tbuckley/cabot-search huggingface dataset:
Mutual repression between steroid and xenobiotic receptor and NF- B signaling pathways links xenobiotic metabolism and inflammation
Authors: C. Zhou
Journal: Journal of Clinical Investigation (2006)

While it has long been known that inflammation and infection reduce expression of hepatic cytochrome P450 (CYP) genes involved in xenobiotic metabolism and that exposure to xenobiotic chemicals can impair immune function, the molecular mechanisms underlying both of these phenomena have remained largely unknown. Here we show that activation of the nuclear steroid and xenobiotic receptor (SXR) by commonly used drugs in humans inhibits the activity of NF-κB, a key regulator of inflammation and the immune response. NF-κB target genes are upregulated and small bowel inflammation is significantly increased in mice lacking the SXR ortholog pregnane X receptor (PXR), thereby demonstrating a direct link between SXR and drug-mediated antagonism of NF-κB. Interestingly, NF-κB activation reciprocally inhibits SXR and its target genes whereas inhibition of NF-κB enhances SXR activity. This SXR/PXR–NF-κB axis provides a molecular explanation for the suppression of hepatic CYP mRNAs by inflammatory stimuli as well as the immunosuppressant effects of xenobiotics and SXR-responsive drugs. This mechanistic relationship has clinical consequences for individuals undergoing therapeutic exposure to the wide variety of drugs that are also SXR agonists.
Redistribution of Renal Intracortical Blood Flow during Dopamine Infusion in Dogs
Authors: WILLIAM T. HARDAKER, ANDREW S. WECHSLER
Journal: Circulation Research (1973)

We determined the effect of intravenous and renal intra-arterial infusion of dopamine on the distribution of intracortical blood flow in kidneys of anesthetized dogs. Total renal and renal intracortical blood flows in dogs receiving dopamine intravenously were quantified by the radioactive microsphere technique with reference sampling. In dogs receiving dopamine by renal intra-arterial infusion, total renal and renal intracortical blood flows were determined from radioactive microsphere and electromagnetic flowmeter data. Tissue perfusion rates for the total kidney, the renal cortex, the renal outer cortex, and the renal inner cortex increased following either intravenous or direct renal intra-arterial infusion of dopamine. Dopamine infusion by either method caused a relative redistribution of renal blood flow from the outer twothirds to the inner one-third of the renal cortex. During direct dopamine infusion into the renal artery, no significant changes in renal hemodynamics occurred in the contralateral kidney. No changes in arterial blood pressure occurred during dopamine infusion by either method. These observations imply that the change in the fractional distribution of renal intracortical blood flow following dopamine infusion is not dependent on a systemic mode of action. This pattern of flow redistribution suggests that the intrarenal dopamine-specific receptor may be in higher number in the inner cortex or that the redistribution of cortical flow after dopamine infusion may reflect differing initial physiological states of the inner and outer cortical receptors for dopamine.
Antineutrophil Cytoplasmic Autoantibody—Associated Glomerulonephritis in Children
Authors: MOTOSHI HATTORI, HIDEAKI KURAYAMA, YASUSHI KOITABASHI
Journal: Journal of the American Society of Nephrology (2001)

Abstract. A retrospective investigation was conducted by members of the Japanese Society for Pediatric Nephrology from 1990 to 1997 to define the clinical features and outcome of antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis in children. Thirty-four ANCA-seropositive Japanese pediatric patients with biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis were identified. Of these, 3 cases associated with Wegener's granulomatosis were excluded because of the small sample size. Among the 31 patients studied, 10 had a diagnosis of necrotizing crescentic glomerulonephritis alone and 21 had microscopic polyangiitis. Females predominated (87%), and the median age at onset was 12 yr. Twenty-six patients received treatment with cyclophosphamide and corticosteroids, and five patients received treatment with corticosteroids alone; 84% of patients achieved remission, and 39% of responders relapsed in a median of 24 mo. ANCA titers correlated with response to treatment and disease activity, with some exceptions. Patients were followed for a median of 42 mo (range, 3 to 96 mo). Nine of 31 patients (29.0%) progressed to end-stage renal disease, 6 (19.4%) had reduced renal function, and 15 (48.4%) had normal renal function at the last observation. One patient (3.2%) died from cytomegalovirus infection 3 mo after initiation of therapy. Life-table analysis showed 75% renal survival at 39 mo. Patients who subsequently developed end-stage renal disease ( n = 9) had significantly higher average peak serum creatinine levels and more chronic pathologic lesions at diagnosis compared with patients with favorable renal outcome ( n = 15). In conclusion, our clinical experience suggests that the clinical disease spectrum of ANCA-associated glomerulonephritis is similar in pediatric and adult patients, but there is a female predominance in children.
Weapon Involvement in Home Invasion Crimes
Authors: Arthur L. Kellermann
Journal: JAMA (1995)

