tbuckley/cabot-search huggingface dataset:
Elevated copper impairs hepatic nuclear receptor function in Wilson’s disease
Authors: Clavia Ruth Wooton-Kee, Ajay K. Jain, Martin Wagner, Michael A. Grusak, Milton J. Finegold, Svetlana Lutsenko, David D. Moore
Journal: Journal of Clinical Investigation (2015)

Wilson's disease (WD) is an autosomal recessive disorder that results in accumulation of copper in the liver as a consequence of mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). WD is a chronic liver disorder, and individuals with the disease present with a variety of complications, including steatosis, cholestasis, cirrhosis, and liver failure. Similar to patients with WD, Atp7b⁻/⁻ mice have markedly elevated levels of hepatic copper and liver pathology. Previous studies have demonstrated that replacement of zinc in the DNA-binding domain of the estrogen receptor (ER) with copper disrupts specific binding to DNA response elements. Here, we found decreased binding of the nuclear receptors FXR, RXR, HNF4α, and LRH-1 to promoter response elements and decreased mRNA expression of nuclear receptor target genes in Atp7b⁻/⁻ mice, as well as in adult and pediatric WD patients. Excessive hepatic copper has been described in progressive familial cholestasis (PFIC), and we found that similar to individuals with WD, patients with PFIC2 or PFIC3 who have clinically elevated hepatic copper levels exhibit impaired nuclear receptor activity. Together, these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels.
Household air pollution and airway obstruction in adult female cooks of rural Nepal: A comparative study among biogas and firewood users
Authors: Maniraj Neupane, Eva A. Rehfuess, Guenter Froeschl, Marcel Wolbers, Buddha Basnyat, Rainald Fischer
Journal: European Respiratory Journal (2014)

75% of Nepalese households use biomass fuel for cooking and are exposed to hundreds of pollutants contained in the resultant household air pollution. Women, culturally responsible for cooking, are discordantly affected.  We investigated the prevalence of airway obstruction (AO) in female cooks aged 30 years or older who had used either firewood or biogas as their primary cooking fuel for at least 10 years. Biogas, obtained by anaerobic digestion of organic waste, is considered a clean fuel.  We conducted a cross-sectional study among 519 cooks, 219 biogas vs. 300 wood users. Household characteristics and kitchen ventilation were assessed. Lung function was measured using the American Thoracic Society guideline with a portable spirometer (EasyOne, NDD). AO was defined by values below the lower normal limit (LLN) using the Global Lung Equation 2012 or, alternatively, by FEV 1 /FVC ratio   486 women performed spirometry, 88% produced reproducible traces. Overall prevalence of AO by LLN was 24.3% (21.9% in biogas vs. 26.1% in wood, p=0.36). Analysis adjusted for age, smoking and socioeconomic status found a significantly lower odds of developing AO among biogas users compared to wood (OR 0.48, 95% CI: 0.27-0.86, p= 0.01). Additional adjustment for ventilation, kitchen characteristics and other fuel use lead to a similar odds ratio (0.51, 0.27-0.95, p=0.03). Using the 70% cutoff yielded similar effect but not significant which may be due to under diagnosis of AO in the younger age.  The prevalence of AO is very high in rural Nepal. Household biogas plants associated with the decreased odds of developing AO could contribute to reducing this disease burden.
Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer
Authors: M. W. Audeh, R. T. Penson, M. Friedlander, B. Powell, K. M. Bell-McGuinn, C. Scott, J. N. Weitzel, J. Carmichael, A. Tutt
Journal: Journal of Clinical Oncology (2009)

