tbuckley/cabot-search huggingface dataset:
Remnant Lipoprotein-Induced Smooth Muscle Cell Proliferation Involves Epidermal Growth Factor Receptor Transactivation
Authors: AkioKawakami, AkiraTanaka, TsuyoshiChiba, KatsuyukiNakajima, KentaroShimokado, MasayukiYoshida
Journal: Circulation (2003)

Background— Remnant lipoproteins (RLPs) have been shown to play a causative role during atherosclerosis. Furthermore, it is known that vascular smooth muscle cell (SMC) proliferation is crucial for the development of atherosclerosis and restenosis after percutaneous coronary intervention. We examined the direct effect of RLPs on the proliferation and signal transduction of SMCs. Methods and Results— Incubation in the presence of RLPs (20 mg cholesterol per dL) for 48 hours induced rat aortic SMC proliferation (2.3-fold over medium alone). RLPs also induced the phosphorylation of epidermal growth factor (EGF) receptor in SMCs, which was followed by the activation of mitogen-activated protein kinases. Moreover, the activation of protein kinase C (PKC) as well as the shedding of membrane-bound soluble heparin-binding EGF-like growth factor (HB-EGF) was observed after RLP treatment of SMCs, whereas PKC inhibitors and metalloprotease inhibitors inhibited RLP-induced EGF receptor transactivation and HB-EGF shed...
A New Criterion for Pediatric AKI Based on the Reference Change Value of Serum Creatinine
Authors: Xin Xu, Sheng Nie, Aihua Zhang, Mao Jianhua, Hai-Peng Liu, Huimin Xia, Hong Xu, Zhangsuo Liu, Shipin Feng, Wei Zhou, Xuemei Liu, Yonghong Yang, Yuhong Tao, Yunlin Feng, Chunbo Chen, Mo Wang, Yan Zha, Jian-Hua Feng, Qingchu Li, Shuwang Ge, Jianghua Chen, Yongcheng He, Siyuan Teng, Chuanming Hao, Bi-Cheng Liu, Ying Tang, Li-Jun Wang, Jin-Lei Qi, Wenjuan He, Pinghong He, Youhua Liu, Fan Fan Hou
Journal: Journal of the American Society of Nephrology (2018)

Background Current definitions of AKI do not take into account serum creatinine’s high variability in children. Methods We analyzed data from 156,075 hospitalized children with at least two creatinine tests within 30 days. We estimated reference change value (RCV) of creatinine on the basis of age and initial creatinine level in children without kidney disease or known AKI risk, and we used these data to develop a model for detecting pediatric AKI on the basis of RCV of creatinine. We defined pediatric AKI according to pediatric reference change value optimized for AKI in children (pROCK) as creatinine increase beyond RCV of creatinine, which was estimated as the greater of 20 μ mol/L or 30% of the initial creatinine level. Results Of 102,817 children with at least two serum creatinine tests within 7 days, 5432 (5.3%) had AKI as defined by pROCK compared with 15,647 (15.2%) and 10,446 (10.2%) as defined by pediatric RIFLE (pRIFLE) and Kidney Disease Improving Global Outcomes (KDIGO), respectively. Children with pROCK-defined AKI had significantly increased risk of death (hazard ratio, 3.56; 95% confidence interval, 3.15 to 4.04) compared with those without AKI. About 66% of patients with pRIFLE-defined AKI and 51% of patients with KDIGO-defined AKI, mostly children with initial creatinine level of &lt;30 μ mol/L, were reclassified as non-AKI by pROCK, and mortality risk in these children was comparable with risk in those without AKI by all definitions. Conclusions pROCK criterion improves detection of “true” AKI in children compared with earlier definitions that may lead to pediatric AKI overdiagnosis.
Ventricular Preexcitation in Children and Young Adults
Authors: CristinaBasso, DomenicoCorrado, LinoRossi, GaetanoThiene
Journal: Circulation (2001)

Background—Sudden death (SD) in ventricular preexcitation (VP) syndrome is believed to be the result of atrial fibrillation with rapid ventricular response over the accessory pathway. Previous reports are anecdotal and often lack autopsy validation. Methods and Results—Prevalence and clinicopathological features of VP were investigated in a series of 273 SDs in children and young adults (aged ≤35 years). Site of accessory atrioventricular (AV) connection was predicted by 12-lead ECG. Right and left AV ring together with the sinoatrial and AV septal junction were studied in serial histological sections. Ten patients (3.6%; male, mean age 24±7 years) had VP: 8 had Wolff-Parkinson-White (WPW) and 2 had Lown-Ganong-Levine (LGL) syndrome. Six patients had previous symptoms, and SD occurred at rest in all but 1. Pathological substrates of LGL consisted of AV-node hypoplasia and right-sided atrio-Hisian tract, respectively. In the 8 WPW patients, 10 total accessory AV pathways consisting of ordinary myocardium w...
Ectopic Cushing Syndrome (ECS)
Authors: Ashwin Singh Parihar, Bhagwant Rai Mittal, Shelvin Kumar Vadi, Rajender Kumar Basher, Anil Bhansali
Journal: Clinical Nuclear Medicine (2018)

