tbuckley/cabot-search huggingface dataset:
Altered Titin Expression, Myocardial Stiffness, and Left Ventricular Function in Patients With Dilated Cardiomyopathy
Authors: Sherif F. Nagueh, Gopi Shah, Yiming Wu, Guillermo Torre-Amione, Nicholas M.P. King, Sunshine Lahmers, Christian C. Witt, Katy Becker, Siegfried Labeit, Henk L. Granzier
Journal: Circulation (2004)

Background— The role of the giant protein titin in patients with heart failure is not well established. We investigated titin expression in patients with end-stage heart failure resulting from nonischemic dilated cardiomyopathy, in particular as it relates to left ventricular (LV) myocardial stiffness and LV function. Methods and Results— SDS-agarose gels revealed small N2B (stiff) and large N2BA (compliant) cardiac titin isoforms with a mean N2BA:N2B expression ratio that was significantly ( P &lt;0.003) increased in 20 heart failure patients versus 6 controls. However, total titin was unchanged. The coexpression ratio was highest in a subsample of patients with an impaired LV relaxation pattern (n=7), intermediate in those with pseudonormal filling (n=6), and lowest in the group with restrictive filling (n=7). Mechanical measurements on LV muscle strips dissected from these hearts (n=8) revealed that passive muscle stiffness was significantly reduced in patients with a high N2BA:N2B expression ratio. Clinical correlations support the relevance of these changes for LV function (assessed by invasive hemodynamics and Doppler echocardiography). A positive correlation between the N2BA:N2B titin isoform ratio and deceleration time of mitral E velocity, A wave transit time, and end diastolic volume/pressure ratio was found. These changes affect exercise tolerance, as indicated by the positive correlation between the N2BA:N2B isoform ratio and peak O 2 consumption (n=10). Upregulated N2BA expression was accompanied by increased expression levels of titin-binding proteins (cardiac ankyrin repeat protein, ankrd2, and diabetes ankyrin repeat protein) that bind to the N2A element of N2BA titin (studied in 13 patients). Conclusions— Total titin content was unchanged in end-stage failing hearts and the more compliant N2BA isoform comprised a greater percentage of titin in these hearts. Changes in titin isoform expression in heart failure patients with dilated cardiomyopathy significantly impact diastolic filling by lowering myocardial stiffness. Upregulation of titin-binding proteins indicates that the importance of altered titin expression might extend to cell signaling and regulation of gene expression.
Costimulation of T Cell Activation by Integrin-associated Protein (CD47) Is an Adhesion-dependent, CD28-independent Signaling Pathway
Authors: Martina I. Reinhold, Frederik P. Lindberg, Gilbert J. Kersh, Paul M. Allen, Eric J. Brown
Journal: The Journal of Experimental Medicine (1997)

The integrin-associated protein (IAP, CD47) is a 50-kD plasma membrane protein with a single extracellular immunoglobulin variable (IgV)-like domain, a multiply membrane-spanning segment, and alternatively spliced short cytoplasmic tails. On neutrophils, IAP has been shown to function in a signaling complex with β3 integrins. However, the function of IAP on T cells, which express little or no β3 integrin, is not yet defined. Here, we show that mAbs recognizing IAP can enhance proliferation of primary human T cells in the presence of low levels of antiCD3, but have no effect on T cell proliferation on their own. Together with suboptimal concentrations of anti-CD3, engagement of IAP also enhances IL-2 production in Jurkat cells, an apparently integrin-independent function of IAP. Nonetheless, costimulation by IAP ligation requires cell adhesion. IAP costimulation does not require CD28. Furthermore, anti-IAP, but not anti-CD28, synergizes with suboptimal anti-CD3 to enhance tyrosine phosphorylation of the CD3 ζ chain and the T cell–specific tyrosine kinase Zap70. Ligation of human IAP transfected into the hemoglobin-specific 3.L2 murine T cell hybridoma costimulates activation for IL-2 secretion both with anti-CD3 and with antigenic peptides on antigen-presenting cells (APCs). Moreover, ligation of IAP but not CD28 can convert antagonist peptides into agonists in 3.L2 cells. Using costimulation by IAP ligation as an assay to analyze the structure–function relationships in IAP signaling, we find that both the extracellular and multiply membrane-spanning domains of IAP are necessary for synergy with the antigen receptor, but the alternatively spliced cytoplasmic tails are not. These data demonstrate that IAP ligation initiates an adhesiondependent costimulatory pathway distinct from CD28. We hypothesize that anti-IAP generates the costimulatory signal because it modulates interactions of the IgV domain with other plasma membrane molecules; this in turn activates effector functions of the multiply membrane-spanning domain of IAP. This model may have general significance for how IAP functions in cell activation.
PTH-009 Ercp Under Propofol: Do Patients Prefer It?
Authors: H Steed, M Potter, J Leithead, K Lau, R Glass, S Hebbar, D Durkin, M Deakin, J Green
Journal: Gut (2014)

