tbuckley/cabot-search huggingface dataset:
Serum bile acids in liver disease
Authors: G. Neale, B. Lewis, V. Weaver, D. Panveliwalla
Journal: Gut (1971)

Serum bile acids have been measured in patients with a wide variety of liver diseases using a technique which separates the major individual conjugated and free bile acids. Total serum bile acids may be elevated up to 100 times the normal concentration in patients with liver disease and this increase consists largely of conjugated bile acids. The ratio of glycine-conjugated to taurine-conjugated bile salts is low in all types of liver disease and this is found particularly in the serum of patients with obstructive jaundice. There is a decrease in the ratio of trihydroxy:dihydroxy cholanic acid in patients with cirrhosis.
Stimulation of Surfactant Production by Oxytocin-Induced Labor in the Rabbit
Authors: Seamus A. Rooney, Laurice I. Gobran, Theresa S. Wai-Lee
Journal: Journal of Clinical Investigation (1977)

The respiratory distress syndrome is believed to be due to insufficient surfactant. It is known that there is a greater incidence of the respiratory distress syndrome among infants delivered by cesarean section before labor than among those delivered after labor at the same gestational age. The purpose of this study was to determine the effect of labor on the production of pulmonary surfactant.
Models for Predicting Type 1 Diabetes in Siblings of Affected Children
Authors: Samy Mrena, Suvi M. Virtanen, Pekka Laippala, Petri Kulmala, Marja-Leena Hannila, Hans K. Åkerblom, Mikael Knip
Journal: Diabetes Care (2006)

To generate predictive models for the assessment of risk of type 1 diabetes and age at diagnosis in siblings of children with newly diagnosed type 1 diabetes.Cox regression analysis was used to assess the risk of progression to type 1 diabetes, and multiple regression analysis was used to estimate the age at disease presentation in 701 siblings of affected children. Sociodemographic, genetic, and immunological variables were included in the analyses. Subanalyses were performed in a group of 77 autoantibody-positive siblings with additional metabolic data.A total of 47 siblings (6.7%) presented with type 1 diabetes during the 15-year observation period. Young age, an increasing number of detectable diabetes-associated autoantibodies at initial sampling and of affected first-degree relatives, and HLA DR-conferred disease susceptibility predicted progression to type 1 diabetes. In the subgroup of 77 autoantibody-positive siblings, young age, HLA DR-conferred susceptibility, an increasing number of autoantibodies, a reduced first-phase insulin response, and decreased insulin sensitivity in relation to first-phase insulin response were associated with increased risk of progression to type 1 diabetes. Age at diagnosis was predicted by age, insulinoma-associated protein 2 antibody levels, and number of autoantibodies at initial sampling (R(2) = 0.76; P < 0.001). In the smaller cohort of autoantibody-positive subjects, first-phase insulin response and HLA DR-conferred susceptibility were additional predictors of age at diagnosis.Information on autoantibody status and levels, HLA-conferred disease susceptibility, and insulin secretion and sensitivity seems to be useful in addition to age and family history of type 1 diabetes when assessing risk of progression to type 1 diabetes and time to diagnosis in siblings of children with newly diagnosed type 1 diabetes.
Carcinoembryonic Antigen–Related Cell Adhesion Molecule 1 Inhibits MMP-9–Mediated Blood–Brain–Barrier Breakdown in a Mouse Model for Ischemic Stroke
Authors: Peter Ludewig, Jan Sedlacik, Mathias Gelderblom, Christian Bernreuther, Yücel Korkusuz, Christoph Wagener, Christian Gerloff, Jens Fiehler, Tim Magnus, Andrea Kristina Horst
Journal: Circulation Research (2013)

Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated.We sought to identify and characterize the relevance of CEACAM1-expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1(-/-) and wild-type mice.Focal ischemia was induced by temporary occlusion of the middle cerebral artery with a microfilament. Using MRI and Evans blue permeability assays, we observed increased stroke volumes, BBB breakdown and edema formation, reduction of cerebral perfusion, and brain atrophy in Ceacam1(-/-) mice. This translated into poor performance in neurological scoring and high poststroke-associated mortality. Elevated neutrophil influx, hyperproduction, and release of neutrophil-related matrix metalloproteinase-9 in Ceacam1(-/-) mice were confirmed by immune fluorescence, flow cytometry, zymography, and stimulation of neutrophils. Importantly, neutralization of matrix metalloproteinase-9 activity in Ceacam1(-/-) mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochemistry of murine and human poststroke autoptic brains congruently identified abundance of CEACAM1(+)matrix metalloproteinase-9(+) neutrophils in the ischemic hemispheres.CEACAM1 controls matrix metalloproteinase-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.
Incidence of arthro-osteitis in patients with pustulosis palmaris et plantaris
Authors: H. Sonozaki, M. Kawashima, O. Hongo, H. Yaoita, M. Ikeno, M. Matsuura, K. Okai, A. Azuma
Journal: Annals of the Rheumatic Diseases (1981)

Arthro-osteitis at the anterior chest wall was found in 12 (9·4%) out of 128 consecutive patients with pustulosis palmaris et plantaris. This finding indicates that the concomitance of arthro-osteitis with PPP is not incidental but is based on some common aetiological factor. We propose a term `pustulotic arthro-osteitis' for this condition.
Fluid Shear Stress Stimulates Phosphorylation of Akt in Human Endothelial Cells
Authors: Stefanie Dimmeler, Birgit Assmus, Corinna Hermann, Judith Haendeler, Andreas M. Zeiher
Journal: Circulation Research (1998)

Abstract —Fluid shear stress alters the morphology and function of the endothelium by activating several kinases. Furthermore, shear stress potently inhibits apoptosis of endothelial cells. Since activation of Akt kinase has been shown to prevent cell death, we investigated the effects of shear stress on Akt phosphorylation. To test the hypothesis that shear stress interacts with the Akt kinase pathway, human umbilical venous endothelial cells were exposed to laminar shear stress (15 dyne/cm 2 ). Western blotting with specific antibodies against the phosphorylated Akt demonstrated a time-dependent stimulation of Akt phosphorylation by shear stress with a maximal increase up to 6-fold after 1 hour of shear stress exposure. The stimulation of Akt phosphorylation by shear stress thereby seemed to be mediated by the phosphoinositide 3-OH kinase (PI3K), as evidenced by the significant inhibition of shear stress–induced Akt phosphorylation by the PI3K inhibitors wortmannin (20 nmol/L) and Ly294002 (10 μmol/L). In addition, pharmacological inhibition of PI3K reduced the antiapoptotic effect of shear stress against growth factor depletion–induced apoptosis. Most important, overexpression of a dominant-negative Akt mutant significantly inhibited the apoptosis-suppressive effect of shear stress against serum depletion–induced apoptosis, thus indicating the direct involvement of shear stress–induced Akt phosphorylation for inhibition of endothelial cell apoptosis. These results define a novel shear stress–stimulated signal transduction pathway, namely, activation of the serine/threonine kinase Akt, which may contribute to the profound changes in endothelial morphology and function by shear stress.
NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats
Authors: Yong-Hoon Kim, Jung Hwan Hwang, Kyung-Shim Kim, Jung-Ran Noh, Gil-Tae Gang, Sang-Woo Kim, Seung Pil Jang, Sang-Ju Lee, Sung-Ho Her, Kyeong-Hoon Jeong, Tae Hwan Kwak, Woo Jin Park, Irina V. Balyasnikova, Minho Shong, Chul-Ho Lee
Journal: Cardiovascular Research (2013)