5500 Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced chemotherapy-refractory ovarian cancer. The secondary aim was to assess the safety and tolerability profile in ovarian cancer patients with BRCA1/2 deficiency. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two patient (pt) sequential cohorts received continuous oral olaparib in 28-day cycles, initially at the MTD, 400 mg bd (33 pts), and subsequently at 100 mg bd (24 pts), a previously shown clinically active and PARP inhibitory dose. Eligibility criteria included confirmed genetic BRCA1/2 mutation and recurrent, measurable, incurable disease (previous chemotherapy, median 3 lines). The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Change in CA125 was a secondary efficacy endpoint. All adverse events were reported using CTCAE v3. Results: At this interim analysis dated October 31, 2008, of 57 enrolled pts (39 BRCA1 deficient and 18 BRCA2 deficient), 33 were evaluable at 400 mg bd and 24 at 100 mg bd. The confirmed RECIST ORR was 33% at 400 mg bd and 12.5% at 100 mg bd. Clinical benefit rate (ORR and/or confirmed &gt;50% decline in CA125) was 57.6% at 400 mg bd and 16.7% at 100 mg bd. Toxicity was mainly mild in severity, reflecting grade 1/2 nausea (44%); fatigue (35%); and anemia (14%). Grade 3 toxicity occurred infrequently, and comprised primarily nausea (7%) and leukopenia (5%). Conclusions: Oral olaparib is well tolerated and highly active in advanced, chemotherapy-refractory BRCA-deficient ovarian cancer, with greater activity seen at the higher dose. Toxicity in BRCA1/2 carriers was similar to that seen in non-carriers. This study provides positive proof of the concept of the activity and tolerability of genetically defined targeted therapy with olaparib in BRCA-deficient ovarian cancers. [Table: see text]
HLA polymorphism among Chinese patients with chronic plaque psoriasis: subgroup analysis
Authors: H.Y. Chiu, P.-Y. Huang, S.-H. Jee, C.-Y. Hu, C.-T. Chou, Y.-T. Chang, C.-Y. Hwang, T.-F. Tsai
Journal: British Journal of Dermatology (2011)

HLA-Cw*06 has a strong influence on the clinical features and the susceptibility to psoriasis in different ethnicities. It is also used as a biomarker to predict the therapeutic efficacy of biologics, with inconsistent results. Additionally, most Asian patients with psoriasis do not carry HLA-Cw*06.To determine additional HLA alleles which confer susceptibility or affect the severity of psoriasis in Chinese Han individuals. In addition, the potential of using HLA to predict treatment outcomes was also investigated.We conducted a case-control association study in 199 Chinese patients with psoriasis and 200 unrelated healthy controls. HLA-B and HLA-C genotyping was performed and correlated with the therapeutic efficacy of the biologics, including alefacept, efalizumab, etanercept and ustekinumab. Patients with psoriasis were divided into group A (high-need patients with moderate to severe psoriasis) and B (general patients with psoriasis).The frequencies of HLA-B*60, HLA-B*75, HLA-Cw*06 and HLA-Cw*10 were significantly increased in patients with psoriasis compared with the healthy controls. However, the prevalence of HLA-Cw*06 was lower in group A compared with group B (6% vs. 17%, Pc=0·04). HLA-B*46 was found to be strongly associated with group A but not with group B patients with psoriasis. HLA-Cw*01/HLA-B*46 was also identified as a risk haplotype for Chinese patients with psoriasis, compatible with the results in Thais. Significant differences in response to biologics were observed between HLA-Cw*01+ and HLA-Cw*01- individuals in the alefacept treatment group, and between HLA-B*37+ and HLA-B*37-, and HLA-B*58+ and HLA-B*58- individuals in the efalizumab treatment group.In addition to HLA-Cw*06, the HLA-Cw*01/HLA-B*46 haplotype was also increased in Chinese patients with psoriasis. High-need patients with psoriasis had a lower frequency of HLA-Cw*06 but a higher prevalence of HLA-B*46 compared with general patients with psoriasis in our population.
Muscle phenotypes in COPD patients: An exploratory cluster analysis
Authors: Fares Gouzi, Aldjia Abdellaoui, Sami Sedraoui, Nicolas Molinari, Edith Pinot, Dalila Laoudj-Chenivesse, Jean-Paul Cristol, Jacques Mercier, Maurice Hayot, Christian Préfaut
Journal: European Respiratory Journal (2012)

Peripheral muscle dysfunction is a key outcome in chronic obstructive pulmonary disease (COPD) and has been well characterized by reductions in fiber cross-sectional area (CSA) and type I fiber proportion. However, it is currently unknown if these two features are linked and consequence of common factors (like the oxidative stress), because of a great heterogeneity in the patients muscle histo-morphology, which overlaps with sedentary healthy subjects (SHS). We therefore tested whether the clustering of COPD patients and SHS would reveal reductions in fiber CSA and type I proportions in distinct or same sub-groups. Then, we aimed to model the occurrence of fiber atrophy and/or reduced type I fiber proportion in a decision tree.