<h3>Introduction</h3> Endoscopic retrograde cholangiopancreatography (ERCP) is an invasive procedure involving heavy sedation. Use of propofol as sedation in ERCP has been demonstrated to be safe, but is it preferred by patients? <h3>Methods</h3> A prospectively collected dataset of patient satisfaction questionnaires post ERCP, using a Likehart scale. Patients excluded were those who declined to do so, those unable to consent for themselves. After 30 days patients were contacted by an ERCP-trained nurse to discuss any problems and complications arising in that time. <h3>Results</h3> 128 questionnaires have been completed and followed up at 30-days. 26 had the procedure under propofol +/- midazolam and fentanyl (administered by an anaesthetist) and 102 under a combination of midazolam and fentanyl as per standard unit practice administered by the ERCPist. 30-day FU: 93 of 103 agreed to contact, 16 of whom were uncontactable (based on 2–3 separate attempts to call them on the number provided), 4 of 23 uncontactable from propofol group. 5 propofol patients reported problems in the 30 day follow up (2 were serious), compared to 24 of the sedation group (4 of which were serious). There was no difference in overall satisfaction between the groups, the propofol group reported less discomfort during the procedure (p &lt; 0.001), less wretching (p = 0.015) and were more willing to have the procedure repeated (p = 0.051). Using a score of 1 and 2 for satisfied and anyone reporting a score of 3–7 as less or not satisfied, the factors associated with less satisaction were discomfort during the procedure (=0.006), overall discomfort (p = 0.001), overall rating of experience and unwillingness to repeat the procedure (p &lt; 0.001). After adjusting for age, gender and number of interventions there was no association between propofol use and non satisfaction (adjusted OR 1.12 (95% CI: 0.28–4.45), p = 0.868). <h3>Conclusion</h3> Patients do prefer ERCP under propofol, but not by much. They get less discomfort (where 0 was a scale of no discomfort and 7 of extreme pain) and therefore are more willing to have the procedure done again. Interestingly propofol procedures are not taking longer than normally-sedated procedures and there are not higher numbers of therapeutic interventions. This may reflect the current bias in selecting a propofol list for a patient or form part of the learning curve of finding the role of propofol-ERCP in the therapeutic strategy. Further data collection is required to see if ERCP under propofol reduces the number of repeat procedures and therefore can justify itself as cost-effective. <h3>Disclosure of Interest</h3> None Declared.
Circulating tumor cells and bone metastases as detected by FDG–PET/CT in patients with metastatic breast cancer
Authors: U. De Giorgi, V. Valero, E. Rohren, M. Mego, G.V. Doyle, M.C. Miller, N.T. Ueno, B.C. Handy, J.M. Reuben, H.A. Macapinlac, G.N. Hortobagyi, M. Cristofanilli
Journal: Annals of Oncology (2009)
Functional role of the 503F variant of the organic cation transporter OCTN1 in Crohn's disease
Authors: D Taubert
Journal: Gut (2005)

Several susceptible gene loci were identified as being involved in the aetiology of Crohn’s disease (CD).1 Recently, a non-synonymous single nucleotide polymorphism in the SLC22A4 gene encoding the organic cation transporter OCTN1 has been linked with CD in Caucasian populations (a 1672CT transversion, resulting in the amino acid substitution L503F).2,3 However, the functional consequences of this alteration are unclear as yet.

