yielded trends for the ASP correlations to be numerically larger than the S-C correlations in both samples. Separate cross-site comparisons revealed several significant differences with regard to several demographic and clinical variables. The possible impact of the cross-site variations on the observed ASP correlations is discussed. CONCLUSIONS: Though familial factors did not appear to have a significant impact on course/severity using this novel design, the suggestive trends need to be examined in larger samples.
Adult↗
Health-related quality of life in axillary node-negative, estrogen receptor-negative breast cancer patients undergoing AC versus CMF chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel Project B-23.
PURPOSE: NSABP Protocol B-23 compared two chemotherapy regimens: (1) cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); and (2) doxorubicin and cyclophosphamide (AC) in terms of relapse-free survival, event-free survival, and overall survival in node-negative and estrogen receptor-negative breast cancer patients. There are no previous data regarding the comparison of quality of life (QOL) between the two regimens in this population of breast cancer patients. QOL information was considered especially relevant given the possibility that the two chemotherapy regimens would prove equivalent in terms of clinical outcome. PATIENTS AND METHODS: One hundred and sixty patients participated in the NSABP B-23 QOL study. Patients in B-23 were randomly assigned to one of four arms: CMF plus 5 years of tamoxifen (TAM), CMF, Comparative health item and general health item plus placebo, AC plus TAM, or AC plus placebo. The questionnaires included the Functional Assessment of Cancer Therapy (FACT-B), the vitality scale from the Medical Outcomes Study 36-item Short Form Health Status Survey (MOS SF-36), a symptom checklist and additional items regarding overall QOL; and return to normal activity. Statistical comparisons between treatment arms were performed with area under the curve analyses, repeated measures analyses, and Fisher exact tests. RESULTS: Overall QOL as measured by the FACT-B did not significantly differ between chemotherapy treatment arms. However, the pattern of vitality over time during treatment differed between chemotherapy groups. The AC group vitality scores dropped more sharply during treatment and returned to baseline levels more quickly after treatment. Patients in the CMF arm were bothered by bladder problems and diarrhea significantly more often than were patients in the AC arm. Otherwise, no significant differences were found between AC and CMF for any of the QOL outcomes in terms of (1) overall QOL during the first 9 months after randomization, (2) the average QOL during treatment, or (3) the rate of recovery to baseline levels of QOL 1year after randomization. CONCLUSION: Overall QOL is equivalent between the two chemotherapy regimens, with some differences in symptoms and in patterns of vitality over time.
Activities of Daily Living↗
Barrier methods, length of preconception intercourse, and preeclampsia.
BACKGROUND: The immune maladaptation theory suggests that tolerance to paternal antigens, resulting from prolonged exposure to sperm, protects against the development of preeclampsia. We tested whether barrier contraception and shorter sexual experience with the father of the pregnancy would increase the risk of preeclampsia. METHODS: Of 2211 women delivering singleton births after enrollment in a pregnancy cohort study, 85 (3.8%) developed preeclampsia as defined by antepartum systolic blood pressure > or = 140 or diastolic blood pressure > or = 90 plus proteinuria. At a mean of 10.2 weeks of gestation, all women in the cohort were asked about preconception contraception and timing of first sexual intercourse with the father of the pregnancy. Odds ratios (OR) comparing cases with preeclampsia to the rest of the cohort were adjusted for age, smoking, parity, and body mass index (BMI). RESULTS: Women using barrier contraception prior to conception were no more likely than women not using barrier contraception to develop preeclampsia (adjusted OR 1.0, 95% CI 0.6-1.6). In unadjusted analyses, a prolonged time to conception was associated with preeclampsia (OR 1.9), however, after adjustment, the association was less prominent (OR 1.6) and after stratification by contraception method, the link between time to conception and preeclampsia was eliminated. CONCLUSION: These data do not support the immune maladaptation theory of preeclampsia.
Adolescent↗
Traumatic grief among adolescents exposed to a peer's suicide.
