tbuckley/cabot-search huggingface dataset:
A case series of fidaxomicin for treatment of Clostridium difficile infection (CDI) in lung transplant (LTx) recipients
Authors: Tobias Welte
Journal: European Respiratory Journal (2014)

Introduction: 

Post-operative bacterial infections are common in LTx recipients. Antibiotic therapies are often administered for prolonged periods and, consequently, CDI is a known complication in these patients. Fidaxomicin (FDX) is approved for treatment of CDI and clinical trials show FDX to be non-inferior to vancomycin in clinical cure and superior in preventing recurrent CDI. This case series presents first experience with FDX in a German LTx follow-up clinic.

Methods: 

Hannover has the largest LTx program in Europe with more than 140 transplants performed each year. In this study, 27 CDI episodes in LTx patients were prospectively recorded from 2005–2013 Metronidazole (MET) 500 mg tid or vancomycin (VAN) 250 mg qid was used as initial therapy. In recurrent CDI, the VAN dose was increased to 500 mg and, since 2012, FDX 200 mg bid has been used.

Results: 

11 cases (40%) of recurrent CDI were observed. One patient died from intra-abdominal sepsis. Five cases of FDX treatment were recorded. In all FDX cases, symptoms ceased within 7 days and no further CDI was reported. No significant adverse events were observed.

Discussion: 

CDI is an important risk factor in patients after LTx due to frequent antibiotic therapy. FDX is an effective treatment option for LTx patients with recurrent CDI.

View this table:

FDX therapy for CDI
Changes in respiratory symptoms and airway hyperresponsiveness after 27 years in a population-based sample of school children
Authors: A de Gooijer, P L Brand, J Gerritsen, G H Koëter, D S Postma, K Knol
Journal: European Respiratory Journal (1993)

We wanted to test the hypothesis that childhood airway hyperresponsiveness, even in the absence of respiratory symptoms, is a risk factor for respiratory disease in adulthood. In a childhood survey of 1963, three groups of 20 children aged 8-11 yrs, were selected from a population sample: 1) a group with recurrent respiratory symptoms (symptomatic group); 2) a group with no symptoms but a positive family history of atopy; and 3) a control group. All children completed assessment of symptoms, atopy, lung function, and airway hyperresponsiveness. At the adulthood survey 27 yrs later, 85% of the original sample were reinvestigated. Only 10 out of 19 subjects (53%) of the original symptomatic group still had symptoms. The significant difference of forced expiratory volume in one second (FEV1) % predicted in childhood between the symptomatic and the control group had disappeared. The prevalence of airway hyperresponsiveness had decreased in all groups. In asymptomatic hyperresponders it had normalized at adult age. The asymptomatic hyperresponders in childhood had lower levels of lung function, both in childhood and in adulthood. In univariate and multivariate analyses, respiratory symptoms at adult age were related to childhood atopy. Results suggest that childhood atopy is a risk factor for respiratory symptoms in young adulthood, but that mild childhood airway hyperresponsiveness is not.
Abstract 96: Epigenetic And Transcriptional Regulation Of Induced Pluripotent Stem Cells In Patients With Hypoplastic Left Heart Syndrome
Authors: Junko Kobayashi, Masashi Yoshida, Suguru Tarui, Shuta Ishigami, Michihiro Okuyama, Shingo Kasahara, Hiroshi Ito, Shunji Sano, Hidemasa Oh
Journal: Circulation Research (2014)

