tbuckley/cabot-search huggingface dataset:
A3.29 Micro-RNA molecules are clearly involved in pathogenesis of idiopathic inflammatory myopathy
Authors: Martina Remakova, Marek Skoda, Marketa Faustova, Lenka Plestilova, Herman Mann, Peter Novota, Jiri Vencovsky
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> MicroRNAs can regulate the gene expression and cellular functions such as cell cycle, differentiation, or apoptosis. Emerging evidence has demonstrated that miRNAs play a vital role also in the regulation of immunological functions, including the development of autoimmunity. Like in most of other autoimmune diseases, the etiopathogenesis of Idiopathic inflammatory myopathy (IIM) is also believed to be triggered by environmental factors in combination with susceptible genetic background. Beside a genetic risk located within the MHC complex, the role of epigenetic regulations including changes in miRNAs expression profiles in autoimmunity development have recently also been implicated. The aim of this study was to look for specific miRNA expression patterns in the serum, peripheral blood mononuclear cells (PBMCs) and muscle biopsies of patients suffering from idiopathic inflammatory myopathy. <h3>Materials and Methods</h3> RNA was isolated from serum, PBMCs and muscle biopsy samples of patients suffering from IIM using modified Trizol-chloroform method. The expression profile of miRNAs was determined by 60K high density microarray from Agilent Company. <h3>Results</h3> In total, 87 miRNAs were found to be differentially expressed at a significant level (p&lt;0.05) in serum samples of patients with IIM. Under the same conditions for comparison, 14 miRNAs were differentially expressed in PBMCs (p&lt;0.05) and 78 miRNAs in muscle biopsies (p&lt;0.05). What more, the expression of 10 miRNA molecules have shown the same expression regulation among either serum and muscle biopsy, or PBMCs and muscle biopsy samples. Nine of them were upregulated in serum and muscle biopsy samples; one of them was upregulated in PBMCs and biopsy samples. Beside this concordance, we could see significant differences in expression between patients and controls in all of these 10 miRNA molecules (p&lt;0.05). <h3>Conclusions</h3> This is the first study providing information about complete expression profile of miRNA molecules found in the serum, PBMCs and muscle biopsy samples of patients with IIM. We have found that a number of miRNAs were differentially expressed in diverse tissue samples indicating tissue specific expression of miRNAs. The "missregulated" miRNAs might potentially act as biomarkers of initiated systemic inflammatory response, or functional molecules related to muscle tissue injury, or molecules involved in regulation of immune response. <h3>Acknowledgement</h3> This study was supported by the Internal Grant Agency of the Ministry of Health in the Czech Republic [MZČR NT 12452-4], Institutional support of MHCR VZ (00023728) and The Charles University Grant Agency (No.621812).
Cell-Specific Transcriptional Regulation of Human Leukotriene B4 Receptor Gene
Authors: Kazuhiko Kato, Takehiko Yokomizo, Takashi Izumi, Takao Shimizu
Journal: The Journal of Experimental Medicine (2000)

Leukotriene B4 (LTB4) is a lipid mediator that activates leukocytes and is involved in host defense and inflammation. BLT1, a high-affinity receptor for LTB4 (originally termed BLT), is expressed exclusively in inflammatory cells and is inducible in macrophages upon activation. The mechanisms of tissue-specific expression and induction of BLT1 are important for the understanding of mechanism of onset and the potential treatment of inflammatory disorders. Here, we report the genomic structure and a promoter analysis of the human BLT1 gene, with an emphasis on the mechanism of cell-specific transcription. No TATA or CAAT elements exist around the transcription initiation sites, but a GC-rich sequence is observed in this region. A reporter gene assay revealed that a region ∼80 basepair upstream from the initiator sequence is required for the basal transcription of the BLT1 gene. Sp1 was found to be a major activator of basal transcription by electrophoretic mobility shift assays and site-directed mutagenesis. The CpG sites of the BLT1 promoter region were highly methylated in BLT1-nonexpressing cells, but not methylated in BLT1-expressing cells. Further, methylation of this region in vitro inhibited the promoter activity to ∼15% of the control. Thus, methylation at CpG sites in the promoter region is important for cell-specific transcription of the BLT1 gene. The promoter region of the BLT1 gene is localized within the open reading frame (ORF) of the BLT2 gene, which encodes a low-affinity receptor for LTB4 (Yokomizo, T., K. Kato, K. Terawaki, T. Izumi, and T. Shimizu. 2000. J. Exp. Med. 192:421–431). To our knowledge, this is the first example of “promoter in ORF” in higher eukaryotes.
Percutaneous Valve Intervention
Authors: Richard J. Shemin
Journal: Circulation (2006)

