tbuckley/cabot-search huggingface dataset:
The role of insulin receptor substrate 2 in hypothalamic and β cell function
Authors: Agharul I. Choudhury, Helen Heffron, Mark A. Smith, Hind Al-Qassab, Allison W. Xu, Colin Selman, Marcus Simmgen, Melanie Clements, Marc Claret, Gavin MacColl, David C. Bedford, Kazunari Hisadome, Ivan Diakonov, Vazira Moosajee, Jimmy D. Bell, John R. Speakman, Rachel L. Batterham, Gregory S. Barsh, Michael L.J. Ashford, Dominic J. Withers
Journal: Journal of Clinical Investigation (2005)

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in β cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and β cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced β cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in β cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.
Renal Outcomes in Patients with Type 1 Diabetes and Macroalbuminuria
Authors: Ian H. de Boer, Maryam Afkarian, Tessa C. Rue, Patricia A. Cleary, John M. Lachin, Mark E. Molitch, Michael W. Steffes, Wanjie Sun, Bernard Zinman
Journal: Journal of the American Society of Nephrology (2014)

Macroalbuminuria, defined as urine albumin excretion rate (AER)≥300 mg/d, has long been considered a stage of irreversible kidney damage that leads reliably to GFR loss. We examined the long-term renal outcomes of persons with type 1 diabetes who developed incident macroalbuminuria during the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. One hundred fifty-nine participants developed incident macroalbuminuria and were subsequently followed for a median duration of 9 years (maximum of 25 years). At the time of macroalbuminuria diagnosis, mean (SD) age was 37 (9) years, mean (SD) duration of diabetes was 17 (5) years, median AER was 524 mg/d, and mean (SD) eGFR was 108 (20) ml/min per 1.73 m2. Ten years after macroalbuminuria diagnosis, the cumulative incidence of a sustained reduction in AER to <300 mg/d was 52%, mostly but not entirely under treatment with renin-angiotensin system inhibitors. The cumulative incidence of impaired GFR (sustained eGFR<60 ml/min per 1.73 m2) 10 years after macroalbuminuria diagnosis was 32%, including 16% who developed ESRD. Lower hemoglobin A1c and BP and regression to AER<300 mg/d were associated with reduced risk of developing impaired GFR. In conclusion, people with type 1 diabetes who develop macroalbuminuria are at high risk of progressive kidney disease. However, through at least 10 years of follow-up, AER could often be controlled, and GFR frequently remained in the normal range.
Human Bone Marrow–Derived Mesenchymal Stem Cells in the Treatment of Gliomas
Authors: Akira Nakamizo, Frank Marini, Toshiyuki Amano, Asadullah Khan, Matus Studeny, Joy Gumin, Julianne Chen, Stephen Hentschel, Giacomo Vecil, Jennifer Dembinski, Michael Andreeff, Frederick F. Lang
Journal: Cancer Research (2005)

Abstract The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow–derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow–derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell–derived factor-1α, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-β (hMSC-IFN-β). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-β against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-β significantly increase animal survival compared with controls (P &amp;lt; 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.
Which intravenous bronchodilators are being administered to children presenting with acute severe wheeze in the UK and Ireland?
Authors: I Morris, M D Lyttle, R O'Sullivan, N Sargant, I J M Doull, C V E Powell
Journal: Thorax (2014)

During a prospective 10-week assessment period, 3238 children aged 1–16 years presented with acute wheeze to Paediatric Emergency Research in the UK and Ireland centres. 110 (3.3%) received intravenous bronchodilators. Intravenous magnesium sulfate (MgSO<sub>4</sub>) was used in 67 (60.9%), salbutamol in 61 (55.5%) and aminophylline in 52 (47.3%) of cases. In 35 cases (31.8%), two drugs were used together, and in 18 cases (16.4%), all three drugs were administered. When used sequentially the most common order was salbutamol, then MgSO<sub>4</sub>, then aminophylline. Overall, 30 different intravenous treatment regimens were used varying in drugs, dose, rate and duration.
Mutations in<i>CYP24A1</i>and Idiopathic Infantile Hypercalcemia
Authors: Karl P. Schlingmann, Martin Kaufmann, Stefanie Weber, Andrew Irwin, Caroline Goos, Ulrike John, Joachim Misselwitz, Günter Klaus, Eberhard Kuwertz-Bröking, Henry Fehrenbach, Anne M. Wingen, Tülay Güran, Joost G. Hoenderop, René J. Bindels, David E. Prosser, Glenville Jones, Martin Konrad
Journal: New England Journal of Medicine (2011)

Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis.
Surveillance of Medical Device–Related Hazards and Adverse Events in Hospitalized Patients
Authors: Matthew H. Samore, R. Scott Evans, April Lassen, Patricia Gould, James Lloyd, Reed M. Gardner, Rouett Abouzelof, Carrie Taylor, Don A. Woodbury, Mary Willy, Roselie A. Bright
Journal: JAMA (2004)

Although adverse drug events have been extensively evaluated by computer-based surveillance, medical device errors have no comparable surveillance techniques.To determine whether computer-based surveillance can reliably identify medical device-related hazards (no known harm to patient) and adverse medical device events (AMDEs; patient experienced harm) and to compare alternative methods of detection of device-related problems.This descriptive study was conducted from January through September 2000 at a 520-bed tertiary teaching institution in the United States with experience in using computer tools to detect and prevent adverse drug events. All 20 441 regular and short-stay patients (excluding obstetric and newborn patients) were included.Medical device events as detected by computer-based flags, telemetry problem checklists, International Classification of Diseases, Ninth Revision (ICD-9) discharge code (which could include AMDEs present at admission), clinical engineering work logs, and patient survey results were compared with each other and with routine voluntary incident reports to determine frequencies, proportions, positive predictive values, and incidence rates by each technique.Of the 7059 flags triggered, 552 (7.8%) indicate a device-related hazard or AMDE. The estimated 9-month incidence rates (number per 1000 admissions [95% confidence intervals]) for AMDEs were 1.6 (0.9-2.5) for incident reports, 27.7 (24.9-30.7) for computer flags, and 64.6 (60.4-69.1) for ICD-9 discharge codes. Few of these events were detected by more than 1 surveillance method, giving an overall incidence of AMDE detected by at least 1 of these methods of 83.7 per 1000 (95% confidence interval, 78.8-88.6) admissions. The positive predictive value of computer flags for detecting device-related hazards and AMDEs ranged from 0% to 38%.More intensive surveillance methods yielded higher rates of medical device problems than found with traditional voluntary reporting, with little overlap between methods. Several detection methods had low efficiency in detecting AMDEs. The high rate of AMDEs suggests that AMDEs are an important patient safety issue, but additional research is necessary to identify optimal AMDE detection strategies.
Predictors of Tumor Progression During Neoadjuvant Chemotherapy in Breast Cancer
Authors: Abigail S. Caudle, Ana M. Gonzalez-Angulo, Kelly K. Hunt, Ping Liu, Lajos Pusztai, W. Fraser Symmans, Henry M. Kuerer, Elizabeth A. Mittendorf, Gabriel N. Hortobagyi, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2010)

PURPOSE Although most breast cancer patients who receive neoadjuvant chemotherapy (NCT) have a tumor response, a small proportion experience progressive disease (PD). Predictors of response have been reported, but predictors for progression have not been identified. We sought to identify predictors of tumor progression during NCT with the ultimate aim of identifying patients who might benefit from a first-line surgical approach or from novel targeted therapies. PATIENTS AND METHODS Data were obtained from reviewing medical records of patients with stage I to III breast cancer who received NCT (anthracycline and/or taxane based). Statistical analysis was performed to compare patients with any response or stable disease with patients with PD. RESULTS One thousand nine hundred twenty-eight patients received NCT; 1,762 patients (91%) had some response, 107 (6%) had stable disease, and 59 (3%) had PD at some point during NCT. Factors predictive of PD included African American race (P = .002), tumor (T) status (P = .002), and American Joint Committee on Cancer clinical stage (P = .02). Histopathologic features of PD were high tumor grade (P = .005), high Ki-67 score (P = .002), and negative estrogen receptor (ER)/progesterone receptor (PR) status (P < .001/P < .001). Pre-NCT T status, race, and ER status were independent predictors of progression in multivariate analysis. Disease progression was a negative predictor of distant disease-free survival and overall survival in multivariate analysis (P < .001). CONCLUSION Factors predictive of PD include race, advanced tumor stage, high nuclear grade, high Ki-67 score, and ER/PR negativity. Because many of these variables are also associated with response to NCT, novel molecular predictors are needed to identify patients at risk for progression on standard NCT.
Obtaining concomitant control of allergic rhinitis and asthma with a nasally inhaled corticosteroid
Authors: P. Camargos, C. Ibiapina, L. Lasmar, A. A. Cruz
Journal: Allergy (2007)