Background: Although a number of studies have uncovered heterozygous mutations in cardiac regulatory genes caused hypoplastic left heart syndrome (HLHS), the identified genetic variants may not be directly correlated with the disease development. The aim of this study is to determine the epigenetic and transcriptional network responsible for myocardial patterning and morphogenesis during cardiac development in HLHS by using patient-derived induced pluripotent stem (iPS) cells. Methods: Five-independent iPS cell lines were generated from HLHS and biventricle (BV) heart-derived cardiac progenitor cells (CPCs). Global gene expression analysis, real-time RT-PCR, mutation analysis, ChIP assay, and cardiac-specific gene promoter activities were examined during differentiation. Results: We found one synonymous single nucleotide polymorphism in NKX2-5 and five in NOTCH1, respectively. Cardiac transcriptional factors such as NKX2-5, HAND1, and NOTCH/HEY, those are known to drive primary heart field and outflow tract development, were significantly reduced in HLHS-derived iPS cells after differentiation compared with BV- and control 201B7 iPS-derived cardiomyocytes. ChIP assay showed that a marked decrease in dimethylated histone H3-lysine 4 and acetylated histone H3 was found within the NKX2-5 promoter regions, whereas a significantly increased trimethylated H3-lysine 27 was identified in differentiated HLHS-derived iPS cells. To specify the target transcripts responsible for cardiac development of HLHS, cardiac troponin-T and natriuretic peptide A promoter analyses were performed. We found that both promoter activities were significantly suppressed in HLHS-derived CPCs and iPS cells compared with those from BV hearts. These repressed promoter activities could be fully restored by transient transfection of NKX2-5, HAND1, and NOTCH1 genes into these stem/progenitor cells by synergistic manner. Conclusions: These findings suggest that patient-specific iPS cells provide a potential to dissecting the complex cardiac malformations in human. The epigenetic and transcriptional regulation of NKX2-5, HAND1, and NOTCH1 may mutually participate in the development of myocardial growth, patterning, and morphogenesis in HLHS.
Prediction of new-onset wheeze based on serum inflammation biomarkers - Evaluation using univariate and multivariate techniques
Authors: Mona Lärstad, Mats Josefson, Kjell Torén, Anna-Carin Olin
Journal: European Respiratory Journal (2012)

Asthma is associated with inflammation in the airways and wheeze. The hypothesis is that increased levels of inflammation biomarkers among subjects without respiratory symptoms are a sign of subclinical airways inflammation.  Objective: To evaluate if increased levels of inflammation biomarkers in serum predicts later onset of wheeze.  Methods: We followed up 2,200 subjects from a general population-based study. At baseline, the subjects were investigated with questionnaires, blood samples, spirometry and FENO. All subjects reporting tobacco smoking, wheeze, asthma, asthma symptoms, or CRP >5 at baseline were excluded. Four years later all subjects got a respiratory questionnaire, which 86.2% completed. The association between baseline levels of a panel of cytokines in serum and incident wheeze was evaluated using non-parametric statistical methods and orthogonal projection to latent structures - discriminant analysis (OPLS-DA). Subjects with FENO levels between the 45th percentile and the 55th percentile served as controls (n=101), and were compared to subjects with new-onset wheeze (n=29).  Results: The median levels of TNF, IL-1, IL-2, IL-4 and IL-12 at baseline were significantly higher among those with new-onset wheeze (p  Conclusions: Our results indicate that the levels of serum inflammation biomarkers in respiratorily healthy subjects were associated with an increased risk of developing wheeze.
The distribution of hepatitis B virus exposure and infection in a population‐based sample of U.S. Hispanic adults
Authors: Molly Jung, Mark H. Kuniholm, Gloria Y.F. Ho, Scott Cotler, Howard D. Strickler, Bharat Thyagarajan, Marston Youngblood, Robert C. Kaplan, Julia del Amo
Journal: Hepatology (2015)

