tbuckley/cabot-search huggingface dataset:
Requirements for the induction and adoptive transfer of cyclosporine-induced syngeneic graft-versus-host disease.
Authors: A C Fischer, W E Beschorner, A D Hess
Journal: The Journal of Experimental Medicine (1989)

These studies further delineate the requirements for the establishment and transfer of SGVHD. We show that (a) two mechanisms distinguishable by radiation and drug sensitivities exist, (b) lethal irradiation correlates with a 100% incidence in the induction of SGVHD, whereas (c) both sublethal or lethal irradiation and cytoxan therapy are effective in ablating the host autoregulatory system in order to transfer autoreactivity, (d) unfractionated as well as nylon wool-nonadherent splenocytes effectively inhibit the transfer of autoimmunity, and (e) OX19 depletion of that population, however, destroys the autoregulatory effect present in normal splenocytes. To demonstrate complete inhibition of immune reactivity, twice the number of unfractionated splenocytes from normal animals was required for every splenocyte from autoimmune donors. Last, the infusion of effector splenocytes on 4, 7, and 14 d after transplantation correlates to a decrease from 100%, 70 to 0% incidence of SGVHD, thus emulating the incidence obtained in a pretransplant rat within 2 wk. These findings further clarify the immunobiological complexity of SGVHD and suggest that since autoregulatory cells already exist in normal animals that CsA-induced autoimmunity is a reflection of not an induced reactivity specific to one therapeutic reagent but the uncoupling of normal immunologic mechanisms essential in controlling autoimmunity.
Variants of Toll-Like Receptor 4 Modify the Efficacy of Statin Therapy and the Risk of Cardiovascular Events
Authors: S. Matthijs Boekholdt, Willem R.P. Agema, Ron J.G. Peters, Aeilko H. Zwinderman, Ernst E. van der Wall, Pieter H. Reitsma, John J.P. Kastelein, J. Wouter Jukema
Journal: Circulation (2003)

Atherosclerosis is increasingly considered to be a chronic inflammatory process. We examined whether genetic variants of the toll-like receptor 4 (TLR4), which are correlated with impaired innate immunity and with progression of carotid atherosclerosis, are also associated with coronary atherosclerosis and predict the risk of cardiovascular events.Two polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) were determined in 655 men with angiographically documented coronary atherosclerosis. All patients participated in a prospective cholesterol-lowering trial evaluating the effect on coronary artery disease and were randomly assigned to either pravastatin or placebo for 2 years. There were no significant differences between genetically defined subgroups with respect to baseline risk factors, treatment, or in-trial changes of lipid, lipoprotein, or angiographic measurements. Genotype was not associated with progression of atherosclerosis. In the pravastatin group, 299Gly carriers had a lower risk of cardiovascular events during follow-up than noncarriers (2.0% versus 11.5%, P=0.045). Among noncarriers, pravastatin reduced the risk of cardiovascular events from 18.1% to 11.5% (P=0.03), whereas among 299Gly carriers this risk was strikingly reduced from 29.6% to 2.0% (P=0.0002, P=0.025 for interaction).Among symptomatic men with documented coronary artery disease, the TLR4 Asp299Gly polymorphism was associated with the risk of cardiovascular events. This variant also modified the efficacy of pravastatin in preventing cardiovascular events, such that carriers of the variant allele had significantly more benefit from pravastatin treatment.
Findings From 752 081 Clinical Breast Examinations Reported to a National Screening Program From 1995 Through 1998
Authors: J. K. Bobo
Journal: JNCI Journal of the National Cancer Institute (2000)