wo articles 1,2 in this issue of Circulation present small series of patients who had either a percutaneous mitral annuloplasty performed via the coronary sinus or a percutaneous aortic valve replacement via a retrograde femoral artery approach.The main thrust of each article was to demonstrate the technical approach, complications, and shortterm results of these techniques.It is clear that this technology is in its infancy.The technical challenges, reliability, and ability to achieve consistent results (not to mention appropriate patient selection) will be an area of active research and development over the foreseeable future.
Long-term Cognitive and Psychological Outcomes in the Awakening and Breathing Controlled Trial
Authors: James C. Jackson, Timothy D. Girard, Sharon M. Gordon, Jennifer L. Thompson, Ayumi K. Shintani, Jason W. W. Thomason, Brenda T. Pun, Angelo E. Canonico, Janet G. Dunn, Gordon R. Bernard, Robert S. Dittus, E. Wesley Ely
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Studies have shown that reducing sedation of critically ill patients shortens time on the ventilator and in the intensive care unit (ICU). Little is known, however, of how such strategies affect long-term cognitive, psychological, and functional outcomes.Objectives: To determine the long-term effects of a wake up and breathe protocol that interrupts and reduces sedative exposure in the ICU.Methods: In this a priori planned substudy conducted at one tertiary care hospital during the Awakening and Breathing Controlled Trial, a multicenter randomized controlled trial, we assessed cognitive, psychological, and functional/quality-of-life outcomes 3 and 12 months postdischarge among 180 medical ICU patients randomized to paired daily spontaneous awakening trials with spontaneous breathing trials (SBTs) or to sedation per usual care plus daily SBTs.Measurements and Main Results: Cognitive impairment was less common in the intervention group at 3-month follow-up (absolute risk reduction, 20.2%; 95% confidence interval, 1.5–36.1%; P = 0.03) but not at 12-month follow-up (absolute risk reduction, −1.9%; 95% CI, −21.3 to 27.1%; P = 0.89). Composite cognitive scores, alternatively, were similar in the two groups at 3-month and 12-month follow-up (P = 0.80 and 0.61, respectively), as were symptoms of depression (P = 0.59 and 0.82) and posttraumatic stress disorder (P = 0.59 and 0.97). Activities of daily living, functional status, and mental and physical quality of life were similar between groups throughout follow-up.Conclusions: In this trial, management of mechanically ventilated medical ICU patients with a wake up and breathe protocol resulted in similar cognitive, psychological, and functional outcomes among patients tested 3 and 12 months post-ICU. The proven benefits of this protocol, including improved 1-year survival, were not offset by adverse long-term outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT 00097630).
SOME PROBLEMS OF DOSE VARIATION IN THE USE OF TRANQUILIZING DRUGS
Authors: BERNARD WILKENS, SIDNEY MALITZ
Journal: American Journal of Psychiatry (1960)

Early published studies of the use of tranquilizers revealed wide variations in the methods of studying the clinical effectiveness of these drugs. Some studies omitted dosages used in arriving at conclusions regarding drug action. Others included dosage schedules but did not establish clearly the criteria on which these dosages were based. Generally the overall approach in these investigations was empirical. Currently, suggested dosage ranges of chlorpromazine, reserpine and meprobamate show a greater consistency than in the past. Three cases are presented to demonstrate some of the clinical problems encountered in the administration of these drugs. They emphasize the necessity of focusing on dose range-clinical response relationships in future investigations. The design of a small pilot study is presented. It is considered that this type of study offers the best opportunity to gain valuable information about dosage and drug effect when carefully and systematically performed.
The elderly patient with acute renal failure.
Authors: J Pascual, F Liaño, J Ortuño
Journal: Journal of the American Society of Nephrology (1995)