Principal component analysis of functional and histo-morphological muscle parameters revealed two clusters of COPD patients. As compared with the two clusters of SHS, both clusters had a reduction in the type I fiber proportion (p<0.05). Reduced fiber CSA and increased protein carbonylation were found only in the most severe cluster of patients (p<0.05). Yet, clusters of patients had the same age (60.4±8.8 yrs vs. 60.8±9.0 yrs; p=0.87). Last, an algorithm including 6-minute walking distance, ventilatory threshold, and body mass index accurately classified 57% of the individuals according to fiber atrophy and/or type I fiber regression.

These clusters may indicate distinct COPD phenotypes, as they are related to clinical outcome (muscle/fiber atrophy). Moreover, patho-biological mechanism and time course may have differed in the two clusters of COPD patients. Decision trees may improve the identification of COPD patients with distinct muscle features.
Contribution of Mast Cell–Derived Interleukin‐1β to Uric Acid Crystal–Induced Acute Arthritis in Mice
Authors: Laurent L. Reber, Thomas Marichal, Jeremy Sokolove, Philipp Starkl, Nicolas Gaudenzio, Yoichiro Iwakura, Hajime Karasuyama, Lawrence B. Schwartz, William H. Robinson, Mindy Tsai, Stephen J. Galli
Journal: Arthritis & Rheumatology (2014)

Objective Gouty arthritis is caused by the precipitation of monosodium urate monohydrate (MSU) crystals in the joints. While it has been reported that mast cells (MCs) infiltrate gouty tophi, little is known about the actual roles of MCs during acute attacks of gout. This study was undertaken to assess the role of MCs in a mouse model of MSU crystal–induced acute arthritis. Methods We assessed the effects of intraarticular (IA) injection of MSU crystals in various strains of mice with constitutive or inducible MC deficiency or in mice lacking interleukin‐1β (IL‐1β) or other elements of innate immunity. We also assessed the response to IA injection of MSU crystals in genetically MC‐deficient mice after IA engraftment of wild‐type or IL‐1β –/– bone marrow–derived cultured MCs. Results MCs were found to augment acute tissue swelling following IA injection of MSU crystals in mice. IL‐1β production by MCs contributed importantly to MSU crystal–induced tissue swelling, particularly during its early stages. Selective depletion of synovial MCs was able to diminish MSU crystal–induced acute inflammation in the joints. Conclusion Our findings identify a previously unrecognized role of MCs and MC‐derived IL‐1β in the early stages of MSU crystal–induced acute arthritis in mice.
Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism
Authors: C Krupka, P Kufer, R Kischel, G Zugmaier, F S Lichtenegger, T Köhnke, B Vick, I Jeremias, K H Metzeler, T Altmann, S Schneider, M Fiegl, K Spiekermann, P A Bauerle, W Hiddemann, G Riethmüller, M Subklewe
Journal: Leukemia (2015)
Optimal videothoracoscopic approach for wedge resections in pulmonary tuberculosis (PTB)
Authors: Alexander Bazhenov, Igor Motus
Journal: European Respiratory Journal (2013)