Mammography programs have received extensive study, but little is known about the outcome of clinical breast examinations (CBEs) performed in community settings. Consequently, we analyzed data from the National Breast and Cervical Cancer Early Detection Program on CBEs provided to low-income women from 1995 through 1998 and determined the percentage of CBEs considered to be abnormal, suspicious for cancer; the rates of cancer detection; and the sensitivity, specificity, and positive predictive value of CBEs.We analyzed data from 752081 CBEs and found that 6.9% of all CBEs were coded abnormal, suspicious for cancer, and that 5.0 cancers were detected per 1000 examinations (95% confidence interval [CI] = 4.9-5.2). The values observed for sensitivity (58.8%) and specificity (93.4%) were comparable to those reported for the CBE component of clinical trials. The observed positive predictive value was 4.3%. About 74% of all records also reported mammography results. The cancer-detection rate among records reporting an abnormal CBE and normal mammography was 7.4 cancers per 1000 records (95% CI = 6. 3-8.4). When the CBE was normal but the mammography was abnormal, the rate was 42.0 cancers per 1000 records (95% CI = 39.9-44.1). When both CBE and mammography results were abnormal, the rate was 170.3 cancers per 1000 records (95% CI = 162.7-177.9). Cancer detection could not be attributed entirely to CBE or mammography on 38% of the records in the latter subset because the tests were performed on the same day.CBEs performed in community-based screening programs can detect breast cancers as effectively as CBEs performed in clinical trials and may modestly improve early-detection campaigns.
The Role of Systemic Immunomodulatory Treatment and Prognostic Factors on Chronic Ocular Complications in Stevens–Johnson Syndrome
Authors: Dong Hyun Kim, Kyung Chul Yoon, Kyoung Yul Seo, Hyo Seok Lee, Sang Chul Yoon, Chie Sotozono, Mayumi Ueta, Mee Kum Kim
Journal: Ophthalmology (2014)
Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo
Authors: O. G. McDonald
Journal: Journal of Clinical Investigation (2005)

Precise control of SMC transcription plays a major role in vascular development and pathophysiology. Serum response factor (SRF) controls SMC gene transcription via binding to CArG box DNA sequences found within genes that exhibit SMC-restricted expression. However, the mechanisms that regulate SRF association with CArG box DNA within native chromatin of these genes are unknown. Here we report that SMC-restricted binding of SRF to murine SMC gene CArG box chromatin is associated with patterns of posttranslational histone modifications within this chromatin that are specific to the SMC lineage in culture and in vivo, including methylation and acetylation to histone H3 and H4 residues. We found that the promyogenic SRF coactivator myocardin increased SRF association with methylated histones and CArG box chromatin during activation of SMC gene expression. In contrast, the myogenic repressor Kruppel-like factor 4 recruited histone H4 deacetylase activity to SMC genes and blocked SRF association with methylated histones and CArG box chromatin during repression of SMC gene expression. Finally, we observed deacetylation of histone H4 coupled with loss of SRF binding during suppression of SMC differentiation in response to vascular injury. Taken together, these findings provide novel evidence that SMC-selective epigenetic control of SRF binding to chromatin plays a key role in regulation of SMC gene expression in response to pathophysiological stimuli in vivo.
Role of Noninsulin Therapies Alone or in Combination in Chromosome 6q24-Related Transient Neonatal Diabetes: Sulfonylurea Improves but Does Not Always Normalize Insulin Secretion
Authors: David Carmody, Flavius A. Beca, Charles D. Bell, Jessica L. Hwang, Jazzmyne T. Dickens, Nancy A. Devine, Deborah J.G. Mackay, I. Karen Temple, Lisa R. Hays, Rochelle N. Naylor, Louis H. Philipson, Siri Atma W. Greeley
Journal: Diabetes Care (2015)

Chromosome 6q24-related transient neonatal diabetes (6q24-TND) is a rare form of diabetes caused by an overexpression of PLAGL1 and HYMAI (1). After remitting in infancy, diabetes recurs in most patients later in life. While the best treatment remains unknown, many patients are managed with insulin (1). We sought to characterize β-cell function and glucose homeostasis in patients with 6q24-TND and assess their response to sulfonylurea (SU) therapy.

