bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti–DNase I Antibody
Authors: Griffo Priscilla , Viana Vilma V. S. T. , Pasoto Sandra G. , Leon Elaine P. , Bonfa Eloisa
Published: September 2018

Background and Objective

Primary Sjögren syndrome (pSS) is a systemic autoimmune rheumatic disease that particularly affects exocrine glands. Dry eye is one of the most important features of this syndrome, and a recent study reported reduced deoxyribonuclease I (DNase I) activity in the tear of patients with dry eye. We therefore postulated that patients with pSS might have antibodies targeting DNAse I.

Methods

We have evaluated in a cross-sectional study 85 patients with pSS (2002 American-European Consensus Group Criteria), 50 rheumatoid arthritis (RA) patients (1987 American College of Rheumatology Criteria) without sicca symptoms, and 88 healthy volunteers. IgG anti–DNase I was detected by enzyme-linked immunosorbent assay using as antigen bovine pancreas enzyme and confirmed by immunoblotting.

Results

Age and sex were alike in the 3 groups (p > 0.05). Anti–DNase I was detected in 43.5% of the pSS patients. In contrast, this reactivity was absent in all RA patients (p = 0.0001). Additional comparison of pSS patients with (n = 37) or without (n = 48) anti–DNase I showed that the former group had higher IgG serum levels (2293.2 ± 666.2 vs 1483.9 ± 384.6 mg/dL, p = 0.0001) and greater rate of non–drug-induced leukopenia (43% vs 19%, p = 0.02). A multivariate logistic regression analysis identified that only IgG levels were independently associated with anti–DNase I.

Conclusions

We describe a high frequency of anti–DNase I antibodies in pSS patients associated with higher serum IgG levels. The lack of this reactivity in RA patients without sicca symptoms suggests that this antibody may be helpful in the differential diagnosis of these diseases.
Atypical Chronic Inflammatory ANCA-Positive Deforming Arthritis After Cocaine-Levamisole Exposure
Authors: Emil N. Suzanne , Cisneros David R. , Penmetsa Santhi , Duchesne Joshua H. , Sibbitt Wilmer L. , Gibb James I. , Noronha Leonard E. , Fangtham Monthida , Fields Roderick A. , Bankhurst Arthur D.
Published: September 2018

Background/Objective

Immunostimulatory drugs including immune checkpoint inhibitors and levamisole can induce inflammatory disease including vasculitis, rashes, tissue necrosis, and arthritis.

Methods

This prospective cohort study determined the 5-year outcomes of cocaine-levamisole–induced inflammatory disease as to outcomes and survival. Thirty-one consecutive cocaine-levamisole autoimmune patients and 45 primary vasculitis patients were characterized as to clinical differentiating features, antineutrophil cytoplasmic antibody (ANCA) status, treatment, the presence of acute and chronic arthritis, and 5-year outcome.

Results

Seventy-one percent (22/31) of cocaine-levamisole vasculopathy cases were ANCA positive (86% p-ANCA and 14% c-ANCA), whereas 53% (23/45) of the primary vasculitis were ANCA positive (p= 0.04). The ANCA-positive cocaine-levamisole cohort at onset were characterized by younger age (45 ± 12 vs 53 ± 14 years,p= 0.04), superficial skin necrosis (82% vs 54%,p= 0.036), depressed complement C3 (27% vs 4%,p= 0.33), antiphospholipid antibodies (50% vs 4%,p< 0.001), neutropenia (18% vs 0%,p= 0.044), and elevated antimyeloperoxidase (MPO) antibody levels (100% vs 67%,p< 0.001). Chronic cocaine-levamisole disease was characterized by severe cicatrical deformities of the face and extremities (45.5% vs 8.3%,p= 0.005). Arthralgias (71% vs 82%,p= 0.19) and acute arthritis (33% vs 32%,p= 0.25) were similar between the 2 groups. However, a substantial proportion cocaine-levamisole–induced autoimmune patients (18% vs 0%,p= 0.045) developed a chronic deforming inflammatory arthritis that was rheumatoid factor, anti–cyclic-citrillinated antibody antibody, and HLA-B27 negative, but p-ANCA-and MPO antibody positive.

Conclusions

Patients exposed to cocaine-levamisole may develop serious chronic sequelae including cicatrical cutaneous and facial deformities and an atypical seronegative, p-ANCA and MPO antibody–positive, HLA-B27–negative chronic deforming inflammatory arthritis.
68Ga-PSMA-11 PET/CT in Newly Diagnosed Prostate Adenocarcinoma
Authors: Ergül Nurhan , Yilmaz Güneş Burçak , Yücetaş Uğur , Toktaş Mahmut Gökhan , Çermik Tevfik Fikret
Published: September 2018

Introduction

Prostate-specific membrane antigen (PSMA) ligand PET/CT is an emerging modality to detect the metastatic disease, especially in intermediate- and high-risk prostate cancer (PCa). In this study, we analyzed the contribution of 68Ga-PSMA-11 PET/CT in staging and therapy management of newly diagnosed PCa.

