tbuckley/cabot-search huggingface dataset:
A Single Functional Group Substitution in C5a Breaks B Cell and T Cell Tolerance and Protects Against Experimental Arthritis
Authors: Christoph Kessel, Kutty S. Nandakumar, Francis B. Peters, Varun Gauba, Peter G. Schultz, Rikard Holmdahl
Journal: Arthritis & Rheumatology (2013)

A deficiency in C5 protects against arthritis development. However, there is currently no approach successfully translating these findings into arthritis therapy, as by targeting the key component, C5a. The aim of this study was to develop a vaccination strategy targeting C5a as therapy for patients with rheumatoid arthritis.An anti-C5a vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (4NPA) into selected sites in the murine C5a molecule. C5a-4NPA variants were screened for their immunogenicity in mice on different arthritis-susceptible class II major histocompatibility complex (MHC) backgrounds. A candidate vaccine was tested for its impact on disease in a murine model of collagen-induced arthritis (CIA). Immunity toward endogenous C5a as well as type II collagen was monitored and characterized.Replacing a single tyrosine residue in position 35 (Y(35) ) with 4NPA allowed the generation of an anti-C5a vaccine, which partly protected mice against the development of CIA while strongly ameliorating the severity of clinical disease. Although differing in just 3 atoms from wild-type C5a (wtC5a), C5aY(35) 4NPA induced loss of T cell and B cell tolerance toward the endogenous protein in mice expressing class II MHC H-2(q) molecules. Despite differential B cell epitope recognition, antibodies induced by both wtC5a and C5aY(35) 4NPA neutralized C5a. Thus, anti-wtC5a IgG titers during arthritis priming were potentially of critical importance for disease protection, because high titers of C5a-neutralizing antibodies after disease onset were unable to reverse the course of arthritis.The results of this study suggest that the most effective anti-C5a treatment in arthritis can be accomplished using a preventive vaccination strategy, and that treatment using conventional biologic or small molecule strategies targeting the C5a/C5aR axis may miss the optimal window for therapeutic intervention during the subclinical priming phase of the disease.
COPD-specific co-morbidity test (COTE) for predicting mortality in COPD – Results of an European, multicenter study
Authors: Daiana Stolz, Renaud Louis, Wim Boersma, Branislava Milenkovic, Kostantinos Kostikas, Francesco Blasi, Joachim Aerts, Gernot Rohde, Alicia Marin, Lucas Boeck, Janko Rakic, Andreas Scherr, Antoni Torres, Tobias Welte, Michael Tamm
Journal: European Respiratory Journal (2014)

BACKGROUND: The COTE index describes 12 comorbidities influencing survival in COPD. It reportedly complements the BODE index thereby improving its survival prediction. We hypothesize that prognostic systemic biomarkers in COPD (proadrenomedullin and copeptin) might be associated with the COTE index and could additionally improve survival prediction.

METHODS: We prospectively evaluated 638 patients with stable COPD for ≥ 6 weeks, > 10 PY and GOLD II-IV seeking care in pulmonary tertiary hospitals in 8 European countries and included in the PROMISE cohort. Comorbidities and circulating biomarkers were assessed at baseline. The primary outcome of the study was death from any cause and from respiratory causes. Median observation time was 24 months.

RESULTS: Coronary artery disease and liver cirrhosis presented the strongest association with mortality (p<0.01 for both). There was no association of the COTE index with an increase in the hazard of death (HR 1.060 95% CI 0.964-1.166). Stratification for the follow-up time (< 18 vs ≥ 18months) did not significantly influenced results. Time to death was similar in patients with low (1-3) or high (≥4) COTE index (p=0.364, log-rank). Results were unaffected by stratification for BODE quartiles. Neither proadrenomedulin nor copeptin differed in COTE strata (p=n.s for both). The AUC of proadrenomedullin and copeptin were higher than the one of the COTE index for mortality prediction at 2 years (0.648 and 0.609 versus 0.574).

CONCLUSION: The COPD-specific co-morbidity test (COTE) did not contribute to assess mortality risk in patient with COPD. Neither proadrenomedullin nor copeptin are significantly associated with the COTE index.
Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver.
Authors: M J O'Connell, D M Nagorney, A M Bernath, G Schroeder, R J Fitzgibbons, J A Mailliard, P Burch, J S Bolton, G Colon-Otero, J E Krook
Journal: Journal of Clinical Oncology (1998)

