tbuckley/cabot-search huggingface dataset:
Colocalization of H-ATPase and H,K-ATPase immunoreactivity in the rat kidney.
Authors: B Bastani
Journal: Journal of the American Society of Nephrology (1995)

Urinary acidification in the collecting duct (CD) is via V-type H-ATPase and P-type H,K-ATPase. The localization and polar distribution of H-ATPase in intercalated cells (IC) have been well studied. The localization of H,K-ATPase to IC has been reported, but its intracellular distribution has not been defined. To colocalize these pumps, a murine monoclonal antibody (E11) to the 31-kd subunit of the H-ATPase and a rabbit antiserum (HK alpha N2) to a synthetic peptide based on the N terminus of the hog gastric H,K-ATPase alpha-subunit were used. In immunocytochemical staining of rat kidney, H,K-ATPase was present only in the IC of the CD with the same polar distribution as H-ATPase. The preabsorption of HK alpha N2 with affinity-purified bovine H-ATPase did not affect the H,K-ATPase staining, whereas preabsorption with the immunizing synthetic peptide eliminated immunoreactivity. HK alpha N2 stained only parietal cells in the rat gastric mucosa, whereas preimmune serum and E11 showed no immunoreactivity. On immunoblots of rat gastric mucosal microsomes, HK alpha N2 labeled a single 94-kd band, and this staining disappeared after preabsorption with the immunizing synthetic peptide. HK alpha N2 labeled no bands on immunoblots of affinity-purified bovine H-ATPase. All immunochemistry was negative with preimmune serum.(ABSTRACT TRUNCATED AT 250 WORDS)
Frequency of sphincter of Oddi dysfunction in patients with previously normal sphincter of Oddi manometry studies
Authors: M. Khashab, J. Watkins, L. McHenry, L. Lazzell-Pannell, S. Schmidt, S. Sherman, G. Lehman, E. Fogel
Journal: Endoscopy (2009)

Sphincter of Oddi manometry (SOM), performed at endoscopic retrograde cholangiopancreatography (ERCP), is the gold standard for diagnosing sphincter of Oddi dysfunction (SOD). The question remains as to whether the short-term manometric recordings reflect the 24-hour pathophysiology of the sphincter. The aim of this study was to determine the frequency of SOD in persistently symptomatic patients with previously normal SOM studies.All patients who underwent ERCP for suspected SOD over a 13-year period (1994 - 2007) were considered for inclusion in the study. Patients with an intact papilla and a previously normal SOM who had a repeat ERCP for persistent symptoms formed the study group. SOM was performed in conventional retrograde fashion.In all, 5352 patients without prior papillary intervention underwent SOM during the study period. A total of 1037 patients had normal SOM, and of these, 30 patients (27 female, mean age 40.1 years) underwent repeat ERCP for persistent symptoms. The median duration between the two ERCPs was 493.5 days (range 52-3538 days). In these 30 patients, SOD classification prior to the initial ERCP was: type I in one patient (not treated in 1994), type II in 17 patients, and type III in 12 patients. Of the 30 patients, 12 (40%) had normal SOM at repeat ERCP; SOD was diagnosed in 18/30 (60%) patients.A single SOM study may not represent the day-to-day physiology of the sphincter of Oddi; sphincter pathology may progress over time. One normal exam may not rule out SOD. A repeat ERCP with manometry may be warranted in a subset of patients with persistent debilitating symptoms and a high index of suspicion for SOD. Outcome data are needed to determine whether this approach justifies the potential risks of ERCP.
Microbiota Modulate Tumoral Immune Surveillance in Lung through a γδT17 Immune Cell-Dependent Mechanism
Authors: Min Cheng, Liting Qian, Guodong Shen, Geng Bian, Tingjuan Xu, Weiping Xu, Gan Shen, Shilian Hu
Journal: Cancer Research (2014)