Materials and Methods

A total of 78 patients with biopsy-proven PCa who were referred for 68Ga-PSMA-11 PET/CT for primary staging were retrospectively analyzed. The patients were divided into risk groups according to the D'Amico risk stratification criteria. All of the patients had undergone pelvic MRI, and 65 patients had bone scintigraphy also. The findings of 68Ga-PSMA-11 PET/CT were compared with these conventional imaging (CI) methods for staging of the disease. The relations between SUVmax of the primary tumors and Gleason scores (GSs), prostate-specific antigen (PSA) levels, and metastatic extent of the disease were analyzed.

Results

Of 78 patients, 5 patients were in low-risk group, 18 patients were in intermediate-risk group, and 55 patients were in high-risk group. Metastatic disease was found in 40 (51.2%) of 78 patients in 68Ga-PSMA-11 PET/CT. Ten patients had regional lymph node metastases, and 30 patients had distant metastases. 68Ga-PSMA-11 PET/CT changed the staging in 44 (56.4%) of 78 patients compared with CI. There was significant difference between the SUVmax of the tumors with GSs of 6 and 7 compared with GSs of 8, 9, and 10 (P = 0.003). The SUVmax were significantly different between the patients with no metastasis (n = 38) and patients with regional lymph node metastases or distant metastases (n = 40; 16.1 ± 10.9, 28.7 ± 25.8, P = 0.003, respectively). There was significant difference between the SUVmax of patients with PSA level less than 10 ng/mL compared with patients with PSA level of 10 or greater and less than 20 ng/mL and PSA 20 ng/mL or greater (P = 0.009). A weak correlation between PSA and primary tumor SUVmax was also found (r = 0.21).

Conclusions

68Ga-PSMA-11 PET/CT is an important imaging modality for primary evaluation of newly diagnosed PCa changing the disease stage substantially. Also the SUVmax of the primary tumor has a relation with GS, metastatic extent of disease, and PSA levels defining the prognosis.
Increased Activity Due to Fractures Does Not Significantly Affect the Accuracy of 68Ga-DOTATATE PET/CT in the Detection of Culprit Tumor in the Evaluation of Tumor-Induced Osteomalacia
Authors: Ding Jie , Hu Guilan , Wang Ling , Li Fang , Huo Li
Published: September 2018

Objective

68Ga-DOTATATE PET/CT is currently the most common imaging modality in localizing culprit tumors, which can result in tumor-induced osteomalacia (TIO). Fracture, which is one of the most common consequences of the TIO, can also lead to increased 68Ga-DOTATATE activity and potentially affect the accuracy of 68Ga-DOTATATE PET/CT imaging. The aim of this investigation is to evaluate whether the increased 68Ga-DOTATATE activity at the sites of the fracture will cause interpretation difficulty in the localizing the culprit tumor causing TIO.

Method

The images of 68Ga-DOTATATE PET/CT scan from a total of 54 patients who had multiple foci of increased 68Ga-DOTATATE PET/CT on PET/CT were retrospectively analyzed. Not only was the intensity of the activity on PET but also the appearance of the activity on CT taken into consideration when the interpretation of the images occurred. The results from imaging analysis were compared with the clinical chart record. All patients had tentative clinical diagnosis of TIO.

Results

The causative tumors in 53 patients were eventually identified. In 1 patient, the causative tumor was not identified. Among the 53 patients with confirmed TIO, 52 tumors were accurately localized.

Conclusions

Mild activity at the sites of fracture is not a major challenging factor in the interpretation of 68Ga-DOTATATE PET/CT in the evaluation of TIO when both intensity on PET and morphology on CT were assessed.
Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation
Authors: von Zur-Mühlen Bengt , Lundgren Torbjörn , Bayman Levent , Berne Christian , Bridges Nancy , Eggerman Thomas , Foss Aksel , Goldstein Julia , Jenssen Trond , Jorns Carl , Morrison Yvonne , Rydén Mikael , Schwieger Traci , Tufveson Gunnar , Nilsson Bo , Korsgren Olle
Published: September 2018

Background.

When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR.

Methods.

The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 ± 10 seconds and 50 ± 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant.

Results.

Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 ± 5 days after the first transplant) between the 2 arms (1.33 ± 1.10 versus 1.56 ± 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups.

Conclusions.

Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to “state-of-the art” treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.
Kinetics of Torque Teno Virus-DNA Plasma Load Predict Rejection in Lung Transplant Recipients
Authors: Frye Björn C. , Bierbaum Sibylle , Falcone Valeria , Köhler Thomas C. , Gasplmayr Markus , Hettich Ina , Dürk Thorsten , Idzko Marco , Zissel Gernot , Hengel Hartmut , Müller-Quernheim Joachim
Published: September 2018

Background.

Lung transplantation is the only therapeutic option in end-stage lung diseases; however, survival after transplantation is limited by acute and chronic rejection or infectious events being results of inappropriate immunosuppression. Torque Teno Viruses (TTVs) are ubiquitous DNA viruses in humans but not found to be causative for any disease. However, some reports suggest that TTV-DNA levels reflect the grade of immunosuppression with higher levels being found in more immunosuppressed individuals.

Methods.

We investigated the TTV-DNA levels in 34 lung transplant recipients within their first year after transplantation by quantitative real-time polymerase chain reaction. Clinical data were extracted from charts.

Results.

