tbuckley/cabot-search huggingface dataset:
Multiple Courses of High-Dose Ifosfamide, Carboplatin, and Etoposide With Peripheral-Blood Progenitor Cells and Filgrastim for Small-Cell Lung Cancer: A Feasibility Study by the European Group for Blood and Marrow Transplantation
Authors: S. Leyvraz, L. Perey, G. Rosti, A. Lange, S. Pampallona, R. Peters, Y. Humblet, L. Bosquée, F. Pasini, M. Marangolo
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To determine the feasibility and safety of multiple sequential courses of high-dose chemotherapy and peripheral-blood progenitor cells (PBPCs) administered in a multicenter setting to patients with small-cell lung cancer. PATIENTS AND METHODS: Sixty-nine patients (limited disease, n = 30; extensive disease, n = 39) treated at 15 European centers were scheduled to receive three courses of high-dose chemotherapy with ifosfamide 10 g/m 2 , carboplatin 1200 mg/m 2 , and etoposide 1200 mg/m 2 (ICE) divided over 4 days at 28-day intervals. PBPCs were harvested before treatment and mobilized with epirubicin 150 mg/m 2 administered via an intravenous bolus divided over 2 days and filgrastim 5 μg/kg/d administered subcutaneously. RESULTS: The performed leukaphereses (one to five per patient) yielded a median of 16.6 × 10 6 /kg (range, 1.0 to 96.6 × 10 6 /kg) CD34 + cells, which was sufficient for three reinfusions. Fifty patients (72%) completed the treatment according to schedule. Nine patients completed two courses, and six patients completed one course of treatment. The increase in dose-intensity was 290% that of a standard ICE regimen. The median duration of myelosuppression was similar between courses, namely 4 days (range, 1 to 12 days) for leukocytes less than 0.5 × 10 9 /L and 4 days (range, 0 to 22 days) for thrombocytes less than 20 × 10 9 /L. Febrile neutropenia developed in 66% of courses, severe diarrhea in 14%, mucositis in 10%, and nausea and vomiting in 21% of courses. There were six cases of toxic death (9%), most of which occurred in the first year of accrual and thus were attributable to the learning curve. The antitumor effect of the regimen was reflected in an 86% remission rate (95% confidence interval [CI], 74% to 93%), with 51% of patients achieving a complete response (95% CI, 38% to 63%). Median overall survival was 18 months for patients with limited disease and 11 months for patients with extensive disease. CONCLUSION: This multiple sequential high-dose ICE regimen could be safely administered on a multicenter basis to patients with small-cell lung cancer. The dose-intensity could be increased to 290% that of standard ICE regimen. The benefit of this approach is currently being tested in a randomized trial that aims to double the long-term rate of survival for patients with small-cell lung cancer.
Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention
Authors: Itzhak Nissim, Oksana Horyn, Yevgeny Daikhin, Ilana Nissim, Bohdan Luhovyy, Peter C. Phillips, Marc Yudkoff
Journal: Cancer Research (2006)

The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and beta-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM. Oxidative phosphorylation was determined with electron donors specific to complexes I, II, III, or IV (C-I, C-II, C-III, or C-IV, respectively). A parallel study was done with (13)C-labeled pyruvate to assess metabolic dysfunction. Ifosfamide treatment significantly inhibited oxidative phosphorylation with only C-I substrates. Inhibition of C-I was associated with a significant elevation of [NADH], depletion of [NAD], and decreased flux through pyruvate dehydrogenase and the TCA cycle. However, administration of AGM with IFO increased [cyclic AMP (cAMP)] and prevented IFO-induced inhibition of C-I. In vitro studies with various metabolites of IFO showed that only CAA inhibited C-I, even with supplementation with 2-mercaptoethane sulfonic acid. Following IFO treatment daily for 5 days with 50 mg/kg, the level of CAA in the renal cortex was approximately 15 micromol/L. Taken together, these observations support the hypothesis that CAA is accumulated in renal cortex and is responsible for nephrotoxicity. AGM may be protective by increasing tissue [cAMP], which phosphorylates NADH:oxidoreductase. The current findings may have an important implication for the prevention of IFO-induced nephrotoxicity and/or mitochondrial diseases secondary to defective C-I.
Leukemia-associated changes identified by quantitative flow cytometry. IV. CD34 overexpression in acute myelogenous leukemia M2 with t(8;21)
Authors: A Porwit-MacDonald, G Janossy, K Ivory, D Swirsky, R Peters, K Wheatley, H Walker, A Turker, AH Goldstone, A Burnett
Journal: Blood (1996)
Tumor necrosis factor alpha/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium.
Authors: A Slungaard, G M Vercellotti, G Walker, R D Nelson, H S Jacob
Journal: The Journal of Experimental Medicine (1990)