Allergic rhinitis (AR) and asthma coexist frequently and a dual treatment is recommended by prescribing topical nasal plus oral inhaled corticosteroids. The purpose of this study was to assess the efficacy of a nasally inhaled corticosteroid aiming at concomitant control of AR and asthma. A controlled trial was conducted among 60 patients with AR and asthma, aged 6–18 years, who were randomized into two groups. During 8 weeks, the experimental group (30 patients) received exclusively fluticasone propionate hydrofluoroalkane (FP‐HFA) inhaled through the nose (mouth closed) using a large volume spacer attached to a face mask. The comparison group (30 patients) received a nasal spray of isotonic saline plus oral inhalation of FP‐HFA through a mouthpiece attached to the same spacer. Clinical scores for AR and asthma, nasal inspiratory peak flow (NIPF), and spirometry were assessed by blinded observers. There was a significant improvement in AR scores and NIPF in the experimental group ( P ≤ 0.01) up to week 8, when a worsening was observed after the intervention was interrupted. Asthma symptoms score, forced expiratory volume (FEV) 1 , and FEF 25−75% were not statistically different between groups at the baseline visit or along follow‐up visits ( P ≥ 0.20). Prebronchodilator FEV 1 (% predicted value) improved by 10% in both groups, comparing values at inclusion with those obtained at the end of follow up. Our results suggest that nasally inhaled FP‐HFA through a spacer may control AR and asthma in children and adolescents. This approach is likely to result in higher compliance, lower costs, and fewer side effects.
TCT-732 Prognostic Value Of Impaired Left Ventricular Function In Patients Undergoing Transapical Versus Transfemoral Transcatheter Aortic Valve Implantation (TAVI)
Authors: Vincent J. Nijenhuis, Robin Heijmen, Martin Swaans, Thomas de Kroon, Jan Van der Heyden, Jurrien M. Ten Berg
Journal: Journal of the American College of Cardiology (2014)
The atopy patch test: an increased rate of reactivity in patients who have an air-exposed pattern of atopic eczema
Authors: U. DARSOW, D. VIELUF, J. RING
Journal: British Journal of Dermatology (1996)

In a subgroup of patients with atopic eczema (AE), eczematous skin lesions can be induced by epicutaneous testing with aeroallergens (the atopy patch test: APT). An increased frequency of positive APT has been found in AE patients showing a predictive lesional pattern affecting air-exposed skin areas. This study investigates the dose-response of the APT in two different patient groups with AE. Petrolatum preparations of house dust mite, cat dander and grass pollen allergens in four concentrations (500-10,000 protein nitrogen units) were tested epicutaneously in 57 patients with AE, who were prospectively divided in two groups according to whether their AE pattern was with (group I) or without (group II) a predictive distribution. Sixty-nine per cent of patients in group I, and 39% in group II, had positive APT reactions (P = 0.02). The reactions in group I were elicitable with lower allergen concentrations (P = 0.03). A clinically recognizable subgroup of patients with AE showed increased cutaneous sensitivity to aeroallergens.
Response to Comment on Vimalananda et al. Depressive Symptoms, Antidepressant Use, and the Incidence of Diabetes in the Black Women’s Health Study. Diabetes Care 2014;37:2211–2217
Authors: Varsha G. Vimalananda, Edward A. Ruiz-Narváez
Journal: Diabetes Care (2015)

Drs. Kivimaki and Singh-Manoux (1) comment on our recent article (2) about symptoms of depression, antidepressant use, and incident diabetes in U.S. black women. In particular, they raise the possibility that the reported association between antidepressant use and increased risk of type 2 diabetes (2 …
Atrophy reversal and cardiocyte redifferentiation in reloaded cat myocardium.
Authors: E W Thompson, T A Marino, C E Uboh, R L Kent, G Cooper
Journal: Circulation Research (1984)

We have recently described rapid cardiac atrophy in response to decreased load. The present study was designed to determine whether this atrophy is solely a degenerative response of damaged myocardium or is, instead, an adaptive response of viable myocardium. A discrete portion of cat myocardium was unloaded by severing the chordae tendinae of a single right ventricular papillary muscle. One week later, the muscle was reloaded by attachment of its apex to the ventricular free wall. This allowed the load to be removed and restored without altering the blood supply, innervation, or frequency of contraction of the tissue. In myocardium unloaded for 1 week, the cardiocyte cross-sectional area and the volume densities of mitochondria and myofibrils decreased significantly. Large areas of cytoplasm were devoid of organelles, and the few remaining myofilaments were oriented in a variety of directions rather than longitudinally within the cell. Upon reloading for 1 week, the cardiocyte cross-sectional area, volume density of mitochondria, and ultrastructural organization all returned to normal. The volume density of the myofibrils increased toward control, and they reoriented with respect to the long axis of the cardiocyte. The contractile function of the papillary muscles, which was depressed as early as 1 day after unloading and almost absent at times later than 3 days after unloading, returned to normal after 2 weeks of reloading. This study demonstrates that adult mammalian myocardium responds to unloading with a marked loss of cellular differentiation, organization, and function which is fully reversible with reloading. This plasticity in response to load may well be the basic mechanism responsible for the development and maintenance of normal cardiac structure and function.
Histamine receptor H1 is required for TCR-mediated p38 MAPK activation and optimal IFN-γ production in mice
Authors: Rajkumar Noubade, Graeme Milligan, James F. Zachary, Elizabeth P. Blankenhorn, Roxana del Rio, Mercedes Rincon, Cory Teuscher
Journal: Journal of Clinical Investigation (2007)