In accordance with previous results TTV-DNA levels increase after lung transplantation reaching a steady state after 3 months. The TTV-DNA levels were not correlated with immunosuppressive trough levels and a selective increase was not observed with other DNA viruses. In steady state TTV-DNA levels were significantly higher in patients with infectious complications compared to the group of patients without. Additionally, TTV-DNA levels decreased significantly before biopsy-proven rejection. Sensitivity of a 10-fold decrease in TTV-DNA levels for a subsequent rejection episode was 0.74 with a specificity of 0.99.

Conclusions.

In summary, TTV-DNA might be used as an additional tool to monitor immunosuppression in lung transplant recipients. Higher TTV-DNA levels reflect more intense immunosuppression, whereas the TTV-DNA kinetic (ie, decrease of TTV-DNA levels) indicate rejection.
Liraglutide, a Glucagon-like Peptide-1 Receptor Agonist, Attenuates Development of Cardiac Allograft Vasculopathy in a Murine Heart Transplant Model
Authors: Wang ZhiMin , Wang Mengjun , Hu Xiaofan , Li Yakun , Ma DongXia , Li ShangLin , Zhao GuangYuan , Xie YaNan , Shu Yanwen , Yang Jun
Published: September 2018

Background.

Advances in immunosuppressive therapy have significantly improved short-term but not long-term survival of cardiac transplant recipients; this is largely due to severe cardiac allograft vasculopathy (CAV). Glucagon-like peptide-1 receptor (GLP-1R)-based therapy exerts physiological effects on the cardiovascular system in addition to its traditional role in controlling glucose. We have investigated the effects of liraglutide, a GLP-1R agonist, on the development of CAV in a murine heart transplant model.

Methods.

Heterotopic murine cardiac transplantation was performed with a major histocompatibility complex class II-mismatched model. Recipient mice were subcutaneously administered vehicle (0.9% saline solution) or liraglutide (300 μg·kg−1 every 12 hours) from the day of transplantation. Allografts were harvested at 2 or 8 weeks and histologically analyzed. Inflammatory infiltrates were measured by immunohistochemistry, and immunofluorescence and western blotting analyzes were used to evaluate GLP-1R expression and markers of endothelial-to-mesenchymal transition (EndMT) in cardiac allografts and human coronary artery endothelial cells challenged with transforming growth factor-beta 1.

Results.

Glucagon-like peptide-1 receptor was predominantly localized to vascular endothelial cells and was upregulated in cardiac allografts after liraglutide treatment. Liraglutide ameliorated CAV and cardiac fibrosis with reduced inflammatory cell infiltration and downregulated expression of adhesion molecules. Liraglutide inhibited EndMT in allografts and attenuated EndMT by inhibiting Smad3 activation in transforming growth factor-beta 1–treated human coronary artery endothelial cells.

Conclusions.

Administration of liraglutide from the time of transplantation upregulated GLP-1R in the transplanted heart and reduced cardiac fibrosis, inflammation, and CAV development. Therefore, liraglutide may be a novel therapy for CAV.
Kidney Transplant in the Era of Modern Therapy for Multiple Myeloma
Authors: Huskey Janna L. , Heilman Raymond L. , Khamash Hasan , Fonseca Rafael
Published: September 2018

Chronic kidney disease is common in patients with multiple myeloma. Historically, individuals with end-stage renal disease and multiple myeloma did poorly with renal transplantation due to higher mortality rates from the malignancy itself or associated comorbidities. However, over the past 2 decades, there have been significant advances in the treatment of multiple myeloma with the advent of new therapeutic agents resulting in an improvement of long-term survival. As a result, more individuals with multiple myeloma are being referred for kidney transplantation, especially those with good functional capacity and minimal comorbidities. Recent literature has suggested that certain patients with multiple myeloma can successfully undergo renal transplantation after stem transplantation with consideration for maintenance therapy, although caution should be used with immunomodulating drugs due to the anecdotally reported risk of acute rejection. Therefore, having a multidisciplinary approach with the transplant team and hematology both before and after transplant is crucial in maximizing the chance of success for these individuals. This review summarizes the literature on renal transplantation in patients with multiple myeloma as well as the therapeutic advancements that have occurred which may allow certain patients to undergo successful transplantation.
Potentiating Renal Regeneration Using Mesenchymal Stem Cells
Authors: Brasile Lauren , Henry Nicholas , Orlando Giuseppe , Stubenitsky Bart
Published: September 2018

Background

The potential of a mesenchymal stem cell (MSC) therapy to accelerate the repair of ischemically damaged human kidneys during 24 hours of warm perfusion was evaluated. The hypothesis was that by administering MSC directly to the renal tissue, there would be an improved opportunity for cellular repair mediated by intrarenal paracrine effects.

Methods

Studies were performed using the exsanguinous metabolic support (EMS) tissue-engineering platform. Five pairs of human kidney allografts from donation after circulatory death donors were studied. One human kidney was EMS perfused for 24 hours (control), whereas its paired kidney was EMS perfused with MSC (1 × 108). The kidneys were evaluated for DNA synthesis, cytokine/chemokine synthesis, cytoskeletal regeneration, and mitosis.

Results

Treatment with MSC resulted in reduced inflammatory cytokines synthesized by the kidneys. Mesenchymal stem cell treatment led to a significant increase in the synthesis of adenosine triphosphate and growth factors resulting in normalization of metabolism and the cytoskeleton. Toluidine Blue staining of MSC-treated kidneys demonstrated a significant increase in the number of renal cells undergoing mitosis (26%) compared with EMS perfusion alone.