Eosinophils (EOs) participate in a variety of inflammatory states characterized by endothelial cell damage, such as vasculitis, pneumonitis, and endocarditis. We find that 100 U/ml TNF-alpha/cachectin (TNF), a concentration attainable in the blood of humans with parasitic infestations, stimulates highly purified populations of EOs to damage human umbilical vein endothelial cells (HUVEC), a model of human endothelium. This TNF-dependent EO cytotoxicity is strongly inhibited by heparin and methyprednisolone but unaffected by the platelet-activating factor antagonist BN52012 or scavengers of superoxide anion and H2O2, superoxide dismutase and catalase. However, addition of a physiologically relevant concentration of Br- (100 microM) enhances EO/TNF damage to HUVEC, implicating the possible participation of EO peroxidase (EPO) in the killing mechanism. EOs adherent to FCS-coated plastic wells more than double their production of superoxide anion and the cytotoxic EPO-derived oxidant HOBr when exposed to TNF, showing that TNF activates the respiratory burst of EOs attached to a "physiologic" surface. Unlike PMNs, EOs were not irreversibly activated to kill unopsonized endothelium by previous exposure to TNF, and did not degranulate or upregulate CR3 expression as detected by Mo1 in the presence of 100 U/ml TNF. HUVEC exposed 18 h to TNF were considerably more susceptible to lysis by PMA-activated EOs and reagent H2O2, demonstrating a direct effect of TNF upon endothelium, perhaps through inhibition of antioxidant defenses. These findings suggest that abnormally elevated serum levels of TNF may provoke EOs to damage endothelial cells and thereby play a role in the pathogenesis of tissue damage in hypereosinophilic states.
Association of Frontal and Posterior Cortical Gray Matter Volume With Time to Alcohol Relapse: A Prospective Study
Authors: Kenneth Rando, Kwang-Ik Hong, Zubin Bhagwagar, Chiang-Shan Ray Li, Keri Bergquist, Joseph Guarnaccia, Rajita Sinha
Journal: American Journal of Psychiatry (2010)

Alcoholism is associated with gray matter volume deficits in frontal and other brain regions. Whether persistent brain volume deficits in abstinence are predictive of subsequent time to alcohol relapse has not been established. The authors measured gray matter volumes in healthy volunteers and in a sample of treatment-engaged, alcohol-dependent patients after 1 month of abstinence and assessed whether smaller frontal gray matter volume was predictive of subsequent alcohol relapse outcomes.Forty-five abstinent alcohol-dependent patients in treatment and 50 healthy comparison subjects were scanned once using high-resolution (T(1)-weighted) structural MRI, and voxel-based morphometry was used to assess regional brain volume differences between the groups. A prospective study design was used to assess alcohol relapse in the alcohol-dependent group for 90 days after discharge from 6 weeks of inpatient treatment.Significantly smaller gray matter volume in alcohol-dependent patients relative to comparison subjects was seen in three regions: the medial frontal cortex, the right lateral prefrontal cortex, and a posterior region surrounding the parietal-occipital sulcus. Smaller medial frontal and parietal-occipital gray matter volumes were each predictive of shorter time to any alcohol use and to heavy drinking relapse.These findings are the first to demonstrate that gray matter volume deficits in specific medial frontal and posterior parietal-occipital brain regions are predictive of an earlier return to alcohol use and relapse risk, suggesting a significant role for gray matter atrophy in poor clinical outcomes in alcoholism. Extent of gray matter volume deficits in these regions could serve as useful neural markers of relapse risk and alcoholism treatment outcome.
Prevention of gram-negative bacillary pneumonia using polymyxin aerosol as prophylaxis. II. Effect on the incidence of pneumonia in seriously ill patients.
Authors: J M Klick, G C du Moulin, J Hedley-Whyte, D Teres, L S Bushnell, D S Feingold
Journal: Journal of Clinical Investigation (1975)