Background. Lung resections for caseomas and localized cavities make up to 60-80% of all operations in PTB in Russia. Videoassisted thoracoscopic resections (VATSR) are the method of choice here but operating conditions are strongly dependent on the correct positions of the thoracoports and tools.  Aims. To find optimal thoracoports placement on the chest wall for performing VATSR according to the evaluation criteria of surgical approaches quality.  Methods. The search of some variants of thoracoport placement points between III-VI intercostal spaces(IS), anterior axillary line(AAL) and posterior axillary line(PAL) was carried out on 50 cadavers. We measured and compared: operational action angles, wound depth, endosurgical operational actions’ angles, distance between thoracoports, angle of operational action axis’s inclination. All of these parameters can be integrate to one – working pyramid.  Results. Points at III, V IS on AAL and VI IS on PAL were found to be optimal approach for wedge resections in PTB according to criteria described above. We operated on 63 patients strictly following these parameters. This working pyramid covered operating space for adhesions dissection, resection and hemostasis. Lack of conversion to thoracotomy, compared to 8.9% of conversion rate (p  Conclusions: VATSR in PTB meets all requirements for PTB surgery under proper choice of the approach.
RCT of chest physiotherapy versus chest physiotherapy and pulmonary rehabilitation in non cystic fibrosis bronchiectasis
Authors: Pallavi Mandal, Manjit Sidhu, Lian Kope, Wendy Pollock, Lorna Stevenson, Shelley MacQuarrie, Kim Turnbull, Joanna Pentland, Adam Hill
Journal: European Respiratory Journal (2012)

Aim

To assess the efficacy of pulmonary rehabilitation(PR) in addition to regular chest physiotherapy in non-cystic fibrosis bronchiectasis.

Methods

Patients with bronchiectasis were invited to participate if their exercise tolerance was limited, due to bronchiectasis, from Edinburgh Bronchiectasis clinic, in a prospective study.15 received chest physiotherapy and 15 received PR+chest physiotherapy. Review was at baseline/4 weeks/8weeks(end of intervention)and 20 weeks(completion of study). Outcome measures were improvement in incremental shuttle walking test(ISWT), endurance walk test(EWT), health related quality of life(HRQoL)-St.Georges Questionnaire(SGRQ) and Leicester Cough Questionnaire(LCQ).

Results

Results are presented as mean(standard error). The minimum clinically important difference(MCID) for SGRQ and LCQ was 4 and 1.3 units respectively. Comparison of changes between the 2 groups was calculated using unpaired t-tests.

View this table:



Conclusion

PR in addition to regular chest physiotherapy, improves exercise tolerance and HRQoL in bronchiectasis and the benefit was sustained at 3months post end of PR.
Abstract 19406: Fusion of Coronary Anatomy from Computed Tomography with Left Ventricular Strain Function from 3D Echocardiography
Authors: Francesco Maffessanti, Victor Mor-Avi, Karima Addetia, Gillian Murtagh, Lynn Weinert, Rolf Baumann, Amit R patel, Roberto M Lang
Journal: Circulation (2014)

Introduction: Cardiac multimodality imaging offers novel ways to display composite information not available with any of the imaging modalities alone. We tested the feasibility of fusion of coronary anatomy and left ventricular (LV) strain, as index of LV function, obtained from computed tomography (CT) and 3D echocardiography (3DE), respectively.

Methods: We enrolled 17 patients undergoing CT coronary angiography and transthoracic 3DE imaging on the same day. CT images were acquired according to standard clinical protocol at 78% of the cardiac cycle (Philips 256-slice). Apical full-volume 3DE images were acquired (Philips iE33). Images were analyzed off-line using dedicated workstations: CT to isolate the coronary tree (Philips) and 3DE to derive a dynamic LV endocardial surface (TomTec) and maps of 3D longitudinal (LS) and radial (RS) strain. Custom software was used to co-register LV surfaces and CT coronary tree, minimizing the distance between corresponding anatomic landmarks, and to map peak systolic values of LS and RS on the 3D endocardial shells.

Results: Three patients were excluded because of the suboptimal quality of the coronary CT (feasibility 88%). The composite display of coronary arteries and parametric images depicting strain abnormalities yielded an identification of the functional significance of the stenosis when present. While patients with normal coronary arteries had uniform parametric images of wall motion, those with significant stenosis (N=3/17), had wall motion abnormality in the area supplied by the stenosed artery (Figure).

Conclusions: The results of this pilot study indicate that fusion of CT coronary angiography and 3DE derived strain is feasible, potentially providing physiologically meaningful and easy-to-interpret combined display of coronary abnormalities and their functional impact. The proposed approach is versatile, as it allows fusion of coronary anatomy with a variety of parameters of cardiac mechanics.