Adults with 6q24-TND and recurrence of hyperglycemia requiring insulin therapy later in life were identified through The University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry) and invited to participate in a trial of SU therapy. Four patients with insulin doses of 0.41–0.76 units/kg/day attempted the trial. Three were available for a mixed-meal test (MMT) and arginine stimulation test (AST) on day one and day five of SU treatment. All insulin products were withheld on the morning of day one. Subjects ingested 7 mL/kg (maximal 360 mL) of BOOST High Protein (http://www.boost.com) within 5 …
Comparison of the Biologic Activity of Biosynthetic Human Insulin and Natural Pork Insulin in Juvenile-onset Diabetic Subjects Assessed by the Glucose Controlled Insulin Infusion System
Authors: M Klier, W Kerner, A A Torres, E F Pfeiffer
Journal: Diabetes Care (1981)

To assess the biologic activity of biosynthetic human insulin (BHI) synthesized by Escherichia coli, six insulin-dependent juvenile-onset diabetic subjects were studied with BHI and natural pork insulin, by means of the glucose controlled insulin infusion system (GCIIS). First, after an overnight normalization of blood glucose levels, the 24-h insulin requirement was determined while the patients were consuming a diet of 30 kcal/kg. Then, the amount of glucose necessary to maintain normal blood glucose levels during a 5-h intravenous infusion of BHI and pork insulin, respectively, was assessed. Both studies demonstrate that in the insulin-dependent diabetic subject, BHI is at least as effective as natural pork insulin and may, therefore, be useful for the treatment of insulin-dependent diabetes mellitus.
Exaggerated Impact of ATP-Sensitive K+ Channels on Afferent Arteriolar Diameter in Diabetes Mellitus
Authors: HIDEKI IKENAGA, JOSEPH P. BAST, RACHEL W. FALLET, PAMELA K. CARMINES
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Experiments were performed to determine the involvement of ATP-sensitive K + channels (K ATP channels) in the renal afferent arteriolar dilation that occurs during the hyperfiltration stage of insulin-dependent diabetes mellitus (IDDM). IDDM was induced in rats by streptozotocin (STZ) injection, and adequate insulin was provided to maintain moderate hyperglycemia. Sham rats received vehicle treatments. Two weeks later, afferent arteriolar function was assessed using the in vitro blood-perfused juxtamedullary nephron technique. Baseline afferent arteriolar lumen diameter was greater in STZ rats (25.9 ± 1.1 μm) than in sham rats (20.8 ± 1.0 μm). Glibenclamide (3 to 300 μM) had virtually no effect on afferent arterioles from sham rats; however, this K ATP antagonist caused concentration-dependent afferent arteriolar constriction in kidneys from STZ-treated rats, restoring lumen diameter to 20.6 ± 1.7 μm ( P &gt; 0.05 versus sham baseline). In both groups of rats, pinacidil (a cyanoguanidine K ATP agonist; 0.3 to 300 μM) evoked concentration-dependent afferent arteriolar dilation, indicating the functional expression of K ATP channels; however, lumen diameter was increased by 73% in STZ kidneys but only by 48% in sham kidneys. The gliben-clamide-sensitive afferent arteriolar dilator response to 1 μM PCO-400 (a benzopyran K ATP agonist) was also accentuated in STZ kidneys. These observations suggest that increases in both the functional availability and basal activation of K ATP channels promote afferent arteriolar vasodilation during the early stage of IDDM, changes that likely contribute to the etiology of diabetic hyperfiltration.
Long-term Survival Following Partial vs Radical Nephrectomy Among Older Patients With Early-Stage Kidney Cancer
Authors: Hung Jui Tan, Edward C. Norton, Zaojun Ye, Khaled S. Hafez, John L. Gore, David C. Miller
Journal: JAMA (2012)