All 744 patients admitted to a Respiratory-Surgical Intensive Care Unit (RSICU) were included in a prospective study of the effects of a polymyxin (2.5 mg/kg body wt/day in six divided doses) or a placebo aerosol sprayed into the posterior pharynx and tracheal tube (if present), during 11 alternating 2-mo treatment cycles. The incidence of upper airway colonization in the RSICU with Pseudomonas aeruginosa was 1.6% during the polymyxin treatment cycles (total 374 patients) and 9.7% during the placebo cycles (370 patients) (X2 equals 23.2, P less than 0.01). 3 patients in the RSICU acquired Pseudomonas pneumonia, as defined by independent "blinded" assessors, during the polymyxin cycles while 17 acquired a Pseudomonas pneumonia during the placebo cycles (X2 equals 10.2, P less than 0.01). The overall mortality was similar in both placebo and polymyxin-treated groups (12.2 vs. 12.0%). Systemic antibiotic usage was similar in the different cycles; 49% of patients in the placebo and 53% in the polymyxin-treated groups received systemic antibiotics while in the RSICU.
Sustained response to long-term biologics and switching in psoriatic arthritis: results from real life experience
Authors: L C Coates, L S Cawkwell, N W F Ng, A N Bennett, D J Bryer, A D Fraser, P Emery, H Marzo-Ortega
Journal: Annals of the Rheumatic Diseases (2007)

To investigate the response to biologic drugs in psoriatic arthritis and to quantify non-response and outcome from switching agents.60 patients (33 men and 27 women, mean age 46 years, median disease duration 16 years) prescribed biologic drugs for psoriatic arthritis between 2001 and 2006 were studied. Response was evaluated using joint counts, C-reactive protein levels and disease activity scores (using 28 joints; DAS28).The mean percentage improvements seen were 56% in tender joint count, 70% in swollen joint count, 64% in C-reactive protein level and 36% in the overall disease activity score. Improvements were sustained beyond 24 months with no loss of effect. Side-effects leading to cessation or switching of first-line therapy were only seen in 5% of patients and non-response occurred in 20% long term. Overall, 90% of patients achieved a significant response, using switching in 20% of cases. Outcomes were similar regardless of drug used, duration of disease and subtype of arthritis.Treatment of active psoriatic arthritis with anti-tumour necrosis factor agents leads to a sustained response over 3 years with most patients tolerating these drugs well. The rate of non-response is low with the majority of patients responding to second- and third-line therapies.
A BMJ for the United States
Authors: D. Payne, F. Godlee
Journal: BMJ (2012)

