tbuckley/cabot-search huggingface dataset:
Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study
Authors: Mickael Basson, Myriam Mezzarobba, Alain Weill, Philippe Ricordeau, Hubert Allemand, Francois Alla, Franck Carbonnel
Journal: Gut (2015)

<h3>Objectives</h3> Severe sprue-like enteropathy associated with olmesartan has been reported, but there has been no demonstration of an increased risk by epidemiological studies. <h3>Aim</h3> To assess, in a nationwide patient cohort, the risk of hospitalisation for intestinal malabsorption associated with olmesartan compared with other angiotensin receptor blockers (ARB) and ACE inhibitors (ACEIs). <h3>Design</h3> From the French National Health Insurance claim database, all adult patients initiating ARB or ACEI between 1 January 2007 and 31 December 2012 with no prior hospitalisation for intestinal malabsorption, no serology testing for coeliac disease and no prescription for a gluten-free diet product were included. Incidence of hospitalisation with a discharge diagnosis of intestinal malabsorption was the primary endpoint. <h3>Results</h3> 4 546 680 patients (9 010 303 person-years) were included, and 218 events observed. Compared with ACEI, the adjusted rate ratio of hospitalisation with a discharge diagnosis of intestinal malabsorption was 2.49 (95% CI 1.73 to 3.57, p&lt;0.0001) in olmesartan users. This adjusted rate ratio was 0.76 (95% CI 0.39 to 1.49, p=0.43) for treatment duration shorter than 1 year, 3.66 (95% CI 1.84 to 7.29, p&lt;0.001) between 1 and 2 years and 10.65 (95% CI 5.05 to 22.46, p&lt;0.0001) beyond 2 years of exposure. Median length of hospital stay for intestinal malabsorption was longer in the olmesartan group than in the other groups (p=0.02). Compared with ACEI, the adjusted rate ratio of hospitalisation for coeliac disease was 4.39 (95% CI 2.77 to 6.96, p&lt;0.0001) in olmesartan users and increased with treatment duration. <h3>Conclusions</h3> Olmesartan is associated with an increased risk of hospitalisation for intestinal malabsorption and coeliac disease.
Decreased Abundance of Collecting Duct Aquaporins in Post-Ischemic Renal Failure in Rats
Authors: PATRICIA FERNÁNDEZ-LLAMA, PETER ANDREWS, RACHEL TURNER, SUBODH SAGGI, JOHN DIMARI, TAE-HWAN KWON, SØREN NIELSEN, ROBERT SAFIRSTEIN, MARK A. KNEPPER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Increased urine flow is often a feature of mild to moderate acute renal failure. This study examines the possible role of dysregulation of collecting duct aquaporins as a factor in this increase. In rats, the left renal pedicle was clamped for 45 min followed by contralateral nephrectomy. Control rats were identical except that the renal pedicle was not clamped. Rats were sacrificed and the kidneys were homogenized at various time points after release of the clamp for semiquantitative immunoblotting of collecting duct aquaporins, as well as the thick ascending limb Na-K-2Cl cotransporter and the proximal tubule water channel, aquaporin-1. Urinary flow rate was significantly increased 18 h after the ischemic insult and remained increased through 72 h. Whole kidney aquaporin-2 protein abundance was 45% of controls at 18 h, 55% of controls at 36 h, and returned to normal 72 h after ischemia. Whole kidney aquaporin-3 protein abundance was 37% of controls at 18 h, 13% of controls at 36 h, and 45% of controls at 72 h. The decline in aquaporin-2 and -3 was confirmed by immunocytochemistry. Abundance of the thick ascending limb Na-K-2Cl cotransporter protein was not significantly decreased. Aquaporin-1 protein abundance was not significantly decreased at 18 h after the ischemic insult, but was significantly reduced after 36 h. Thus, the post-ischemic state is associated with decreased levels of the collecting duct aquaporins, coinciding with an increase in water excretion. It is concluded that decreased aquaporin protein abundance in collecting duct cells is a contributing factor in the increased urine flow seen in moderate post-ischemic acute renal failure.
Abstract 3210: Early Invasive Management of Acute Coronary Syndromes without ST-elevation does not Improve Long-term Mortality: insights from the Randomized Trials with the most Recent Follow-up Data
Authors: Freek W Verheugt, Marc A Brouwer
Journal: Circulation (2007)

