tbuckley/cabot-search huggingface dataset:
Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis
Authors: Malin E V Johansson, Jenny K Gustafsson, Jessica Holmén-Larsson, Karolina S Jabbar, Lijun Xia, Hua Xu, Fayez K Ghishan, Frederic A Carvalho, Andrew T Gewirtz, Henrik Sjövall, Gunnar C Hansson
Journal: Gut (2013)

<h3>Objective</h3> The inner mucus layer in mouse colon normally separates bacteria from the epithelium. Do humans have a similar inner mucus layer and are defects in this mucus layer a common denominator for spontaneous colitis in mice models and ulcerative colitis (UC)? <h3>Methods and results</h3> The colon mucus layer from mice deficient in Muc2 mucin, Core 1 <i>O</i>-glycans, Tlr5, interleukin 10 (IL-10) and Slc9a3 (Nhe3) together with that from dextran sodium sulfate-treated mice was immunostained for Muc2, and bacterial localisation in the mucus was analysed. All murine colitis models revealed bacteria in contact with the epithelium. Additional analysis of the less inflamed IL-10<sup>−/−</sup> mice revealed a thicker mucus layer than wild-type, but the properties were different, as the inner mucus layer could be penetrated both by bacteria in vivo and by fluorescent beads the size of bacteria ex vivo. Clear separation between bacteria or fluorescent beads and the epithelium mediated by the inner mucus layer was also evident in normal human sigmoid colon biopsy samples. In contrast, mucus on colon biopsy specimens from patients with UC with acute inflammation was highly penetrable. Most patients with UC in remission had an impenetrable mucus layer similar to that of controls. <h3>Conclusions</h3> Normal human sigmoid colon has an inner mucus layer that is impenetrable to bacteria. The colon mucus in animal models that spontaneously develop colitis and in patients with active UC allows bacteria to penetrate and reach the epithelium. Thus colon mucus properties can be modulated, and this suggests a novel model of UC pathophysiology.
Diffuse Large B-cell Lymphoma in the Elderly: A Review of Potential Difficulties
Authors: Clémentine Sarkozy, Bertrand Coiffier
Journal: Clinical Cancer Research (2013)

Half of patients with diffuse large B-cell lymphoma (DLBCL) are more than 65 years old. These elderly patients frequently have other diseases, some of them severe, which may alter their ability to receive standard curative therapy. However, these associated diseases are heterogeneous and only a few contraindicate chemotherapy treatments. We reviewed all potential difficulties, such as the evaluation of comorbidities, the heterogeneous functional status of this population, and the consequences of the aging process that might be associated with treating these patients, and now propose solutions. As standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy may cure the majority of patients, it must always be the first proposed option. With this approach, elderly patients with DLBCL treated with a curative intent can reach a complete remission and have a similar outcome as younger patients. Reduced dose intensity must be applied for very elderly patients or those unfit for full-dose anthracycline. The critical question for a physician is why these patients cannot be treated with the standard regimen, namely R-CHOP.
Administration of hepatic stimulatory substance alone or with other liver growth factors does not ameliorate acetaminophen-induced liver failure
Authors: Antonio Francavilla, Alessandro Azzarone, Guiseppe Carrieri, Umberto Cillo, David Van Thiel, Vladimir Subbottin, Thomas E. Starzl
Journal: Hepatology (1993)

Sixty-two beagle dogs were given three doses of acetaminophen over a period of 24 hr in a fulminant liver failure model that is 70% lethal in 72 hr. Treatment of the animals with hepatic stimulatory substance alone or in a mixture with insulin, transforming growth factor-α and insulin-like growth factor II had no effect on mortality. Evidence of maximum regeneration with a mitotic index 20 to 25 times resting was the same in treated and untreated animals. Similarly, the biochemical and hematological indexes of liver injury were unaffected by therapy. These studies illustrate the futility of treating fulminant liver failure with exogenous growth factors that apparently are already present in large amounts in the natural response to liver injury. The results suggest that on-going liver injury by mechanisms other than lack of growth factors is the central problem of fulminant liver failure. If so, provision of regeneration-stimulating substance is an inappropriate therapeutic strategy. (Hepatology 1993;17:429-433.)
Use of Health Services by Previously Uninsured Medicare Beneficiaries
Authors: J. Michael McWilliams, Ellen Meara, Alan M. Zaslavsky, John Z. Ayanian
Journal: New England Journal of Medicine (2007)