To study the epidemiology of home invasion crimes and determine the frequency with which firearms are used to resist these crimes.Prospective case series.Atlanta, Ga (population 402,877).Between June 1 and August 31, 1994; Atlanta Police Department reports were screened to identify every case of unwanted entry into an occupied, single-family dwelling. Cases of sexual assault and incidents that involved cohabitants were excluded.A total of 198 cases were identified during the study interval. Half (99 cases) involved forced entry into the home. The victim and offender were acquainted in one third of cases. A firearm was carried by one or more offenders in 32 cases (17%). Seven offenders (3.5%) carried knives. In 42% of cases, the offender fled without confronting the victim. Victims who avoided confrontation were more likely to lose property but much less likely to be injured than those who were confronted by the offender. Resistance was attempted in 62 cases (31%), but the odds of injury were not significantly affected by the method of resistance. Forty cases (20%) resulted in one or more victims' being injured, including six (3%) who were shot. No one died. Three victims (1.5%) employed a firearm in self-protection. All three escaped injury, but one lost property.A minority of home invasion crimes result in injury. Measures that increase the difficulty of forced entry or enhance the likelihood of detection could be useful to prevent these crimes. Although firearms are often kept in the home for protection, they are rarely used for this purpose.
Increased platelet depleted plasma 5-hydroxytryptamine concentration following meal ingestion in symptomatic female subjects with diarrhoea predominant irritable bowel syndrome
Authors: L A Houghton
Journal: Gut (2003)

<b>Background:</b> Meal ingestion is often associated with exacerbation of gastrointestinal symptoms in subjects with irritable bowel syndrome (IBS). Furthermore, recent preliminary data suggest that 5-hydroxytryptamine (5-HT) concentration in platelet poor plasma is elevated following meal ingestion in some subjects with diarrhoea predominant IBS (d-IBS) compared with healthy subjects, although it is not known whether this is related to postprandial symptomatology. <b>Aim:</b> To expand on previous data by evaluating a larger number of subjects but also to assess plasma 5-hydroxyindole acetic acid (5-HIAA) concentrations, 5-HT turnover, platelet 5-HT stores, and any relationship to symptomatology. <b>Methods:</b> We assessed platelet depleted plasma 5-HT and 5-HIAA concentrations for two hours (60 minute intervals) under fasting conditions, and then for a further four hours (30 minute intervals) after a standard carbohydrate meal (457 kcal), together with fasting platelet 5-HT concentrations in 39 female subjects with d-IBS (aged 19–52 years; mean age 33) and 20 healthy female volunteers (aged 20–46 years, mean age 28). IBS symptomatology, in particular abdominal pain and bloating, and urgency to defecate were assessed throughout the study <b>Results:</b> When related to fasting levels, there was no statistically significant difference in postprandial plasma 5-HT concentrations between d-IBS and healthy subjects. However, when fasting levels were not taken into consideration, d-IBS subjects exhibited higher postprandial plasma 5-HT concentrations compared with healthy subjects (p=0.040). Furthermore, d-IBS subjects who exhibited postprandial symptomatology had higher levels of postprandial plasma 5-HT, whether assessed with respect to fasting baseline levels (p=0.069) or not (p=0.047), compared with d-IBS subjects who did not report postprandial symptomatology. This appeared to be associated with a concomitant increase in plasma 5-HIAA (p=0.161) but reduction in turnover (p=0.058). Lastly, d-IBS subjects had higher platelet concentrations of 5-HT than healthy subjects (p=0.009). <b>Conclusions:</b> These data suggest that postprandial symptomatology may be associated with increased platelet depleted plasma 5-HT concentrations in female subjects with d-IBS. In addition, the presence of increased platelet stores of 5-HT may act as a useful marker for the diagnosis and management of d-IBS.
MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMDMO)
Authors: Ann M. Kennedy, Masaki Inada, Stephen M. Krane, Paul T. Christie, Brian Harding, Carlos López-Otín, Luis M. Sánchez, Anna A.J. Pannett, Andrew Dearlove, Claire Hartley, Michael H. Byrne, Anita A.C. Reed, M. Andrew Nesbit, Michael P. Whyte, Rajesh V. Thakker
Journal: Journal of Clinical Investigation (2005)

