tbuckley/cabot-search huggingface dataset:
Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen Aα-Chain Amyloidosis
Authors: Julian D. Gillmore, Helen J. Lachmann, Dorota Rowczenio, Janet A. Gilbertson, Cai-Hong Zeng, Zhi-Hong Liu, Lei-Shi Li, Ashutosh Wechalekar, Philip N. Hawkins
Journal: Journal of the American Society of Nephrology (2008)

Mutations in the fibrinogen A alpha-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A alpha-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0-12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.
Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome
Authors: John A. Martignetti, Aida Al Aqeel, Wafaa Al Sewairi, Christine E. Boumah, Marios Kambouris, S. Al Mayouf, K.V. Sheth, W. Al Eid, Oonagh Dowling, Juliette Harris, Marc J. Glucksman, Sultan Bahabri, Brian F. Meyer, Robert J. Desnick
Journal: Nature Genetics (2001)
NetPath: a public resource of curated signal transduction pathways
Authors: Kumaran Kandasamy, S Sujatha Mohan, Rajesh Raju, Shivakumar Keerthikumar, Ghantasala S Sameer Kumar, Abhilash K Venugopal, Deepthi Telikicherla, J Daniel Navarro, Suresh Mathivanan, Christian Pecquet, Sashi Kanth Gollapudi, Sudhir Gopal Tattikota, Shyam Mohan, Hariprasad Padhukasahasram, Yashwanth Subbannayya, Renu Goel, Harrys KC Jacob, Jun Zhong, Raja Sekhar, Vishalakshi Nanjappa, Lavanya Balakrishnan, Roopashree Subbaiah, YL Ramachandra, B Abdul Rahiman, TS Keshava Prasad, Jian-Xin Lin, Jon CD Houtman, Stephen Desiderio, Jean-Christophe Renauld, Stefan N Constantinescu, Osamu Ohara, Toshio Hirano, Masato Kubo, Sujay Singh, Purvesh Khatri, Sorin Draghici, Gary D Bader, Chris Sander, Warren J Leonard, Akhilesh Pandey
Journal: Genome biology (2010)

Abstract We have developed NetPath as a resource of curated human signaling pathways. As an initial step, NetPath provides detailed maps of a number of immune signaling pathways, which include approximately 1,600 reactions annotated from the literature and more than 2,800 instances of transcriptionally regulated genes - all linked to over 5,500 published articles. We anticipate NetPath to become a consolidated resource for human signaling pathways that should enable systems biology approaches.
Gli3-mediated hedgehog inhibition in human pluripotent stem cells initiates and augments developmental programming of adult hematopoiesis
Authors: Brendan A. S. McIntyre, Veronica Ramos-Mejia, Shravanti Rampalli, Rami Mechael, Jong-Hee Lee, Cantas Alev, Guojun Sheng, Mickie Bhatia
Journal: Blood (2013)
Loss of Adenomatous Poliposis Coli-α3 Integrin Interaction Promotes Endothelial Apoptosis in Mice and Humans
Authors: Vinicio A. de Jesus Perez, Ke Yuan, Mark E. Orcholski, Hirofumi Sawada, Mingming Zhao, Caiyun Grace Li, Nancy F. Tojais, Nils Nickel, Viswanathan Rajagopalan, Edda Spiekerkoetter, Lingli Wang, Roop Dutta, Daniel Bernstein, Marlene Rabinovitch
Journal: Circulation Research (2012)