Conclusions

To our knowledge, our work is the first to have demonstrated actual renal regeneration while ischemically damaged human kidneys are perfused ex vivo for 24 hours. The observed regeneration entails: increased synthesis of adenosine triphosphate, a reduced inflammatory response, increased synthesis of growth factors, normalization of the cytoskeleton and mitosis. The ability to regenerate renal tissue ex vivo sufficiently to result in immediate function could revolutionize transplantation by solving the chronic organ shortage.
VCA Deceased Donors in the United States
Authors: Wainright Jennifer L. , Wholley Christopher L. , Rosendale John , Cherikh Wida S. , Di Battista Darren , Klassen David K.
Published: September 2018

Background.

Vascularized composite allograft (VCA) transplants include diverse organ types and are made possible primarily by deceased donors.

Methods.

We used Organ Procurement and Transplantation Network data to characterize VCA deceased donors (n = 66 of 70) in the United States from 1998 to 2017 and compare their characteristics with those of kidney donors in 2017.

Results.

Through December 31, 2017, 20 transplant programs performed 72 deceased-donor VCA transplants, with organs donated by 70 donors, including 30 upper limb (17 unilateral and 13 bilateral) and 11 face donors. Other donors donated both upper limbs and face (n = 2), uterus (n = 4), abdominal wall (n = 19), larynx (n = 2), penis (n = 1), and scalp (n = 1). About a third of VCA donors were female, and the majority (86.4%) were white. Almost half (45.5%) were between the ages 18 and 34 years. Smaller proportions were younger than 18 years (19.7%), 35 to 44 years (15.2%), 45 to 54 years (13.6%), and older than 55 years (6.1%). Median body mass index for all VCA donors was 24.9 and varied widely, especially for upper limb and face donors. There was considerable variation in Kidney Donor Profile Index among VCA donors (median, 27.5; interquartile range, 11–59). Donor causes of death included head trauma (39.4%), cerebrovascular/stroke (25.8%), and anoxia (31.8%). VCA donors also donated solid organs that were transplanted, including 87.1% of kidneys, 93.9% of livers, 40.2% of lungs, and 56.1% of hearts.

Conclusions.

donors are a demographically and clinically diverse group. Understanding this diversity and future trends in VCA donor characteristics is critical in supporting this life-changing field of transplantation.
Equivalent Outcomes With Retransplantation and Primary Liver Transplantation in the Direct-acting Antiviral Era
Authors: Croome Kristopher P. , Mathur Amit K. , Pungpapong Surakit , Lee David D. , Moss Adyr A. , Rosen Charles B. , Heimbach Julie K. , Taner C. Burcin
Published: September 2018

Background.

The present multicenter study investigated whether equivalent outcomes to primary liver transplant (LT) could be achieved with liver retransplant (reLT) and whether improvements in outcomes have taken place over time, particularly in the direct-acting antiviral era.

Methods.

All reLT performed at Mayo Clinic Florida, Mayo Clinic Rochester, and Mayo Clinic Arizona were divided into era 1 (2002–2007), era 2 (2008–2012), and era 3 (2013–2017) based on the date of reLT.

Results.

Improvement in graft survival (GS) after reLT was seen over the 3 eras (P < 0.001). In era 1, GS after reLT was inferior to primary LT (P < 0.001), whereas no difference was seen between reLT and primary LT in era 2 (P = 0.68) or era 3 (P = 0.36). A significantly higher proportion of patients achieved sustained viral response (SVR) within the first year after reLT in each subsequent era (era 1: 10.3%, era 2: 22.5%, and era 3: 100%) (P < 0.001). Graft survival was superior in patients undergoing reLT for recurrent hepatitis C virus who achieved SVR after reLT compared with those who did not (P = 0.03).

Conclusions.

Results similar to primary LT were achieved in era 3. These improvements coincide with the availability of direct-acting antivirals, which resulted in a 100% SVR rate in era 3 and a decrease in the number of patients undergoing reLT for recurrent hepatitis C virus. The historic dogma that reLT results in inferior outcomes should be revisited.
Kaposi Sarcoma in HIV-positive Solid-Organ Transplant Recipients: A French Multicentric National Study and Literature Review
Authors: Charpentier Chloé , Delyon Julie , Glotz Denis , Peraldi Marie-Noelle , Rerolle Jean-Philippe , Barrou Benoît , Ducroux Emilie , Coilly Audrey , Legeai Camille , Barete Stéphane , Lebbé Céleste
Published: September 2018

Background

Kaposi sarcoma is a vascular tumor related to herpesvirus-8 and is promoted by immunosuppression. For the last 15 years, human immunodeficiency virus (HIV) patients have had access to organ transplantation. The dual immunosuppression of HIV and immunosuppressive treatments might increase the risk and severity of Kaposi sarcoma.

Methods

We conducted a multicentric retrospective study by collecting cases from French databases and society members of transplanted patients, among which 7 HIV-infected patients who subsequently developed Kaposi sarcoma were included.