Previously uninsured adults who enroll in the Medicare program at the age of 65 years may have greater morbidity, requiring more intensive and costlier care over subsequent years, than they would if they had been previously insured.We used longitudinal data from the nationally representative Health and Retirement Study to assess self-reported health care use and expenditures from 1992 through 2004 among 5158 adults who were privately insured or uninsured before Medicare coverage began at the age of 65 years. We used propensity-score methods to compare health care use and expenditures for previously insured and uninsured beneficiaries who were similar across numerous characteristics at 59 to 60 years of age and adjusted for differences in supplemental and prescription-drug coverage after 65 years of age.Among 2951 adults with hypertension, diabetes, heart disease, or stroke diagnosed before 65 years of age, previously uninsured adults who acquired Medicare coverage at the age of 65 reported significantly greater increases in the numbers of doctor visits (P<0.001) and hospitalizations (P=0.001) and in total medical expenditures (P=0.02) than did previously insured adults. Significant differential increases were not evident among the 2207 adults without these conditions (P>0.12 for all comparisons). In analyses adjusted for supplemental and prescription-drug coverage, previously uninsured adults with these conditions reported more doctor visits (13% relative difference, P=0.04), more hospitalizations (20% relative difference, P=0.04), and higher total medical expenditures (51% relative difference, P=0.09) from ages 65 to 72 years than did previously insured adults.The costs of expanding health insurance coverage for uninsured adults before they reach the age of 65 years may be partially offset by subsequent reductions in health care use and spending for these adults after the age of 65, particularly if they have cardiovascular disease or diabetes before the age of 65 years.
Acute pleural service: Experience and pathways
Authors: Burhan Khan, Marika Townsend
Journal: European Respiratory Journal (2011)

Introduction: Pleural effusions are common and may be the first sign of malignancy or can develop in patients with a confirmed malignancy. It generally indicates advanced disease, forbears deterioration in performance status, increased symptom load, and limited life expectancy. However, not all of these patients necessarily need hospitalisation or a chest drain.

Aims: To ascertain the qualitative and quantitative benefits of providing an acute pleural service.

Methods: A prospective analysis of experience in a district general hospital of providing an acute pleural service.

Results: From July 2010 to date 25 patients were referred to the Acute Pleural Service. The types of pleural pathologies and pathway are shown below.

View this table:

Aetiology of pleural disease of patients in Acute Pleural Service





![Figure][1] 



Conclusion: Patients with either known malignant pleural effusion and those on first presentation may be managed as elective day admissions in an Acute Pleural Service pathway delivered by a Chest Physician with competency in thoracic ultrasound. This enables rapid assessment for prompt diagnosis, relief of symptoms and onward referral for VATS, medical thoracoscopy, PleurX, chest tube pleurodesis, or repeated pleural drainages as appropriate. This also represents another modality in managing patients with recurrent pleural effusion accumulation, and avoids unnecessary admission & hospitalisation to an acute hospital.

 [1]: pending:yes
How Mitochondrial Dynamism Orchestrates Mitophagy
Authors: Orian S. Shirihai, Moshi Song, Gerald W. Dorn
Journal: Circulation Research (2015)

Mitochondria are highly dynamic, except in adult cardiomyocytes. Yet, the fission and fusion-promoting proteins that mediate mitochondrial dynamism are highly expressed in, and essential to the normal functioning of, hearts. Here, we review accumulating evidence supporting important roles for mitochondrial fission and fusion in cardiac mitochondrial quality control, focusing on the PTEN-induced putative kinase 1-Parkin mitophagy pathway. Based in part on recent findings from in vivo mouse models in which mitofusin-mediated mitochondrial fusion or dynamin-related protein 1-mediated mitochondrial fission was conditionally interrupted in cardiac myocytes, we propose several new concepts that may provide insight into the cardiac mitochondrial dynamism-mitophagy interactome.
Accuracy of the Preoperative Assessment in Predicting Pulmonary Risk after Nonthoracic Surgery
Authors: Finlay A. McAlister, Nadia A. Khan, Sharon E. Straus, Miltiadis Papaioakim, Bruce W. Fisher, Sumit R. Majumdar, Ognjen Gajic, Malcolm Daniel, George Tomlinson
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