PURPOSE Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control. METHODS Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression. RESULTS Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed. CONCLUSION Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.
Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression
Authors: Ives Cavalcante Passos, Mirela Paiva Vasconcelos-Moreno, Leonardo Gazzi Costa, Maurício Kunz, Elisa Brietzke, João Quevedo, Giovanni Salum, Pedro V Magalhães, Flávio Kapczinski, Márcia Kauer-Sant'Anna
Journal: The Lancet Psychiatry (2015)
A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy.
Authors: J Bonneterre, B Chevallier, R Metz, P Fargeot, E Pujade-Lauraine, M Spielmann, M Tubiana-Hulin, D Paes, J Bons
Journal: Journal of Clinical Oncology (1990)

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.
Asthma and metabolic syndrome in search of the incipient interfaces
Authors: Suchita Singh, Sutapa Sinha, Y.S. Prakash, Manish Kumar, Tanveer Ahmad, V.P. Singh, Balaram Ghosh, Anurag Agrawal
Journal: European Respiratory Journal (2013)

The emerging interface of asthma and metabolic syndrome merits attention. Markers of metabolic syndrome such as insulin resistance (IR) have been associated with reduced lung function and asthma. Direct impact of hyperinsulinemia and IR on lung function, and inflammation is not fully understood. Studying the effect of hyperinsulinemia on lung cellular physiology is a useful step towards understanding the link between metabolic syndrome and asthma.  Methods: Endogenous diet induced and exogenous insulin intranasal models of hyperinsulinemia were developed in mice. Consequences of hyperinsulinemia on lung morphology, airway hyperresponsiveness, and cell stress parameters were measured and confirmed in cultured human lung cells.  Results: Hyperinsulinemia or intranasal exposure to insulin, led to airway hyperresponsiveness, bronchial apoptosis, peribronchial collagen deposit and inflammation. Increased levels of Wnt/β-catenin signaling were found to be involved in insulin as well as in IL-13-induced changes in lung epithelium, suggesting a common point of integration between allergic and metabolic mechanisms of asthma pathogenesis. Mitochondrial dysfunction, that has previously been causally implicated in asthma pathogenesis, was induced by insulin in lung epithelial cells. We also observed that insulin potentiates the intracellular calcium response to histamine and acetylcholine in primary human airways smooth muscle cells, and promotes proliferation.  Conclusion: Our work provides initial understanding of how systemic and cellular metabolic changes are critical to asthma pathogenesis and this is a multifaceted process driven not only by inflammatory mechanisms, but also processes independent of inflammatory cells.
Histopathologic and immunohistochemical characterization of antioxidants profiles in different compartments in severe COPD
Authors: Beata T. Olejnicka, Andrzej Rubaj, Clas-Göran Lödahl, Cecilia Andersson, Michico Mori, Jonas Erjefalt
Journal: European Respiratory Journal (2013)

Background : Reactive oxygen/nitrogen species (ROS/RNS) are generally acknowledged as potent immunoregulatory and tissue-destructive molecules in tobacco-induced COPD. The excessive ROS/RNS are rapidly scavenged by the primary-line-antioxidants: superoxide dismutases (SODs), catalase (CAT), and glutathione peroxidase. The thioredoxin (TRX) system plays decisive role in the maintenance of a reduced intracellular redox state. However, there is little known about the detailed interrelationships between antioxidants profiles and proliferative( PI ), inflammatory- ( II ), destructive-index ( DI ) in small airways/lung in the same individual.  Methods:  The micro-localizations of macrophages (MQ), mast cells, neutrophils, SODs (CuZn-SOD, Mn-SOD, EC-SOD), catalase (CAT), thioredoxin (TRX) were investigated by immunocytochemistry using paraffin-embedded lung sections from non-smokers (n=10) and COPD patients (n=10). Histological/immunohistochemical analyses were performed using the same Region-of-Interest (ROI: well-preserved bronchiolar epithelium, pulmonary vessels, alveolar tissue) for each subject.  Results:  The percentage of CuZn-SOD/TRX immunoreactivity was significantly higher (p DI/  II  showed a positive statistic correlation with immunoreactivity for CuZn-SOD/CAT, and TRX.  PI  showed an increased immunoreactivity for Mn-SOD and CAT in the same section.  In summary , our results indicate an increase expression and upp-down regulation of antioxidants in the same subject and correlates with the local-regional severity of COPD.
Heterogeneity in prevalence and underdiagnosis of COPD: Results from BOLD, EPI-SCAN, PLATINO, and PREPOCOL
Authors: Bernd Lamprecht, Michael Studnicka, Joan Soriano, Peter Burney, Louisa Gnatiuc, Sonia Buist, Bernhard Kaiser, Lowie Vanfleteren, Marc Miravitlles, Carlos Torres-Duque, Andres Caballero, Mauricio González-García, Ana Menezes, Rogelio Perez-Padilla, Maria Montes de Oca, Francisco García-Rio, Julio Ancochea
Journal: European Respiratory Journal (2013)

Background & Objective 

We evaluate heterogeneity in prevalence of COPD and factors associated with underdiagnosis using data from four general populations surveys: BOLD (Burden of Obstructive Lung Disease), EPI-SCAN (Epidemiologic Study of COPD in Spain), PLATINO (Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar), and PREPOCOL (Prevalencia de EPOC en Colombia).

