tbuckley/cabot-search huggingface dataset:
Role of ABCG2 in liver injury associated with erythropoietic protoporphyria
Authors: Madhav Sachar, Xiaochao Ma
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: We argue against the opinion in the article by Hagiwara et al. that decreased ABCG2 expression might be associated with severe liver damage in erythropoietic protoporphyria (EPP).1 Cholestasis is the major type of liver injury in EPP patients and is dependent on protoporphyrin IX (PPIX)–mediated bile duct blockage.2 The authors documented cholestatic injury in the elder brother by observing high levels of alkaline phosphatase (690 U/L) and total bilirubin (7 mg/dL) in serum.1 The authors also observed PPIX accumulation in hepatocytes, but not in the biliary system, in the same patient.1 These observations do not match each other because less PPIX in the bile ducts should cause fewer bile duct blockages and less cholestatic injury. Actually, the data in this study contradict those of a previous study using genetically engineered EPP mouse models, in which PPIX accumulation in hepatocytes attenuated liver damage.3 The current study determined PPIX location together with ABCG2 expression using the same fluorescence method.1 It is unknown whether this fluorescence method is specific for PPIX detection. In addition, liver biopsy of the elder brother showed bile thrombi,1 which should be the PPIX plugs, because PPIX is highly hydrophobic and the cause of bile duct blockage.2 We suggest that the authors reevaluate PPIX distribution in the liver using the standard methods for PPIX analysis.4 Furthermore, because the authors reported ABCG2 down‐regulation in only one EPP patient and measured ABCG2 expression after liver injury,1 it is difficult to determine whether ABCG2 down‐regulation is a cause or an effect of EPP‐associated liver injury. Finally, the risk of liver injury increases in EPP patients with increased age.5 The current study showed liver injury in the elder brother but did not provide the age of the younger brother.1 In summary, the facts do not support the assertion that decreased ABCG2 expression is the cause of liver damage in EPP.
Tree years survival rates of COPD patients that hospitalized for acute excecerbation of COPD
Authors: Hakan Tanriverdi, Tacettin Örnek, Fatma Erboy, Bülent Altinsoy, Firat Uygur, Figen Atalay, Elif Peynir, Müge Meltem Tor
Journal: European Respiratory Journal (2014)

Aim  Aims of these study are to determine the three years survival rate of COPD patients who were hospitalized for acute exacerbation and to determine the factors that may be affect the survival rate.  Material and methods  The patients who admitted to hospital for acute exacerbation of COPD (AECOPD) and were included the ERS COPD audit study in 2009 from Zonguldak, Turkey were eligible for this study. Descriptive data of patients were reviewed. Three years survival rates of patients, hospitalisation frequency, duration of hospitalisation and current therapies for COPD were investigated.  Results  56 patients (37 male, 19 female) whose mean age was 70,1 were included to study. Death rates of AECOPD patients for 90 days , one year and three years after the exacerbation were 44,6% , 53,6% and 66,0%, respectively. There was no significant difference between groups in terms of long term oxigen therapy, hypercapnea, age, gender, mean FEV1 % of predicted.  mean duration of hospitalisation and number of hospitalisation of patients who survived three years were 82 days and 6,7i, respectively.  Discussion  Long term survival rate of AECOPD patients after an exacerbation that requires hospitalisation was low (34%). Exacerbation is an important factor that affects mortality and morbidity in patients with COPD.
Diagnostic value of cervical mediastinoscopy: Report of 506 cases
Authors: Mehmet Erol, Hüseyin Melek, Ahmet Bayram, Tayfun Kermenli, Funda Coskun, Elif Akyildiz, Cengiz Gebitekin
Journal: European Respiratory Journal (2013)