Results

In the CRISTAL database (114 511 patients) and the DIVAT (Données Informatisées et VAlidées en Transplantation) database (19 077 patients), the prevalence of Kaposi sarcoma was 0.18% and 0.46%, respectively, in transplanted patients; these values compare with 0.66% and 0.50%, respectively, in transplanted patients with HIV. The median time from HIV infection to Kaposi sarcoma was 20 years. Kaposi sarcoma occurred during the first year after transplantation in most cases, whereas HIV viral load was undetectable. Only 2 patients had visceral involvement. Five patients were treated with conversion of calcineurin inhibitor to mammalian target of rapamycin inhibitor, and 5 patients were managed by decreasing immunosuppressive therapies. At 1 year, 4 patients had a complete response, and 3 had a partial response.

Conclusions

In our study, Kaposi sarcoma in transplanted patients with HIV did not show any aggressive features and was treated with the usual posttransplant Kaposi sarcoma management protocol.
Urinary Retention Associated With Cariprazine: A Case Report
Authors: Kapulsky Leonid , Brody Benjamin D.
Published: September 2018

Urinary retention is a well-documented adverse effect of antipsychotic medications and is thought to be mediated by anticholinergic, adrenergic, and other neurotransmitter effects. Whereas urinary retention has been reported with typical and some atypical antipsychotics, there have been no reports of urinary retention with the novel antipsychotic cariprazine. We report on a case of urinary retention associated with cariprazine. Possible mechanisms for this adverse effect are discussed.
Natalizumab Treatment for Relapsing-Remitting Multiple Sclerosis: The Experience From Saudi Arabia
Authors: Algahtani Hussein , Shirah Bader , Abobaker Hind , Alghanaim Nebras , Kamel Fatemah
Published: September 2018

Background

Natalizumab is the first targeted humanized monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab appears to be more effective than current first-line disease-modifying therapies. In our study, we aimed to evaluate the outcome of Saudi patients with active RRMS treated with natalizumab and compare the results with other outcomes in the Gulf and international trials.

Methods

We conducted a retrospective single-center observational study involving 32 patients with RRMS at King Abdulaziz Medical City in Jeddah, Saudi Arabia. The inclusion criteria included all patients diagnosed with RRMS according to the revised McDonald criteria who are currently receiving or received natalizumab treatment in the past for a minimum of 6 months.

Results

The mean baseline Expanded Disability Status Scale score was 4.50 ± 1.80 (range, 1.5–6; median, 5), whereas the mean Expanded Disability Status Scale at the follow-up was 4.02 ± 2.08 (range, 1–6; median, 4.25) (P = 0.3274). The mean annualized relapse rate was significantly reduced from 2.41 ± 2.48 at baseline to 0.16 ± 0.37 at the last follow-up (P < 0.0001). Twenty-seven patients (84.4%) had no relapses since the treatment with natalizumab was started, whereas 5 patients (15.6%) had only 1 relapse. In addition to clinically measurable improvement, radiological improvement was observed through magnetic resonance imaging. Magnetic resonance imaging activity was significantly improved at follow-up magnetic resonance imaging studies when compared with baseline.

Conclusions

Our single-center study in Saudi Arabia provides further support for the efficacy of natalizumab in the clinical practice setting. The sharp decrease in relapse rate and progression of disability following the initiation of natalizumab treatment was similar to other observational studies conducted in different countries across the globe. Natalizumab was a satisfactory therapy for the management of our MS population, both from the patients' and the physicians' perspectives.
Fludarabine-Induced Posterior Reversible Encephalopathy Syndrome in a Pediatric Patient With β-Thalassemia: Case Report and Literature Review
Authors: Navarro Cristian Eduardo , Rodríguez Paula Juliana , Espitia Oscar Mauricio
Published: September 2018

Posterior reversible encephalopathy syndrome is a disorder of reversible subcortical vasogenic brain edema in the context of different diseases or exposure to cytotoxic drugs such as fludarabine. We present the case of a pediatric patient with β-thalassemia who develops a fludarabine-induced posterior reversible encephalopathy while he received an induction regimen to achieve an allogenic hematopoietic cell transplantation. The clinical presentation consists in altered mental state, headache, status epilepticus, visual disturbance, and hypertension. His treatment was carried out with the suspension of the medication and the control of hypertension and status epilepticus; the final outcome was positive without additional complications. There are published reports about fludarabine toxicity in the central nervous system with different doses of the drug in different clinical context. We also made a review of the literature available and conclude that fludarabine is not an extraordinary cause of posterior reversible encephalopathy syndrome.
Molecular basis of human asparagine synthetase inhibitor specificity
Authors: Zhu Wen , Radadiya Ashish , Bisson Claudine , Nordin Brian E. , Baumann Patrick , Imasaki Tsuyoshi , Wenzel Sabine A. , Sedelnikova Svetlana E. , Berry Alexandria H. , Nomanbhoy Tyzoon K. , Kozarich John W. , Jin Yi , Takagi Yuichiro , Rice David W. , Richards Nigel G. J.
Published: September 2018