We have now discovered that L-ergothioneine (ET, 2-mercaptohistidine trimethylbetaine), a naturally occurring water soluble thiol compound of dietary origin, is the physiological substrate of OCTN1.4 Analysis of the concentration dependence of ET transport in OCTN1 transfected HEK293 fibroblasts by liquid chromatography tandem mass spectrometry revealed that the 503F variant was associated with a threefold higher substrate affinity (1/Km) and a twofold lower maximal transport velocity (Vmax), which resulted in a 50% higher initial transport capacity (Vmax/Km (503F) ≈ 1.5 × Vmax/Km (503L)) at low ET levels (⩽10 µmol/l) (fig 1A). Analysis of the time course of ET transport showed a higher clearance for …
A randomised controlled trial evaluating the use of enteral nutritional supplements postoperatively in malnourished surgical patients
Authors: A H Beattie
Journal: Gut (2000)

<h3>BACKGROUND</h3> Patients who undergo surgery are at risk of malnutrition due to periods of starvation, the stress of surgery, and subsequent increase in metabolic rate. There are limited data on nutritional outcome of surgical patients. <h3>AIMS</h3> To investigate changes in nutritional status and the influence of oral supplements on nutritional status, morbidity, and quality of life in postoperative surgical patients. <h3>METHODS</h3> Entry was determined by the presence of malnutrition, as defined by a body mass index (BMI) ⩽20 kg/m<sup>2</sup>, anthropometric measurements ⩽15th percentile on admission, or initiation of oral diet postoperatively and/or a weight loss of 5% or more during the operative period. We studied 101 patients: 52 were randomised to the treatment group (TG) and prescribed a 1.5 kcal/ml nutritional supplement; 49 patients were randomised to the control group (CG) and continued with routine nutritional management. Nutritional status was assessed by weight, anthropometry, and grip strength, with measurements taken at two weekly intervals for 10 weeks. Complications, namely wound infection, chest infection, and antibiotic use were documented. Quality of life (QOL) was assessed using the UK SF-36 questionnaire. <h3>RESULTS</h3> Patients in the control group lost a maximum mean (SD) of 5.96 (4.21) kg in weight over a period of eight weeks while patients in group TG lost less weight overall (maximum mean (SD) 3.40 (0.89) kg (p&lt;0.001) occurring at four weeks and progressively regained weight from week 4). Anthropometry, grip strength, and QOL were similarly significantly different between groups (p&lt;0.001). Fewer patients in the treatment group (7/52) required antibiotic prescriptions compared with the control group (15/49). <h3>CONCLUSIONS</h3> Nutritional status declined for two months after discharge. Postoperative nutritional supplementation improved nutritional status, QOL, and morbidity in these patients.
Antihypertensive Efficacy of Aliskiren
Authors: Franz H. Messerli, Sripal Bangalore
Journal: Circulation (2009)

T he thorough prospective, randomized, double-blind trial of Schmieder et al 1 in the current issue of Circulation convincingly documents that aliskiren treatment provided significantly greater blood pressure (BP) reduction than hydrochlorothiazide.The study is well done; the number of patients (nϭ1124) is impressive; and the efficacy variables were analyzed, as is appropriate for an intention-to-treat population, with the last observation carried forward method.The authors concluded that aliskiren provided "more effective BP lowering than a thiazide-type diuretic, the drug class recommended by JNC 7 [Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure] guidelines 2 as first-line therapy for the treatment of hypertension."Indeed, not only JNC 7 but also JNC VI, V, IV, III, and I have recommended a thiazide-type diuretic, most commonly hydrochlorothiazide in the United States, as first-line therapy.Thus, over the years and decades, the JNC has elevated hydrochlorothiazide to the gold standard of antihypertensive therapy.Not surprisingly, therefore, hydrochlorothiazide remains the most prescribed drug in the United States.In 2007, Ͼ130 million prescriptions for hydrochlorothiazide, either alone or in combination, were written in this country.The doses of hydrochlorothiazide almost exclusively prescribed are 12.5 and 25 mg/d.This begs the question as to how solid the evidence is that hydrochlorothiazide in the dose of 12.5 to 25 mg reduces cardiovascular events (ie, stroke and heart attacks).A thorough scrutiny of the literature reveals little, if any, outcome evidence for low-dose hydrochlorothiazide.All outcome studies were done with higher doses, with hydrochlorothiazide in fixed combinations with a potassium-sparing diuretic, or with chlorthalidone, which obviously is an entirely different antihypertensive drug. 3Hydrochlorothiazide was compared with and found to be inferior to enalapril in the Australian National Blood Pressure 2 study, but the dose is not specified. 4Thus, we have to conclude that for the most prescribed drug in the United States, outcome evidence is paltry.
Studies on a patient with leucocytoclastic vasculitis ‘pyoderma gangrenosum’ and paraproteinaemia
Authors: DOROTHY M. THOMPSON, ROBERT A. MAIN, J. SWANSON BECK, FRANK ALBERT-RECHT
Journal: British Journal of Dermatology (2006)

