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Orphan disease

Naiqian Zhao, Xiaoyan Li, Ying Feng, Jinxiang Han, Ziling Feng, Xifeng Li, Yanfang Wen
Excessive triglyceride accumulation in hepatocytes is the hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). Elevated levels of the saturated free fatty acid palmitate in obesity are a major contributor to excessive hepatic lipid accumulation. The nuclear orphan receptor Nur77 is a transcriptional regulator and a lipotoxicity sensor. Using human HepG2 hepatoma cells, this study aimed to investigate the functional role of Nur77 in palmitate-induced hepatic steatosis. The results revealed that palmitate significantly induced lipid accumulation and suppressed lipolysis in hepatocytes...
March 19, 2018: Scientific Reports
Ravi Gupta, Thomas J Bollyky, Matthew Cohen, Joseph S Ross, Aaron S Kesselheim
OBJECTIVES: To evaluate whether off-patent prescription drugs at risk of sudden price increases or shortages in the United States are available from independent manufacturers approved in other well regulated settings around the world. DESIGN: Observational study. SETTING: Off-patent drugs in the USA and approved by the Food and Drug Administration, up to 10 April 2017. STUDY COHORT: Novel tablet or capsule prescription drugs approved by the FDA since 1939 that were no longer protected by patents or other market exclusivity and had up to three generic versions...
March 19, 2018: BMJ: British Medical Journal
Shu-Long Li, Yun Yu, Peng Yang, Hui Wang, Cheng Zhang, Min Liu, Jia-Xiang Zhang, Tong Shen, Changhao Wu, Qi-Xing Zhu
The role of environmental factors in autoimmune diseases has been increasingly recognized. While major advance has been made in understanding biological pathogen-induced autoimmune diseases, chemically triggered autoimmunity is poorly understood. Trichloroethylene (TCE), a common environmental pollutant, has recently been shown to induce autoimmunity. This study explored whether TCE could cause imbalance of T helper (Th) cell subsets which would contribute to the pathogenesis of TCE-induced medicamentosa-like dermatitis...
January 1, 2018: International Journal of Toxicology
Rong Liang, Yan Lin, Chun-Ling Yuan, Zhi-Hui Liu, Yong-Qiang Li, Xiao-Ling Luo, Jia-Zhou Ye, Hai-Hong Ye
Colorectal cancer (CRC) is one of the most common types of malignancy with high morbidity and mortality rates worldwide. This biologically heterogeneous disease results in diverse therapeutic responses, thus, novel prognostic biomarkers are required to improve CRC treatment. Estrogen-related receptor α (ERRα) is a nuclear orphan receptor, which is associated with estrogen receptor α. The present study aimed to investigate the expression of ERRα in patients with CRC, and explore the association between ERRα expression and clinicopathological factors, local recurrence and prognosis...
April 2018: Oncology Letters
Marie Madsen, Peter Riis Hansen, Lars Bo Nielsen, Renata Martins Cardoso, Miranda van Eck, Tanja Xenia Pedersen
Psoriasis is a chronic inflammatory skin disorder associated with several comorbidities including atherosclerosis. Disease mechanisms that may affect both psoriasis and atherosclerosis include activation of T helper 1 and T helper 17 cells. Imiquimod application is an established mouse model of psoriasis-like skin inflammation. The cardiac glycoside digoxin inhibits the master transcription factor of T helper 17 differentiation, retinoid acid receptor-related orphan nuclear receptor γt, and attenuates interleukin-17-dependent pathologies in mice...
March 12, 2018: American Journal of Pathology
Keigo Tsushida, Katsuyuki Tanabe, Kana Masuda, Satoshi Tanimura, Hiromasa Miyake, Yuka Arata, Hitoshi Sugiyama, Jun Wada
Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERRα deficiency on the progression of AKI induced by cisplatin...
March 12, 2018: Biochemical and Biophysical Research Communications
Iwao Sugitani, Naoyoshi Onoda, Ken-Ichi Ito, Shinichi Suzuki
Anaplastic thyroid carcinoma (ATC) accounts for only 1 to 2% of all thyroid carcinomas, but it is one of the most lethal neoplasms in humans. To obtain further insights into this "orphan disease," we have established the ATC Research Consortium of Japan (ATCCJ) in 2009. It represents a multicenter registry for ATC that have been treated in Japan. To date, 67 institutions have taken part in the collaborative research system and over 1,200 cases have been accumulated in its database. Using this big data, several retrospective studies were carried out to evaluate 1) prognostic factors to determine initial treatment policy, 2) significance of extended radical surgery for Stage IVB cases, 3) characteristics of ATC incidentally found on pathological examination and 4) pathological features of ATC with long-term survival...