Background Randomized trials evaluating an early invasive against a conservative strategy show a benefit over a conservative approach in the composite of death, MI and revascularisation/recurrent ischemia. However, by the necessarily open design MI and revascularisation/ recurrent ischemia are relatively weak endpoints. Since MI is both an entry criterion and an endpoint, it is difficult to evaluate, since it may be induced by intervention and, therefore, its definition in the trials is cumbersome. Thus, long-term mortality is the best outcome parameter to evaluate the above strategies. Recently, the very long follow-up data of 3 major trials RITA-3, FRISC-2 and ICTUS have been published. Methods and Results We analyzed the 9 trials carried out between 1996 and 2004, which randomized 10,558 patients with non-ST-elevation acute coronary syndromes to an early invasive or an ischemia-guided conservative strategy. F/U ranged from 6 months to 5 years with a total of 30,932 patients-years. RR for long-term mortality is for invasive versus conservative from completed follow-up data is 0.94 (95%CI 0.83–1.06, p = 0.32, see figure ). Conclusion Although most trials on non ST-elevation ACS reported a reduction in the composite of death, MI and revascularisation/recurrent ischemia, an early invasive strategy does not lead to improved survival on the very long-term. These findings should be mentioned in future guidelines.
Thyroid hormone, L-T3, stimulates the expression of the angiotensinogen gene in cultured opossum kidney (OK) cells.
Authors: J S Chan, A H Chan, Z R Nie, R Sikstrom, S Lachance, S Hashimoto, S Carrière
Journal: Journal of the American Society of Nephrology (1992)

Angiotensinogen (ANG) messenger RNA is expressed in opossum kidney (OK) proximal tubular cells. To examine whether thyroid hormone, L-T3, could stimulate the expression of the ANG gene in OK proximal tubular cells, fusion genes, consisting of various lengths of the 5'-flanking region of the rat angiotensinogen gene linked to a human growth hormone reporter gene, were constructed and introduced into OK cells. As a negative control, they were introduced into a nonkidney cell line, a human choriocarcinoma cell line (JEG-3). The level of the expression of fusion genes in these cells were determined by the level of immunoreactive human growth hormone secreted into the culture medium. The expression of ANG-growth hormone (ANG-GH) fusion genes pOGH (ANG N-1498/+18), pOGH (ANG N-688/+18), pOGH (ANG N-110/+18), pOGH (ANG N-53/+18), and pOGH (ANG N-35/+18) was 226-, 4.5-, 1.0-, 12-, and 2.5-fold higher than promoterless pOGH in the expression of growth hormone activity in OK cells. No significant expression of any of these ANG-GH fusion genes over the promoterless pOGH was observed in JEG-3 cells. The addition of L-T3 stimulates the expression of pOGH (ANG N-1498/+18) in a dose-dependent manner with a maximal and half-maximal effect at 10(-7) M and at 10(-8) to 10(-9) M, respectively. Thyroid hormone (10(-7) M) also stimulates the expression of pOGH (ANG N-688/+18) but not pOGH (ANG N-110/+18), pOGH (ANG N-53/+18), or pOGH (ANG N-35/+18).(ABSTRACT TRUNCATED AT 250 WORDS)
Mutation in WDR4 impairs tRNA m7G46 methylation and causes a distinct form of microcephalic primordial dwarfism
Authors: Ranad Shaheen, Ghada M H Abdel-Salam, Michael P. Guy, Rana Alomar, Mohamed S. Abdel-Hamid, Hanan H. Afifi, Samira I. Ismail, Bayoumi A. Emam, Eric M. Phizicky, Fowzan S. Alkuraya
Journal: Genome biology (2015)

Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity. Two presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m7G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m7G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m7G46 modification causes a growth deficiency phenotype in yeast. Our study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification.
Influenza infection of human lung macrophages increases PDL1 expression
Authors: Karl J. Staples, Ben Nicholas, C. Mirella Spalluto, Richard T. McKendry, Ratko Djukanovic, Tom M.A. Wilkinson
Journal: European Respiratory Journal (2013)

Macrophages are an important defence against influenza infection in the human lung. However infection of macrophages themselves can dysregulate cellular function contributing to secondary bacterial infections that are postulated to be the prime causes of mortality due to influenza. Recent work has shown that acute immune responses to influenza are modulated by the T cell exhaustion pathway with increased lung PD-L1 expression leading to rapid impairment of CD8+ T cell responses in a murine model 1 . The aim of the present study was to investigate how human macrophages regulate their PD-L1 expression in response to influenza infection. Human lung and monocyte-derived macrophages (MDMs) were exposed to H3N2 X31 influenza virus or UV-irradiated virus (UVX31). No infection of lung macrophages or MDM was seen upon exposure to UVX31 but incubation with X31 resulted in a mean infection rate of 18% and 29% respectively. Influenza infection significantly increased cell surface expression of PD-L1 on lung macrophages and MDM as measured by flow cytometry. Using RT-PCR, we observed an increase of PD-L1 mRNA after X31 infection suggesting that this protein is transcriptionally regulated. In addition, we saw an increase in type I interferon expression by MDMs in response to X31 infection, but no expression of IFNγ. When MDM were incubated with IFNβ, this cytokine caused increased expression of PD-L1 steady state mRNA. These data indicate that influenza-induced release of type I IFNs by macrophages regulates surface expression of PD-L1, which may predispose to secondary bacterial infection by impairing CD8 T cell function.  1. Erickson et al (2012) J Clin Invest doi: 10.1172/JCI62860.
Expiratory timing in obstructive sleep apnoeas
Authors: F Cibella, O Marrone, S Sanci, V Bellia, G Bonsignore
Journal: European Respiratory Journal (1990)

Diaphragmatic electromyogram was recorded during NREM sleep in 4 patients affected by obstructive sleep apnoea (OSA) syndrome in order to evaluate the behaviour of expiratory time (TE) in the course of the obstructive apnoea-ventilation cycle. The two components of TE, i.e. time of post-inspiratory inspiratory activity (TPIIA) and time of expiratory phase 2 (TE2) were separately analysed. TPIIA showed a short duration, with only minor variations, within the apnoea, while its duration was more variable and longer in the interapnoeic periods: the longest TPIIA values were associated with the highest inspiratory volumes in the same breaths. This behaviour seemed regulated according to the need of a more or less effective expiratory flow braking, probably as a result of pulmonary stretch receptors discharge. Conversely TE2 showed a continuous gradual modulation, progressively increasing in the pre-apnoeic period, decreasing during the apnoea and increasing in the post-apnoeic period: these TE2 variations seemed related to oscillations in chemical drive. These data show that TE in the obstructive apnoea-ventilation cycle results from a different modulation in its two components and suggest that both mechanical and chemical influences play a role in its overall duration.
Pituitary surgery for acromegaly
Authors: R N Clayton, P M Stewart, S M Shalet, J A H Wass
Journal: BMJ (1999)

The objective of treatment in acromegaly is not only to alleviate symptoms, improve quality of life, and prevent complications but also to reverse the increased (two to threefold) mortality from vascular and respiratory disease and colon cancer. That this can be achieved if “target” basal growth hormone concentrations of <5 mU/l (2.5 ng/ml) are reached has been shown,1 2 with the proviso that serum insulin-like growth factor 1 (IGF-1) values may need to be reduced to the normal age-related reference range.3 Transsphenoidal adenomectomy is the most rapid means of reducing serum growth hormone and IGF-1 in acromegaly. The question then arises of how effective surgery is at achieving the target growth hormone and IGF-1 values. Subsidiary issues are: ( a ) what determines the outcome of surgery? ( b ) what is the relapserate? ( c ) what is the complication rate? and ( d ) what is the most cost effective service provision?