MMPs, which degrade components of the ECM, have roles in embryonic development, tissue repair, cancer, arthritis, and cardiovascular disease. We show that a missense mutation of MMP13 causes the Missouri type of human spondyloepimetaphyseal dysplasia (SEMD(MO)), an autosomal dominant disorder characterized by defective growth and modeling of vertebrae and long bones. Genome-wide linkage analysis mapped SEMD(MO) to a 17-cM region on chromosome 11q14.3-23.2 that contains a cluster of 9 MMP genes. Among these, MMP13 represented the best candidate for SEMD(MO), since it preferentially degrades collagen type II, abnormalities of which cause skeletal dysplasias that include Strudwick type SEMD. DNA sequence analysis revealed a missense mutation, F56S, that substituted an evolutionarily conserved phenylalanine residue for a serine in the proregion domain of MMP13. We predicted, by modeling MMP13 structure, that this F56S mutation would result in a hydrophobic cavity with misfolding, autoactivation, and degradation of mutant protein intracellularly. Expression of wild-type and mutant MMP13s in human embryonic kidney cells confirmed abnormal intracellular autoactivation and autodegradation of F56S MMP13 such that only enzymatically inactive, small fragments were secreted. Thus, the F56S mutation results in deficiency of MMP13, which leads to the human skeletal developmental anomaly of SEMD(MO).
Oral Etoposide in Treatment of Advanced Refractory Sarcomas
Authors: C. E. KAMPE, S. LOWENBRAUN, J. FOSTER, G. ROSEN
Journal: JNCI Journal of the National Cancer Institute (1992)

levels.We also examined other known prognostic factors for patients with metastatic renal cancer (10).Unfortunately, this group of patients was relatively uniform and had a poor overall prognosis.There was some variability in the number of metastatic sites, and we thus divided patients into groups of those who had one, two, or three or more metastatic sites.When patients with one or two metastatic sites were compared with those with three or more sites, there was a significant difference in survival (Fig. 1,B).A Cox Proportional Hazards Model showed that the number of metastatic sites retained its significance (P = .05)but that an abnormal IL-6 level was no longer an independent predictor of survival (P = .26).There was no interaction between the number of metastatic sites and the IL-6 level, by Fisher's Exact Test (F = .41).We conclude that an abnormal IL-6 level (>5 pg/mL) confers a worse prognosis to patients with metastatic renal cell carcinoma but that the number of metastatic sites is an even stronger predictor of survival.We thus confirm and extend the recent observations of Blay et al. {11), who showed that serum IL-6 levels greater than 76 pg/mL correlated with survival in 138 patients with metastatic renal cancer.
Health-Related Quality of Life and Psychosocial Status in Breast Cancer Prognosis: Analysis of Multiple Variables
Authors: Pamela J. Goodwin, Marguerite Ennis, Louise J. Bordeleau, Kathleen I. Pritchard, Maureen E. Trudeau, Jarley Koo, Nicky Hood
Journal: Journal of Clinical Oncology (2004)