Abstract Commensal bacteria are crucial to maintain immune homeostasis in mucosal tissues and disturbances in their ecology can affect disease susceptibility. Here, we report evidence that commensal bacteria shape the efficiency of immune surveillance in mucosal tissues. Antibiotic-treated (Abt) mice were more susceptible to development of engrafted B16/F10 melanoma and Lewis lung carcinoma, exhibiting a shortened mean survival time with more numerous and larger tumor foci in the lungs. The defective antitumor response of Abt mice was independent of dehydration caused by antibiotics. Host defenses relied upon intact commensal bacteria with no class specificity. Mechanistic investigations revealed a defective induction of the γδT17 cell response in lungs of Abt mice; here, more aggressive tumor development was observed, possibly related to a reduction in IL6 and IL23 expression there. Adding normal γδT cells or supplementing IL17 restored the impaired immune surveillance phenotype in Abt mice. Overall, our results demonstrated the importance of commensal bacteria in supporting the host immune response against cancer, defined an important role for γδT17 responses in the mechanism, and suggested deleterious effects of antibiotic treatment on cancer susceptibility and progression. Cancer Res; 74(15); 4030–41. ©2014 AACR.
Tumor Necrosis Factor-α Drives 70% of Cigarette Smoke–induced Emphysema in the Mouse
Authors: Andrew Churg, Rong D. Wang, Hsin Tai, Xiaoshan Wang, Changshi Xie, Joanne L. Wright
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Mice lacking tumor necrosis factor-α (TNF-α) receptors (TNFRKO mice) do not develop an inflammatory infiltrate or matrix breakdown after a single acute cigarette smoke exposure. To determine the role of TNF-α in the long-term development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice demonstrated an 11% increase in mean linear intercept; wild-type mice had a 38% increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in lavage fluid. Whole lung matrix metalloprotease (MMP)-2, MMP-9, MMP-12, MMP-13, and matrix type-1 (MT1)-MMP proteins were increased in wild-type mice, but smaller increases in MMP-12, MMP-13, and MT1-MMP were also seen in TNFRKO mice. Lavage matrix breakdown products were elevated in wild-type mice and only partially reduced by anti-neutrophil antibody, implying both neutrophil- and non–neutrophil-mediated matrix breakdown. We conclude that TNF-α–mediated processes, probably driving neutrophil influx, are responsible for approximately 70% of airspace enlargement and the majority of inflammatory cell influx/matrix breakdown in the mouse model. TNF-α causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second TNF-α–independent process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.
An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy
Authors: Jussi J. Saukkonen, David L. Cohn, Robert M. Jasmer, Steven Schenker, John A. Jereb, Charles M. Nolan, Charles A. Peloquin, Fred M. Gordin, David Nunes, Dorothy B. Strader, John Bernardo, Raman Venkataramanan, Timothy R. Sterling
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.
M-Type Phospholipase A<sub>2</sub>Receptor as Target Antigen in Idiopathic Membranous Nephropathy
Authors: Laurence H. Beck, Ramon G.B. Bonegio, Gérard Lambeau, David M. Beck, David W. Powell, Timothy D. Cummins, Jon B. Klein, David J. Salant
Journal: New England Journal of Medicine (2009)

Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown.We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody.Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A(2) receptor (PLA(2)R). Reactive serum specimens recognized recombinant PLA(2)R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA(2)R antibody. Anti-PLA(2)R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA(2)R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA(2)R.A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R. PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease.
Neural reuse: A fundamental organizational principle of the brain
Authors: Michael L. Anderson
Journal: Behavioral and Brain Sciences (2010)

An emerging class of theories concerning the functional structure of the brain takes the reuse of neural circuitry for various cognitive purposes to be a central organizational principle. According to these theories, it is quite common for neural circuits established for one purpose to be exapted (exploited, recycled, redeployed) during evolution or normal development, and be put to different uses, often without losing their original functions. Neural reuse theories thus differ from the usual understanding of the role of neural plasticity (which is, after all, a kind of reuse) in brain organization along the following lines: According to neural reuse, circuits can continue to acquire new uses after an initial or original function is established; the acquisition of new uses need not involve unusual circumstances such as injury or loss of established function; and the acquisition of a new use need not involve (much) local change to circuit structure (e.g., it might involve only the establishment of functional connections to new neural partners). Thus, neural reuse theories offer a distinct perspective on several topics of general interest, such as: the evolution and development of the brain, including (for instance) the evolutionary-developmental pathway supporting primate tool use and human language; the degree of modularity in brain organization; the degree of localization of cognitive function; and the cortical parcellation problem and the prospects (and proper methods to employ) for function to structure mapping. The idea also has some practical implications in the areas of rehabilitative medicine and machine interface design.
Age dependence of the development of ventricular arrhythmias in a canine model of sudden cardiac death
Authors: N Moïse
Journal: Cardiovascular Research (1997)