OBJECTIVE: The phenomenology of grief among children and adolescents is not well studied. A syndrome of traumatic grief, distinct from depression and anxiety, has been described among bereaved adults. The purpose of this study was to describe the symptoms and course of traumatic grief among adolescents exposed to a peer's suicide and to examine the relationship between traumatic grief and depression and posttraumatic stress disorder (PTSD) in this population. METHOD: A total of 146 friends and acquaintances of 26 suicide victims were included in this study. Subjects were interviewed at 6, 12-18, and 36 months after the peer's suicide. A subgroup was also interviewed 6 years afterward. The Texas Revised Inventory of Grief was administered at 6, 12-18, and 36 months; the Inventory of Complicated Grief was administered at the 6-year assessment. RESULTS: Principal component analysis of the Texas Revised Inventory of Grief resulted in two factors: one assessing a traumatic grief reaction and another assessing a milder or even normal grief reaction. The occurrence of traumatic grief was found to be independent from that of depression and PTSD. Traumatic grief at 6 months predicted the onset or course of depression and PTSD at subsequent assessments. CONCLUSIONS: Similar to adults, adolescents experience a traumatic grief reaction after exposure to a peer's suicide. Clinicians should be alerted to the occurrence of traumatic grief reactions among adolescents and the need to assess these reactions and address them in their treatment approaches.
Adaptation, Psychological↗
A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee.
OBJECTIVE: To investigate the efficacy and tolerability of a course of 5 injections of hyaluronan (HA) given at intervals of one week in patients with symptomatic, mild to moderate osteoarthritis (OA) of the knee. METHODS: A double blind, randomized, parallel group, multicenter (17 centers), saline vehicle-controlled study was conducted over 18 weeks. Patients received either 25 mg (2.5 ml) HA in a phosphate buffered solution or 2.5 ml vehicle containing only the buffer by intraarticular injection. Five injections were given at one week intervals and the patients were followed for a further 13 weeks. The Western Ontario McMaster (WOMAC) OA instrument was used as the primary efficacy variable and repeated measures analysis of covariance was used to compare the 2 treatments over Weeks 6, 10, 14, and 18. RESULTS: Of 240 patients randomized for inclusion in the study, 223 were evaluable for the modified intention to treat analysis. The active treatment and control groups were comparable for demographic details, OA history, and previous treatments. Scores for the pain and stiffness subscales of the WOMAC were modestly but significantly lower in the HA-treated group overall (Weeks 6 to 18; p < 0.05) and the statistically significant difference from the control was not apparent until after the series of injections was complete. The physical function subscale did not reach statistical significance (p = 0.064). Tolerability of the procedure was good and there were no serious adverse events that were considered to have a possible causal relationship with the study treatment. CONCLUSION: Intraarticular HA treatment was significantly more effective than saline vehicle in mild to moderate OA of the knee for the 13 week postinjection period of the study.
Adjuvants, Immunologic↗
COX-2: where are we in 2003?--distinction from NSAIDs becoming blurred.
The distinction between cyclooxygenase-2-selective inhibitors (CSIs) and nonsteroidal anti-inflammatory drugs ultimately must be clinical and must be clinically and economically relevant. This distinction needs to be demonstrated in a substantial and clinically relevant difference in the respective rates of serious adverse reactions of the upper gastrointestinal tract. Event-driven, randomized, blinded, controlled trials with sufficient power are required to resolve uncertainties concerning the relative risk of thrombotic cardiovascular events in patients taking CSIs who have risk factors for these events. Patients and situations more representative of those in primary-care practice - elderly, comorbidities, comedication - need to be included in larger studies to provide a better understanding of the risks and benefits of CSIs.
Animals↗
Major depressive disorder in adolescents exposed to a friend's suicide.