Purpose Evidence that psychosocial status and health-related quality of life (HRQOL) are associated with breast cancer (BC) outcomes is weak and inconsistent. We examined prognostic effects of these factors in a prospective cohort study. Patients and Methods Three hundred ninety-seven women with surgically resected T1 to T3, N0/N1, M0 BC completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Core 30 items), Profile of Mood States, Psychosocial Adjustment to Illness Scale, Impact of Events Scale, Mental Adjustment to Cancer Scale, and the Courtauld Emotional Control Scale 2 months after diagnosis and 1 year later. Data on tumor-related factors, treatment, and outcomes were obtained prospectively from medical records, and Cox survival analyses were performed. Results Mean age was 52.0 ± 9.9 years. Two hundred twenty-five women had T1, 136 women had T2, 16 women had T3, and 20 women had TX tumors; 127 were N1. One hundred thirteen women received adjuvant chemotherapy, 130 received hormone therapy, 45 received both, and 109 received neither. We investigated 140 prognostic associations; four were found to be statistically significant at a P value of ≤ .05 (three fewer than expected by chance). Two were in the hypothesized direction of effect, and two were in the opposite direction. All arose from measurements 1 year after diagnosis, which were most susceptible to confounding by treatment. There was no evidence of consistency of associations across outcomes or questionnaires. These results are in keeping with chance as the explanation for our statistically significant findings. Conclusion HRQOL and psychosocial status at diagnosis and 1 year later are not associated with medical outcome in women with early-stage BC.
Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis
Authors: Christian Thiede, Christine Steudel, Brigitte Mohr, Markus Schaich, Ulrike Schäkel, Uwe Platzbecker, Martin Wermke, Martin Bornhäuser, Markus Ritter, Andreas Neubauer, Gerhard Ehninger, Thomas Illmer
Journal: Blood (2002)
A stochastic analysis of three viral sequences.
Authors: G A Watterson
Journal: Molecular Biology and Evolution (1992)

This paper analyzes the nucleotide sequences of three viruses: Kunjin, west Nile, and yellow fever. Each virus has one long open reading frame of greater than 10,200 nucleotides that codes for four structural and seven nonstructural genes. The Kunjin and west Nile viruses are the most closely related pair, when assessed on the basis of matches between their nucleotide sequences. As would be expected, the matching is least for bases at third-position codon sites and is greatest for second-position sites. Statistics are presented for the numbers of mismatches that are transitions or transversions. Nucleotide base usage is also reported. To each of the 33 virus-gene segments, nonhomogeneous Markov chain models have been fitted to describe the sequences of nucleotide bases. The models allow for different transition probabilities ("transition" is used in the mathematical sense here) and for different degrees of dependency, at the three sites in the codons. Reasonably satisfactory fits can be obtained for many of the genes by using models that are first order for both first- and second-position sites in the codon but that are second order for third-position sites. One consequence of such a model is that the correlation between one amino acid and the next is limited to the correlation of the last base of the former with the first base of the latter. Other consequences are that the model can (and does) prohibit the occurrence of stop codons within a gene and that subsequences of only first-position bases, or only third-position bases, are also first-order Markov chains. In theory, second-position subsequences may not be Markov chains at all. In practice, the data suggest that each of these subsequences is effectively a zero-order Markov chain, i.e., bases spaced three apart are statistically independent. Stationarity of nucleotide base distributions can be interpreted in either of two ways: (1) spatially along the sites or (2) temporally at each site. These interpretations must often be inconsistent, when the former allows for Markov dependence between adjacent sites whereas the latter assumes independence between sites. The inconsistency can be overcome, for these viruses, if subsequences at different codon positions are analyzed separately.
Intramuscular Administration of Steroids in Treatment of Rheumatoid Arthritis
Authors: J. Zuckner, J. Uddin, R. H. Ramsey
Journal: Annals of the Rheumatic Diseases (1964)