Methods 

Representative samples of adults aged ≥40 yrs were randomly selected from well-defined administrative areas at studied sites. Post-bronchodilator spirometry and face-to-face interviews were performed. Post-BD FEV1/FVC<LLN was used to define chronic airflow limitation consistent with COPD. Doctor-diagnosed COPD was self-reported. Underdiagnosed COPD was considered when participants had a FEV1/FVC<LLN and did not report previous diagnosis of COPD by a doctor or health professional.

Results 

Among 30,874 participants with a mean age of 56 yrs, 55.8% were female, and 22.9% were current smokers. Prevalence of reported doctor-diagnosed COPD ranged from 0.1% in Pune (India) to 22.4% in Lexington (US). 26.4% of all participants reported having-had a lung function test before, with a major rate of 97.6% in Norway and the lowest rate of 0.5% in Nigeria. Prevalence of COPD ranged from 3.6% in Baranquilla (Colombia) to 19.0% in Cape-Town (SA). 81.4% were undiagnosed with the highest rate in Ile-Ife, Nigeria (98.3%) and the lowest rate in Lexington, US (50.0%). Male gender, lower age, current smoking, and less severe airflow limitation were associated with underdiagnosis.

Conclusion 

There is substantial heterogeneity in prevalence and underdiagnosis of COPD worldwide. The majority of COPD cases remain undetected.
Antibody to Genital Herpes Simplex Virus: Association With Cervical Atypia and Carcinoma&lt;italic&gt;In Situ&lt;/italic&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Laure Aurelian, Ivor Royston, Hugh J. Davis
Journal: JNCI Journal of the National Cancer Institute (1970)

Multiplicity analyses using an artificial mixture of two strains of herpes simplex virus, a prototype of the genital strain (HSV-2) and a laboratory strain designated HSV-MP, were used to differentiate antibodies to the oral and genital strains of herpes simplex virus in sera from patients with cervical carcinoma. The studies indicate that the prevalence of antibodies to the genital variant of the virus was identical in patients with cytologically, histologically, and colposcopically confirmed atypia, carcinoma in situ, and invasive carcinoma. Statistically significant differences (P <0.0005) were observed between HSV-2 antibodies in these patients and a matched control population, differences which do not exist in two other venereally transmitted diseases. Epidemiologic evidence has long implicated a venereally transmitted factor in the etiology of cervical carcinoma. This investigation supports the hypothesis that genital herpes simplex virus may be responsible for the induction of squamous neoplasia in the human cervix.
What's So Special about Being 65? The Challenge Facing Eldercare Departments
Authors: Douglas G MacMahon
Journal: Journal of the Royal Society of Medicine (1994)

There is no abrupt change in physiology, pathology or pharmacology occurring at or around the age of 65 years. There is some evidence of a change in the effect of illness, and of the prevalence of disability with advancing age. However, these changes are individual and gradual, and more associated with passing 75–80 years rather than 65. The main change occurring in the seventh decade arises from retirement from paid employment, and is therefore financial. Hence, in contrast to personal financial support, Health and Social Services departments would be ill advised to use the age of 65 as a threshold. Age-related admission policies may perpetuate ageism, and needs-related policies may therefore be preferable. The challenge facing departments of geriatric medicine and psychiatry is to present their services attractively to patients, carers and purchasers, who need to recognize the rationale for the purchase of these forms of care, with reference not only to benefit to patients, but also to their informal carers.
Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group.
Authors: J R Anderson, R D Jenkin, J F Wilson, C R Kjeldsberg, R Sposto, R R Chilcote, P F Coccia, P R Exelby, S Siegel, A T Meadows
Journal: Journal of Clinical Oncology (1993)