Objectives: The age-dependence of the development of ventricular arrhythmias was studied in German shepherd dogs with inherited ventricular arrhythmias and sudden death. Background: A colony of German shepherd dogs has been established that exhibit inherited ventricular arrhythmias and sudden death. The incidence of arrhythmias increases with age. Because ventricular tachycardia is associated with bradycardia, it was hypothesized that the increased incidence of arrhythmias was related to age-dependent slowing of heart rate. Methods: Arrhythmia counts and RR intervals were measured from serial ambulatory ECG recordings obtained in 71 dogs (1–48 weeks). In addition, 19 dogs were challenged with phenylephrine (10 μg/kg i.v.) at 15, 28, and 45 weeks of age, 10 dogs were challenged with epinephrine (1 μg/kg i.v.) at 3, 5, 7, 9, 11, 18, and 28 weeks of age, and 10 dogs were challenged at 28 weeks with epinephrine (2.5 μg/kg i.v.), before and after propranolol (0.5 mg/kg i.v.). Results: The incidence and severity of ventricular arrhythmias increased between 7 and 28 weeks of age and decreased between 28 and 44 weeks of age. The age-dependent increase in the incidence of ventricular tachycardia was associated with age-dependent reductions in sinus rate. Baroreflex-mediated slowing of the heart rate unmasked arrhythmias in young animals that did not spontaneously display arrhythmias and exacerbated existing arrhythmias in older animals. However, the magnitude of baroreflex-induced bradycardia was similar from 7–18 weeks of age, yet the incidence of arrhythmias increased progressively. Moreover, the waning of ventricular arrhythmias in older animals was not associated with more rapid sinus rates. Conclusion: The risk for sudden death in dogs with inherited ventricular arrhythmias increases with age in part because of age-dependent slowing of heart rate and in part because of other heart-rate-independent factors. The correspondence between the development of ventricular tachycardia and sinus pauses is consistent with the hypothesis that ventricular arrhythmias are initiated by early afterdepolarization-induced triggered activity.
Child health is under threat from NHS reforms, says report
Authors: A. O'Dowd
Journal: BMJ (2011)

Children’s health services could suffer as a result of the NHS reforms and leave youngsters’ health and welfare split between several different organisations, warns a report.

The danger of responsibility for children and young people’s needs falling between different organisations with little joined up care is a possibility under the reforms proposed in the Health and Social Care Bill.

This warning was made in the report Children and young people’s health—where next? published on 8 December by the NHS Confederation—the representative body for NHS organisations—the Royal College of Paediatrics and Child Health (RCPCH) and the Office of Public Management.

The report warns that insufficient attention has been paid to what the reforms will mean for child health and the government should act urgently to clarify how services will work together and go on to produce a cross government strategy.

The report says: “Despite the range of child health policies and strategies within individual government departments and ministries . . . there is still no sufficiently …
Systolic Dysfunction Portends Increased Mortality among Those Waiting for Renal Transplant
Authors: Angelo M. de Mattos, Andrew Siedlecki, Robert S. Gaston, Gilbert J. Perry, Bruce A. Julian, Clifton E. Kew, Mark H. Deierhoi, Carlton Young, John J. Curtis, Ami E. Iskandrian
Journal: Journal of the American Society of Nephrology (2008)

Individuals waiting for a renal transplant experience excessive cardiovascular mortality, which is not fully explained by the prevalence of ischemic heart disease in this population. Overt heart failure is known to increase the mortality of patients with ESRD, but the impact of lesser degrees of ventricular systolic dysfunction is unknown. For examination of the association between left ventricular ejection fraction(LVEF) and mortality of renal transplant candidates, the records of 2718 patients evaluated for transplantation at one institution were reviewed. During 6355 patient-years (median 27 mo) of follow-up, 681 deaths occurred. Patients with systolic dysfunction (LVEF <or= 0.40) had significantly lower survival than those with higher systolic function (median 49 +/- 3.1 versus 72 +/- 4.0 mo; P 0.001) but had similar survival to patients with ischemia (48 +/- 2.5 mo). Multivariate modeling showed that those with systolic dysfunction were nearly twice as likely to die as those with normal systolic function, adjusted for risk factors including diabetes, left ventricular hypertrophy, and ischemia (adjusted hazard ratio 1.7; 95%confidence interval 1.43 to 2.07). In addition, a graded, reverse association between LVEF and mortality was identified. In conclusion, systolic dysfunction is strongly associated with mortality, in a graded manner, in renal transplant candidates.
Canagliflozin Provides Durable Glycemic Improvements and Body Weight Reduction Over 104 Weeks Versus Glimepiride in Patients With Type 2 Diabetes on Metformin: A Randomized, Double-Blind, Phase 3 Study
Authors: Lawrence A. Leiter, Kun-Ho Yoon, Pablo Arias, Gisle Langslet, John Xie, Dainius A. Balis, Dawn Millington, Frank Vercruysse, William Canovatchel, Gary Meininger
Journal: Diabetes Care (2014)