We examined the accuracy of preoperative assessment in predicting postoperative pulmonary risk in a prospective cohort of 272 consecutive patients referred for evaluation before nonthoracic surgery. Outcomes were assessed by an independent investigator who was blinded to the preoperative data. There were 22 (8%) postoperative pulmonary complications. Statistically significant predictors of pulmonary complications (all p ⩽ 0.005) were as follows: hypercapnea of 45 mm Hg or more (odds ratio, 61.0), a FVC of less than 1.5 L/minute (odds ratio, 11.1), a maximal laryngeal height of 4 cm or less (odds ratio, 6.9), a forced expiratory time of 9 seconds or more (odds ratio, 5.7), smoking of 40 pack-years or more (odds ratio, 5.7), and a body mass index of 30 or more (odds ratio, 4.1). Multiple regression analyses revealed three preoperative clinical factors that are independently associated with pulmonary complications: an age of 65 years or more (odds ratio, 1.8; p = 0.02), smoking of 40 pack-years or more (odds ratio, 1.9; p = 0.02), and maximum laryngeal height of 4 cm or less (odds ratio, 2.0; p = 0.007). Thus, preoperative factors can identify those patients referred to pulmonologists or internists who are at increased risk for pulmonary complications after nonthoracic surgery.
The Role of Peptides in T Cell Alloreactivity Is Determined by Self–Major Histocompatibility Complex Molecules
Authors: Reinhard Obst, Nikolai Netuschil, Karsten Klopfer, Stefan Stevanović, Hans-Georg Rammensee
Journal: The Journal of Experimental Medicine (2000)

By analyzing T cell responses against foreign major histocompatibility complex (MHC) molecules loaded with peptide libraries and defined self- and viral peptides, we demonstrate a profound influence of self-MHC molecules on the repertoire of alloreactive T cells: the closer the foreign MHC molecule is related to the T cell's MHC, the higher is the proportion of peptide-specific, alloreactive (“allorestricted”) T cells versus T cells recognizing the foreign MHC molecule without regard to the peptide in the groove. Thus, the peptide repertoire of alloreactive T cells must be influenced by self-MHC molecules during positive or negative thymic selection or peripheral survival, much like the repertoire of the self-restricted T cells. In consequence, allorestricted, peptide-specific T cells (that are of interest for clinical applications) are easier to obtain if T cells and target cells express related MHC molecules.
Effects of Interferon-γ 1b on Biomarker Expression in Patients with Idiopathic Pulmonary Fibrosis
Authors: Robert M. Strieter, Karen M. Starko, Richard I. Enelow, Imre Noth, Vincent G. Valentine
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