Little is known regarding the prevalence and distribution of hepatitis B virus (HBV) infection in U.S. Hispanics/Latinos. We sought to determine the prevalence of HBV exposure (serum HBV core antibody; anti-HBc), active HBV infection (serum HBV surface antigen; HBsAg), and vaccine-induced HBV immunity (antibody against HBV surface antigen; anti-HBs) in U.S. Hispanics/Latinos and consider how these data inform clinical screening recommendations. Our analysis included 11,999 women and men of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based, household survey in four urban communities (Bronx, NY; Miami, FL; Chicago, IL; and San Diego, CA) of U.S. civilian, noninstitutionalized self-identifying Hispanic/Latino adults ages 18-74. Vaccine-induced immunity was defined as detection of anti-HBs, but not anti-HBc. However, if anti-HBc were present, it was considered evidence of exposure to HBV, with detection of HBsAg used to distinguish those with active HBV infection. Mean age was 45.7 years, and 7,153 were women. Vaccine-induced immunity was greatest among those ages 18-29 years (60.2% in women, 54% in men) and decreased with increasing age, regardless of country of birth. The prevalence of active HBV infection was 0.29% (95% confidence interval: 0.19-0.43), but varied by country of birth. Those born in the Dominican Republic had the highest prevalence of HBV exposure (20.3% in women, 29.7% in men) and active HBV infection (0.95%).
Platelet Membrane Defects in Glanzmann's Thrombasthenia
Authors: David R. Phillips, Patricia Poh Agin
Journal: Journal of Clinical Investigation (1977)

Platelets from patients with Glanzmann's thrombasthenia have a distinct molecular alteration of the plasma membrane surface, namely decreased amounts of a major glycoprotein designated as IIb (apparent mol wt 142,000). To identify other possible surface defects of thrombasthenic platelets, we labeled the membrane polypeptides of normal and thrombasthenic platelets by two different techniques: lactoperoxidase-catalyzed iodination and galactose oxidase oxidation, followed by reduction with tritiated sodium borohydride. Labeling patterns were determined after the polypeptides were separated by two-dimensional polyacrylamide gel electrophoresis. Before the second dimension was run, platelet samples were incubated with a reducing agent, β-mercapto-ethanol, to cleave the disulfide bonds of certain glycoproteins; the resulting changes in electrophoretic mobility permitted better resolution of individual molecules. Comparison of the labeled polypeptides of normal and thrombasthenic samples after reduction indicated decreased labeling of two major glycoproteins in thrombasthenic platelets: IIb and III (apparent mol wt 114,000). The relative proportions of radioactivity incorporated by these polypeptides were about 60 and 80% less than control values, respectively. With either Coomassie Blue or periodic acid-Schiff's reagent, glycoprotein III stained much less intensely in thrombasthenic compared to normal samples, indicating that the observed labeling deficit was caused by a decreased concentration of the molecule rather than steric inaccessibility on the membrane surface. Analysis of normal plasma membranes by affinity chromatography showed that glycoprotein IIb has receptors for lectin from Lens culinaris, the common lentil, whereas III does not. We conclude that a characteristic feature of Glanzmann's thrombasthenia is a decreased concentration of two discrete glycoproteins in the platelet plasma membrane.
Operation Everest III (Comex '97): Modifications of Cardiac Function Secondary to Altitude-induced Hypoxia
Authors: ALAIN BOUSSUGES, FLORENCE MOLENAT, HENRI BURNET, EMMANUEL CAUCHY, BERNARD GARDETTE, JEAN-MARIE SAINTY, YVES JAMMES, JEAN-PAUL RICHALET
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