OBJECTIVE: To evaluate whether the risk of DSM-III major depressive disorder (MDD) is uniform across the 6 months after adolescent exposure to a friend's suicide, and to examine potential moderating or mediating processes that may influence the risk of new-onset MDD. METHOD: One-month incidence rates of MDD were compared between 129 adolescents who were exposed to a friend's suicide between December 1988 and March 1991 and 145 similar-aged, unexposed community controls participating in the Youth Exposed to Suicide study. Clinical, family, and social factors that antedated the exposure were examined as predictors of new-onset MDD within 1 month of the suicide. RESULTS: Exposed adolescents had a markedly increased risk of developing new-onset MDD that was restricted to a narrow period of time, within 1 month after exposure. In contrast, there were no differences in the incidence of MDD between the groups in months 2 to 6. Past history of alcohol abuse increased the risk of exposure to suicide, which subsequently increased the risk of new-onset MDD within 1 month of exposure. Exposed youths who had both a family history of MDD and feelings of accountability for the death were at considerably increased risk of new-onset MDD. CONCLUSIONS: For adolescents exposed to a friend's suicide, events surrounding the death interact with family history of MDD to greatly increase the risk for new-onset MDD.
Adolescent↗
Hypertension in the patient with arthritis: have we been underestimating its significance?
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Arthritis, Rheumatoid↗
Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome.
Chemokines are important mediators of cell trafficking during immune inductive and effector activities, and dysregulation of their expression might contribute to the pathogenesis of human immunodeficiency virus type 1 and the related simian immunodeficiency virus (SIV). To understand better the effects of SIV infection on lymphoid tissues in rhesus macaques, we examined chemokine messenger RNA (mRNA) expression patterns by using DNA filter array hybridization. Of the 34 chemokines examined, the interferon gamma (IFN-gamma)-inducible chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma (CXCL9/Mig) was one of the most highly up-regulated chemokines in rhesus macaque spleen tissue early after infection with pathogenic SIV. The relative levels of expression of CXCL9/Mig mRNA in spleen and lymph nodes were significantly increased after infection with SIV in both quantitative image capture and analysis and real-time reverse transcriptase-polymerase chain reaction assays. In addition, in situ hybridization for CXCL9/Mig mRNA revealed that the patterns of expression were altered after SIV infection. Associated with the increased expression of CXCL9/Mig were increased numbers of IFN-gamma mRNA-positive cells in tissues and reduced percentages of CXC chemokine receptor (CXCR) 3(+)/CD3(+) and CXCR3(+)/CD8(+) lymphocytes in peripheral blood. We propose that SIV replication in vivo initiates IFN-gamma-driven positive-feedback loops in lymphoid tissues that disrupt the trafficking of effector T lymphocytes and lead to chronic local inflammation, thereby contributing to immunopathogenesis.
Animals↗
Adverse reactions to TNF-alpha inhibitors in rheumatoid arthritis.
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Antibodies, Monoclonal↗
Another selective COX-2 inhibitor: more questions than answers?
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Arthritis, Rheumatoid↗
The effect of sunlight on postoperative analgesic medication use: a prospective study of patients undergoing spinal surgery.
OBJECTIVE: Exposure to natural sunlight has been associated with improvement in mood, reduced mortality among patients with cancer, and reduced length of hospitalization for patients who have experienced myocardial infarction. Our aim was to evaluate whether the amount of sunlight in a hospital room modifies a patient's psychosocial health, the quantity of analgesic medication used, and the pain medication cost. METHODS: A prospective study of pain medication use was conducted in 89 patients undergoing elective cervical and lumbar spinal surgery where they were housed on either the "bright" or "dim" side of the same hospital unit. Analgesic medication was converted to standard morphine equivalents for interpatient comparison. The intensity of sunlight in each hospital room was measured daily and psychologic questionnaires were administered on the day after surgery and at discharge. RESULTS: Patients staying on the bright side of the hospital unit were exposed to 46% higher-intensity sunlight on average (p = .005). Patients exposed to an increased intensity of sunlight experienced less perceived stress (p = .035), marginally less pain (p = .058), took 22% less analgesic medication per hour (p = .047), and had 21% less pain medication costs (p = .047). Age quartile was the only other variable found to be a predictor of analgesic use, with a significant negative correlation (p <.001). However, patients housed on the bright side of the hospital consistently used less analgesic medications in all age quartiles. CONCLUSION: The exposure postoperatively of patients who have undergone spinal surgery to increased amounts of natural sunlight during their hospital recovery period may result in decreased stress, pain, analgesic medication use, and pain medication costs.
Age Factors↗