Ectopic Cushing syndrome constitutes approximately 10% of all patients with Cushing syndrome. The clinical features of hypercortisolism result from elevated levels of adrenocorticotropic hormone produced by a tumor. The present case presented with clinical and biochemical parameters suggestive of Cushing syndrome with normal pituitary and adrenals on imaging. Ga-DOTANOC PET/CT done to localize an ectopic adrenocorticotropic hormone-producing tumor revealed metastatic medullary carcinoma of the thyroid as the culprit lesion.
The reversible effects of glial cell line–derived neurotrophic factor (GDNF) in the human brain
Authors: Abiola Abdulrahman Ayanlaja, Baole Zhang, GuangQuan Ji, Yue Gao, Jie Wang, Kouminin Kanwore, DianShuai Gao
Journal: Seminars in Cancer Biology (2018)

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor, and a member of the transforming growth factor β (TGF-β) superfamily acting on different neuronal activities. GDNF was originally identified as a neurotrophic factor crucially involved in the survival of dopaminergic neurons of the nigrostriatal pathway and is currently an established therapeutic target in Parkinson's disease. However, GDNF was later reported to be highly expressed in gliomas, especially in glioblastomas, and was demonstrated as a potent proliferation factor involved in the development and migration of gliomas. Here, we review our current understanding and progress made so far by researchers in our laboratories with references to relevant articles to support our discoveries. We present past and recent discoveries on the mechanisms involved in the protection of neurons by GDNF and examine its emerging roles in gliomas, as well as reasons for the abnormal expression in Glioblastoma Multiforme (GBM). Collectively, our work establishes a paradigm by which the ability of GDNF to protect dopaminergic neurons from degradation and its corresponding effects on glioma cells points to an underlying biological vulnerability in the effects of GDNF in the normal brain which can be subverted for use by cancer cells. Hence, presenting novel opportunities for intervention in glioma therapies.
Allogeneic Mesenchymal Stem Cells Therapy for the Treatment of Hepatitis B Virus–Related Acute‐on‐Chronic Liver Failure
Authors: Changhui Zhou, Weihua Wang, Ying Mu
Journal: Hepatology (2018)

Dear Editor, We read with great interest the recent publication by Lin et al.(1) Recently, mesenchymal stem cells (MSC) have been considered a novel and effective therapy for liver diseases such as liver fibrosis, cirrhosis, and liver failure. In this paper, the authors demonstrated the significant survival benefit of allogeneic bone marrow MSC (BMSC) for hepatitis B virus–related acute‐on‐chronic liver failure (ACLF) in comparison with standard medical treatment. However, optimization of this therapeutic strategy is more valuable for MSC treatment. There are several aspects that should be taken into consideration. First, the number of infused MSC is the primary consideration. In this study, patients in the BMSC group received different infusion doses ranging from 1.0 to 10 × 105 cells/kg. Several previous studies revealed that a larger number of infused MSC was associated with more satisfied efficacy. Nakamura et al.(2) study showed that transplantation of human CD34+ cells after chronic liver injury aroused the regeneration of liver function in a dose‐dependent manner. Therefore, in BMSC efficacy assessment, it is necessary to conduct subgroup analysis based on the different cell dosages. Second, studies showed that infusion of MSC through hepatic artery improved liver function more effectively than intravenous perfusion.(3) This may be because transplantation through hepatic artery can deliver a larger number of transplanted cells to the damaged liver parts, thereby stimulating hepatic regeneration more efficiently. Therefore, investigation of the different effects of BMSC for ACLF using different routes of cell administration will benefit its clinical application. Lastly, allogeneic BMSC were used for the treatment ACLF in this study. Human umbilical cord is another source of MSC that demonstrates advantages over BMSC with a wider range of collection sources, easier noninvasive approach, and fewer ethical constraints.(4) Therefore, using umbilical cord instead of bone marrow as the cell source may be more feasible for the treatment of ACLF. On the other hand, the number of cells extracted from an umbilical cord specimen is far more than that of a bone marrow specimen, which can eliminate the individual differences of MSC therapeutic effects. In summary, it would be more meaningful if the authors could investigate these aspects in the curative effects of BMSC therapy. Potential conflict of interest Nothing to report.
Effects of two instrument-generation changes on adenoma detection rate during screening colonoscopy: results from a prospective randomized comparative study
Authors: Katharina Zimmermann-Fraedrich, Stefan Groth, Susanne Sehner, Stefan Schubert, Jens Aschenbeck, Michael Mayr, Alireza Aminalai, Andreas Schröder, Jens-Peter Bruhn, Michael Bläker, Thomas Rösch, Guido Schachschal
Journal: Endoscopy (2018)