Rationale: Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins promote pulmonary angiogenesis by recruiting the Wnt/β-catenin pathway, we proposed that β-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH. Objective: This study aims to establish the role of β-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury. Methods and Results: To assess the impact of β-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli ( Apc Min/+ ) mouse, where reduced APC causes constitutive β-catenin elevation. Surprisingly, hypoxic Apc Min/+ mice displayed greater PH and small PA loss compared with control C57Bl6J littermates. PA endothelial cells isolated from Apc Min/+ demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the α3 integrin, to stabilize focal adhesions and activate integrin-linked kinase-1 and phospho Akt. We found that PA endothelial cells from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin, and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC. Conclusions: We show that APC is integral to PA endothelial cells adhesion and survival and is reduced in PA endothelial cells from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.
The HDM Slit-Tablet Reduces Symptoms of House Dust Mite Allergic Rhinitis Independently of Asthma Status and Allergen Sensitisation Type; A Subgroup Analysis of Results from a Dbpc Phase III Trial (MERIT)
Authors: Joerg R. Kleine-Tebbe, Kjersti Moen, Dorte Rehm, Pascal M. Demoly
Journal: Journal of Allergy and Clinical Immunology (2015)
Stem cells and alopecia: a review of pathogenesis
Authors: K. Al-Refu
Journal: British Journal of Dermatology (2012)

Recent work has focused on the hair follicle as the main source of multipotent stem cells in the skin. The hair follicle bulge contains multipotent stem cells that can form the epidermis, hair follicles and sebaceous glands and help in repopulation of the epidermis after injury. The localization of these stem cells to the bulge area may explain why some types of inflammatory alopecia cause permanent loss of hair (cicatricial alopecia) (such as lichen planopilaris and discoid lupus erythematosus), while others (such as alopecia areata) are reversible (noncicatricial alopecia). The lack of distinctive bulge morphology in human hair follicles has hampered studies of bulge cells. To date, the best marker for bulge stem cells in human hair is cytokeratin (CK) 15; human bulge cells have been reported to express CK15 selectively throughout all stages of the hair cycle in different types of follicles. There is direct evidence in the mouse, and indirect evidence in the human, that compromising the integrity of the sebaceous gland and/or bulge is important in the development of alopecia. Several interesting studies have been done in the last few years to investigate the role of stem cells in alopecia, especially nonscarring types. This is a review about the role of stem cells in the pathogenesis of alopecia (scarring and nonscarring).
Pharmacogenomic insights into treatment and management of statin-induced myopathy
Authors: Bas JM Peters, Olaf H Klungel, Frank L Visseren, Anthonius de Boer, Anke-Hilse Maitland-van der Zee
Journal: Genome Medicine (2009)

Although statins are generally well tolerated, the most common adverse drug reaction from statin therapy is myopathy. This article reviews the current pharmacogenomic knowledge of statin-induced myopathy. Furthermore, we will discuss the importance of recent pharmacogenetic advances for the treatment and management of statin-induced myopathy. Variation in the SLCO1B1 gene is associated with increased incidence of statin-induced myopathy, particularly with simvastatin and less so with other statins. If different pharmacokinetic enzymes and transporters are responsible for susceptibility to myopathy, this may explain differences in the occurrence of statin-induced myopathy in individual patients. Genotyping in patients suffering from statin-induced myopathy may help to personalize the choice of statin for the lowest chance of developing myopathy.
Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic peptide.
Authors: P Aichele, H Hengartner, R M Zinkernagel, M Schulz
Journal: The Journal of Experimental Medicine (1990)

Induction in vivo of antiviral cytotoxic T cell response was achieved in a MHC class I-dependent fashion by immunizing mice three times with a free unmodified 15-mer peptide derived from the nucleoprotein of lymphocytic choriomeningitis virus in IFA. The effector T cells are CD8+, restricted to the class I Ld allele of the analyzed mouse strain, and are specific both at the level of secondary restimulation in vitro and at the effector T cell level. These results suggest that cocktails of viral peptides may be used as antiviral T cell vaccines.
K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration
Authors: Julia Schiemann, Falk Schlaudraff, Verena Klose, Markus Bingmer, Susumu Seino, Peter J Magill, Kareem A Zaghloul, Gaby Schneider, Birgit Liss, Jochen Roeper
Journal: Nature Neuroscience (2012)
Somatosensory evoked potentials in subclinical portosystemic encephalopathy: A comparison with psychometric tests
Authors: Sien-Sing Yang, Chi-Hwa Wu, Tsuey-Ru Chiang, Ding-Shinn Chen
Journal: Hepatology (1998)

