bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice
Authors: Zhan Xianbao , Wan Jianhua , Zhang Guowei , Song Lele , Gui Fu , Zhang Yuebo , Li Yinghua , Guo Jia , Dawra Rajinder K. , Saluja Ashok K. , Haddock Ashley N. , Zhang Lizhi , Bi Yan , Ji Baoan 
Published: April 2019

Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW & NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.
Rapid geometric feature signaling in the simulated spiking activity of a complete population of tactile nerve fibers
Authors: Delhaye Benoit P. , Xia Xinyue , Bensmaia Sliman J. 
Published: April 2019

Tactile feature extraction is essential to guide the dexterous manipulation of objects. The longstanding theory is that geometric features at each location of contact between hand and object are extracted from the spatial layout of the response of populations of tactile nerve fibers. However, recent evidence suggests that some features (e.g., edge orientation) are extracted very rapidly (<200 ms), casting doubt that this information relies on a spatial code, which ostensibly requires integrating responses over time. An alternative hypothesis is that orientation is conveyed in precise temporal spiking patterns. Here we simulate, using a recently developed and validated model, the responses of the two relevant subpopulations of tactile fibers from the entire human fingertip (~800 afferents) to edges indented into the skin. We show that edge orientation can be quickly (<50 ms) and accurately (<3°) decoded from the spatial pattern of activation across the afferent population, starting with the very first spike. Next, we implement a biomimetic decoder of edge orientation, consisting of a bank of oriented Gabor filters, designed to mimic the documented responses of cortical neurons. We find that the biomimetic approach leads to orientation decoding performance that approaches the limit set by optimal decoders and is actually more robust to changes in other stimulus features. Finally, we show that orientation signals, measured from single units in the somatosensory cortex of nonhuman primates (2 macaque monkeys, 1 female), follow a time course consistent with that of their counterparts in the nerve. We conclude that a spatial code is fast and accurate enough to support object manipulation. NEW & NOTEWORTHY The dexterous manipulation of objects relies on the rapid and accurate extraction of the objects’ geometric features by the sense of touch. Here we simulate the responses of all the nerve fibers that innervate the fingertip when an edge is indented into the skin and characterize the time course over which signals about its orientation evolve in this neural population. We show that orientation can be rapidly and accurately decoded from the spatial pattern of afferent activation using spatial filters that mimic the response properties of neurons in cortical somatosensory neurons along a time course consistent with that observed in cortex. We conclude that the classical model of tactile feature extraction is rapid and accurate enough to support object manipulation.
Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis
Authors: Jeong Jong Jin , Gu Xiaorong , Nie Ji , Sundaravel Sriram , Liu Hui , Kuo Wen-Liang , Bhagat Tushar D. , Pradhan Kith , Cao John , Nischal Sangeeta , McGraw Kathy L. , Bhattacharyya Sanchari , Bishop Michael R. , Artz Andrew , Thirman Michael J. , Moliterno Alison , Ji Peng , Levine Ross L. , Godley Lucy A. , Steidl Ulrich , Bieker James J. , List Alan F. , Saunthararajah Yogen , He Chuan , Verma Amit , Wickrema Amittha 
Published: April 2019

Abstract

Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor–associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin. The activating JAK2V617F mutation seen in myeloproliferative disease patient samples and in mouse models is associated with increased TET activity and cytosine hydroxymethylation as well as genome-wide loss of cytosine methylation. These epigenetic and functional changes are also associated with increased expression of several oncogenic transcripts. Thus, we demonstrate that JAK2-mediated TET2 phosphorylation provides a mechanistic link between extracellular signals and epigenetic changes during hematopoiesis.

Significance:
Identification of TET2 phosphorylation and activation by cytokine-stimulated JAK2 links extracellular signals to chromatin remodeling during hematopoietic differentiation. This provides potential avenues to regulate TET2 function in the context of myeloproliferative disorders and myelodysplastic syndromes associated with the JAK2V617F-activating mutation.
This article is highlighted in the In This Issue feature, p. 681
Tumor Neurobiology and the War of Nerves in Cancer
Authors: Faulkner Sam , Jobling Phillip , March Brayden , Jiang Chen Chen , Hondermarck Hubert 
Published: April 2019

Abstract

Nerves are emerging regulators of cancer progression. Cancer cells induce the outgrowth of nerves in the tumor microenvironment through the release of neurotrophic factors, and in return nerves liberate neurotransmitters that activate cancer growth and dissemination. Although sympathetic nerves drive tumor angiogenesis via the liberation of noradrenaline, sensory and parasympathetic nerves stimulate cancer stem cells. Interestingly, recent evidence indicates that parasympathetic nerves can eventually inhibit tumor progression, suggesting a yin–yang type of regulation of cancer by nerves. From a broader perspective, the question of a higher level of control of cancer development by the central nervous system should be raised.