PURPOSE We analyzed the long-term results of a Childrens Cancer Group (CCG) randomized study comparing cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) versus LSA2L2 as treatment for childhood non-Hodgkin's lymphoma. The initial results were previously reported (N Engl J Med 308:559, 1983). PATIENTS AND METHODS A total of 429 patients are reported here, 68 with localized disease and 361 with disseminated disease. The distribution of disseminated-disease patients by histologic type was 164 lymphoblastic, 60 large-cell, and 137 undifferentiated lymphomas. Median follow-up duration of surviving patients is 8 years. RESULTS Event-free survival (EFS) of patients with localized disease was 84% at 5 years. No differences were seen between the two treatment regimens. Results for patients with disseminated disease was dependent on histologic subtype: patients with lymphoblastic lymphoma did better when treated with LSA2L2 (5-year EFS of 64% v 35% for COMP); COMP produced better results for patients with undifferentiated lymphoma (5-year EFS of 50% v 29% for LSA2L2). Results for large-cell lymphoma patients were similar (5-year EFS of 52% for COMP v 43% for LSA2L2). Five percent of patients died of treatment-related complications while on therapy (primarily infections). Only four deaths without progression have been observed off-therapy (two from restrictive lung disease, one from an acute asthma attack, one from colon cancer). Patient survival rates after recurrence were poor. CONCLUSION Treatment success can be expected in 84% of pediatric patients with localized non-Hodgkin's lymphoma. For patients with disseminated disease, treatment success can be expected in 64% of those with lymphoblastic and 50% of those with undifferentiated or large-cell disease. To date, late adverse events are rare.
Molecular Pathogenesis of Cholestasis
Authors: E Elias
Journal: Gut (2004)

M Trauner, P L M Jansen. New York: Kluwer Academic/Plenum Publishers, 2003, £93.00, pp 366. ISBN 0 306 48240 1

This book represents a timely and up to date review of a rapidly developing field. The pattern is generally one of concise overviews which are extensively referenced. Those who have always regarded bile as dark and unfathomable would find a large array of related subjects which have been illuminated to provide clinically meaningful …
P-VABEC: a prospective study of a new weekly chemotherapy regimen for elderly aggressive non-Hodgkin's lymphoma.
Authors: M Martelli, C Guglielmi, S Coluzzi, G Avvisati, S Amadori, M Giovannini, C Torromeo, F Mandelli
Journal: Journal of Clinical Oncology (1993)

PURPOSE To evaluate, in a prospective trial, a new combination chemotherapy specifically designed for elderly patients. PATIENTS AND METHODS From October 1988 to December 1990, 60 previously untreated patients older than 60 years of age with aggressive non-Hodgkin's lymphoma (NHL) were treated at our institution with a new weekly alternating six-drug chemotherapy regimen, P-VABEC. The schedule consisted of doxorubicin, etoposide, and cyclophosphamide alternated weekly with vincristine and bleomycin. Oral prednisone was administered daily during the entire treatment period. Twenty-six of 60 patients were treated for a total of eight courses and 34 of 60 for 12 courses. RESULTS A total of 45 patients (75%) achieved a complete response (CR), 10 (17%) a partial response (PR), and five (8%) no response. So far, 20 of 45 CR patients have relapsed, four of 10 PR patients have progressed, and three patients have died while in CR. Twenty-eight patients are still alive and responding (22 CRs, six PRs) after a median follow-up of 25 months. The projected overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) rates at 2 years were 64%, 57%, and 55%, respectively. The outcome of patients treated with eight courses was similar to that of those who received 12 courses of P-VABEC in terms of CR rate and actuarial curves of OS, DFS, and EFS. Hematologic toxicity was mild in all patients. CONCLUSION The P-VABEC regimen is active, well tolerated, and one of the briefest first-line chemotherapy regimens so far reported in the treatment of elderly patients with aggressive NHL. However, prospective randomized trials are needed to establish the real advantage of this regimen compared with other standard chemotherapy regimens.
Tuberculosis in prison
Authors: Valeri Andreev, Antoaneta Karcheva, Kamelia Petrova, Emilia Lazarova
Journal: European Respiratory Journal (2011)

Introduction: Prison tuberculosis is a major problem because society “behind the walls” is overcrowded and isolation of patients is difficult and time-consuming. The program for improvement of the control on tuberculosis in Bulgarian prisons was started in order to solve these conditions.

Aims and objectives: Our aim is to present the ability of the program to provide better care for patients and contact people and better working conditions for medical personnel on both sides of the walls.

Methods: We observed a one year period from the beginning of the program in the Pleven prison. Measures like regular screening questionnaires, bacteriology, chest radiology and consultations with a supervising pulmonologist were provided regularly. Patients with pulmonary tuberculosis were isolated and sent to the prison hospital. Contact people were tested with a tuberculin test and were given isoniazid.

Results: This prison is inhabited by 600 prisoners and only 2 of them were diagnosed as sufferers of active tuberculosis. Other 2 continued therapy in prison after active hospital treatment. Prevalence of prison tuberculosis is about 900 out of every 100 000 prisoners. 421 questionnaires were filled, 110 prisoners gave sputum for bacteriology and 52 tuberculin tests were done. A room was built for induction of sputum and another for patient isolation.

Conclusion: The above measures guarantee the ability of the program to provide good medical service to prisoners, however most of them contracted tuberculosis outside the walls before imprisonment.