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Radiation-associated breast cancer after Hodgkin's disease: risks and screening in perspective.
Authors: C L Shapiro, P M Mauch
Journal: Journal of Clinical Oncology (1992)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1992.10.11.1662 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 1403048 Radiation-associated breast cancer after Hodgkin's disease: risks and screening in perspective. C L ShapiroxC L ShapiroSearch for articles by this author , P M MauchxP M MauchSearch for articles by this author https://doi.org/10.1200/JCO.1992.10.11.1662 First Page PDF © 1992 by American Society of Clinical Oncology
Pulmonary actinomycosis: Successful treatment with oral antibiotics
Authors: Nicole Skehan, David Walter, Raja Reddy
Journal: European Respiratory Journal (2013)

Endobronchial actinomycosis is a rare but important differential of exophytic endobronchial tumors. We report the case of an 84 year old woman presenting with a 1 year history of productive cough, haemoptysis and weight loss. Computed tomography (CT) revealed complete right upper lobe obstruction with secondary bronchiectasis. Bronchoscopy showed an exophytic tumour. Histology showed filamentous bacteria consistent with actinomycosis. The patient refused intravenous (IV) antibiotics for personal reasons and was commenced on oral doxycycline 200mg daily due to multiple antibiotic allergies. At 3 month follow up there was significant clinical and radiological improvement. Subsequent CT chest showed resolution of the endobronchial lesion with persistence of the distal bronchiectasis.  Endobronchial actinomyces is usually caused by aspirated oropharyngeal secretions, hence a predilection for the dependent lobes and rarely upper lobe involvement. Treatment of choice is penicillin G IV followed by oral antibiotics but actinomyces also sensitive to a number of other antibiotics. Traditionally treatment required prolonged courses of IV antibiotics, stemming from an era when disease was advanced at presentation. But recent reports have shown good responses with short courses. A significant number of cases are associated with a foreign body or broncholithiasis; removal is key for successful treatment. A follow up bronchoscopy is important to confirm resolution. Our patient refused, but had a reconstructed CT bronchoscopy which confirmed resolution.  Treatment duration should be tailored to the individual, shorter antibiotic courses appear to be adequate in those with low infection burden like endobronchial actinomycosis.
12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression)
Authors: G I Keitner, C E Ryan, I W Miller, R Kohn, N B Epstein
Journal: American Journal of Psychiatry (1991)

Inpatients with major depressive illness often have coexistent nonaffective psychiatric and/or medical conditions. The authors' objective is to address the following questions: 1) What is the effect of comorbid illness on the severity of major depression and associated psychosocial factors? 2) How does the course of depression differ for patients with and without concurrent illness? 3) Do patients with compound depression differ in rate of recovery and time to recovery from patients with pure depression? The subjects were 78 patients with a DSM-III diagnosis of major depression who were consecutively admitted to an acute care university-affiliated psychiatric hospital; 37 of these patients had major depression only and 41 had major depression compounded by a coexisting axis I, II, or III condition. The patients were studied while hospitalized and for 12 months after hospital discharge. Instruments used included the Modified Hamilton Rating Scale for Depression, the Global Assessment Scale, and the Social Readjustment Rating Scale. Patients with compound depression reported significantly poorer functioning over the 12-month follow-up period and had lower recovery rates than the patients with pure depression. There were no differences in recovery rates between men and women with compound depression, but significantly more men than women with pure depression recovered. Compound depression is a common clinical occurrence, the course of illness is more difficult for patients with compound depression than for patients with pure depression, and the recovery rate of patients with compound depression is lower than that of patients with pure depression.
Modafinil does enhance cognition, review finds
Authors: Nigel Hawkes
Journal: BMJ (2015)

A drug developed to treat narcolepsy may be the world’s first safe “smart drug,” say researchers from Oxford and Harvard Universities who have carried out a systematic review of the evidence.1

Modafinil has had a long under-the-counter career among students and academics who claim that it can increase their mental sharpness. As long ago as 2008 the journal Nature invited its readers to own up if they had used cognition enhancing drugs, and one fifth said that they had. Modafinil had been used by 44% of these, who cited improving concentration as the most popular reason.2

The new review, published in European Neuropsychopharmacology ,1 showed that they may have been right. Ruairidh Battleday and Anna-Katharine Brem found 24 randomised controlled trials published from …