Introduction  In this study we present analysis of our cases that had diagnostic mediastinoscopy.  Objectives  The most frequently applied area of mediastinoscopy is staging of lung cancer. The second most common use is for diagnostic procedures. It is a convenient and minimally invasive procedure for diagnosis of mediastinal adenopathies (LAP), and the masses. In this study we present analysis of our cases that had diagnostic mediastinoscopy.  Methods  We retrospectively evaluated our 1102 cases of cervical mediastinoscopy between 1997 - 2012. We included our 506 cases that we had diagnostic mediastinoscopy (45%). In all cases of with enlarged lymph nodes detected in thoracic computed tomography (CT) biopsy samples were taken.  Results  Diagnostic mediastinoscopy rate was 45% (506). we performed diagnostic video mediastinoscopy in 67 % of cases (340. Average procedure time was 26.4 min (18-48) and no intraoperative or postoperative mortality occured.  Diagnosis was obtained in 93% of cases. Among cases, 31 (7%) did not have a positive pathological diagnosis in the lymph nodes biopsied. Sarcoidosis was a occupied the widest area in the diagnostic scale chart.  Conclusions  In order to perform a biopsy of mediastinal lymph nodes and masses; EBUS and EUS methods have been began to be used in recent years. However, expensive installation process and need of experienced endoscopist limits its widely use yet. These diagnostic methods are methods that complement each other. Mediastinoscopy allows the surgeon to see lesions with the naked eye and biopsy material ensures larger biopsy specimens compared to other methods. In addition, in cases that were not given a diagnosis with other methods mediastinoscopy ensures definite diagnosis.
Long term treatment outcome in multi drug resistant tuberculosis
Authors: Rajendra Prasad, Abhijeet Singh, Sanjay Verma, Ramawadh singh Kushwaha, Rajiv Garg, Sanjeev Kumar Verma, Rahul Srivastava, Amita Jain
Journal: European Respiratory Journal (2012)

Background: Multi Drug Resistant tuberculosis (MDR-TB) is an increasing worldwide problem which is difficult to treat and has greater risk of relapse.  Aims and Objective: To analyze long term treatment outcome with second line drugs in patients with MDR-TB.  Methods: A descriptive analyses of 93 consecutive patients with MDR-TB attending the Dept of Pulmonary Medicine, CSMMU, between June 1998 to February 2008 with follow-up till December 2010. All patients were admitted for average duration of 70 days and received a regimen chosen from Kanamycin, PAS, Ethionamide, Cycloserine, Flouroquinolone, Isoniazid, Ethambutol and Pyrazinamide. Patients outcome was considered as cure when atleast two of the last three (At 12, 18 & 24 m) cultures were negative and as failure when the same were positive.  Results: All the patients had resistance to at least Isoniazid and Rifampicin with mean no. of 3.38 drugs. Average duration of pretreatment chemotherapy was 34.5 (10-62) months. Out of 93 patients enrolled, 75 completed the treatment as planned, 5 patients died during treatment, and 13 patients abandoned it or lost to follow up. Considering the best scenario cure rate was 93.33% (70/75) and in worst scenario cure rate was 75.27 % (70/93). Out of 75 cured, 68 came for follow-up for mean duration of 53.3 (10-98) months.Relapse rate was 9.33%(7/75). Significant side effects were experienced in 13 (13.98%) patients.  Conclusions: In MDR-TB patients, regimen consisting of Ethionamide, PAS, fluoroquinolone and Cycloserine with injection Kanamycin in initial 4-8 months appears to be safe and effective. MDR TB can be cured successfully with appropriate combination chemotherapy for an adequate duration requiring a strategic approach.
Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group.
Authors: J A Ortega, M D Krailo, J E Haas, D R King, A R Ablin, J J Quinn, J Feusner, J R Campbell, D A Lloyd, J Cherlow
Journal: Journal of Clinical Oncology (1991)