During Operation Everest III (Comex '97), to assess the consequences of altitude-induced hypoxia, eight volunteers were decompressed in a hypobaric chamber, with a decompression profile simulating the climb of Mount Everest. Cardiac function was assessed using a combination of M-mode and two-dimensional echocardiography, with continuous and pulsed Doppler at 5,000, 7,000, and 8,000 m as well as 2 d after return to sea level (RSL). On simulated ascent to altitude, aortic and left atrial diameters, left ventricular (LV) diameters, and right ventricular (RV) end-systolic diameter fell regularly. Heart rate (HR) increased at all altitudes accompanied by a decrease in stroke volume; in total, cardiac output (Q˙) remained unchanged. LV filling was assessed on transmitral and pulmonary venous flow profiles. Mitral peak E velocity decreased, peak A velocity increased, and E/A ratio decreased. Pulmonary venous flow velocities showed a decreased peak D velocity, a decreased peak S velocity, and a reduction of the D/S ratio. Systolic pulmonary arterial pressure (Ppa) showed a progressive and constant increase, as seen on the elevation of the right ventricular/right atrial (RV/RA) gradient pressure from 19.0 ± 2.4 mm Hg at sea level up to 40.1 ± 3.3 mm Hg at 8,000 m (p < 0.05), and remained elevated 2 d after recompression to sea level (SL) (not significant). In conclusion, this study confirmed the elevation of pulmonary pressures and the preservation of LV contractility secondary to altitude-induced hypoxia. It demonstrated a modification of the LV filling pattern, with a decreased early filling and a greater contribution of the atrial contraction, without elevation of LV end-diastolic pressure. Boussuges A, Molenat F, Burnet H, Cauchy E, Gardette B, Sainty J-M, Jammes Y, Richalet J-P. Operation Everest III (Comex '97): modifications of cardiac function secondary to altitude-induced hypoxia. An echocardiographic and Doppler study.
Granzyme B expression in lung of fatal asthmatics
Authors: Yvonne Nussbaumer-Ochsner, Luiz Silva, Annemarie van Schadewijk, Marisa Dolhnikoff, Thais Mauad, Klaus Rabe, Pieter Hiemstra
Journal: European Respiratory Journal (2011)

Introduction:  Granzymes are serine proteases mainly produced by CD8 and NK cells, and are involved in the pathogenesis of many inflammatory disorders. Granzyme B (GzmB) is released towards target cells, but can also be released nonspecifically and is capable of cleaving extracellular matrix (ECM) components contributing to ECM degradation and remodeling in chronic inflammation. Recent studies have also shown participation of GzmB in allergic inflammation, but there are no descriptions of the its expression in fatal asthmatics.   Methods:  We studied large and small airways and lung parenchyma of 12 patients that died of fatal asthma (FA) and 8 controls (CTR). Using image analysis we measured the number of GzmB positive cells in the inner layer (IL), smooth muscle (SM) and outer layer (OL) of both large (LA) and small airways (SA) and in peribronchiolar (PS) and distal (DS) alveolar septa. Values [median (IQR)] were expressed as GmzB+ cells/BM length (cells/mm) in OL and IL, GmzB+ cells/SM area (cells/mm 2 ) in SM, and as GmzB+ cells/septal length (cells/μm) in PS and DS.   Results:  In LA we found a higher number of GmzB+ cells in IL [FA=12.9 (5.1), CTR=5.8 (3.1), p=0.02)] and OL ([FA=27.2 (9.3), CTR=7.5 (2.4), p=0.001)] in FA, but no differences were observed in SM. In SA, the number of GmzB+ cells was also higher in IL [FA=8.3 (4.4), CTR=2.8 (1.8), (p=0.03)] and OL [FA=15.9 (5.3), CTR=5.2 (4.1), (p=0.002)] in FA, but no differences were observed in SM. In the parenchyma, there was a higher number of GmzB+ cells in PS of FA comparing to CTR (p=0.02), but no differences were observed in DS.   Conclusion:  The results show that GzmB expression is increased in FA and may contribute to the previously described process of airway remodeling in these patients.
Improvement in COPD symptoms with aclidinium bromide vs placebo and tiotropium: A phase IIIb study
Authors: Jutta Beier, Anne-Marie Kirsten, Robert Mróz, Rosa Segarra, Ferran Chuecos, Cynthia Caracta, Esther Garcia Gil
Journal: European Respiratory Journal (2013)

Background: The efficacy and safety of aclidinium bromide vs tiotropium and placebo in COPD has been evaluated in a randomized, double-blind, Phase IIIb study.