Structural and functional changes observed in the aging kidney predispose the elderly patient to acute renal failure. Up to 36% of the patients with acute renal failure from this institution were over 70 yr, and the literature is full of similar experiences. The elderly patient with abrupt cessation of adequate renal function requires a special work-up in diagnosis and treatment. Prerenal and obstructive causes are of particular interest. Although the question of whether or not age has an independent prognostic importance during an episode of acute renal failure remains debated; when these and other authors compared the outcome of young and old populations with these disorders, a similar evolution was always observed. Age should not be used as a discriminant factor in therapeutic decisions concerning acute renal failure.
Conus Venom Peptide Pharmacology
Authors: Richard J. Lewis, Sébastien Dutertre, Irina Vetter, MacDonald J. Christie
Journal: Pharmacological Reviews (2012)

Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (∼0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (ω-, μ-, μO-, δ-, ι-, and κ-conotoxins), ligand-gated ion channels (α-conotoxins, σ-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (ρ-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (χ-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies.
Increased alveolar nitric oxide concentration and high levels of leukotriene B4 and 8-isoprostane in exhaled breath condensate in patients with asbestosis
Authors: H. Lehtonen, P. Oksa, L. Lehtimaki, A. Sepponen, R. Nieminen, H. Kankaanranta, S. Saarelainen, R. Jarvenpaa, J. Uitti, E. Moilanen
Journal: Thorax (2007)

Inhaled asbestos fibres can cause inflammation and fibrosis in the lungs called asbestosis. However, there are no non-invasive means to assess and follow the severity of the inflammation. Exhaled nitric oxide (NO) measured at multiple exhalation flow rates can be used to assess the alveolar NO concentration and bronchial NO flux, which reflect inflammation in the lung parenchyma and airways, respectively. The aim of the present study was to investigate whether exhaled NO or markers in exhaled breath condensate could be used to assess inflammation in asbestosis.Exhaled NO and inflammatory markers (leukotriene B(4) and 8-isoprostane) in exhaled breath condensate were measured in 15 non-smoking patients with asbestosis and in 15 healthy controls. Exhaled NO concentrations were measured at four constant exhalation flow rates (50, 100, 200 and 300 ml/s) and alveolar NO concentration and bronchial NO flux were calculated according to the linear model of pulmonary NO dynamics.The mean (SE) alveolar NO concentration was significantly higher in patients with asbestosis than in controls (3.2 (0.4) vs 2.0 (0.2) ppb, p = 0.008). There was no difference in bronchial NO flux (0.9 (0.1) vs 0.9 (0.1) nl/s, p = 0.93) or NO concentration measured at ATS standard flow rate of 50 ml/s (20.0 (2.0) vs 19.7 (1.8) ppb, p = 0.89). Patients with asbestosis had increased levels of leukotriene B4 (39.5 (6.0) vs 15.4 (2.9) pg/ml, p = 0.002) and 8-isoprostane (33.5 (9.6) vs 11.9 (2.8) pg/ml, p = 0.048) in exhaled breath condensate and raised serum levels of C-reactive protein (2.3 (0.3) vs 1.1 (0.2) mug/ml, p = 0.003), interleukin-6 (3.5 (0.5) vs 1.7 (0.4) pg/ml, p = 0.007) and myeloperoxidase (356 (48) vs 240 (20) ng/ml, p = 0.034) compared with healthy controls.Patients with asbestosis have an increased alveolar NO concentration and high levels of leukotriene B4 and 8-isoprostane in exhaled breath. Measurement of exhaled NO at multiple exhalation flow rates and analysis of inflammatory markers in exhaled breath condensate are promising non-invasive means for assessing inflammation in patients with asbestosis.
Mycophenolate Mofetil or Intravenous Cyclophosphamide for Lupus Nephritis
Authors: Ellen M. Ginzler, Mary Anne Dooley, Cynthia Aranow, Mimi Y. Kim, Jill Buyon, Joan T. Merrill, Michelle Petri, Gary S. Gilkeson, Daniel J. Wallace, Michael H. Weisman, Gerald B. Appel
Journal: New England Journal of Medicine (2005)