<h3>Background:</h3> Discussions about racism, ethnicity, sexism, discrimination, and diversity have increased within medicine, and their impact on the physician workforce, advancement, hiring, wage inequities, mistreatment, and scholarly output, to name a few. Most medical organizations have created policies and initiatives on diversity and inclusion, focusing on supporting underrepresented minorities. Similar discussions are taking place online, including on Twitter, via specific hashtags, such as #BlackMenInMedicine, #ILookLikeASurgeon. News reports suggested some of these hashtags were “trending.” We set out to assess selected hashtags and analyze their spread, as well as whether or how health professional organizations publicized or amplified this emerging discourse on Twitter. <h3>Methodology:</h3> We computed tweet volume, retweet volume impressions, and spread for selected hashtags and for health-profession organizations. <h3>Results:</h3> The overall volume was average or below average when compared with all active Twitter users; however, the retweet percentage was 60%, suggesting high levels of engagement. There was modest spread of most of the messages containing the hashtags, with the exception of #ilooklikeasurgeon tweets, due to its relationship to the cover of a major nonmedical magazine. Spread for some hashtags, despite very low initial retweets, was increased due to retweeting by accounts with high volume of followers. Medical societies9 contributions to dissemination were very minor. <h3>Conclusion:</h3> Strengthening, deepening and, ultimately, expanding the conversation on diversity and inclusion in medicine on Twitter requires an intentional and strategic use of hashtags, photographs and links; Engaging “influencers” such as mainstream media and medical organizations is also critical to more widespread dissemination.
Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression
Authors: Sabrina Giglio, Aldesia Provenzano, Benedetta Mazzinghi, Francesca Becherucci, Laura Giunti, Giulia Sansavini, Fiammetta Ravaglia, Rosa Maria Roperto, Silvia Farsetti, Elisa Benetti, Mario Rotondi, Luisa Murer, Elena Lazzeri, Laura Lasagni, Marco Materassi, Paola Romagnani
Journal: Journal of the American Society of Nephrology (2014)

In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid-resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner.
Astley Paston Cooper (1768–1841): anatomist, radical and surgeon
Authors: Druin Burch
Journal: Journal of the Royal Society of Medicine (2010)

Astley Paston Cooper's father was a Norfolk clergyman who married well and lived well. When he died, an obituary tempered its praise with a suggestion that he paid a little too much attention to appearances. The family arrived at Sunday services via a coach and four; the four black horses a glorious sight, but somewhat needless given they lived next door to the church. The Reverend Samuel Cooper's sermons sold well, preaching solid Church and King values, but his wife's novels did rather better. Written in the form of letters, Maria Susanna Cooper's stories were sentimental and idealistic, pushing the values of the contemporary orthodoxy: both with and without a capital letter, the couple were conservative.
Psychosocial Problems of Teenagers Who Have a Parent With Cancer: A Population-Based Case-Control Study (Young-HUNT Study)
Authors: Elisabeth Jeppesen, Ingvar Bjelland, Sophie D. Fosså, Jon H. Loge, Alv A. Dahl
Journal: Journal of Clinical Oncology (2013)

High prevalence of psychosocial problems has been observed in clinical studies of teenagers who have a parent with cancer. In contrast, we used a population-based design to study such problems in teenagers who have a parent with cancer (cases) compared with matched teenagers with cancer-free parents (controls). We hypothesized that higher prevalence of psychosocial problems would be observed in cases compared with controls and that sex differences would be observed between cases and controls.We used data from a cross-sectional population-based survey of teenagers (Young-HUNT study). Among 8,986 teenage participants, 120 of their parents had invasive cancer before the Young-HUNT study according to the Norwegian Cancer Registry. These parents had 143 teenagers (cases) participating in the Young-HUNT study. Matched on sex, age, and municipality, 429 control teenagers with cancer-free parents were drawn from the Young-HUNT study. Six psychosocial problems were studied.No significant differences in psychosocial problems were observed between cases and controls in the total sample. Fewer case daughters reported eating problems compared with control daughters, and more case sons reported eating problems compared with control sons. More case daughters than case sons reported somatic stress symptoms and low self-esteem and displayed more caseness of anxiety/depression. These three sex differences were also observed among controls, indicating that they were general sex differences.In this population-based study, teenagers who had a parent with cancer did not have higher prevalence of psychosocial problems than controls. Sex differences observed in previous clinically based studies were confirmed but may simply reflect sex differences observed among teenagers in general.
Scale, Causes, and Implications of the Primary Care Nursing Shortage
Authors: Logan MacLean, Susan Hassmiller, Franklin Shaffer, Kathleen Rohrbaugh, Tiffany Collier, Julie Fairman
Journal: Annual Review of Public Health (2014)