2018: Journal of Nippon Medical School, Nippon Ika Daigaku Zasshi
Andoni Ramirez-Garcia, Aize Pellon, Aitor Rementeria, Idoia Buldain, Eliana Barreto-Bergter, Rodrigo Rollin-Pinheiro, Jardel Vieira de Meirelles, Mariana Ingrid D S Xisto, Stephane Ranque, Vladimir Havlicek, Patrick Vandeputte, Yohann Le Govic, Jean-Philippe Bouchara, Sandrine Giraud, Sharon Chen, Johannes Rainer, Ana Alastruey-Izquierdo, Maria Teresa Martin-Gomez, Leyre M López-Soria, Javier Peman, Carsten Schwarz, Anne Bernhardt, Kathrin Tintelnot, Javier Capilla, Adela Martin-Vicente, Jose Cano-Lira, Markus Nagl, Michaela Lackner, Laszlo Irinyi, Wieland Meyer, Sybren de Hoog, Fernando L Hernando
Species of Scedosporium and Lomentospora are considered as emerging opportunists, affecting immunosuppressed and otherwise debilitated patients, although classically they are known from causing trauma-associated infections in healthy individuals. Clinical manifestations range from local infection to pulmonary colonization and severe invasive disease, in which mortality rates may be over 80%. These unacceptably high rates are due to the clinical status of patients, diagnostic difficulties, and to intrinsic antifungal resistance of these fungi...
April 1, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Ning Wei, Michelle L Gumz, Anita T Layton
Major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion are known to exhibit circadian oscillations. However, the underlying mechanisms that govern these variations have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the renal circadian clock, and coupled that model to an epithelial transport model of the proximal convoluted cell of the rat kidney. The activity of the Na$^+$-H$^+$ exchanger 3 (NHE3) is assumed to be regulated by changes in transcription of the NHE3 mRNA due to regulation by circadian clock proteins...
March 14, 2018: American Journal of Physiology. Renal Physiology
Miguel A Lanaspa, Ana Andres-Hernando, David J Orlicky, Christina Cicerchi, Cholsoon Jang, Nanxing Li, Tamara Milagres, Masanari Kuwabara, Michael F Wempe, Joshua D Rabinowitz, Richard J Johnson, Dean R Tolan
Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of a particular aldolase, aldolase B, results in the accumulation of intracellular phosphorylated fructose thus leading to phosphate sequestration and depletion, increased ATP turnover and a plethora of conditions leading to clinical manifestations including fatty liver, hyperuricemia, Fanconi syndrome and severe hypoglycemia...
March 13, 2018: Journal of Clinical Investigation
Yahel Segal, Shani Dahan, Kassem Sharif, Nicola Luigi Bragazzi, Abdulla Watad, Howard Amital
Autoimmune Syndrome Induced by Adjuvant (ASIA) is a definition aimed to describe the common etiological process at the root of five clinical entities sharing similar symptomatology: macrophagic myofasciitis syndrome (MMF), Gulf War Syndrome (GWS), sick building syndrome (SBS), siliconosis, and post vaccination autoimmune phenomena. ASIA illustrates the role of environmental immune stimulating agents, or adjuvants, in the instigation of complex autoimmune reactions among individuals bearing a genetic preponderance for autoimmunity...
March 8, 2018: Autoimmunity Reviews
Joanna Drozd-Sokołowska, Krzysztof Mądry, Anna Waszczuk-Gajda, Przemysław Biecek, Paweł Szwedyk, Katarzyna Budziszewska, Magdalena Raźny, Magdalena Dutka, Agata Obara, Ewa Wasilewska, Krzysztof Lewandowski, Agnieszka Piekarska, Grażyna Bober, Helena Krzemień, Beata Stella-Hołowiecka, Katarzyna Kapelko-Słowik, Waldemar Sawicki, Małgorzata Paszkowska-Kowalewska, Rafał Machowicz, Jadwiga Dwilewicz-Trojaczek
Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses...
March 7, 2018: Hematological Oncology
Maryam Majd, Aref Hosseini, Kamran Ghaedi, Abbas Kiani-Esfahani, Somayeh Tanhaei, Hanieh Shiralian-Esfahani, Seyed Yahya Rahnamaee, Seyed Javad Mowla, Mohammad Hossein Nasr-Esfahani
Objectives: Multiple sclerosis (MS) is considered as a chronic type of an inflammatory disease characterized by loss of myelin of CNS. Recent evidence indicates that Interleukin 17 (IL-17)-producing T helper cells (Th17 cells) population are increased and regulatory T cells (Treg cells) are decreased in MS. Despite extensive research in understanding the mechanism of Th17 and Treg differentiation, the role of microRNAs in MS is not completely understood. Thereby, as a step closer, we analyzed the expression profile of miR-9-5p and miR-106a-5p, and protein level of retinoic acid receptor (RAR)-related orphan receptor C ( RORC ; Th17 master transcription factor) as direct target of miR-106a-5p and forkhead box P3 ( FOXP3 ; Treg master transcription factor) as indirect target of miR-9-5p in CD4+ T cells in two groups of relapsing and remitting in our relapsing-remitting MS (RR-MS) patients...