A patient with leucocytoclastic vasculitis, pyoderma gangrenosum, chronic pyelonephritis and a paraprotein of IgA type is described. The vasculitis responded favourably to dapsone therapy, while the pyoderma gangrenosum improved only when steroids were also given. During an exacerbation following withdrawal of dapsone, the serum IgG level fell early, but the β1c globulin level remained normal. Immunofluorescence studies on a vasculitic lesion showed granular deposits of IgG and β1c the walls of the blood vessels and a more extensive exudate of fibrin. Skin testing with bacterial antigens and patch testing to potassium iodide produced lesions which clinically, histologically and immunologically resembled the spontaneous vasculitic lesion.
Regeneration of Human Infarcted Heart Muscle by Intracoronary Autologous Bone Marrow Cell Transplantation in Chronic Coronary Artery Disease
Authors: Bodo E. Strauer, Michael Brehm, Tobias Zeus, Thomas Bartsch, Christina Schannwell, Christine Antke, Rüdiger V. Sorg, Gesine Kögler, Peter Wernet, Hans-Wilhelm Müller, Matthias Köstering
Journal: Journal of the American College of Cardiology (2005)
Deletion Rate Evolution and Its Effect on Genome Size and Coding Density
Authors: M. E. Pettersson, C. G. Kurland, O. G. Berg
Journal: Molecular Biology and Evolution (2009)

Deletion rates are thought to be important factors in determining the genome size of organisms in nature. Although it is indisputable that deletions, and thus deletion rates, affect genome size, it is unclear how, or indeed if, genome size is regulated via the deletion rate. Here, we employ a mathematical model to determine the evolutionary fate of deletion rate mutants. Simulations are employed to explore the interactions between deletions, deletion rate mutants, and genome size. The results show that, in this model, the fate of deletion rate mutants will depend on the fraction of essential genomic material, on the frequency of sexual recombination, as well as on the population size of the organism. We find that there is no optimal deletion rate in any state. However, at one critical coding density, all changes in deletion rate are neutral and the rate may drift either up or down. As a consequence, the coding density of the genome is expected to fluctuate around this critical density. Characteristic differences in the impact of deletion rate mutations on prokaryote and eukaryote genomes are described.
Inborn errors of immunity to infection
Authors: Jean-Laurent Casanova, Laurent Abel
Journal: The Journal of Experimental Medicine (2005)

The immune system's function is to protect against microorganisms, but infection is nonetheless the most frequent cause of death in human history. Until the last century, life expectancy was only ∼25 years. Recent increases in human life span primarily reflect the development of hygiene, vaccines, and anti-infectious drugs, rather than the adjustment of our immune system to coevolving microbes by natural selection. We argue here that most individuals retain a natural vulnerability to infectious diseases, reflecting a great diversity of inborn errors of immunity.
Optimization of adenoviral vector-mediated transgene expression in the canine brain in vivo, and in canine glioma cells in vitro
Authors: Marianela Candolfi, G. Elizabeth Pluhar, Kurt Kroeger, Mariana Puntel, James Curtin, Carlos Barcia, A.K.M. Ghulam Muhammad, Weidong Xiong, Chunyan Liu, Sonali Mondkar, William Kuoy, Terry Kang, Elizabeth A. McNeil, Andrew B. Freese, John R. Ohlfest, Peter Moore, Donna Palmer, Phillip Ng, John D. Young, Pedro R. Lowenstein, Maria G. Castro
Journal: Neuro-Oncology (2007)