Expression of the enzyme human asparagine synthetase (ASNS) promotes metastatic progression in breast cancer, which affects L-asparagine levels and tumor cell invasiveness. Human ASNS has therefore emerged as abona fidedrug target for cancer therapy. We have reported a slow-onset, tight binding ASNS inhibitor with nanomolar affinity, but our compound exhibits poor cell permeability. On the other hand, we show here that this inhibitor exhibits remarkable selectivity for the human ASNS in HCT-116 cell lysates. By determining the first high-resolution (1.85 Å) X-ray crystal structure for human ASNS, we have built a computational model of the enzyme complexed to our inhibitor, which provides the first insights into the intermolecular interactions mediating specificity. These findings should facilitate the development of a second generation of ASNS inhibitors, leading to the discovery of drugs to prevent metastasis.
Minimum Information for Reusable Arthropod Abundance Data (MIReAAD)
Authors: Rund Samuel , Braak Kyle , Cator Lauren , Copas Kyle , Emrich Scott J. , Giraldo-Calderón Gloria I. , Johansson Michael A. , Heydari Naveed , Hobern Donald , Kelly Sarah A. , Lawson Daniel , Lord Cynthia , MacCallum Robert M , Roche Dominique G. , Ryan Sadie J. , Schigel Dmitry , Vandegrift Kurt , Watts Matthew , Zaspel Jennifer M. , Pawar Samraat
Published: September 2018

Arthropods play a dominant role in natural and human-modified terrestrial ecosystem dynamics. Spatially-explicit population time-series are crucial for statistical or mathematical models of these dynamics and assessment of their veterinary, medical, agricultural, and ecological impacts. Arthropod data have been collected world-wide for over a century, but remain scattered and largely inaccessible. With the ever-present and growing threat of arthropod vectors of infectious diseases and pest species, there are enormous amounts of historical and ongoing surveillance. These data are currently reported in a wide variety of formats, typically lacking sufficient metadata to make reuse and re-analysis possible. We present the first minimum information standard for arthropod abundance. Developed with broad stakeholder collaboration, it balances sufficiency for reuse with the practicality of preparing the data for submission. It is designed to optimize data (re-)usability from the “FAIR,” (Findable, Accessible, Interoperable, and Reusable) principles of public data archiving (PDA). This standard will facilitate data unification across research initiatives and communities dedicated to surveillance for detection and control of vector-borne diseases and pests.
Reconstructing the human first trimester fetal–maternal interface using single cell transcriptomics
Authors: Vento-Tormo Roser , Efremova Mirjana , Botting Rachel A. , Turco Margherita Y. , Vento-Tormo Miquel , Meyer Kerstin B. , Park Jongeun , Stephenson Emily , Polański Krzysztof , Payne Rebecca P. , Goncalves Angela , Zou Angela , Henriksson Johan , Wood Laura , Lisgo Steve , Filby Andrew , Wright Gavin J. , Stubbington Michael J. T. , Haniffa Muzlifah , Moffett Ashley , Teichmann Sarah A.
Published: September 2018

During the early weeks of human pregnancy, the fetal placenta implants into the uterine mucosa (decidua) where placental trophoblast cells intermingle and communicate with maternal cells. Here, we profile transcriptomes of ∼50,000 single cells from this unique microenvironment, sampling matched first trimester maternal blood and decidua, and fetal cells from the placenta itself. We define the cellular composition of human decidua, revealing five distinct subsets of decidual fibroblasts with differing growth factors and hormone production profiles, and show that fibroblast states define two distinct decidual layers. Among decidual NK cells, we resolve three subsets, each with a different immunomodulatory and chemokine profile. We develop a repository of ligand-receptor pairs (www.CellPhoneDB.org) and a statistical tool to predict the probability of cell-cell interactions via these pairs, highlighting specific interactions between decidual NK cells and invading fetal extravillous trophoblast cells, maternal immune and stromal cells. Our single cell atlas of the maternal-fetal interface reveals the cellular organization and interactions critical for placentation and reproductive success.
Alternative translation initiation generates a functionally distinct isoform of the stress-activated kinase MK2
Authors: Trulley Philipp , Snieckute Goda , Bekker-Jensen Dorte , Menon Manoj B. , Freund Robert , Kotlyarov Alexey , Olsen Jesper V. , Diaz-Muñoz Manuel D. , Turner Martin , Bekker-Jensen Simon , Gaestel Matthias , Tiedje Christopher
Published: September 2018

Shaping of the proteome by alternative translation is an important mechanism of post-transcriptional gene regulation. It can lead to the expression of multiple protein isoforms originating from the same mRNA. Here we show that a novel, abundant and long isoform of the stress/p38MAPK-activated kinase MK2, a key regulator of transcription, migration, death signaling and post-transcriptional gene regulation, is constitutively translated from an alternative CUG translation initiation start site located in the 5′UTR of its mRNA. GC-rich sequences and putative G-quadruplex structures influence the usage of that codon as a translation initiation start site and the RNA helicase eIF4A1 is needed to ensure alternative isoform translation. We recapitulated the usage of the alternative start codon and determined the molecular properties of the short and a long MK2 isoforms. Phenotypically, only the short isoform phosphorylated Hsp27, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling by quantitative mass-spectrometry revealed short isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains additional putative phosphorylation sites in its unique N-terminus. In sum, our data reveal a longer and previously non-described isoform of MK2 with distinct physiological properties originating from alternative translation.
Group ICA for Identifying Biomarkers in Schizophrenia: ‘Adaptive’ Networks via Spatially Constrained ICA Show More Sensitivity to Group Differences than Spatio-temporal Regression
Authors: Salman Mustafa S , Du Yuhui , Lin Dongdong , Fu Zening , Damaraju Eswar , Sui Jing , Chen Jiayu , Yu Qingbao , Mayer Andrew , Posse Stefan , Mathalon Daniel , Ford Judith M. , Van Erp Theodorus , Calhoun Vince D
Published: September 2018