In a preliminary report (Zuckner, 1961) on intra- muscular steroid therapy in patients with rheumatoid arthritis, results of approximately 100 injections of triamcinolone acetonide (hereafter referred to as TACTN)* and triamcinolone diacetate (or TDAC)t were described.The responses to this method of steroid administration were satisfactory in most cases, and compared favourably with those following the oral administration of steroids.In about 25 per cent. of cases, the anti-rheumatic effect was superior.This study has been continued, and in the ensuing 18 months another 820 injections have been evaluated.Other steroids were also tried for comparison of their antirheumatic effectiveness by intra- muscular administration.These included the depot preparation of 6-methyl prednisolone (referred to as DM)", triamcinolone acetonide tertiary-butyl- acetate (TATBA)t, and triamcinolone acetonide monoenanthate (TM) §.The chemical formulae of these preparations are shown in the figure oppo- site.Procedure TACTN, TDAC, DM, TATBA, and TM were in- jected intramuscularly into 86 patients with rheumatoid arthritis.These patients were classified (Table I) according to criteria of Steinbrocker, Traeger, and Batterman (1949), the majority being in Stage II, Class II.Their ages ranged from 32 to 75 years, most being in their fifties.There were 66 females and twenty males.The duration of disease was less than 5 years in about 40 per cent.and more than 10 years in one-third of the cases.Disease activity was graded 1 to 4 plus, and approximately 90 per cent. of the patients were considered to have 2 or 3 plus changes at the onset of the study.
When Overall Survival Fails to Confirm Event-Free Survival, Should the Latter Be Used to Set the Standard of Care?
Authors: Nai-Kong V. Cheung, Shakeel Modak, Irina Ostrovnaya, Stephen S. Roberts, Ellen M. Basu, Kim Kramer, Brian H. Kushner
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: We suggest that the far-reaching conclusion based on a landmark phase III trial concerning high-risk neuroblastoma (HR-NB) should be reconsidered, given the major statistical error in the recent update. 1 The initial report in 1999 prompted the worldwide adoption of myeloablative therapy with autologous stemcell transplantation (ASCT) as the standard of care for patients with HR-NB in first remission. Now, 15 years later, we learn that this intervention made no statistically significant difference in overall survival (OS) when tested in a randomized fashion (P .39 by log rank; P.08 at 5 years). 1 OS stands out as the gold standard for evaluation of treatment efficacy, the acid test for US Food and Drug Administration drug approval, and the driving force for advances in cancer therapeutics. 2 OS is 100% accurate for event and time; it takes into account both safety(toxiccomplications)andefficacy.Event-freesurvival(EFS)isa surrogateendpointthatallowsanearlierassessmentofresults,butits validity requires confirmation, either through correlation with OS or by meta-analysis. 2-4 Unless improvement in quality of life can be documented, delaying asymptomatic events without prolonging survival is not clinically meaningful. 3 In short, a surrogate end point should be used with caution as the basis to establish standard of care. In this landmark study, 1 why did OS fail to show significance, whileEFSdid?Thisdiscrepancypointstothewelcomepossibilitythat,
Tuberculosis in patients with HIV infection who receive corticosteroids for presumed Pneumocystis carinii pneumonia.
Authors: B E Jones, E K Taikwel, A L Mercado, S U Sian, P F Barnes
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

To determine if the use of corticosteroids for presumed Pneumocystis carinii pneumonia exacerbated undiagnosed tuberculosis or increased the likelihood of reactivation tuberculosis, we reviewed medical records of 144 hospitalized HIV-infected patients who received antipneumocystis therapy. Ninety-four patients (Group C) received corticosteroids and 50 patients (Group NC) did not. One hundred and thirty-seven patients (97%) had acid-fast stains and mycobacterial cultures performed. Group C and Group NC were similar in ethnicity, distribution of HIV risk factors and CD4 cell count. Eight (9%) Group C patients and seven (14%) Group NC patients had culture-proven tuberculosis during their hospitalization. After a median followup of 16 mo after discharge, one (2%) Group C patient and two (4%) Group NC patients developed tuberculosis. Only one patient in Group C died of tuberculosis, despite receiving antituberculosis therapy. We conclude that the use of corticosteroids for presumed P. carinii pneumonia does not increase morbidity from undiagnosed tuberculosis or increase the frequency of reactivation tuberculosis.