Angiotensin-converting enzyme (ACE) plays a key role in blood pressure (BP) homeostasis via regulation of angiotensin II. Active ACE ectodomain is enzymatically cleaved and released into body fluids, including plasma, and elevated plasma ACE levels are associated with increased BP. β-lapachone (βL) has been shown to increase cellular NAD+/NADH ratio via activation of NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, we evaluated whether NQO1 activation by βL modulates BP through regulation of ACE shedding in an animal model of hypertension. Spontaneously hypertensive rats (SHR) and a human ACE-overexpressing rat lung microvascular endothelial cell line (RLMVEC-hACE) were used to investigate the mechanism by which βL exerts a hypotensive effect. In vitro studies revealed that βL significantly increased intracellular Ca2+ ([Ca2+]i) levels and CaMKII Thr286 phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of βL-induced [Ca2+]i level changes through intracellular Ca2+ chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only βL-induced increase in [Ca2+]i levels and CaMKII phosphorylation, but also βL-mediated decrease in ACE shedding. The effect of βL on ACE shedding was also blocked by inhibition of CaMKII. In SHR, βL reduced BP following increase of CaMKII Thr286 phosphorylation in the lung and decrease of ACE activity and angiotensin II levels in plasma. This is the first study demonstrating that ACE shedding is regulated by NQO1 activation, which is possibly correlated with relieving hypertension in SHR. These findings provide strong evidence suggesting that NQO1 might be a new target for ACE modulation and BP control.
Accuracy and Predictive Value of Classification Schemes for Ketosis-Prone Diabetes
Authors: Ashok Balasubramanyam, Gilberto Garza, Lucille Rodriguez, Christiane S. Hampe, Lakshmi Gaur, Åke Lernmark, Mario R. Maldonado
Journal: Diabetes Care (2006)

OBJECTIVE—Ketosis-prone diabetes (KPD) is an emerging, heterogeneous syndrome. A sound classification scheme for KPD is essential to guide clinical practice and pathophysiologic studies. Four schemes have been used and are based on immunologic criteria, immunologic criteria and insulin requirement, BMI, and immunologic criteria and β-cell function (Aβ classification). The aim of the present study is to compare the four schemes for accuracy and predictive value in determining whether KPD patients have absent or preserved β-cell function, which is a strong determinant of long-term insulin dependence and clinical phenotype. RESEARCH DESIGN AND METHODS—Consecutive patients (n = 294) presenting with diabetic ketoacidosis and followed for 12–60 months were classified according to all four schemes. They were evaluated longitudinally for β-cell autoimmunity, clinical and biochemical features, β-cell function, and insulin dependence. β-Cell function was defined by peak plasma C-peptide response to glucagon ≥1.5 ng/ml. The accuracy of each scheme to predict absent or preserved β-cell function after 12 months of follow-up was tested using multiple statistical analyses. RESULTS—The “Aβ” classification scheme was the most accurate overall, with a sensitivity and specificity of 99.4 and 95.9%, respectively, positive and negative likelihood ratios of 24.55 and 0.01, respectively, and an area under the receiver operator characteristic curve of 0.972. CONCLUSIONS—The Aβ scheme has the highest accuracy and predictive value in classifying KPD patients with regard to clinical outcomes and pathophysiologic subtypes.
Reflex Alterations in Venomotor Tone Produced by Venous Congestion
Authors: ROBERT S. ALEXANDER
Journal: Circulation Research (1956)

Changes in venous tone produced by partial occlusion of the thoracic inferior vena cava, or of the mitral orifice, have been studied in acute experiments on anesthetized dogs, employing distensibility diagrams obtained from injections into the veins of a loop of intestine to measure venous tone. The results demonstrate a reflex mechanism producing venous dilation in response to venous congestion which is mediated by vagal afferents and inhibition of sympathetic efferents.
Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies
Authors: Jean-Laurent Casanova, Mary Ellen Conley, Stephen J. Seligman, Laurent Abel, Luigi D. Notarangelo
Journal: The Journal of Experimental Medicine (2014)