Histamine receptor H1 (H1R) is a susceptibility gene in both experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune orchitis (EAO), 2 classical T cell-mediated models of organ-specific autoimmune disease. Here we showed that expression of H1R in naive CD4+ T cells was required for maximal IFN-gamma production but was dispensable for proliferation. Moreover, H1R signaling at the time of TCR ligation was required for activation of p38 MAPK, a known regulator of IFN-gamma expression. Importantly, selective reexpression of H1R in CD4+ T cells fully complemented both the IFN-gamma production and the EAE susceptibility of H1R-deficient mice. These data suggest that the presence of H1R in CD4+ T cells and its interaction with histamine regulates early TCR signals that lead to Th1 differentiation and autoimmune disease.
Prevention of gastrointestinal tumors based on adenomatous polyposis coli gene mutation by dendritic cell vaccine
Authors: Toshio Iinuma, Sadamu Homma, Tetsuo Noda, Donald Kufe, Tsuneya Ohno, Gotaro Toda
Journal: Journal of Clinical Investigation (2004)

Here we describe the effect of immunization with dendritic cells loaded with syngeneic tumor cells (DC/Ts) by polyethylene glycol treatment, on tumor development in adenomatous polyposis coli (APC) gene mutant mouse models, APC1309 and APCMin–/+, in which adenomatous polyps of the gastrointestinal tracts develop with a high incidence. Treatment with DC/Ts prevented the development of gastrointestinal tumors, and coadministration of DC/Ts and IL-12 caused a further reduction in tumor incidence. Splenocytes from APC1309 mice treated with DC/Ts and IL-12 showed no cytotoxic activity toward the tumor cells, but serum antibody specific to them was detected. IgG from the treated mice exhibited cytotoxic activity against the tumor cells in vitro. Predominance of Th2 cell response over Th1 response was also suggested by ELISPOT assays in the treated mice. Depletion in vivo of CD4+ T cells, not CD8+ T cells, by the intraperitoneal administration of corresponding mAb's decreased the antitumor effect of DC/T inoculation. Immunofluorescence microscopic studies showed that Ig was attached to tumor cells in mice treated with DC/Ts and IL-12. These findings indicate that DC/T vaccination prevents tumor development through APC gene mutation and that its preventive effects are mediated by humoral antitumor immunity.
Hemodynamics in humans during conventional and experimental methods of cardiopulmonary resuscitation.
Authors: R D Swenson, W D Weaver, R A Niskanen, J Martin, S Dahlberg
Journal: Circulation (1988)

High-fidelity hemodynamic recordings of aortic and right atrial pressures and the coronary perfusion gradient (the difference between aortic and atrial pressure) were made in nine patients during cardiopulmonary resuscitation (CPR). Findings during conventional manual CPR were compared with those during high-impulse CPR (rate, 120 cycles/min with a shorter compression:relaxation ratio) as well as during pneumatic vest CPR with and without simultaneous ventilation and abdominal binding. Aortic peak pressure during conventional CPR averaged 61 +/- 29 mm Hg but varied widely (range, 39-126 mm Hg) among patients. Although the magnitude of improvement was modest, the high-impulse method was the only technique tested that significantly elevated both aortic peak pressure and the coronary perfusion gradient during cardiac arrest. During conventional CPR, aortic pressure rose from 61 +/- 29 to 80 +/- 39 mm Hg during high-impulse CPR, and the gradient rose from 9 +/- 11 to 14 +/- 15 mm Hg, respectively; p less than 0.01. The pneumatic vest method significantly improved peak aortic pressure but not the coronary perfusion gradient. Simultaneous ventilation and chest compression created high end-expiratory pressure and lowered the coronary perfusion gradient. Abdominal binding had no significant hemodynamic effects. This evaluation of experimental resuscitation methods in humans shows that the high-impulse chest compression method augments aortic pressure over levels achieved during conventional CPR methods; however, the improvement in pressure is modest and may not be clinically important. Simultaneous ventilation as well as abdominal binding during CPR were associated with no benefit; in fact, simultaneous ventilation appears to adversely affect cardiac perfusion and, therefore, should not be used during clinical resuscitation.