The Childrens Cancer Study Group (CCSG) undertook a study (CCG-823F) to test the feasibility of administering continuous infusion doxorubicin (CI DOX) and cisplatin (CDDP) in patients with unresectable or incompletely resected hepatoblastoma (HB) or hepatocellular carcinoma (HCC). Chemotherapy consisted of CI DOX 20 mg/m2/d for days 1 to 4 and CDDP 100 mg/m2 on day 1 followed by a 21-day rest period. Second-look surgery was performed after the administration of four chemotherapy courses. Forty-seven (47) assessable patients were entered on study, 33 with HB and 14 with HCC; of these, 34 (26 HB and eight HCC) completed the initial four courses of chemotherapy. Of the 26 HB patients, 25 were evaluated as responding to chemotherapy before the scheduled second-look procedure and were considered surgically resectable at that time. Surgery was performed on 22 patients; three patients refused the second-look surgery. Nine patients had no evidence of residual malignant disease, seven underwent surgical resection of remaining tumor, four were left with microscopic residual disease, one had a partial resection with gross tumor left behind, and one remained unresectable. Nine HCC patients completed four chemotherapy courses. Eight patients achieved a partial remission and second-look surgery was attempted on seven. Only two had all malignant disease removed at the second procedure. Data from 225 courses of chemotherapy were evaluated for toxicity. Neutropenia (absolute granulocyte count less than 500/mL) was observed in 68 courses, and five of these episodes were associated with sepsis. Severe mucositis was documented in 21 courses, and hypomagnesemia (magnesium less than 1.2 mg) was noted in 30 patients. Two patients developed decreased left ventricular shortening fraction, which resolved when chemotherapy was discontinued. In summary, CI DOX plus CDDP is a well-tolerated and effective regimen in inducing surgical resectability in HB patients who are unresectable at diagnosis and significantly improves survival for this group of patients to 66.6%.
Effect of enzyme replacement therapy (ERT) on lung involvement and changes of different peripheral blood T-cell subsets in Fabry disease patients
Authors: Balazs Odler, Tamas Constantin, Gyorgy Fekete, Gyorgy Losonczy, Aron Cseh, Lilla Tamasi, Veronika Muller
Journal: European Respiratory Journal (2013)

Fabry disease (α-galactosidase A deficiency) is a lysosomal storage disorder, causing accumulation of globotriaosylceramid in different organs. The most effective treatment is ERT, which stabilizes the condition of the patient. Glycolipids activate different immune cells leading to inflammation. Lung manifestation is characterized by airway inflammation; however data on severity and effects of ERT are missing.

Six affected and 5 carrier patients were screened for pulmonary manifestations. Repetitive measurements were performed on 6 patients on ERT (average follow-up 3 years). Patients with Fabry disease (n=3) and control volunteers (n=13) were included into peripheral blood cell measurements.

Lung involvement was present in all patients and one carrier, all having also other organ involvement and required ERT (age: 34.4±13.0 years). Symptoms suggestive for lung disease were scarce, however in all patients on ERT non reversible obstructive ventilatory disorder was present (FVC: 3.5±1.1L (87.2±16.5 %), FEV1: 2.1±0.9 L (63.3±24.7 %)). ERT resulted in stabilization of lung function in all treated patients (ΔFVC: 0.14±0.42 L (7.5±10%); ΔFEV1: 0.13±0.31 L (7.4±14.0%)). Increased level of Th1 (70.1±11.1 vs. 51.7±21.8%; p<0.05), decrease in Treg cells (1.51±1.12 vs. 2.80±0.98%;. p<0,05) were detected in Fabry patients.

Fabry disease in affected patients results mainly in asymptomatic non-reversible obstructive ventilatory disorder, stabilized by ERT. Significant increase of Th1 while decrease in Treg cells were detected in peripheral blood of Fabry patients.
Liver injury in treatment of latent tuberculosis infection - is the age cut-off for treatment justified?
Authors: Alison L. Gill, Su Ann Leong, Toby G.D. Capstick, John P. Watson
Journal: European Respiratory Journal (2014)

Background   Screening for latent tuberculosis infection (LTBI) is recommended for close contacts of active tuberculosis (TB) cases, new entrants from high incidence countries, and prior to anti-TNF treatment. NICE recommends chemoprophylaxis to reduce progression to active TB for patients under the age of 35, and for high-risk patients above this age. We hypothesised that rates of liver dysfunction are low and not strongly related to age, which would favour chemoprophylaxis in older patients.   Methods   We retrospectively identified all patients treated for LTBI in Leeds during 2012 from our pharmacy database. We recorded LFTs at baseline and during treatment. We identified all patients with evidence of liver dysfunction during treatment, defined as symptomatic and >3x upper limit of normal (ULN), or >5xULN. We compared rates of liver dysfunction in the under-35 and over-35 groups.   Results   112 patients received chemoprophylaxis during 2012. Of these, 66 were aged under 35 years. Four patients (3.6%) developed deranged LFTs (ALT>3xULN) during treatment (three over-35). Of these, two (1.8%) developed ALT>5xULN (one from each age group) and required cessation or interruption of treatment. There was no significant difference between the under-35 and over-35 groups for either level of derangement.   Conclusion   This study shows little difference in hepatotoxicity between those below and above the 35-year age cut-off. This data supports chemoprophylaxis at higher ages. Further work is needed into other predictors of LFT derangement, including co-morbidities, other medications and genotypic factors. We plan to extend this analysis to all patients treated from 2007 onwards.
Protection from nausea and vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research.
Authors: F Roila, M Tonato, C Basurto, M Picciafuoco, S Bracarda, D Donati, P Malacarne, L Monici, F Di Costanzo, L Patoia
Journal: Journal of Clinical Oncology (1989)