In a recent study of IFN-γ 1b in 330 patients with idiopathic pulmonary fibrosis (IPF), progression-free survival was unchanged; however, a trend toward lower mortality was seen in IFN-γ 1b–treated patients compared with placebo-treated patients (9.9 vs. 16.7%; p = 0.08). The purpose of this randomized, double-blind, placebo-controlled trial was to characterize molecular effects of subcutaneous IFN-γ 1b (200 μg) thrice weekly for 6 months versus placebo in 32 patients with IPF. Messenger RNA in transbronchial lung biopsies and bronchoalveolar lavage cell pellet and protein levels in bronchoalveolar lavage fluid (BALF) and plasma were evaluated. After IFN-γ 1b treatment, IFN-inducible T cell-α chemoattractant/CXCL11 (a chemokine with immunomodulatory, antiangiogenic, and defensin-like antimicrobial properties) increased in BALF (p = 0.016) and plasma (p < 0.001); BALF levels of epithelial neutrophil-activating protein-78/CXCL5 (p = 0.054), platelet-derived growth factor A (p = 0.033), and Type I procollagen (p = 0.096) were lower; and IFN-γ levels were higher (p = 0.093) versus placebo. For messenger RNA in transbronchial biopsies, trends (p > 0.05 and ⩽ 0.10) associated with IFN-γ 1b treatment included an increase in IFN-inducible T cell-α chemoattractant/CXCL11, a decrease in elastin, and smaller increases for Type III procollagen and platelet-derived growth factor B. Changes in biomarkers of fibrosis, angiogenesis, proliferation, immunomodulation, and antimicrobial activity suggest that IFN-γ 1b may affect IPF through multiple pathways.
Defining remission in rheumatoid arthritis
Authors: David Felson
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Given the inconsistency of remission definitions in rheumatoid arthritis (RA) trials, the goal of this American College of Rheumatology/European League Against Rheumatism committee was to define remission. <h3>Methods</h3> The committee instructed a working group that a new remission definition, among other requirements, needed to allow for little, if any, active clinical disease and to be defined using the core set of outcome measures for RA trials and that those in remission at one time needed to have a low risk of later worsening function or radiograph progression. Remission was to be defined using trial data for use in trials but needed to anticipate use in a practice setting. <h3>Results</h3> The working group started by evaluating the thresholds for core set measures compatible with remission and determined that patient-reported outcomes contributed importantly to the ability of outcome assessment to distinguish more from less effective treatments. The group created a candidate group of remission definitions to test, including Boolean versions and widely used indexes. Testing how well these candidate definitions predicted later good outcomes, the group found that Disease Activity Score 28 thresholds for remission performed worse than Simplified Disease Activity Index/Clinical Disease Activity Index or Boolean versions. Also, persons with low Disease Activity Score 28 occasionally had high joint counts, which were incompatible with remission. The parent committee chose two definitions: one Boolean (patient had to have all of the following: tender joint count, swollen joint count ≤1, C reactive protein ≤1 mg/dl) and patient global assessment ≤1 (on a 0–10 scale) and one Simplified Disease Activity Index ≤3.3. <h3>Conclusion</h3> The American College of Rheumatology/European League Against Rheumatism has promulgated two new similar definitions of remission for RA trials.
Helping the homogeneous
Authors: H. E. Fessler, D. Feller-Kopman
Journal: European Respiratory Journal (2010)

he National Emphysema Treatment Trial (NETT) [1] helped clarify the patient selection criteria and expected risks and benefits of lung volume reduction surgery (LVRS) for patients with advanced emphysema.The NETT built on numerous earlier case series which showed that the greatest symptomatic and functional benefit accrued to patients with a predominantly upper lobe distribution of emphysema.In such patients who also had very low exercise tolerance, the surgery lowered their mortality risk over the next 5 yrs by about half.Importantly for patients in the USA, findings from the study were used to establish the criteria for Medicare coverage of the procedure.This opened the door for thousands of qualifying patients to undergo this life-enhancing and life-extending procedure.
ERCC1 influence on the incidence of brain metastases in patients with non-squamous NSCLC treated with adjuvant cisplatin-based chemotherapy
Authors: B. Besse, C. Massard, V. Haddad, F. Andre, A. Dunant, R. Pirker, K.A. Olaussen, E. Brambilla, P. Fouret, J.C. Soria
Journal: Annals of Oncology (2010)
STUDIES ON THE PATHOGENESIS OF FEVER
Authors: Robert D. Collins, W. Barry Wood
Journal: The Journal of Experimental Medicine (1959)

Study in vitro of the interaction of bacterial endotoxin with rabbit polymorphonuclear leucocytes has resulted in the following findings: 1. Incubation of endotoxin and leucocytes in saline results in: (a) the release of leucocytic pyrogen, and (b) the inactivation of endotoxin. 2. Cell-free extracts of leucocytes also inactivate endotoxin. 3. Incubation of leucocytes in "physiological" saline causes rapid discharge of leucocytic pyrogen. In contrast, relatively little pyrogen is released by leucocytes incubated in fresh serum. 4. The release of leucocytic pyrogen in serum is markedly stimulated by the presence of endotoxin. 5. Leucocytes obtained from tolerant rabbits interact with endotoxin in essentially the same manner as leucocytes from normal rabbits. The pertinence of these findings to the pathogenesis of fever and to related information concerning human leucocytes has been discussed.
Clusterin Attenuates the Development of Renal Fibrosis
Authors: Gwon-Soo Jung, Mi-Kyung Kim, Yun-A Jung, Hye-Soon Kim, In-Sun Park, Bon-Hong Min, Ki-Up Lee, Jung-Guk Kim, Keun-Gyu Park, In-Kyu Lee
Journal: Journal of the American Society of Nephrology (2011)