Can genetic and clinical findings made in a single patient be considered sufficient to establish a causal relationship between genotype and phenotype? We report that up to 49 of the 232 monogenic etiologies (21%) of human primary immunodeficiencies (PIDs) were initially reported in single patients. The ability to incriminate single-gene inborn errors in immunodeficient patients results from the relative ease in validating the disease-causing role of the genotype by in-depth mechanistic studies demonstrating the structural and functional consequences of the mutations using blood samples. The candidate genotype can be causally connected to a clinical phenotype using cellular (leukocytes) or molecular (plasma) substrates. The recent advent of next generation sequencing (NGS), with whole exome and whole genome sequencing, induced pluripotent stem cell (iPSC) technology, and gene editing technologies—including in particular the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology—offer new and exciting possibilities for the genetic exploration of single patients not only in hematology and immunology but also in other fields. We propose three criteria for deciding if the clinical and experimental data suffice to establish a causal relationship based on only one case. The patient’s candidate genotype must not occur in individuals without the clinical phenotype. Experimental studies must indicate that the genetic variant impairs, destroys, or alters the expression or function of the gene product (or two genetic variants for compound heterozygosity). The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, or by default via a relevant animal phenotype. When supported by satisfaction of rigorous criteria, the report of single patient–based discovery of Mendelian disorders should be encouraged, as it can provide the first step in the understanding of a group of human diseases, thereby revealing crucial pathways underlying physiological and pathological processes.
Transcranial direct current brain stimulation for chronic pain
Authors: N. E. O'Connell, B. M. Wand
Journal: BMJ (2015)

Not recommended; early promise is fading fast as trial methods improve

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that delivers low intensity direct current stimulation to the brain through electrodes applied to the skin over the target area. It has been found to modulate cortical excitability at the target site leading some researchers to investigate it as a possible treatment for chronic pain and a host of other conditions. tDCS has clear appeal; it is cheap, relatively easy to use, and seems to be safe. In a linked article, Luedtke and colleagues (doi:10.1136/bmj.h1640) report the results of a randomised controlled trial of transcranial direct current stimulation for chronic low back pain.1

The motor cortex is the most common target of brain stimulation for chronic pain. Based largely on studies of invasive epidural stimulation of the motor cortex, researchers hypothesised that tDCS might reduce pain by modulating activity in cortical and subcortical areas of the brain involved in pain processing and by facilitating descending inhibitory mechanisms.2 3 4 As the experience of pain is ultimately generated by …
Studies on factors predicting GORD response to proton-pump inhibitors: NERD subpopulations need to be analysed separately
Authors: Edoardo Savarino, Patrizia Zentilin, Vincenzo Savarino
Journal: Gut (2011)

We read with interest the paper by Zerbib et al 1 on the factors predicting the response of patients with gastro-oesophageal reflux disease (GORD) to proton pump inhibitors (PPIs) therapy and believe that the results they obtained must be interpreted with caution.

The French authors concluded that multivariate analysis, including both clinical and physiological parameters, did not identify any reflux pattern associated with PPI failure. This is at variance with many previous findings, which have clearly shown that an increased oesophageal acid exposure is a robust predictor of reflux response to PPIs. We believe that the surprising result achieved by Zerbib et al is probably due to the fact …
Effect of c-neu/ ErbB2 Expression Levels on Estrogen Receptor α–Dependent Proliferation in Mammary Epithelial Cells: Implications for Breast Cancer Biology
Authors: Gopalan Shyamala, Yu-Chien Chou, Robert D. Cardiff, Elizabeth Vargis
Journal: Cancer Research (2006)