March 2018: Iranian Journal of Basic Medical Sciences
Mitsunori Kono, Atsuko Ochida, Tsuneo Oda, Takashi Imada, Yoshihiro Banno, Naohiro Taya, Shinichi Masada, Tetsuji Kawamoto, Kazuko Yonemori, Yoshi Nara, Yoshiyuki Fukase, Tomoya Yukawa, Hidekazu Tokuhara, Robert Skene, Bi-Ching Sang, Isaac D Hoffman, Gyorgy P Snell, Keiko Uga, Akira Shibata, Keiko Igaki, Yoshiki Nakamura, Hideyuki Nakagawa, Noboru Tsuchimori, Masashi Yamasaki, Junya Shirai, Satoshi Yamamoto
A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower logD value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [cis-3-({(5R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile...
March 6, 2018: Journal of Medicinal Chemistry
William Raymond Lumry
This review will discuss the cost burden of hereditary angioedema on patients, healthcare systems, and society. The impact of availability of and access to novel and specific therapies on morbidity, mortality, and the overall burden of disease will be explored along with potential changes in treatment paradigms to improve effectiveness and reduce cost of treatment. The prevalence of orphan diseases, legislative incentives to encourage development of orphan disease therapies and the impact of orphan disease treatment on healthcare payment systems will be discussed...
2018: Frontiers in Medicine
Nidhi Malhotra, Juan Manuel Leyva-Castillo, Unmesh Jadhav, Olga Barreiro, Christy Kam, Nicholas K O'Neill, Francoise Meylan, Pierre Chambon, Ulrich H von Andrian, Richard M Siegel, Eddie C Wang, Ramesh Shivdasani, Raif S Geha
Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (TH 2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor α (RORα) in skin-resident T regulatory cells (Tregs ) is important for restraining allergic skin inflammation. In both models, targeted deletion of RORα in mouse Tregs led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and TH 2 cells...
March 2, 2018: Science Immunology
Monique J L Mastboom, Floortje G M Verspoor, Daniël Uittenbogaard, Gerard R Schaap, Paul C Jutte, H W Bart Schreuder, Michiel A J van de Sande
BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a rare, benign, monoarticular entity. Many case-series in adults are described, whereas TGCT is only incidentally reported in children. Therefore, its incidence rate and natural history in children are unknown. QUESTIONS/PURPOSES: (1) How many cases have been reported of this condition, and what were their characteristics? (2) What is the standardized pediatric incidence rate for TGCT? (3) Is there a clinical difference in TGCT between children and adults? (4) What is the risk of recurrence after open resection in children compared with adults? METHODS: Data were derived from three sources: (1) a systematic review on TGCT in children, seeking sources published between 1990 and 2016, included 17 heterogeneous, small case-series; (2) the nationwide TGCT incidence study: the Dutch pediatric incidence rate was extracted from this nationwide study by including patients younger than 18 years of age...
February 8, 2018: Clinical Orthopaedics and related Research
Anne E O'Donnell
PURPOSE OF REVIEW: Bronchiectasis, once thought to be an orphan disease, is being diagnosed with increased frequency in the United States and around the world. The present review aims to provide an update on recent publications on the diagnosis and management of bronchiectasis. RECENT FINDINGS: Two large bronchiectasis patient registries have published initial reports regarding demographics and other patient data in 2017. Updates on the microbiology, microbiome, and inflammation in patients with bronchiectasis are clarifying the complexities of airway infection in this disease...
April 2018: Current Opinion in Infectious Diseases
Katherine A Strynatka, Michelle C Gurrola-Gal, Jason N Berman, Christopher R McMaster
Genetic diseases are both inherited and acquired. Many genetic diseases fall under the paradigm of orphan diseases, a disease found in < 1 in 2000 persons. With rapid and cost-effective genome sequencing becoming the norm, many causal mutations for genetic diseases are being rapidly determined. In this regard, model organisms are playing an important role in validating if specific mutations identified in patients drive the observed phenotype. An emerging challenge for model organism researchers is the application of genetic and chemical genetic platforms to discover drug targets and drugs/drug-like molecules for potential treatment options for patients with genetic disease...
March 2018: Genetics
Han Gao, Lianrong Dou, Liang Shan, Yan Sun, Wentao Li
Neural stem cells (NSCs) are important cellular sources of transplantation therapies for Parkinson's disease. This study aimed to determine the effects of extracts of radix astragali on the proliferation and differentiation into dopamine (DA) neurons in NSCs. NSCs were dealt with astragaloside IV (ASI), astragalus polysaccharide (APS), and astraisoflavan (ASF), the main active ingredients of radix astragali. First, the results from cell-count kit-8 (CCK-8) assay showed that ASI, ASF, and APS had positive effects on the proliferation of NSCs...
February 23, 2018: Neuroreport
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