Abstract Background Previous studies have shown that multiple colonoscope features have to be changed before an improvement in adenoma detection rate (ADR) becomes obvious, such as with changing from one instrument generation to the next but one. We wanted to evaluate whether such an effect can also be observed in a private-practice screening setting. Methods In a randomized study, we compared the latest generation colonoscopes from one company (Olympus Exera III, 190) with the next to last one (Olympus 165), including only patients presenting for screening colonoscopy. The primary outcome was ADR achieved with 190 colonoscopes (190-C) in comparison with 165 colonoscopes (165-C). Results 1221 patients (46.1 % men; mean age 62.2 years, standard deviation 6.6) were included (599 screened with the Olympus Exera III, 190). The ADR difference in favor of the 190-C instrument (32 % [95 % confidence interval (CI) 26 % to 39 %] vs. 28 % [95 %CI 22 % to 34 %] in the 165-C group) failed to reach statistical significance (P = 0.10); only the rate of small (&lt; 5 mm) adenomas was significantly increased at 22.5 % (95 %CI 19 % to 26 %) vs. 15.6 % (95 %CI 13 % to 18 %; P = 0.002). Furthermore, significantly more adenomas were found in the 190-C group, with an adenoma rate (all adenomas/all patients) of 0.57 (95 %CI 0.53 to 0.61) vs. 0.47 (95 %CI 0.43 to 0.51; P &lt; 0.001). Conclusions This randomized comparative trial in a private-practice screening setting only partially confirmed the results of prior studies that, with multiple imaging improvements achieved over two instrument generations, an increase in overall adenoma number becomes measurable.
Abstract 17628: Perforin-positive Cardiac Cell Infiltration and Male Gender Predict Adverse Long-term Mortality in Virus-negative Inflammatory Cardiomyopathy
Authors: Felicitas Escher, Uwe Kuehl, Dirk Lassner, Dirk Westermann, Burkert Pieske, Carsten Tschope, Wolfgang Poller, Heinz-Peter Schultheiss
Journal: Circulation (2016)

Aims:  We analysed possible influence of perforin-dependent infiltration upon long-term mortality in patients with inflammatory cardiomyopathy (CMi). We previously demonstrated that left ventricular function deteriorates and progresses to substantial cardiac dysfunction in patients with perforin-positive cardiac cell infiltration.   Methods and Results:  Between 2003 and 2013, 2389 consecutive patients with clinically suspected CMi who underwent endomyocardial biopsy (EMB) were enrolled. EMBs were performed at first admission after exclusion of ischemic of valvular heart disease, and CMi was confirmed in 1717 patients. Follow-up was up to 10.0 years (mean 17.8±25.4 months) and information on vital status was obtained from official resident data files. Multivariable statistical analysis was conducted for all CMi patients regarding significant predictors of all-cause mortality or need for heart transplantation (HTX). Multiple Cox regression analysis revealed perforin above the calculated the cut off point of 2.9/mm 2  as a strong predictor of impaired survival with hazard ratio (HR) of 1.881, 95% confidence interval (CI) 1.177-3.008, p=0.008, independent of LV function and other myocardial inflammation markers (CD3, Mac-1, LFA-1, HLA-1, and ICAM-1). Unexpectedly, male sex emerged as another strong adverse predictor of survival in CMi (HR 1.863, CI 1.096-3.168, p=0.022). Whereas LVEF course is adversely affected by myocardial perforin, multivariate analysis indicates that LVEF explains only part of the observed overall mortality.   Conclusion:  Perforin-positive cardiac cell infiltration and male gender are interacting adverse predictors of long term-mortality in CMi, independent of LV function and other myocardial inflammation markers. Furthermore, exact quantification of immune cells is necessary to assess the prognosis.
Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy
Authors: Dongsheng Duan
Journal: Molecular Therapy (2018)