Abstract Mammary development and tumorigenesis are profoundly influenced by signaling pathways under the control of c-erbB2/c-neu and estrogen receptor α (ERα). Signaling through ERα is essential for ductal growth during puberty. In mice overexpressing wild-type c-neu in mammary epithelial cells, Tg (c-neu), ductal growth is impaired. An impeded signaling through ERα is also observed in a subset of human mammary tumors that overexpress erbB2. However, ductal growth is also impaired in the absence of c-neu in mouse mammary epithelial cells. To resolve this apparent paradox, we examined the relationship between c-neu expression and estrogen/ERα–dependent cell proliferation in pubertal Tg (c-neu). We report that proliferation in both terminal end buds and ducts is associated with ERα-positive cells, including those that coexpress c-neu, and is abolished in the absence of circulating estradiol. Tg (c-neu) contains hyperplastic mammary ducts with high proliferative index and coexpression of both ERα and c-neu in the dividing cells. These findings suggest that c-neu promotes ERα-dependent proliferation, and that this is responsible for the presence of hyperplastic ducts. Some of the hyperplastic ducts have acinar structures, indicative of morphologic differentiation. These ducts have low proliferative index and accompanied by a vast decrease in proliferation of ERα-positive cells, including those that express c-neu. As such, c-neu has dual but opposing effects on ERα-dependent proliferation in mammary epithelial cells. Therefore, depending on the physiologic setting, ductal morphogenesis will be compromised both in the absence and overexpression of c-neu, thus explaining the paradox. (Cancer Res 2006; 66(21): 10391-8)
A recurrent idiotype on monoclonal anti-human Ia antibodies.
Authors: V Quaranta, M Zanetti, R A Reisfeld
Journal: The Journal of Experimental Medicine (1982)

We report a recurrent idiotype on a remarkably high fraction (4/19) of murine monoclonal antibodies specific for human Ia monomorphic determinants and elicited by separate immunizations. For three of them, the shared idiotype is associated with the antigen-combining site. These results indicate that the spectrum of mouse antibody responses to human Ia antigens may be based on recurrent idiotypes, suggesting a limited potential repertoire of murine monoclonal antibodies to human Ia antigens. Anti-idiotypic reagents might be helpful in dissecting this repertoire and to generate a mirror image of a human Ia antigenic map. Furthermore, antisera to the idiotype of antibodies specific for human Ia monomorphic determinants might help in elucidating the interactions between Ia molecules and receptors on immune cells.
Survival of Functionally Anuric Patients on Automated Peritoneal Dialysis
Authors: Edwina A. Brown, Simon J. Davies, Peter Rutherford, Frederique Meeus, Mercedes Borras, Werner Riegel, Jose C. Divino Filho, Edward Vonesh, Monique Van Bree
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The European APD Outcome Study (EAPOS) is a 2-yr, prospective, multicenter study of the feasibility and clinical outcomes of automated peritoneal dialysis (APD) in anuric patients. A total of 177 patients were enrolled with a median age of 54 yr (range, 21 to 91 yr). Previous median total time on dialysis was 38 mo (range, 1.6 to 259 mo), and 36% of patients had previously been on hemodialysis for &gt;90 d. Diabetes and cardiovascular disease were present in 17% and 46% of patients, respectively. The APD prescription was adjusted at physician discretion to aim for creatinine clearance (Ccrea) ≥60 L/wk per 1.73 m 2 and ultrafiltration (UF) ≥750 ml/24 h during the first 6 mo. Baseline solute transport status (D/P) was determined by peritoneal equilibration test. At 1 yr, 78% and 74% achieved Ccrea and UF targets, respectively; median drained dialysate volume was 16.2 L/24 h with 50% of patients using icodextrin. Baseline D/P was not related to UF achieved at 1 yr. At 2 yr, patient survival was 78% and technique survival was 62%. Baseline predictors of poor survival were age (&gt;65 yr; P = 0.006), nutritional status (Subjective Global Assessment grade C; P = 0.009), diabetic status ( P = 0.008), and UF (&lt;750 ml/24 h; P = 0.047). Time-averaged analyses showed that age, Subjective Global Assessment grade C and diabetic status predicted patient survival with UF the next most significant variable (risk ratio, 0.5/L per d; P = 0.097). Baseline Ccrea, time-averaged Ccrea, and baseline D/P had no effect on patient or technique survival. This study shows that anuric patients can successfully use APD. Baseline UF, not Ccrea or membrane permeability, is associated with patient survival. E-mail: e.a.brown@imperial.ac.uk