Surgical outcomes in terms of safe target growth hormone concentrations have recently been reported …
Alterations in respiratory mechanics and pulmonary ventilation induced by Chlamydia psittaci
Authors: Carola Ostermann, Petra Reinhold
Journal: European Respiratory Journal (2012)

Chlamydia psittaci  ( Cp ) is capable of inducing acute pulmonary zoonotic disease (psittacosis) or persistent infection occurring in patients with pulmonary emphysema and/or COPD. To elucidate the pathogenesis of this infection, a defined respiratory model in calves was recently introduced  [1] , which resembles the situation in humans more closely than mice. This investigation was undertaken to identify pulmonary dysfunctions induced by  Cp .  Eighteen calves were inoculated with  Cp , whereas another 18 control calves received uninfected cell culture. Respiratory disorders were characterized non-invasively applying pulmonary function tests from human medicine (i.e. impulse oscillometry and capnography) to spontaneously breathing animals from 7 days before challenge until 14 days post inoculation.  Compared to control calves, calves exposed to  Cp  had significantly increased respiratory resistance at low frequencies (≤ 5 Hz), while respiratory reactance at all frequencies (3 – 15 Hz) decreased significantly, indicating that both obstructive and restrictive pulmonary disorders were induced by the pathogen. In spontaneous breathing, expiration was more impaired than inspiration. Alveolar hypoventilation was confirmed by decreased tidal volume, increased dead space ventilation, increased FRC, and decreased end-tidal CO 2 .   In conclusion,  this bovine model has been found to be suitable for studying functional host-pathogen interactions in the mammalian lung. Pulmonary dysfunctions assessed in this model provide relevant insights into the pathophysiology of acute respiratory illness induced by  Cp  .    [1]  Reinhold P.  et al.  (2012) PLoS ONE 7(1): e30125.
Deep Sequencing Reveals Occurrence of Subclonal <i>ALK</i> Mutations in Neuroblastoma at Diagnosis
Authors: Angela Bellini, Virginie Bernard, Quentin Leroy, Thomas Rio Frio, Gaelle Pierron, Valérie Combaret, Eve Lapouble, Nathalie Clement, Herve Rubie, Estelle Thebaud, Pascal Chastagner, Anne Sophie Defachelles, Christophe Bergeron, Nimrod Buchbinder, Sophie Taque, Anne Auvrignon, Dominique Valteau-Couanet, Jean Michon, Isabelle Janoueix-Lerosey, Olivier Delattre, Gudrun Schleiermacher
Journal: Clinical Cancer Research (2015)

Abstract Purpose: In neuroblastoma, activating ALK receptor tyrosine kinase point mutations play a major role in oncogenesis. We explored the potential occurrence of ALK mutations at a subclonal level using targeted deep sequencing. Experimental Design: In a clinically representative series of 276 diagnostic neuroblastoma samples, exons 23 and 25 of the ALK gene, containing the F1174 and R1275 mutation hotspots, respectively, were resequenced with an extremely high depth of coverage. Results: At the F1174 hotspot (exon 23), mutations were observed in 15 of 277 samples (range of fraction of mutated allele per sample: 0.562%–40.409%). At the R1275 hotspot (exon 25), ALK mutations were detected in 12 of 276 samples (range of fraction of mutated allele: 0.811%–73.001%). Altogether, subclonal events with a mutated allele fraction below 20% were observed in 15/27 ALK-mutated samples. The presence of an ALK mutation was associated with poorer 5-year overall survival (OS: 75% vs. 57%, P = 0.0212 log-rank test), with a strong correlation between F1174 ALK mutations and MYCN amplification being observed. Conclusions: In this series, deep sequencing allows the detection of F1174 and R1275 ALK mutational events at diagnosis in 10% of cases, with subclonal events in more than half of these, which would have gone undetected by Sanger sequencing. These findings are of clinical importance given the potential role of ALK mutations in clonal evolution and relapse. These findings also demonstrate the importance of deep sequencing techniques for the identification of patients especially when considering targeted therapy. Clin Cancer Res; 21(21); 4913–21. ©2015 AACR. See related commentary by George, p. 4747
Tolerability and adherence to sublingual immunotherapy with mite vaccines with different schedule in asthmatic children
Authors: Mirta Alvarez, Raul Castro, Mayda González, Mercedes Ronquillo, Jose Rodríguez, Maytee Mateo, Mary Carmen Reyes, Alexis Labrada
Journal: European Respiratory Journal (2014)