Expression of the immune-stimulatory molecule Fms-like tyrosine kinase 3 ligand (Flt3L) and the conditional cytotoxic enzyme herpes simplex virus type 1 thymidine kinase (HSV1-TK) provides long-term immune-mediated survival of large glioblastoma multiforme (GBM) models in rodents. A limitation for predictive testing of novel antiglioma therapies has been the lack of a glioma model in a large animal. Dogs bearing spontaneous GBM may constitute an attractive large-animal model for GBM, which so far has remained underappreciated. In preparation for a clinical trial in dogs bearing spontaneous GBMs, we tested and optimized adenovirus-mediated transgene expression with negligible toxicity in the dog brain in vivo and in canine J3T glioma cells. Expression of the marker gene beta-galactosidase (beta-Gal) was higher when driven by the murine (m) than the human (h) cytomegalovirus (CMV) promoter in the dog brain in vivo, without enhanced inflammation. In the canine brain, beta-Gal was expressed mostly in astrocytes. beta-Gal activity in J3T cells was also higher with the mCMV than the hCMV promoter driving tetracycline-dependent (TetON) transgene expression within high-capacity adenovirus vectors (HC-Ads). Dog glioma cells were efficiently transduced by HC-Ads expressing mCMV-driven HSV1-TK, which induced 90% reduction in cell viability in the presence of ganciclovir. J3T cells were also effectively transduced with HC-Ads expressing Flt3L under the control of the regulatable TetON promoter system, and as predicted, Flt3L release was stringently inducer dependent. HC-Ads encoding therapeutic transgenes under the control of regulatory sequences driven by the mCMV promoter are excellent vectors for the treatment of spontaneous GBM in dogs, which constitute an ideal preclinical animal model.
Cytokine mRNA gene expression in active and nonactive pulmonary sarcoidosis
Authors: EM Minshall, A Tsicopoulos, Z Yasruel, B Wallaert, H Akoum, H Vorng, AB Tonnel, Q Hamid
Journal: European Respiratory Journal (1997)

Sarcoidosis is a multisystem granulomatous disease associated with the expansion and activation of CD4+ T-lymphocytes and macrophages. To investigate the immunopathology of active and nonactive pulmonary sarcoidosis, we have examined the expression of cytokine gene transcripts in bronchoalveolar lavage cells from 15 patients with active pulmonary sarcoidosis, eight patients with non-active pulmonary sarcoidosis, and nine normal controls. Using in situ hybridization, the percentage of cells expressing messenger ribonucleic acid (mRNA) for interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 and interferon-gamma (IFN-gamma) were compared in the groups studied. In individuals with active sarcoidosis, there were significantly greater proportions of cells expressing mRNA for IL-2, IL-10, IL-12 and IFN-gamma than in subjects with nonactive disease and normal controls (p &lt; 0.01). There was no significant difference in the percentage of positive cells expressing IL-10 and IL-12 mRNA in the nonactive group compared to the normal controls (p &gt; 0.05). No significant differences in the percentages of IL-3, IL-4 and IL-5 mRNA positive cells were observed between active and nonactive sarcoidosis patients and normal controls (p &gt; 0.05). These results demonstrate that there is a preferential expression of T-helper type 1 cytokines in pulmonary sarcoidosis, and that cytokines related to macrophage activation are the most prominent. In addition, these data implicate an elevated expression of interleukin-2, -10 and -12 and interferon-gamma in active compared to nonactive sarcoidosis.
John Anthony Calvert
Authors: T. Slater
Journal: BMJ (2010)

As a student, John Anthony Calvert was senior president of the Royal Medical Society. He rejected a career in academic medicine in favour of general practice, and gained early experience in Coldstream and Norfolk. Attracted by the chance of health centre practice, he came to Stranraer in 1969 and remained until his retirement 30 years later.

John was …
Effect of Sleeping in a Head-Up Position on Intraocular Pressure in Patients with Glaucoma
Authors: Yvonne M. Buys, Tariq Alasbali, Ya-Ping Jin, Michael Smith, Pieter Gouws, Noa Geffen, John G. Flanagan, Colin M. Shapiro, Graham E. Trope
Journal: Ophthalmology (2010)
Histological evaluation of chronic pancreatitis by endoscopic ultrasound-guided fine needle biopsy
Authors: J Iglesias-Garcia, I Abdulkader, J Larino-Noia, J Forteza, J E Dominguez-Munoz
Journal: Gut (2006)

Collagenous sprue is a rare clinicopathological condition of the small bowel. It is characterised by abnormal subepithelial collagen deposition and is typically associated with malabsorption, diarrhoea and weight loss. The clinical features of collagenous sprue often resemble those of coeliac disease and together with frequent histological findings like mucosal thinning and intraepithelial lymphocytosis the diagnosis may be hard to reach without awareness of this condition. While coeliac disease is treated using gluten restriction, collagenous sprue is, however, not improved by this intervention. In cases of diet-refractory 'coeliac disease' it is therefore essential to consider collagenous sprue to initiate treatment at an early stage to prevent the fibrotic progression. Here, we report a case of a 78-year-old man with collagenous sprue and present the clinical and histological manifestations as well as the successful treatment course that he underwent.