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin gene mutation. Conceptually, replacing the mutated gene with a normal one would cure the disease. However, this task has encountered significant challenges due to the enormous size of the gene and the distribution of muscle throughout the body. The former creates a hurdle for viral vector packaging and the latter begs for whole-body therapy. To address these obstacles, investigators have invented the highly abbreviated micro-dystrophin gene and developed body-wide systemic gene transfer with adeno-associated virus (AAV). Numerous microgene configurations and various AAV serotypes have been explored in animal models in many laboratories. Preclinical data suggests that intravascular AAV micro-dystrophin delivery can significantly ameliorate muscle pathology, enhance muscle force, and attenuate dystrophic cardiomyopathy in animals. Against this backdrop, several clinical trials have been initiated to test the safety and tolerability of this promising therapy in DMD patients. While these trials are not powered to reach a conclusion on clinical efficacy, findings will inform the field on the prospects of body-wide DMD therapy with a synthetic micro-dystrophin AAV vector. This review discusses the history, current status, and future directions of systemic AAV micro-dystrophin therapy.
A pain in the back
Authors: Nadia Hitchen, Harriet Weststrate, Arshad Sheriff
Journal: BMJ (2018)

Video 1 
Axial contrast enhanced computed tomography of the abdomen and pelvis demonstrating a left renal infarct. A 2 mm non-obstructive calculus is identified within the mid-pole of the right kidney. The remainder of the solid abdominal organs are unremarkable.

A 72 year old man with a history of atrial fibrillation was admitted with a basal ganglia interventricular haemorrhage. Warfarin was stopped on admission. Five days after presentation, he developed gradual, cramping, left sided abdominal pain radiating to the flank with urinary frequency but no haematuria. His inflammatory markers were elevated, serum urea and creatinine were normal, and urine microscopy was negative for blood, white cells, and bacteria. A computed tomography scan was arranged (fig 1). What does it show?



Fig 1 
Axial computed tomography abdominal slice



Wedge shaped low attenuation areas …
Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination
Authors: Yasushi Akahori, Linan Wang, Motohiro Yoneyama, Naohiro Seo, Satoshi Okumura, Yoshihiro Miyahara, Yasunori Amaishi, Sachiko Okamoto, Junichi Mineno, Hiroaki Ikeda, Takehiro Maki, Hiroshi Fujiwara, Yoshiki Akatsuka, Takuma Kato, Hiroshi Shiku
Journal: Blood (2018)
Bawa-Garba’s original suspension was right decision, argues lawyer in appeal against erasure
Authors: Clare Dyer
Journal: BMJ (2018)

The decision to suspend Hadiza Bawa-Garba for 12 months rather than strike her off the medical register after a conviction for gross negligence manslaughter was “humane and balanced,” her QC has told the Court of Appeal.

Because that decision was overturned by the High Court, the NHS lost a “young and talented” paediatrician, said James Laddie QC.

Bawa-Garba, 41, a junior doctor specialising in paediatrics, was found guilty of manslaughter by a jury for contributing to the death of 6 year old Jack Adcock from sepsis at Leicester Royal Infirmary in 2011.1 She was denied permission to appeal the manslaughter conviction because none of her grounds for appeal were “arguable.”2

A medical practitioners tribunal, which took account of systemic failures at the hospital, decided to suspend her from practice rather than strike her off. …
Effect of heavy load carriage on cardiorespiratory responses with varying gradients and modes of carriage
Authors: Subhojit Chatterjee, Tirthankar Chatterjee, Debojyoti Bhattacharyya, Suranjana Sen, Madhusudan Pal
Journal: Military Medical Research (2018)