Although partial nephrectomy is the preferred treatment for many patients with early-stage kidney cancer, recent clinical trial data, which demonstrate better survival for patients treated with radical nephrectomy, have generated new uncertainty regarding the comparative effectiveness of these treatment options.To compare long-term survival after partial vs radical nephrectomy among a population-based patient cohort whose treatment reflects contemporary surgical practice.We performed a retrospective cohort study of Medicare beneficiaries with clinical stage T1a kidney cancer treated with partial or radical nephrectomy from 1992 through 2007. Using an instrumental variable approach to account for measured and unmeasured differences between treatment groups, we fit a 2-stage residual inclusion model to estimate the treatment effect of partial nephrectomy on long-term survival.Overall and kidney cancer-specific survival.Among 7138 Medicare beneficiaries with early-stage kidney cancer, we identified 1925 patients (27.0%) treated with partial nephrectomy and 5213 patients (73.0%) treated with radical nephrectomy. During a median follow-up of 62 months, 487 (25.3%) and 2164 (41.5%) patients died following partial or radical nephrectomy, respectively. Kidney cancer was the cause of death for 37 patients (1.9%) treated with partial nephrectomy, and 222 patients (4.3%) treated with radical nephrectomy. Patients treated with partial nephrectomy had a significantly lower risk of death (hazard ratio [HR], 0.54; 95% CI, 0.34-0.85). This corresponded with a predicted survival increase with partial nephrectomy of 5.6 (95% CI, 1.9-9.3), 11.8 (95% CI, 3.9-19.7), and 15.5 (95% CI, 5.0-26.0) percentage points at 2, 5, and 8 years posttreatment (P < .001). No difference was noted in kidney cancer-specific survival (HR, 0.82; 95% CI, 0.19-3.49).Among Medicare beneficiaries with early-stage kidney cancer who were candidates for either surgery, treatment with partial rather than radical nephrectomy was associated with improved survival.
Transient loss of consciousness--initial assessment, diagnosis, and specialist referral: summary of NICE guidance
Authors: M. Westby, I. Bullock, P. N. Cooper, S. Davis
Journal: BMJ (2010)

Transient loss of consciousness is a spontaneous loss of consciousness with complete recovery, affecting a quarter to half of the population at some point in their lives.1 2 3 The condition has many possible causes, including cardiovascular disorders (ranging from cardiac arrhythmias to vasovagal syncope), epilepsy, and psychogenic attacks. Diagnosis is often inaccurate, inefficient, and delayed, and management varies considerably.1 Experience shows that the importance of obtaining information on the event itself and the need for early electrocardiography are not widely appreciated. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the management of transient loss of consciousness in people aged 16 and over.4 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group's experience and opinion of what constitutes good practice. The recommendations emphasise elements of the diagnostic algorithm published in the Quick Reference Guide version of the NICE guidance, to which the reader should refer.4 Evidence levels for the recommendations are given in italic in square brackets ### Initial assessment
A9.15 Higher disease damage among african americans with familial versus sporadic systemic lupus erythematosus
Authors: April Barnado, Lee Wheless, Stephanie Slan, Gary S Gilkeson, Diane L Kamen
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Studies in Caucasian cohorts have found no significant clinical or serologic differences in systemic lupus erythematosus (SLE) patients with a family history of SLE compared to those with no family history. Using a unique cohort of African Americans with SLE and a high prevalence of multipatient families, we examined whether having a family history of SLE would impact autoantibodies, age at SLE diagnosis, ACR criteria, and disease damage. <h3>Methods</h3> Utilizing data from a cohort of African Americans with SLE, familial SLE was defined as having a confirmed family history of SLE versus sporadic SLE defined as no known family history of SLE. SSA, SSB, ds-DNA, anticardiolipin, and lupus anticoagulant were tested. Cumulative damage was measured using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Chi-square testing was used for comparing categorical and Student's t-test used for comparing continuous variables. The association between familial vs. sporadic SLE and SDI was modeled using Poisson regression adjusting for covariates. Two-sided p-values &lt; 0.05 were significant. <h3>Results</h3> 400 African American females had SLE, 55 of who were familial SLE cases. Mean age of familial cases was 47.1 + 13.9 years vs. 43.3 + 14.7 for sporadic cases (p = 0.08). Mean age at diagnosis was 28.1 + 11.5 years for familial vs. 31.0 + 13.0 for sporadic (p = 0.13). Mean disease duration was 18.7 + 9.1 years for familial vs. 12.3 + 7.1 for sporadic (p &lt; 0.01). Familial SLE cases had similar rates of dsDNA, SSA, SSB, anticardiolipin, and lupus anticoagulant positivity compared to sporadic cases. Familial cases had similar rates of being on dialysis as sporadic cases. Familial cases were significantly more likely to fulfill ACR criterion of photosensitivity (65.3% vs. 49.3%, p = 0.04) but no significant differences in the other ACR criteria. Familial cases had significantly higher SDI scores (2.8 + 2.6 vs. 1.6 + 1.8, p = 0.02) compared to sporadic cases. After adjustment for age at diagnosis and disease duration, familial SLE was still associated with a significantly higher SDI (p &lt; 0.01). <h3>Conclusion</h3> Consistent with Caucasian SLE cohorts, we found African American SLE familial and sporadic cases had similar serologic and clinical profiles. However, familial SLE cases had significantly higher SDI scores compared to sporadic cases, even after adjusting for age at diagnosis and disease duration. Further studies are underway to elucidate the causes of higher disease damage in familial versus sporadic SLE.
Interaction Between Rat Glioma Cells and Normal Rat Brain Tissue in Organ Culture&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: S K Steinsvåg, O D Laerum, R Bjerkvig
Journal: JNCI Journal of the National Cancer Institute (1985)