Despite treatment, emesis remains a major problem with cisplatin (CDDP) chemotherapy. Reasons for variability in antiemetic response among patients and in subsequent cycles are largely unknown and toxicity is sometimes severe. We have, therefore, carried out a multicenter, double-blind randomized trial comparing a combination of high-dose metoclopramide (MTC) (1 mg/kg x 4) and methylprednisolone (P) (treatment A) with a shorter but higher single-dose schedule of metoclopramide (3 mg/kg x 2) combined with dexamethasone (DEX) and diphenhydramine (DIP) to prevent extrapyramidal reactions (treatment B). Three hundred sixty-seven consecutive patients treated with various chemotherapy combinations containing CDDP were studied. Complete protection from vomiting/nausea was, at first cycle, 72.5%/79.5% with treatment B and 55.8%/65.1% with treatment A, a statistically significant difference (P less than .002/P less than .005). In subsequent cycles, protection from emesis significantly decreased with no difference between the two treatments. Multifactorial analysis shows that women, younger patients, outpatients, and patients who experienced emesis in previous cycles were at higher risk of suffering nausea and/or vomiting. Both regimens were well tolerated, but patients treated with treatment B had significantly less extrapyramidal reactions (1.7%/6.1%, P = .053). Treatment B is preferred due to its greater efficacy and lower incidence of extrapyramidal reactions. Trials on antiemetic therapy should take into account the important variables able to influence the efficacy of treatment. There is still a need for improving prevention of emesis in CDDP-treated patients.
Bidirectional association between wheezing and mental health problems in adolescencce: Pelotas, birth cohort, 1993
Authors: Ana Maria Menezes, Natalia Gomez-Cofre, Jeovany Martinez-Mesa, Ricardo Noal, Pedro C. Hallal, Maria Cecilia Assunção, Cora L. Araujo, Luciana Anselmi
Journal: European Respiratory Journal (2013)

Introduction: several studies have shown association between wheezing and mental health problems in children and adolescents that can occur in both directions.

Objective: to assess longitudinally the bidirectional association between wheezing and mental health problems in adolescents at 11 and 15 years of age.

Methods: individuals belonging to the 1993 birth cohort, in Pelotas, Brazil, were followed at 11 and 15 years old. Wheezing was assessed as “presence of wheezing in the last 12 months”, based on the International Study of Asthma and Allergies in Childhood (ISAAC). Mental health problems were assessed with the Strengths and Difficulties Questionnaire (SDQ). For the analysis, the total of subjects was divided in two samples from which teenagers with the outcomes (wheezing/mental health problems) at 11 years old were excluded.

Results: in the crude analysis for mental health problems at age 11 as predictor of wheezing at age 15, there was a statistical significant association for both sexes: males [RI = 1.64 (95% CI 1.16, 2.31), p = 0.005], and females [RI = 1.68 (95% CI 1.28, 2.19), p <0.001]; after adjustment for confounders, the association was maintained only for females [RI = 1.66 (95% CI 1, 16, 2.36), p = 0.005]. When wheezing at age 11 was evaluated as predictor of mental health problems at 15 years old, there was a statistical significant association in the crude analysis only for boys [β = 0.98 (95% CI 0.09, 1.87), p = 0.031]; after adjusting for confounders, this association was no longer statistically significant (p = 0.652).