Since anecdotal series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable.We conducted a 24-week randomized, open-label, noninferiority trial comparing oral mycophenolate mofetil (initial dose, 1000 mg per day, increased to 3000 mg per day) with monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area, increased to 1.0 g per square meter) as induction therapy for active lupus nephritis. A change to the alternative regimen was allowed at 12 weeks in patients who did not have an early response. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary end point was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements). A secondary end point was partial remission at 24 weeks.Of 140 patients recruited, 71 were randomly assigned to receive mycophenolate mofetil and 69 were randomly assigned to receive cyclophosphamide. At 12 weeks, 56 patients receiving mycophenolate mofetil and 42 receiving cyclophosphamide had satisfactory early responses. In the intention-to-treat analysis, 16 of the 71 patients (22.5 percent) receiving mycophenolate mofetil and 4 of the 69 patients receiving cyclophosphamide (5.8 percent) had complete remission, for an absolute difference of 16.7 percentage points (95 percent confidence interval, 5.6 to 27.9 percentage points; P=0.005), meeting the prespecified criteria for noninferiority and demonstrating the superiority of mycophenolate mofetil to cyclophosphamide. Partial remission occurred in 21 of the 71 patients (29.6 percent) and 17 of the 69 patients (24.6 percent), respectively (P=0.51). Three patients assigned to cyclophosphamide died, two during protocol therapy. Fewer severe infections and hospitalizations but more diarrhea occurred among those receiving mycophenolate.In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.
The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons.
Authors: R A Pixley, R De La Cadena, J D Page, N Kaufman, E G Wyshock, A Chang, F B Taylor, R W Colman
Journal: Journal of Clinical Investigation (1993)

The hypotension and disseminated intravascular coagulation (DIC) in bacteremia is thought to be mediated by the combined actions of cytokines, prostaglandins, and complement. The contact system, via the release of bradykinin and the activation of Factor XI, has been postulated to be contributing to the observed hypotension and DIC. Using a mAb to Factor XII (C6B7), we blocked the activation of the contact system in an established experimental baboon model in which Escherichia coli was infused to produce lethal bacteremia with hypotension. The untreated group (n = 5) displayed contact activation, manifested by a significant decrease in high molecular weight kininogen (HK) and a significant increase in alpha 2 macroglobulin-kallikrein complexes (alpha 2M-Kal). The C6B7-treated group (n = 5) showed an inactivation of Factor XII and the changes in HK and alpha 2M-Kal complexes were prevented. Both groups developed DIC manifested by a decrease in platelet, fibrinogen, and Factor V levels. The untreated group developed irreversible hypotension. The treated group experienced an initial hypotension that was reversed and extended the life of the animals. This study suggests that irreversible hypotension correlates with prolonged activation of the contact system, and specific antibody therapy can modulate both the pathophysiological and biochemical changes.
GI highlights from the literature
Authors: Mairi H McLean
Journal: Gut (2017)

### Understanding the pathogenesis of pouchitis

▸ Morgan XC, Kabakchiev B, Waldron L, et al . Associations between host gene expression, the mucosal microbiome, and clinical outcome in the pelvic pouch of patients with inflammatory bowel disease. Genome Biol 2015:16:67. doi:10.1186/s13059-015-0637-x

Approximately 10%–35% of patients with UC will require colectomy with pouch reconstruction, and half of these patients will develop pouchitis. In addition, one-fifth will ultimately suffer pouch failure. Therefore, defining the basis of pouchitis is clearly of utmost importance. Similar to IBD, both host genetics and the microbiota are implicated in the pathogenesis of pouchitis. However, how these factors interact in this condition is not well understood. Interestingly, pouch construction is also performed for patients with familial adenomatous polyposis, although pouchitis is rare in this group. To investigate the basis of potential host–microbe interactions, this study by Morgan and colleagues collected paired host transcriptome and microbial metagenome data from a large J-pouch cohort. Modest associations between groups of host transcripts involved in inflammation including enrichment for complement cascade genes and the interleukin-12 pathway were identified. Activation of these pathways was inversely correlated with clades, including Sutterella, Akkermansia, Bifidobacterium and Roseburia, and positively correlated with Escherichia coli abundance. However, these associations did not account for the greatest sources of variation. Unsurprisingly, antibiotic usage was demonstrated as the strongest effect on gut microbiome differences. The transcriptome demonstrated large variation within individuals between presurgery and postsurgery samples while microbial communities remained consistent. The findings suggest that an individual's gut microbe composition may not be shaped by local transcriptional activity on a long-term basis. The findings point more to the influence of other factors, including diet and early-life events. The study also highlights the need for additional well-powered studies in this field to further our understanding.