Aim: To report additional endpoints capturing the effect of treatment on COPD daily symptoms.

Methods: 414 patients with COPD (FEV1 1.6 L; 56% predicted) received aclidinium bromide 400 µg BID (metered dose; equivalent to aclidinium 322 µg delivered dose), tiotropium 18 µg QD or placebo for 6 weeks. Symptoms were assessed daily with the EXACT-Respiratory Symptoms (E-RS) and COPD additional symptoms questionnaires. Relief medication use was assessed.

Results: Results are summarized (Table).

View this table:

Change from baseline (difference vs placebo) over 6 weeks





Conclusions: Aclidinium provides significant COPD daily symptom improvement vs placebo, including less severe early-morning and night-time symptoms, and a greater number of relief medication-free days. Improvements were consistently numerically greater with aclidinium vs tiotropium.
NF-κB: Regulation by Methylation
Authors: Tao Lu, George R. Stark
Journal: Cancer Research (2015)

Abstract In normal cells exposed to stress, the central transcription factor NF-κB is activated only transiently, to modulate the activation of downstream immune responses. However, in most cancers, NF-κB is abnormally activated constitutively, contributing thus to oncogenesis and tumor progression. Therefore, downregulating NF-κB activity is an important goal of cancer treatment. In order to control NF-κB activity therapeutically, it is helpful to understand the molecular mechanisms that normally govern its activation and how dysregulated NF-κB activity may aid the development of disease. Recent evidence from our laboratories and others indicates that, in addition to various posttranslational modifications of NF-κB that have been observed previously, including phosphorylation, ubiquitination, and acetylation, NF-κB can be methylated reversibly on lysine or arginine residues by histone-modifying enzymes, including lysine and arginine methyl transferases and demethylases. Furthermore, these methylations are required to activate many downstream genes. Interestingly, amplifications and mutations of several such enzymes have been linked to cancer. We propose that some of these mutations may alter the methylation not only of histones but also of NF-κB, making them attractive therapeutic targets. Cancer Res; 75(18); 3692–5. ©2015 AACR.
Exacerbations in patients with chronic obstructive lung disease (COPD) and concomitant asthma
Authors: Galina Sergeeva, Alexander Emelyanov, Oxana Korovina, Antonina Znakhurenko, Eugenia Leshenkova
Journal: European Respiratory Journal (2014)

The aim of this study was to investigate frequency and severity of exacerbations in patients with COPD and concomitant asthma during 3 yr follow-up.  Methods: Ninety four outpatients (62% male) with COPD (aged 41 - 82 yrs, mean age 61 yrs) were treated by long-acting bronchodilators ± ICS for 3 yrs. Concomitant asthma was diagnosed in 44% patients (COPD+asthma). These patients were more often females (67% vs 20%, p  Results: Baseline frequency of exacerbations per year in COPD+ asthma group was higher than in COPD-asthma (1.9 vs 1.5, p 0.05) in patients with COPD+ asthma, while was reduced in patients with COPD alone (1.5 vs 0.6, p 0.05).  Conclusion: combination of COPD with asthma was associated with more frequent exacerbations, increased the use of antibiotics and systemic corticosteroids. These patients may require regular treatment with higher doses of ICS and long-acting bronchodilators.
Nephrogenic systemic fibrosis is found only among gadolinium‐exposed patients with renal insufficiency: a case–control study from Denmark
Authors: T.R. Elmholdt, M. Pedersen, B. Jørgensen, K. Søndergaard, J.D. Jensen, M. Ramsing, A.B. Olesen
Journal: British Journal of Dermatology (2011)

Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease associated with exposure to gadolinium-based contrast agents (GBCA) in patients with renal insufficiency.To report the prevalence of NSF in a well-defined cohort of patients with renal insufficiency exposed to GBCA, to investigate if GBCA-unexposed controls showed signs of NSF and to evaluate selected risk factors among NSF cases and GBCA-exposed controls.A study among GBCA-exposed patients with renal insufficiency (n=565) was conducted to identify cases of NSF. The NSF cases found were age and sex matched and clinically compared with GBCA-exposed and unexposed patients with renal insufficiency in a case-control study.We identified 17 NSF cases. No signs of NSF were observed among the controls. The prevalence of NSF was 4·7%, highest among patients with chronic kidney disease (CKD) stage 5 exposed to GBCA and undergoing haemodialysis or peritoneal dialysis. Three NSF cases were identified among patients with CKD stage 3 and 4. Three patients developed NSF after macrocyclic GBCA exposure. NSF cases had a tendency to have higher serum phosphate concentrations than GBCA-exposed controls.Our study supports the view that GBCA is a major risk factor for NSF. Importantly, we found that patients with CKD stage 3 and 4 can be at risk of NSF. NSF may also be triggered by macrocyclic GBCA. Further, we observed a trend for higher phosphate levels in NSF cases compared with controls. The important findings drawn from this case-control study indicate that NSF is not an overlooked condition among patients with renal insufficiency not exposed to GBCA.
Neoadjuvant Chemotherapy and Extrapleural Pneumonectomy (Epp) of Malignant Pleural Mesothelioma (Mpm) with or Without Hemithoracic Radiotherapy: Final Results of the Randomized Multicenter Phase Ii Trial Sakk17/04
Authors: R.A. Stahel, O. Riesterer, X. Alexandros, I. Opitz, M. Beyeler, A. Ochsenbein, M. Früh, R. Cathomas, K. Nackaerts, S. Peters, C. Mamot, A. Zippelius, C. Mordasini, K. Clemens, K. Eckhardt, R. Schmid, W. Nagel, D. Aebersold, O. Gautschi, W. Weder
Journal: Annals of Oncology (2014)
Sequential infusion of donor‐derived dendritic cells with donor lymphocyte infusion for relapsed hematologic cancers after allogeneic hematopoietic stem cell transplantation
Authors: Vincent T. Ho, Haesook T. Kim, Grace Kao, Corey Cutler, James Levine, Jacalyn Rosenblatt, Robin Joyce, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz, David Avigan, Edwin P. Alyea
Journal: American Journal of Hematology (2014)

Donor lymphocyte infusion (DLI) is often given to induce a graft‐versus‐leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (HSCT). However, efficacy of DLI is limited in most hematologic cancers. As antigen presenting cells, dendritic cells (DC) bolster immune responses. We conducted a Phase I trial testing the coinfusion of DC followed by DLI. DC were generated by culturing peripheral blood mononuclear cells from HLA matched‐related donors in GM‐CSF and IL‐4 for 7 days, followed by TNF‐α for 3 days. DC were administered intravenously on 3 dose levels (5 × 10 6 ; 1 × 10 7 ; 5 × 10 7 cells). DLI (3 × 10 7 CD3+ cells/kg) was administered intravenously 1 day after the DC. Sixteen patients with hematologic cancers relapsed after HSCT were treated. A maximum tolerated dose for DC was not reached. Two of 16 patients met criteria for DLT within 10 weeks of the infusion: 1 idiopathic respiratory failure, 1 ventricular cardiac arrest. None developed grade III/IV GVHD. One patient developed grade II acute intestinal graft‐vs.‐host disease (GVHD) and 1 chronic GVHD within 6 months of the infusion. Both resolved with corticosteroids. Four of 14 patients evaluable for disease response achieved durable remissions and are alive and cancer free 6.7, 8.4, 8.8, and 10.1 years from infusion. Sequential infusion of donor‐derived DC with DLI is feasible in patients with relapsed hematologic cancers after allogeneic HSCT. Future studies may consider donor DC preloaded with tumor antigens to investigate whether DC infusion could augment the GVL effect. Am. J. Hematol. 89:1092–1096, 2014. © 2014 Wiley Periodicals, Inc.