Upregulation of clusterin occurs in several renal diseases and models of nephrotoxicity, but whether this promotes injury or is a protective reaction to injury is unknown. Here, in the mouse unilateral ureteral obstruction model, obstruction markedly increased the expression of clusterin, plasminogen activator inhibitor-1 (PAI-1), type I collagen, and fibronectin. Compared with wild-type mice, clusterin-deficient mice exhibited higher levels of PAI-1, type I collagen, and fibronectin and accelerated renal fibrosis in response to obstruction. In cultured rat tubular epithelium-like cells, adenovirus-mediated overexpression of clusterin inhibited the expression of TGF-β-stimulated PAI-1, type I collagen, and fibronectin. Clusterin inhibited TGF-β-stimulated Smad3 activity via inhibition of Smad3 phosphorylation and its nuclear translocation. Moreover, intrarenal delivery of adenovirus-expressing clusterin upregulated expression of clusterin in tubular epithelium-like cells and attenuated obstruction-induced renal fibrosis. In conclusion, clusterin attenuates renal fibrosis in obstructive nephropathy. These results suggest that upregulation of clusterin during renal injury is a protective response against the development of renal fibrosis.
Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models
Authors: K. Geletneky, I. Kiprianova, A. Ayache, R. Koch, M. Herrero y Calle, L. Deleu, C. Sommer, N. Thomas, J. Rommelaere, J. R. Schlehofer
Journal: Neuro-Oncology (2010)

Oncolytic virotherapy is a potential treatment modality under investigation for various malignancies including malignant brain tumors. Unlike some other natural or modified viruses that show oncolytic activity against cerebral neoplasms, the rodent parvovirus H-1 (H-1PV) is completely apathogenic in humans. H-1PV efficiently kills a number of tumor cells without harm to corresponding normal ones. In this study, the concept of H-1PV-based virotherapy of glioma was tested for rat (RG-2 cell-derived) and for human (U87 cell-derived) gliomas in immunocompetent and immunodeficient rat models, respectively. Large orthotopic rat and human glioma cell-derived tumors were treated with either single stereotactic intratumoral or multiple intravenous (iv) H-1PV injections. Oncolysis was monitored by magnetic resonance imaging and proven by histology. Virus distribution and replication were determined in brain and organs. In immunocompetent rats bearing RG-2-derived tumors, a single stereotactic intratumoral injection of H-1PV and multiple systemic (iv) applications of the virus were sufficient for remission of advanced and even symptomatic intracranial gliomas without damaging normal brain tissue or other organs. H-1PV therapy resulted in significantly improved survival (Kaplan–Meier analysis) in both the rat and human glioma models. Virus replication in tumors indicated a contribution of secondary infection by progeny virus to the efficiency of oncolysis. Virus replication was restricted to tumors, although H-1PV DNA could be detected transiently in adjacent or remote normal brain tissue and in noncerebral tissues. The results presented here and the innocuousness of H-1PV for humans argue for the use of H-1PV as a powerful means to perform oncolytic therapy of malignant gliomas.
Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction
Authors: K.-E. Andersson
Journal: Pharmacological Reviews (2011)

Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, both autonomic and somatic, and supraspinal influences from visual, olfactory, and imaginary stimuli. Several central transmitters are involved in the erectile control. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropin/α-melanocyte-stimulating hormone, have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. The balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa (CC) and determines the functional state of the penis. Noradrenaline contracts both CC and penile vessels via stimulation of α<sub>1</sub>-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and CC. The role of other mediators, released from nerves or endothelium, has not been definitely established. Erectile dysfunction (ED), defined as the "inability to achieve or maintain an erection adequate for sexual satisfaction," may have multiple causes and can be classified as psychogenic, vasculogenic or organic, neurologic, and endocrinologic. Many patients with ED respond well to the pharmacological treatments that are currently available, but there are still groups of patients in whom the response is unsatisfactory. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including oral phosphodiesterase inhibitors and intracavernosal injections of prostaglandin E<sub>1</sub>. Irrespective of the underlying cause, these drugs are effective in the majority of cases. Drugs with a central site of action have so far not been very successful. There is a need for therapeutic alternatives. This requires identification of new therapeutic targets and design of new approaches. Research in the field is expanding, and several promising new targets for future drugs have been identified.