As the demand for health care consistently rises and many individuals, even within developed countries, lack access to primary care services, a better understanding of how primary care is defined, the main causes of the primary care shortage both within the United States and across the globe, and key solutions to these issues are paramount. Upon review of the US and international primary care literature, the authors first briefly discuss the fluidity of how primary care is defined and how it is applied in nations with differing levels of health care infrastructure. The main causes of the deficit both domestically and globally are then examined. Finally, upon careful review of the research produced within the past seven years, this article suggests strategies that maximize the primary care workforce: the effective use of technology, task shifting, interprofessional teams, and more consistent primary care data to build workforce strategies.
Insulin B chain functions as an effective competitor of antigen presentation via peptide homologies present in the thymus.
Authors: G G Miller, J F Hoy, J W Thomas
Journal: The Journal of Experimental Medicine (1989)

The B chain of mammalian insulins contains appropriately spaced amino acids that predict recognition by T cells. However, all T cell clones from an HLA-DR1, Dw6 diabetic donor recognize epitopes associated with the A chain, and the B chain was found to inhibit these responses. Effective intramolecular competition at the level of the APC, not a direct effect on the T cell, is responsible for the inhibition. Insulin B chain contains two clusters of amino acid homology with the TCR beta chain and B chain peptides lacking these clusters do not compete for antigen presentation. A hole in the repertoire for T cells that recognize this portion of the insulin molecule may arise in the thymus by deletion of T cells that recognize similar peptides.
Hepatic stem cells and transforming growth factor β in hepatocellular carcinoma
Authors: Avijit Majumdar, Steven A. Curley, Xifeng Wu, Powel Brown, Jessica P. Hwang, Kirti Shetty, Zhi-Xing Yao, Aiwu Ruth He, Shulin Li, Lior Katz, Patrizia Farci, Lopa Mishra
Journal: Nature Reviews Gastroenterology & Hepatology (2012)
Mechanisms for Renal Blood Flow Control Early in Diabetes as Revealed by Chronic Flow Measurement and Transfer Function Analysis
Authors: Tracy D. Bell, Gerald F. DiBona, Ying Wang, Michael W. Brands
Journal: Journal of the American Society of Nephrology (2006)

The purpose of this study was to establish the roles of the myogenic response and the TGF mechanism in renal blood flow (RBF) control at the very earliest stages of diabetes. Mean arterial pressure (MAP) and RBF were measured continuously, 18 h/d, in uninephrectomized control and diabetic rats, and transfer function analysis was used to determine the dynamic autoregulatory efficiency of the renal vasculature. During the control period, MAP averaged 91 ± 0.5 and 89 ± 0.4 mmHg, and RBF averaged 8.0 ± 0.1 and 7.8 ± 0.1 ml/min in the control and diabetic groups, respectively. Induction of diabetes with streptozotocin caused a marked and progressive increase in RBF in the diabetic rats, averaging 10 ± 6% above control on day 1 of diabetes and 22 ± 3 and 34 ± 1% above control by the end of diabetes weeks 1 and 2. MAP increased approximately 9 mmHg during the 2 wk in the diabetic rats, and renal vascular resistance decreased. Transfer function analysis revealed significant increases in gain to positive values over the frequency ranges of both the TGF and myogenic mechanisms, beginning on day 1 of diabetes and continuing through day 14. These very rapid increases in RBF and transfer function gain suggest that autoregulation is impaired at the very onset of hyperglycemia in streptozotocin-induced type 1 diabetes and may play an important role in the increase in RBF and GFR in diabetes. Together with previous reports of decreases in chronically measured cardiac output and hindquarter blood flow, this suggests that there may be differential effects of diabetes on RBF versus nonrenal BF control.