Significance:
Nerves are emerging regulators of cancer initiation, progression, and metastasis. Here, we review the evidence to date and explore the basic and clinical ramifications of these findings.
Analysis of Extracellular Fluid Volume in Peritoneal Dialysis Patients before and after Kidney Transplantation
Authors: Sakai Ken , Hyoudou Youji , Nihei Hiroshi , Kawamura Takeshii 
Published: April 2019

Background/Aims: To examine the relationship of extracellular fluid (ECF) volume and osmotic excess with treatment modality, we retrospectively analyzed spontaneous body weight loss and osmotic excretion versus true body weight after kidney transplantation in peritoneal dialysis (PD) patients and preemptive transplant recipients compared with hemodialysis (HD) patients. We also examined maximum bladder volume in other transplant recipients on PD. Methods: From 2005 to 2011, 42 PD patients underwent kidney transplantation at our institution. Patients aged <12 years and cadaveric transplantations were excluded; we enrolled 27 PD patients (PD group; age 35.7 ± 14.4 years at transplantation; dialysis duration 36.5 ± 31.2 months) and 14 adult preemptive kidney transplant patients (preemptive group; age 31.7 ± 15.7 years; estimated glomerular filtration rate 8.26 ± 1.8 mL/min/1.73 m2 at transplantation). From 2005 to 2006, 29 adult living-related donor kidney transplant recipients on HD support (HD group) were enrolled as controls (age 36.4 ± 11.3 years; dialysis duration 37.5 ± 55.2 months). Results: Percentage body weight loss at 1 month after transplantation was 5% from ideal body weight for the PD group (51.2 ± 14.3 to 48.6 ± 13.0 kg, p = 0.002), 5.1% for the preemptive group (56.7 ± 17.4 to 53.8 ± 16.5 kg, p = 0.0005), and 1% for the HD group (52.9 ± 12.4 to 52.1 ± 12.5 kg, p = 0.079); post-transplantation 24-h osmotic excretion was greater in the PD and preemptive groups (387.3 ± 175.7 mOsm) groups than in HD (250 ± 124 mOsm; p = 0.006. Another 69 adult living-related donor kidney transplant recipients (PD and HD support) with dialysis duration ≤5 years were examined. Mean dialysis duration differed in the HD (17.5 ± 13.1 months) and PD (29.6 ± 20.4 months, p = 0.015) groups; mean urine volume and maximum desire to void (MDV) were similar. Conclusion: ECF volume and osmotic excess occurred in the PD and preemptive groups compared with the HD group pre-transplantation. Although PD maintains MDV and residual and total urine volume, ECF volume and osmotic excess should be monitored before transplant; pre-transplant HD support should always be considered in PD and preemptive transplant patients.
Administration of Curcumin Alleviates Neuropathic Pain in a Rat Model of Brachial Plexus Avulsion
Authors: Xie Wenji , Xie Wenqin , Kang Zhenming , Jiang Changcheng , Liu Naizhen 
Published: April 2019

<b><i>Background/Aims:</i></b> Brachial plexus avulsion (BPA) generally causes a chronic persistent pain that lacks efficacious treatment. Curcumin has been found to possess anti-inflammatory abilities. However, little is known about the mechanisms and effects of curcumin in an animal model of BPA. <b><i>Methods:</i></b> Mechanical withdrawal thresholds (MWT) were examined by von Frey filaments. Cold allodynia was tested by the acetone spray test. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in rat spinal cords were analyzed by the enzyme-linked immunosorbent assay, and the expression levels of c-Fos and nerve growth factor (NGF) were measured by Western blot. The expression level of glial fibrillary acidic protein (GFAP) was observed by immunofluorescence and Western blot. <b><i>Results:</i></b> After curcumin treatment, the MWT showed a significant increase when compared to the BPA group on both hind paws. A remarkable decrease of paw-withdrawal response frequency was observed compared with the BPA group. In addition, curcumin treatment significantly decreased the levels of TNF-α and IL-6 in rat spinal cords that were exceedingly upregulated in the BPA group. The protein levels of c-Fos and NGF were decreased by treatment with curcumin compared with the corresponding protein levels in the BPA group. Besides, curcumin reduced the number of GFAP positive cells and GFAP expression. <b><i>Conclusions:</i></b> Our findings suggest that curcumin significantly extenuates the BPA-induced pain and inflammation by reducing the expression level of proinflammatory cytokines and pain-associated proteins and inhibiting the activity of astrocytes.
What is related to the well-being of the siblings of patients with schizophrenia: An evaluation within the Lazarus and Folkman’s Transactional Stress and Coping Model
Authors: Avcıoğlu Muazzez Merve , Karanci Ayşe Nuray , Soygur Haldun 
Published: April 2019