The present study was undertaken to determine the effect of different uphill and downhill gradients on cardiorespiratory and metabolic responses of soldiers while carrying heavy military loads in two different modes. Eight physically fit male soldiers with a mean age 32.0 ± 2.0 years, a mean height of 169.5 ± 4.9 cm, and a mean weight of 63.8 ± 8.4 kg volunteered for this study. Each volunteer completed treadmill walking trials at a speed of 3.5 km/h while carrying no external load, 31.4 kg load in a distributed mode (existing load carriage ensembles) and compact mode (new back pack) over 5 different downhill and uphill gradients (- 5, - 10%, 0, 5, 10%) for 6 min at each gradient. During the walking trials, heart rate (HR), oxygen uptake (VO2), respiratory frequency (RF) and energy expenditure (EE) were determined by the process of breath-by-breath gas analysis using a K4b2 system. The average of the last 2 min data from each 6 min walking trial for each individual was subjected to statistical analysis. All parameters (HR, VO2, RF, and EE) gradually increased with the change in gradient from downhill to level to uphill. The distributed mode showed higher values compared to compact mode for all gradients, e.g., for VO2, there was a 10.7, 7.4, 5.1, 28.2 and 18.7% increase in the distributed mode across the 5 different gradients. It can be concluded from the present study that the compact mode of load carriage is more beneficial than the distributed mode in terms of cardiorespiratory responses while walking on downhill and uphill surfaces with a 31.4 kg load.
Real-Time Tumor Gene Expression Profiling to Direct Gastric Cancer Chemotherapy: Proof-of-Concept “3G” Trial
Authors: Wei Peng Yong, Sun Young Rha, Iain Bee-Huat Tan, Su-Pin Choo, Nicholas L. Syn, Vivien Koh, Shi-Hui Tan, Bernadette Reyna Asuncion, Raghav Sundar, Jimmy Bok-Yan So, Asim Shabbir, Chee-Seng Tan, Hyo-Song Kim, Minkyu Jung, Hyun Cheol Chung, Matthew C.H. Ng, David Wai-Meng Tai, Ming-Hui Lee, Jeanie Wu, Khay Guan Yeoh, Patrick Tan
Journal: Clinical Cancer Research (2018)

Purpose: The oxaliplatin plus S-1 and cisplatin plus S-1 regimens are interchangeably used in the management of advanced gastric cancer. The previously reported G-intestinal (G1) and G-diffuse (G2) intrinsic gene expression signatures showed promise for stratifying patients according to their tumor sensitivity to oxaliplatin or cisplatin.Experimental Design: The proof-of-concept, multicenter, open-label phase II "3G" trial was done to prospectively evaluate the feasibility and efficacy of using genomic classifiers to tailor treatment in gastric cancer. Patients' tumors were classified as "G1" or "G2" using a nearest-prediction template method, or "G3" (unclear assignment) when FDR ≥ 0.05. The first 30 patients in the "G1" cohort were assigned oxaliplatin plus S-1 (SOX) chemotherapy; thereafter, subsequently recruited "G1" patients were treated with cisplatin plus S-1 (SP) chemotherapy. "G2" patients and "G3" patients were treated with SP and SOX chemotherapy, respectively.Results: A total of 48, 21, and 12 patients, respectively, were given "G1," "G2," and "G3" genomic assignments. Median turnaround time was 7 days (IQR, 5-9). Response rates were 44.8%, 8.3%, 26.7%, and 55.6% for the "G1-SOX," "G1-SP," "G2," "G3" cohorts, respectively; and was higher in G1 patients treated with SOX compared with SP (P = 0.033). Exploratory analyses using the genomic classifier of Lei and colleagues validated the utility of the metabolic signature as a biomarker for predicting benefit from chemotherapy (log-rank P = 0.004 for PFS), whereas the Asian Cancer Research Group classifier did not demonstrate any predictive value.Conclusions: This bench-to-bedside effort establishes a reasonable turnaround time for gene expression profiling and possible utility of genomic classifiers in gastric cancer treatment stratification. Clin Cancer Res; 24(21); 5272-81. ©2018 AACR.
Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact, and Mechanisms
Authors: Karen D Corbin, Kimberly A Driscoll, Richard E Pratley, Steven R Smith, David M Maahs, Elizabeth J Mayer-Davis
Journal: Endocrine Reviews (2018)

There has been an alarming increase in the prevalence of obesity in people with type 1 diabetes in recent years. Although obesity has long been recognized as a major risk factor for the development of type 2 diabetes and a catalyst for complications, much less is known about the role of obesity in the initiation and pathogenesis of type 1 diabetes. Emerging evidence suggests that obesity contributes to insulin resistance, dyslipidemia, and cardiometabolic complications in type 1 diabetes. Unique therapeutic strategies may be required to address these comorbidities within the context of intensive insulin therapy, which promotes weight gain. There is an urgent need for clinical guidelines for the prevention and management of obesity in type 1 diabetes. The development of these recommendations will require a transdisciplinary research strategy addressing metabolism, molecular mechanisms, lifestyle, neuropsychology, and novel therapeutics. In this review, the prevalence, clinical impact, energy balance physiology, and potential mechanisms of obesity in type 1 diabetes are described, with a special focus on the substantial gaps in knowledge in this field. Our goal is to provide a framework for the evidence base needed to develop type 1 diabetes–specific weight management recommendations that account for the competing outcomes of glycemic control and weight management.