Conclusions: girls who present mental health problems at age 11 have a high risk for developing wheezing at 15 years old.
National Health Action Party beats Liberal Democrats in three seats and vows to fight on
Authors: G. Iacobucci
Journal: BMJ (2015)

The political party set up to defend the NHS has secured 20 000 votes across 12 constituencies in the UK general election, including three fourth place finishes.

The National Health Action Party, formed by doctors and health campaigners in 2012 to protest against the government’s stewardship of the NHS, did not unseat any of its high profile target MPs in the 12 areas in which it fielded candidates for election. But the party’s co-leader, the oncologist Clive Peedell, said that the result was “a great effort in our first general election” and pledged to continue to carry the …
Enhanced Antitumor Activity of an Anti-5T4 Antibody–Drug Conjugate in Combination with PI3K/mTOR inhibitors or Taxanes
Authors: Boris Shor, Jennifer Kahler, Maureen Dougher, Jane Xu, Michelle Mack, Ed Rosfjord, Fang Wang, Eugene Melamud, Puja Sapra
Journal: Clinical Cancer Research (2015)

Targeted treatment of solid or liquid tumors with antibody-drug conjugates (ADCs) can lead to promising clinical benefit. The aim of the study is to investigate combination regimens of auristatin-based ADCs in preclinical models of cancer.An auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and auristatin payloads were combined with the dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of tumor cell lines. Drug interactions in vitro were evaluated using cell viability assays, apoptosis induction, immunofluorescence, mitotic index, and immunoblotting. Breast cancer cells treated with auristatin analogue or 5T4-ADC were profiled by total- and phospho-proteomics. Antitumor efficacy of selected combinations was evaluated in 5T4-positive human breast or lung tumor xenografts in vivo.In vitro, auristatin-based agents displayed strong synergistic or additive activity when combined with PF-384 or taxanes, respectively. Further, treatment of 5T4-ADC plus PF-384 resulted in stronger induction of apoptosis and cell line-specific attenuation of pAKT and pGSK. Interestingly, proteomic analysis revealed unique effects of auristatins on multiple components of mRNA translation. Addition of PF-384 further amplified effects of 5T4-ADC on translational components, providing a potential mechanism of synergy between these drugs. In human tumor xenografts, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/paclitaxel produced substantially greater antitumor effects with longer average survival as compared with monotherapy treatments.Our results provide a biologic rationale for combining 5T4-ADC with either PI3K/mTOR pathway inhibitors or taxanes and suggest that mechanisms underlying the synergy may be attributed to cellular effects of the auristatin payload.
Skeletal and Reticular Tissue Disorders Produced in Mice by Agent(s) From Sarcoma 37
Authors: Ruth M. Merwin, Lena W. Redmon
Journal: JNCI Journal of the National Cancer Institute (1969)

We isolated from Sarcoma 37 a filterable, serially transmissible agent that caused skeletal changes in BALB/c mice. Intramembranous ossification starting in the endosteum filled the medullary cavities with spongy bone. The distal large bones of the limbs were affected before the proximal ones, and the sternum and other bones were affected later. The isolate also caused reticular tissue disorders including marked splenomegaly, lymphocytic neoplasms, and reticulum cell neoplasms, type B. Splenomegaly arose mainly in one line of passage of the isolate where transmission was by agent from enlarged spleens. Skeletal changes occurred in most mice with reticular tissue disorders, except in males dying less than 5 months after inoculation. Skeletal changes also arose in the absence of reticular tissue disorders, but we were unable to obtain an agent that induced skeletal changes alone. Only BALB/c or BALB/c hybrids developed skeletal abnormalities, though the agent was transmitted by mice of other strains. We found that the Moloney leukemia virus, which was isolated by Moloney from Sarcoma 37, also caused skeletal changes.
Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide Synthase
Authors: Hervé Duplain, Rémy Burcelin, Claudio Sartori, Stéphane Cook, Marc Egli, Mattia Lepori, Peter Vollenweider, Thierry Pedrazzini, Pascal Nicod, Bernard Thorens, Urs Scherrer
Journal: Circulation (2001)

Background Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown. Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure. Methods and Results To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS −/− mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS −/− mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal. Conclusions These results indicate that eNOS is important for the control not only of arterial pressure but also of glucose and lipid homeostasis. A single gene defect, eNOS deficiency, may represent the link between metabolic and cardiovascular disease.