Background: Schizophrenia is a chronic mental illness that strongly affects not only the patients with schizophrenia, but also their families and close relatives. So far, family research on patients with schizophrenia has mainly focused on parents, but has neglected siblings. Aim: This study aims to evaluate the well-being of 103 siblings of patients with schizophrenia within the Lazarus and Folkman’s Transactional Coping and Stress Model. Materials: A Sociodemographic Information Form, Subjective Well-being Scale, Zarit Caregiver Burden Scale, Multidimensional Perceived Social Support Scale, Ways of Coping Scale and Shortened Perceived Parental Rearing Styles Form were administered to the siblings of patients with schizophrenia. Results: The results of this study revealed that well-being was associated with perceived mother overprotection, perceived social support, problem-focused coping and indirect coping. Social support moderated the relationship between burden and well-being as a buffering factor. Conclusion: Therefore, siblings of patients with schizophrenia should be given access to social support and their problem-focused coping strategies should be strengthened. Besides, parents should be supported to provide suitable care for the siblings of patients with schizophrenia.
Anesthetic management of radical nephrectomy in patients with renal cell carcinoma involving renal vein or inferior vena cava
Authors: Chen Kun , Wang Juan , Dai Jinzhen , Luo Ailin , Tian Yuke , Guan Zhonghui , Wang Xueren 
Published: April 2019

Objective: To investigate the perioperative anesthetic management of patients diagnosed with renal cell carcinoma (RCC) metastasized into the renal vein or inferior vena cava (IVC) after undergoing radical nephrectomy to provide clinical evidence for rational anesthetic interventions. Methods: A total of 81 patients with RCC extending into the renal vein or IVC, aged 17–73 years, undergoing radical nephrectomy were recruited. Preoperative status, intraoperative management, average operation time, average estimated blood loss, postanesthesia outcomes, and postoperative complications were retrospectively analyzed. Results: The mean operation time was 288 minutes (range 146–825 minutes). The mean estimated blood loss was recorded as 1905 mL (range 200–7000 mL). Among 81 cases, 9 patients (11.1%, 1 level II, 3 level III, and 5 level IV) were switched to undergo cardiopulmonary bypass. Significant hemodynamic fluctuations were observed in 39 patients who presented with level II–IV of tumor thrombus. One patient had pulmonary embolism and died of active cardiopulmonary resuscitation. The mean postoperative hospital stay was 12.8 days. Twenty-five cases with level III–IV tumor thrombus were transferred to the intensive care unit with endotracheal intubation due to massive intraoperative blood loss. The remaining 55 cases were transferred to the postanesthesia care unit 2 hours before being transferred to the ward. One patient had postoperative acute coronary syndrome and was discharged after effective interventions. Conclusion: Anesthetic management and intensive postoperative care play a pivotal role in the success of complete resection of RCC that metastasize into the IVC.
Clinical and Radiological Predictors of Functional Outcome After Isolated Medial Patellofemoral Ligament Reconstruction at Midterm Follow-up
Authors: Neri Thomas , Parker David Anthony , Putnis Sven , Klasan Antonio , Trombert-Paviot Beatrice , Farizon Frederic , Philippot Remi 
Published: April 2019