Introduction: In Cuba, the mite allergen vaccines of Dermatophagoides pteronyssinus, Dermatophagoides siboney and Blomia tropicalis, have been evaluated about efficacy and safety in adults, but not adherence and tolerability in children.Objective: to determine the tolerability and adherence to sublingual immunotherapy with these standardized mite allergen vaccines using two dose schedules in asthmatic children. Method: One hundred fifty allergic patients (5 to 15 years old) with mild to moderate persistent asthma attended in General Calixto Garcia University Hospital have been chosen for each treatment schedule. Two schedules of sublingual vaccines were used: scheme 1 (maximum of three daily drops in the phase of increase and maintenance, until 2000 UB) and scheme 2 (maximum of 10 daily drops and maintenance: 2 drops, the Mondays and Friday, until 20000 UB/mL). The phase of increase was used by 24 days and the one of maintenance during 253 days. Results: The treatment adherence with the scheme 2 was of 85.4%, bigger that the registered with the scheme 1 with a significant difference (p
Circulating Levels of Antioxidant Vitamins Correlate with Better Lung Function and Reduced Exposure to Ambient Pollution
Authors: Cristina Menni, Sarah J. Metrustry, Robert P. Mohney, Sean Beevers, Ben Barratt, Tim D. Spector, Frank J. Kelly, Ana M. Valdes
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

aggressive, population-wide modalities of diagnostics, treatments, and secondary prevention (11).In support of this interpretation, a TB intervention in a community of 3,000 homeless people at Burnside, Oregon, that included skin testing, radiologic and sputum examination and treatment, coupled with education and outreach, obtained an 89% drop in active disease over the first 10 years of the program (12).
Effect of Glutathione Depletion by L-Buthionine Sulfoximine on the Cytotoxicity of Cyclophosphamide in Single and Fractionated Doses to EMT6/SF Mouse Tumors and Bone Marrow&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: K Ono, D C Shrieve
Journal: JNCI Journal of the National Cancer Institute (1987)

The combined cytotoxicity of cyclophosphamide [(CYC) CAS: 50-18-0] and glutathione [(GSH) CAS: 70-18-8] depletion by buthionine sulfoximine (BSO) toward EMT6/SF tumors and mouse bone marrow was studied in male BALB/c mice. Tumor GSH was depleted to 28.7 and 7.8% of control by 1 or 2 doses of BSO (5 mmol/kg), respectively, administered ip at 12-hour intervals prior to assay. Tumor GSH could be maintained at a level 8% of control by daily dosing with BSO for 3 days. The same BSO administration schedule lowered bone marrow cell GSH to 31% of control for the 3-day period studied. Tumor growth and bone marrow cell counts were unaffected by all BSO treatments studied. However, BSO pretreatment enhanced the cytotoxicity of CYC to tumor cells, as measured by an in vitro colony-forming assay, but it did not enhance the depletion of bone marrow cells in CYC-treated mice. The magnitude of the enhancement of CYC cytotoxicity by BSO depended on the extent of GSH depletion, tumor size, and the CYC dosing schedule: Single and double doses of BSO enhanced the cytotoxicity of a single dose of CYC by factors of 1.5 and 2.0, respectively, in 7-day-old tumors, based on the dose of CYC required to produce a surviving fraction of 4 X 10(-3). The response of 9-day-old tumors to CYC suggested the presence of a subpopulation of cells that were relatively resistant to CYC. There was no evidence for this subpopulation in BSO-pretreated tumors. Multiple doses of BSO and CYC also combined to give enhanced (1.65-fold) tumor cell killing compared to tumors treated with CYC alone. The data suggest a possible role for BSO as a clinical chemosensitizer, which could be combined with fractionated doses of CYC and may be effective on small cancerous lesions.