OBJECTIVE To assess the efficacy/safety of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS In this randomized, double-blind study, patients (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTS At week 104, reductions from baseline in A1C were −0.65%, −0.74%, and −0.55% (−7.1, −8.1, and −6.0 mmol/mol) with canagliflozin 100 and 300 mg and glimepiride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in body weight (−4.1%, −4.2%, and 0.9%, respectively) and systolic blood pressure (−2.0, −3.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glimepiride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respectively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis–related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glomerular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONS Canagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks.
Exercise therapy after corticosteroid injection for moderate to severe shoulder pain: large pragmatic randomised trial
Authors: D. P. Crawshaw, P. S. Helliwell, E. M. A. Hensor, E. M. Hay, S. J. Aldous, P. G. Conaghan
Journal: BMJ (2010)

<b>Objective</b> To compare the effectiveness of subacromial corticosteroid injection combined with timely exercise and manual therapy (injection plus exercise) or exercise and manual therapy alone (exercise only) in patients with subacromial impingement syndrome. <b>Design</b> Pragmatic randomised clinical trial. <b>Setting</b> Primary care based musculoskeletal service. <b>Patients</b> Adults aged 40 or over with subacromial impingement syndrome with moderate or severe shoulder pain. <b>Interventions</b> Injection plus exercise or exercise only. <b>Main outcome measures</b> Primary outcome was the difference in improvement in the total shoulder pain and disability index at 12 weeks. <b>Results</b> 232 participants were randomised (115 to injection plus exercise, 117 to exercise only). The mean age was 56 (range 40-78), 127 were women, and all had had a median of 16 weeks of shoulder pain (interquartile range 12-28). At week 12 there was no significant difference between the groups in change in total pain and disability index (mean difference between change in groups 3.26 (95% confidence interval −0.81 to 7.34), P=0.116). Improvement was significantly greater in the injection plus exercise group at week 1 (6.56, 4.30 to 8.82) and week 6 (7.37, 4.34 to 10.39) for the total pain and disability index (P&lt;0.001), with no differences at week 24 (−2.26, −6.77 to 2.25, P=0.324). <b>Conclusions</b> In the treatment of patients with subacromial impingement syndrome, injection plus exercise and exercise only are similarly effective at 12 weeks. <b>Trial registration</b> ISRCT 25817033; EudraCT No 2005-003628-20.
Nontypeable haemophilus influenzae (NTHi) and lung oxidative stress
Authors: Jyotika Prasad, Steven Lim, Nagmeh Radhakrishna, Peter Maclaughlin, Michael Farmer, Daniel Steinfort, Stavros Selemidis, Philip Bardin, Stephen Holdsworth, Peter Holmes, Paul King
Journal: European Respiratory Journal (2013)

Background:  COPD is characterized by ongoing airway inflammation that continues after smoking cessation. The production of reactive oxygen species (ROS) to produce oxidative stress and lung damage is a key feature of this ongoing inflammatory process. The lung phagocytes (macrophages and neutrophils) are thought to have a key role in ROS production. Nontypeable  Haemophilus influenzae  (NTHi) is the dominant bacterium found in the lungs of patients with COPD. It is not known if NTHi has a role in ROS production.   Aims:  To assess the effect of NTHi on the production of ROS by lung phagocytes. Methods:  Bronchoalveolar samples were obtained from 51 patients so far (22 patients with COPD and 29 controls). Cells were stimulated with both live and killed NTHi. Cells were analyzed for ROS production using 3 different methods 1), flow cytometry (neutrophils and macrophages), 2), confocal microscopy (macrophages), and 3), chemiluminescence (macrophages). The effect of the cytokine interferon gamma (IFN-g) on ROS production was measured. The association with the phagolysosome was also assessed by confocal microscopy. Results:  NTHi stimulation caused a significant increase in ROS production by lung macrophages (in all 3 methods (p  Conclusions:  NTHi causes the release of reactive oxygen species from lung phagocytes and may be an important cause of oxidative stress.