Background: Isolated medial patellofemoral ligament reconstruction (iMPFLR) is increasingly used for the surgical treatment of recurrent patellofemoral instability. Purpose: The purpose of this study was to identify the clinical and radiological predictors that can significantly influence the functional outcomes after an iMPFLR. Study Design: Case series; Level of evidence, 4. Methods: A total of 107 patients (112 ligament reconstructions) who underwent iMPFLR were evaluated with a mean ± SD follow-up of 59 ± 33 months (range, 12-123 months). Functional International Knee Documentation Committee (IKDC) and Kujala scores were assessed preoperatively and every 12 months. Radiological assessment of patellar height and tilt (Laurin angle, Merchant angle, Maldague classification) and computed tomography (CT) scan measurement of patellar tilt (contracted and relaxed quadriceps) and tibial tubercle–trochlear groove distance were performed preoperatively and at 6 months. Femoral tunnel position was assessed following the criteria formulated by Schöttle. The amount of femoral tunnel widening was measured by means of 3-dimensional CT scan at 6 months. Predictors were determined from univariate and multivariate regression analyses integrating clinical and radiological criteria pre- and postoperatively. The dependent variable was defined as the difference between pre- and postoperative scores. Results: Between pre- and postoperative measurement at last follow-up, a significant improvement for IKDC and Kujala functional scores was observed (Kujala: 57 ± 11.3 to 87 ± 12.9, P < .001; IKDC: 47.8 ± 13.1 to 79 ± 15.8, P < .001). Demographics (age, body mass index, sex), dislocation characteristics (number of dislocations, time between first dislocation and surgery, age at first dislocation, mechanism of first dislocation, knee side), clinical data (frontal limb alignment, hyperlaxity, recurvatum, pre- and postoperative range of motion), and complications (quadriceps atrophy, complex regional pain syndrome) did not influence functional scores. The predictors of lower improvement in functional scores included small correction of the patellar tilt reported on the CT scan measurement, malpositioning of the femoral tunnel, and a widening of this tunnel near the medial cortex. Malpositioning of the femoral tunnel was correlated with tunnel widening, and patients with anterior and proximal malpositioning experienced stiffness in flexion. Conclusion: Overall, iMPFLR demonstrated good outcomes. Predictors influencing the functional results were identified. Less improvement in clinical outcome was reported for patients with a high preoperative patellar tilt and only a small correction in tilt and for those who had femoral tunnel malpositioning, which was correlated with tunnel widening.
Correlation Between Magnetic Resonance Imaging and Surgical Exploration of the Anterolateral Structures of the Acute Anterior Cruciate Ligament–Injured Knee
Authors: Monaco Edoardo , Helito Camilo Partezani , Redler Andrea , Argento Giuseppe , De Carli Angelo , Saithna Adnan , Helito Paulo Victor Partezani , Ferretti Andrea 
Published: April 2019

Background: Combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction is associated with improved clinical outcomes as compared with isolated intra-articular reconstruction, but the indications are not precisely defined. It may be the case that patients with proven anterolateral injury on preoperative imaging are most likely to benefit, but the accuracy of magnetic resonance imaging (MRI) is not known. Purpose/Hypothesis: To evaluate the correlation between MRI and surgical exploration in acute ACL-injured knees. The hypothesis was that a positive correlation would be identified between imaging and surgical findings for ALL/capsule and iliotibial band (ITB) injuries and that MRI would be highly sensitive, specific, and accurate. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Between January and May 2016, patients presenting with acute ACL injuries were considered for study eligibility. Included patients underwent 1.5-T MRI, which was evaluated by 3 investigators who attributed a Ferretti grade of injury to the anterolateral structures. At the time of ACL reconstruction, a lateral exploration was undertaken, and macroscopic injuries were identified. An evaluation of correlation between MRI and surgical exploration findings was performed. Results: Twenty-six patients participated in the study, and 96% had an ALL/capsule injury. The sensitivity, specificity, and accuracy of MRI and the correlation ( K) with surgical exploration findings were as follows, respectively: any ALL/capsule abnormality—88%, 100%, 88.5%, and 0.47; differentiating partial or complete ALL/capsule tears—78.6%, 41.7%, 61.5%, and 0.23; ITB injuries—62.5%, 40%, 50%, and 0.27. The percentage agreement between MRI and surgical findings was 88% for ALL/capsule injury, 65% for ITB injury, and 53% for Ferretti grading. Conclusion: Surgical exploration demonstrates that injuries occur to the anterolateral structures in almost all acute ACL-injured knees. MRI is highly sensitive, specific, and accurate for detection of abnormalities of the ALL/capsule and shows a high percentage of agreement with surgical findings. MRI has low sensitivity, specificity, and accuracy for the diagnosis of ITB injury. The Ferretti grade could not be reliably established from MRI, and there was only fair agreement between MRI and surgical findings with respect to ITB abnormalities and determination of whether ALL/capsular tears were partial or complete.