We prospectively studied the role of somatosensory evoked potentials (SEPs) and psychometric tests in the assessment of subclinical portosystemic encephalopathy (PSE) in 61 cirrhotic patients with grade 0 PSE and 20 controls. Six additional uneducated controls underwent only psychometric tests. Median nerve-evoked cortical responses were recorded for N20-N65 interpeak latencies (IPLs). Psychometric tests were conducted within 4 hours of SEP testing. Seven (26.9%) controls and 30 (49.2%) cirrhotic patients had abnormal psychometric test results (writing sample tests, 20; five-point star tests, 17; number-connection tests, 19; and following-a-track tests, 18); seven controls and 25 cirrhotic patients had 6 or fewer years of education; 7 controls and 28 cirrhotics were older than 50 years of age. Cirrhotic patients (47.6 ± 8.3 milliseconds) had higher N20-N65 IPLs than controls (40.2 ± 3.0 milliseconds; P &lt; .001). Twenty-nine (47.5%) cirrhotic patients had abnormal N20-N65 IPLs. Of the 26 cirrhotic patients with more than 6 years of education, 15 (57.7%) had abnormal N20-N65 IPLs and 5 (19.2%) had abnormal psychometric test results ( P = .005). Our data show that N20-N65 IPLs of SEPs are helpful in the assessment of subclinical PSE; 47.5% of cirrhotic patients had subclinical PSE. Poorly educated and older subjects tended to have abnormal psychometric test results. SEPs were not affected by education and age and were more sensitive than psychometric tests in the assessment of subclinical PSE in better-educated cirrhotic patients.
Formation of porous membranes for drug delivery systems
Authors: P. van de Witte, H. Esselbrugge, A.M.P. Peters, P.J. Dijkstra, J. Feijen, R.J.J. Groenewegen, J. Smid, J. Olijslager, J.M. Schakenraad, M.J.D. Eenink, A.P. Sam
Journal: Journal of Controlled Release (1993)
Congenital mitral incompetence and coarctation of aorta: Report of two cases treated surgically
Authors: A. K. Terzaki, R. D. Leachman, M. K. Ali, G. L. Hallman, D. A. Cooley
Journal: Thorax (1972)

Two patients with congenital mitral incompetence and coarctation of the aorta are presented. One patient had associated patent ductus arteriosus, bicuspid aortic valve, and endocardial fibroelastosis. The diagnosis in the two patients presented is well established by clinical, laboratory, and surgical findings and also by necropsy examination in one case. It is proposed that the rarity of reported cases in the literature may have resulted from the frequent diagnosis of left ventricular failure in infancy secondary to coarctation, leading to the assumption that a mitral insufficiency murmur, when present, is due to functional regurgitation. Likewise, the murmur may be mistakenly thought to originate from a ventricular septal defect. The diagnosis of coarctation of the aorta presented no problem in either patient, while detection of the mitral incompetence was difficult. Coarctation of the aorta complicated by pulmonary hypertension in the absence of intracardiac shunt should draw attention to the possibility of associated mitral incompetence. Congestive heart failure, especially after correction of coarctation, was also an indication of possible associated mitral insufficiency. The two patients were treated by repair of coarctation of the aorta at 3 months and 3 years of age and by mitral valve replacement at the age of 18 months and 5 years, respectively. One patient was in terminal heart failure and died following mitral valve surgery. The other patient benefited from the operation and her case has been followed for over one year. Correction of coarctation of the aorta provided only temporary relief of heart failure. Until both anomalies are corrected response will generally be unsatisfactory. The aetiology of combined mitral incompetence and coarctation of the aorta can be explained on a congenital basis. Endocardial fibroelastosis of the left ventricle is thought to be secondary to coarctation of the aorta, mitral incompetence, or both.
Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort
Authors: C van Walraven, M M Mamdani, P S Wells, J I Williams
Journal: BMJ (2001)

To determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding.Retrospective cohort study from population based databases.Ontario, Canada.317 824 elderly people observed for more than 130 000 person years. The patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper gastrointestinal bleed, or died or the study ended.Admission to hospital for acute upper gastrointestinal bleeding.Overall, 974 bleeds were observed, with an overall bleeding rate of 7.3 per 1000 person years. After controlling for age or previous gastrointestinal bleeding, the risk of bleeding significantly increased by 10.7% and 9.8%, respectively, with increasing inhibition of serotonin reuptake. Absolute differences in bleeding between antidepressant groups were greatest for octogenarians (low inhibition of serotonin reuptake, 10.6 bleeds/1000 person years v high inhibition of serotonin reuptake, 14.7 bleeds/1000 person years; number needed to harm 244) and those with previous upper gastrointestinal bleeding (low, 28.6 bleeds/1000 person years v high, 40.3 bleeds/1000 person years; number needed to harm 85).After age or previous upper gastrointestinal bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper gastrointestinal bleeding. These increases are clinically important for elderly patients and those with previous gastrointestinal bleeding.
Impaired oxidation of debrisoquine in patients with perhexiline liver injury.
Authors: M Y Morgan, R Reshef, R R Shah, N S Oates, R L Smith, S Sherlock
Journal: Gut (1984)

Perhexiline maleate is an antianginal agent which depends on hepatic oxidation for its elimination. Its use may be complicated by the development of peripheral neuropathy and liver damage. The majority of patients with perhexiline neuropathy have an impaired ability to effect metabolic drug oxidation which is genetically determined. Information has not been available on drug oxidation capacity in patients with perhexiline liver injury. Drug oxidation was measured using an oxidation phenotyping procedure in four patients with perhexiline liver injury and in 70 patients with chronic liver disease serving as a control group. All four patients with perhexiline liver damage showed a substantial metabolic defect; three of the four patients (75%) showed a genetically determined impairment of oxidation capacity. The incidence of severely impaired oxidation capacity in the perhexiline group was significantly greater than in the patients with chronic liver disease (6/70; 8.6%) and in the healthy population (9%) (F = 0.0048). A clear association exists between perhexiline liver injury and diminished drug metabolic activity, suggesting that the propensity to develop perhexiline liver injury is, at least in part, genetically determined.
Effect of Zoledronate on Oral Wound Healing in Rats
Authors: Junro Yamashita, Kiyono Koi, Dong-Ye Yang, Laurie K. McCauley
Journal: Clinical Cancer Research (2010)

Osteonecrosis of the jaw (ONJ) is a growing concern in patients who receive bisphosphonates that target osteoclasts. As osteoclasts play multifunctional roles in the bone marrow, their suppression likely affects bone homeostasis and alters wound healing of the jaw. The objective was to delineate the impact of osteoclast suppression in the bone marrow and wound healing of the jaw.Zoledronate was administered to senile rats for 14 weeks. A portion of the gingiva was removed to denude the palatal bone. Gene expression in the bone marrow was assessed and histologic sections were analyzed to determine the wound healing status.Angiogenesis-related genes, CD31 and VEGF-A, were not altered by zoledronate. VEGF-C, which plays a role in lymphangiogenesis, was suppressed. There was a decrease in gene expression of Tcirg1 and MMP-13. Bone denudation caused extensive osteocyte death indicative of bone necrosis. In zoledronate-treated rats, the necrotic bone was retained in the wound while, in controls, osteoclastic resorption of the necrotic bone was prominent. Even though large necrotic bone areas existed in zoledronate-treated rats, overlaying soft tissue healed clinically. Immunohistochemical staining showed rich vascularity in the overlaying soft tissue.Zoledronate therapy impacts bone marrow by suppressing genes associated with lymphangiogenesis and tissue remodeling, such as VEGF-C and MMP-13. Zoledronate was associated with impaired osseous wound healing but had no effect on angiogenic markers in the bone marrow or soft tissue wound healing. Zoledronate selectively blunts healing in bone but does not affect soft tissue healing in the oral cavity.
Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration.
Authors: E C Van Os, B J Zins, W J Sandborn, D C Mays, W J Tremaine, D W Mahoney, A R Zinsmeister, J J Lipsky
Journal: Gut (1996)