### The molecular basis of tumour resistance to chemotherapy

▸ Siravegna G, Mussolin B, Buscarino M, et al . Clonal evolution and …
Kidney Disease and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study
Authors: Ian H. de Boer
Journal: Diabetes Care (2013)

OBJECTIVE Kidney disease manifests clinically as elevated albumin excretion rate (AER), impaired glomerular filtration rate (GFR), or both, and is a cause of substantial morbidity and mortality in type 1 diabetes (T1D). The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study tested whether intensive diabetes therapy (INT) aimed at lowering glucose concentrations as close as safely possible to the normal range reduces the risks of kidney disease and other diabetes complications. RESEARCH DESIGN AND METHODS In the DCCT, 1,441 participants with T1D were randomly assigned to INT or conventional diabetes therapy (CON) for a mean duration of 6.5 years. Subsequently, participants have been followed for 18 years in the ongoing observational EDIC. Standardized longitudinal measurements of AER, estimated GFR, and blood pressure were made throughout the DCCT/EDIC. RESULTS During the DCCT, INT reduced the risks of incident microalbuminuria (AER ≥40 mg/24 h) and macroalbuminuria (AER ≥300 mg/24 h) by 39% (95% CI 21–52%) and 54% (29–74%), respectively. During EDIC years 1–8, participants previously assigned to DCCT INT continued to experience lower rates of incident microalbuminuria and macroalbuminuria, with risk reductions of 59% (39–73%) and 84% (67–92%), respectively. Beneficial effects of INT on the development of impaired GFR (sustained estimated GFR &amp;lt;60 mL/min/1.73 m2) and hypertension became evident during combined DCCT/EDIC follow-up, with risk reductions of 50% (18–69%) and 20% (6–21%), respectively, compared with CON. CONCLUSIONS In the DCCT/EDIC, INT resulted in clinically important, durable reductions in the risks of microalbuminuria, macroalbuminuria, impaired GFR, and hypertension.
Ventilatory drive and ventilatory response during rebreathing
Authors: N. Maranetra, M. C. F. Pain
Journal: Thorax (1974)

Maranetra, N. and Pain, M. C. F. (1974). <i>Thorax</i>, 29, 578-581. Ventilatory drive and ventilatory response during rebreathing. The increase in inspiratory airway pressure generated against a transiently occluded airway during rebreathing is proposed as a simple index of ventilatory drive (ΔP/ΔPco<sub>2</sub>). A study of this index in 12 normal subjects and 50 patients with chronic airways obstruction demonstrated no significant difference between normals and patients in ΔP/ΔPco<sub>2</sub> despite an overall reduction in the ventilatory response to carbon dioxide (ΔV̇e/ΔPco<sub>2</sub>) in the patients. A significant association was demonstrated between the ventilatory response to carbon dioxide, ΔP/ΔPco<sub>2</sub> and the degree of airways obstruction. Patients with a low ΔP/ΔPco<sub>2</sub> showed greater hypoxaemia, hypercapnia, and polycythaemia than patients with a higher ΔP/ΔPco<sub>2</sub> for the same degree of airways obstruction.
Automatic segmentation of occluded vasculature via pulsatile motion analysis in endoscopic robot-assisted partial nephrectomy video
Authors: Alborz Amir-Khalili, Ghassan Hamarneh, Jean-Marc Peyrat, Julien Abinahed, Osama Al-Alao, Abdulla Al-Ansari, Rafeef Abugharbieh
Journal: Medical Image Analysis (2015)