Brain functional networks identified from fMRI data can provide potential biomarkers for brain disorders. Group independent component analysis (GICA) is popular for extracting brain functional networks from multiple subjects. In GICA, different strategies exist for reconstructing subject-specific networks from the group-level networks. However, it is unknown whether these strategies have different sensitivities to group differences and abilities in distinguishing patients. Among GICA, spatio-temporal regression (STR) and spatially constrained ICA approaches such as group information guided ICA (GIG-ICA) can be used to propagate components (indicating networks) to a new subject that is not included in the original subjects. In this study, based on the same a priori network maps, we reconstructed subject-specific networks using these two methods separately from resting-state fMRI data of 151 schizophrenia patients (SZs) and 163 healthy controls (HCs). We investigated group differences in the estimated functional networks and the functional network connectivity (FNC) obtained by each method. The networks were also used as features in a cross-validated support vector machine (SVM) for classifying SZs and HCs. We selected features using different strategies to provide a comprehensive comparison between the two methods. GIG-ICA generally showed greater sensitivity in statistical analysis and better classification performance (accuracy 76.45±8.9%, sensitivity 0.74±0.11, specificity 0.79±0.11) than STR (accuracy 67.45±8.13%, sensitivity 0.65±0.11, specificity 0.71±0.11). Importantly, results were also consistent when applied to an independent dataset including 82 HCs and 82 SZs. Our work suggests that the functional networks estimated by GIG-ICA are more sensitive to group differences, and GIG-ICA is promising for identifying image-derived biomarkers of brain disease.
Pathogen Detection and Microbiome Analysis of Infected Wheat Using a Portable DNA Sequencer
Authors: Hu Yiheng , Green Gamran S. , Milgate Andrew W. , Stone Eric A. , Rathjen John P. , Schwessinger Benjamin
Published: September 2018

Fungal diseases of plants are responsible for major losses in agriculture, highlighting the need for rapid and accurate identification of plant pathogens. Disease outcomes are often defined not only by the main pathogen but are influenced by diverse microbial communities known as the microbiome at sites of infection. Here we present the first use of whole genome shot-gun sequencing with a portable DNA sequencing device as a method for the detection of fungal pathogens from wheat(Triticum aestivum)in a standard molecular biology laboratory. The data revealed that our method is robust and applicable to the diagnosis of fungal diseases including wheat stripe rust (caused byPuccinia striiformisf. sp.tritici),septoria tritici blotch (caused byZymoseptoria tritici)and yellow leaf spot (caused byPyrenophora tritici repentis).We also identified the bacterial genusPseudomonasco-present withPucciniaandZymoseptoriabut notPyrenophorainfections. One limitation of the method is the over-representation of redundant wheat genome sequences from samples. This could be addressed by long-range amplicon-based sequencing approaches in future studies, which specifically target non-host organisms. Our work outlines a new approach for detection of a broad range of plant pathogens and associated microbes using a portable sequencer in a standard laboratory, providing the basis for future development of an on-site disease monitoring system.
Widespread gene duplication and adaptive evolution in the RNA interference pathways of the Drosophila obscura group
Authors: Crysnanto Danang , Obbard Darren
Published: September 2018

Background: RNA interference (RNAi) related pathways provide defense against viruses and transposable elements, and have been implicated in the suppression of meiotic drive elements. Genes in these pathways often exhibit high levels of adaptive substitution, and over longer timescales show gene duplication and los--most likely as a consequence of their role in mediating conflict with these parasites. This is particularly striking for Argonaute 2 (Ago2), which is ancestrally the key effector of antiviral RNAi in insects, but has repeatedly formed new testis-specific duplicates in the recent history of the obscura species-group of Drosophila. Results: Here we take advantage of publicly available genomic and transcriptomic data to identify six further RNAi-pathway genes that have duplicated in this clade of Drosophila, and examine their evolutionary history. As seen for Ago2, we observe high levels of adaptive amino-acid substitution and changes in sex-biased expression in many of the paralogs. However, our phylogenetic analysis suggests that co-duplications of the RNAi machinery were not synchronous, and our expression analysis fails to identify consistent male-specific expression. Conclusions: These results confirm that RNAi genes, including genes of the antiviral and piRNA pathways, have undergone multiple independent duplications and that their history has been particularly labile within the obscura group. However, they also suggest that the selective pressures driving these changes have not been consistent, implying that more than one selective agent may be responsible.
Comparison of tri-exponential decay vs. bi-exponential decay and full fitting vs. segmented fitting for modeling liver intravoxel incoherent motion diffusion MRI
Authors: Chevallier Olivier , Zhou Nan , Cercueil Jean-Pierre , He Jian , Loffroy Romaric , Wáng Yì Xiáng J.
Published: September 2018

Purpose

To determine whether bi- or tri-exponential models, and full or segmented fittings, better fit IVIM imaging signal of healthy livers.