BACKGROUND: 6-Mercaptopurine and its prodrug azathioprine are effective medications for refractory inflammatory bowel disease. However, use of these drugs has been limited by concerns about their toxicity. Colonic delivery of azathioprine may reduce its systemic bioavailability and limit toxicity. AIM: To determine the bioavailability of 6-mercaptopurine after administration of azathioprine via three colonic delivery formulations. METHODS: Twenty four healthy human subjects each received 50 mg of azathioprine by one of four delivery formulations (each n = 6): oral; delayed release oral; hydrophobic rectal foam; and hydrophilic rectal foam. All subjects also received a 50 mg dose of intravenous azathioprine during a separate study period. Plasma concentrations of 6-mercaptopurine were determined by high pressure liquid chromatography. RESULTS: The bioavailabilities of 6-mercaptopurine after colonic azathioprine administration via delayed release oral, hydrophobic rectal foam, and hydrophilic rectal foam (7%, 5%, 1%; respectively) were significantly lower than the bioavailability of 6-mercaptopurine after oral azathioprine administration (47%) by Wilcoxon rank sum pairwise comparison. CONCLUSIONS: Azathioprine delivered to the colon by delayed release oral and rectal foam formulations considerably reduced systemic 6-mercaptopurine bioavailability. The therapeutic potential of these colonic delivery methods, which can potentially limit toxicity by local delivery of high doses of azathioprine, should be investigated in patients with inflammatory bowel disease.
Medical treatment for reflux oesophagitis does not consistently improve asthma control: a systematic review
Authors: J L Coughlan
Journal: Thorax (2001)

<h3>BACKGROUND</h3> A systematic literature review was conducted to assess the effect of treating reflux oesophagitis on asthma outcomes. <h3>METHODS</h3> Randomised controlled trials of reflux oesophagitis treatment in adults or children that reported asthma health outcomes were included and assessed in accordance with the standard Cochrane systematic review process. Patients were typically adults with asthma and concurrent symptomatic gastro-oesophageal reflux who received interventions that included pharmacological therapy, conservative management, and surgery. The following outcome measures were assessed: lung function, peak expiratory flow, asthma symptoms, asthma medications, and nocturnal asthma. <h3>RESULTS</h3> From 22 potentially relevant published and unpublished randomised controlled trials, 12 were included. Treatment duration ranged from 1 week to 6 months. Eight trials reported that treatment improved at least one asthma outcome, but these outcomes differed between trials. Overall, treatment of reflux oesophagitis did not consistently improve forced expiratory volume in one second (FEV<sub>1</sub>), peak expiratory flow rate, asthma symptoms, nocturnal asthma symptoms, or use of asthma medications in asthmatic subjects. Significant improvement in wheeze was reported in two studies. <h3>CONCLUSIONS</h3> The published literature does not consistently support treatment of reflux oesophagitis as a means of controlling asthma. Further large randomised controlled trials in subjects with a demonstrated temporal relationship between gastro-oesophageal reflux and asthma are needed. These trials should be conducted over at least 6 months to allow adequate time to observe a treatment effect.
Predictors of clinical outcomes in elderly patients with heart failure
Authors: Luis Manzano, Daphne Babalis, Michael Roughton, Marcelo Shibata, Stefan D. Anker, Stefano Ghio, Dirk J. van Veldhuisen, Alain Cohen-Solal, Andrew J. Coats, Philip P.A. Poole-Wilson, Marcus D. Flather
Journal: European Journal of Heart Failure (2011)