A system for coculture between normal rat brain fragments and multicellular spheroids of rat glioma cells is described. The tumor cells were derived from fetal BD IX rats treated transplacentally with the carcinogen N-ethyl-N-nitrosourea (CAS: 759-73-9). Brain fragments were obtained from fetal BD IX rats and precultured for 20 days before confrontation with multicellular tumor spheroids. The cocultures were grown in nonadherent stationary organ culture for 30 days. Due to morphologic similarities between normal brain cells and tumor cells, the tumor cells were labeled with tritiated thymidine, which made them easily recognizable in autoradiographs. The two structures adhered to each other, and glioma cells progressively invaded and replaced the normal brain tissue. Invasion and replacement are characteristic features of brain tumors in vivo. Therefore, this organotypic and syngeneic model may be useful for investigation of these phenomena outside the body.
Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer
Authors: Francesco Graziano, Annamaria Ruzzo, Fotios Loupakis, Emanuele Canestrari, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Umberto Torresi, Irene Floriani, Gaia Schiavon, Francesca Andreoni, Paolo Maltese, Eliana Rulli, Bostjan Humar, Alfredo Falcone, Lucio Giustini, Giuseppe Tonini, Andrea Fontana, Gianluca Masi, Mauro Magnani
Journal: Journal of Clinical Oncology (2008)

Purpose Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy. Patients and Methods Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A&gt;G, EGF receptor (EGFR) 216G&gt;T, EGFR 497G&gt;A, EGFR intron-1 (CA) n dinucleotide short (S)/long (L) variant, cyclin-D1 870A&gt;G, immunoglobulin-G fragment-C receptors RIIIa 158G&gt;T, and RIIa 131G&gt;A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response. Results In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (χ 2 test = 12.7; P = .001) and treatment response (χ 2 test = 9.45; P = .008) than EGFR intron-1 L/L carriers. Conclusion Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.
Psychiatric Attitudes of Young Physicians: II. The Effects of Postgraduate Training and Clinical Practice
Authors: G. J. TUCKER, R. F. REINHARDT
Journal: American Journal of Psychiatry (1969)

The authors discuss the effects of psychiatric education on the changing attitudes of a large group of physicians toward psychiatry, psychiatrists, psychotherapy, and psychiatric patients. They conclude that general physicians' attitudes toward mental illness can be affected by training whereas their attitudes toward psychiatrists and psychotherapy change only minimally.