Materials and methods

Diffusion-weighted images were acquired with a 3-T scanner using respiratory-triggered echo-planar sequence and 16 b-values (0∼800 s/mm2). Eighteen healthy volunteers had liver scanned twice in the same session, and then once again in another session. Region of interest (ROI)-based measurements were processed with bi-exponential model full fitting and segmented fitting (threshold b-value = 80 s/mm2), as well as tri-exponential model full fitting and segmented fitting (threshold b-value = 200 s/mm2).

Results

With all scans’ signal averaged, bi-exponential model full fitting showed Dslow=1.14, Dfast=193.6×10-3 mm2/s, and PF=16.9%, and segmented fitting showed Dslow=1.03, Dfast=56.7×10-3 mm2/s, and PF=21.3%. IVIM parameters derived from tri-exponential model were similar for full fitting and segmented fitting, with a slow (D’slow=0.98×10-3 mm2/s; F’slow=76.4 or 76.6%), a fast (D’fast=15.1 or 15.4×10-3 mm2/s; F’fast=11.8 or 11.7%) and a very fast (D’Vfast=445.0 or 448.8×10-3 mm2/s; F’Vfast=11.8 or 11.7 %) diffusion compartments. Tri-exponential model provided an overall better fit than bi-exponential model. For bi-exponential model, full fitting provided better fit at very low and low b-values compared with segmented fitting with the later tended to underestimate Dfast, however, segmented method demonstrated lower error in signal prediction for high b-values. Compared with full fitting, tri-exponential segmented fitting offered better scan-rescan reproducibility.

Conclusion

For healthy liver, tri-exponential modelling is preferred than bi-exponential modelling. For bi-exponential model, segmented fitting underestimates Dfast, but offers more accurate estimation of Dslow.
LTMG: A novel statistical modeling of transcriptional expression states in single-cell RNA-Seq data
Authors: Wan Changlin , Chang Wennan , Zhang Yu , Shah Fenil , Lu Xiaoyu , Zang Yong , Zhang Anru , Cao Sha , Fishel Melissa L. , Ma Qin , Zhang Chi
Published: September 2018

A key challenge in modeling single-cell RNA-seq (scRNA-seq) data is to capture the diverse gene expression states regulated by different transcriptional regulatory inputs across single cells, which is further complicated by a large number of observed zero and low expressions. We developed a left truncated mixture Gaussian (LTMG) model that stems from the kinetic relationships between the transcriptional regulatory inputs and metabolism of mRNA and gene expression abundance in a cell. LTMG infers the expression multi-modalities across single cell entities, representing a gene’s diverse expression states; meanwhile the dropouts and low expressions are treated as left truncated, specifically representing an expression state that is under suppression. We demonstrated that LTMG has significantly better goodness of fitting on an extensive number of single-cell data sets, comparing to three other state of the art models. In addition, our systems kinetic approach of handling the low and zero expressions and correctness of the identified multimodality are validated on several independent experimental data sets. Application on data of complex tissues demonstrated the capability of LTMG in extracting varied expression states specific to cell types or cell functions. Based on LTMG, a differential gene expression test and a co-regulation module identification method, namely LTMG-DGE and LTMG-GCR, are further developed. We experimentally validated that LTMG-DGE is equipped with higher sensitivity and specificity in detecting differentially expressed genes, compared with other five popular methods, and that LTMG-GCR is capable to retrieve the gene co-regulation modules corresponding to perturbed transcriptional regulations. A user-friendly R package with all the analysis power is available at https://github.com/zy26/LTMGSCA.
SMARTer single cell total RNA sequencing
Authors: Karen Verboom , Celine Everaert , Nathalie Bolduc , Kenneth Livak J. , Nurten Yigit , Dries Rombaut , Jasper Anckaert , Morten Venø T , Jørgen Kjems , Frank Speleman , Pieter Mestdagh , Jo Vandesompele
Published: September 2018

Single cell RNA sequencing methods have been increasingly used to understand cellular heterogeneity. Nevertheless, most of these methods suffer from one or more limitations, such as focusing only on polyadenylated RNA, sequencing of only the 3’ end of the transcript, an exuberant fraction of reads mapping to ribosomal RNA, and the unstranded nature of the sequencing data. Here, we developed a novel single cell strand-specific total RNA library preparation method addressing all the aforementioned shortcomings. Our method was validated on a microfluidics system using three different cancer cell lines undergoing a chemical or genetic perturbation. We demonstrate that our total RNA-seq method detects an equal or higher number of genes compared to classic polyA[+] RNA-seq, including novel and non-polyadenylated genes. The obtained RNA expression patterns also recapitulate the expected biological signal. Inherent to total RNA-seq, our method is also able to detect circular RNAs. Taken together, SMARTer single cell total RNA sequencing is very well suited for any single cell sequencing experiment in which transcript level information is needed beyond polyadenylated genes.
Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1
Authors: Arkinson Connor , Chaugule Viduth K. , Toth Rachel , Walden Helen
Published: September 2018

The DNA damage response depends on ubiquitin signalling to orchestrate DNA repair. The Fanconi Anemia pathway for interstrand crosslink repair, and the translesion synthesis pathway for DNA damage tolerance, both require cycles of monoubiquitination and deubiquitination. The ubiquitin specific protease USP1 regulates both these pathways by deubiquitinating monoubiquitinated PCNA, FANCD2 and FANCI. Loss of USP1 activity gives rise to chromosomal instability. While many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1’s specificity for multiple substrates is poorly understood. Here we show that the molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We find that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.