tbuckley/cabot-search huggingface dataset:
Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter
Authors: Randi J Parks, Sara Menazza, Kira M Holmström, Georgios Amanakis, Maria Fergusson, Hanley Ma, Angel M Aponte, Paolo Bernardi, Toren Finkel, Elizabeth Murphy
Journal: Cardiovascular Research (2018)

Knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice abrogates mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice.
Pathological Issues in Dystrophinopathy in the Age of Genetic Therapies
Authors: Nazima Shahnoor, Emily M. Siebers, Kristy J. Brown, Michael W. Lawlor
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

Dystrophinopathy is a class of genetic skeletal muscle disease characterized by myofiber degeneration and regeneration due to insufficient levels or functioning of dystrophin. Pathological evaluation for dystrophinopathy includes the identification of dystrophic skeletal muscle pathology and the immunohistochemical evaluation of dystrophin epitopes, but biopsies have become rare in recent years. However, the evaluation of dystrophin expression in the research setting has become critically important due to recent advances in genetic therapies, including exon skipping and gene therapy. Given the number of these therapies under evaluation in patients, it is likely that the traditional methods of evaluating dystrophinopathy will need to evolve in the near future. This review discusses current muscle biopsy diagnostic practices in dystrophinopathy and further focuses on how these practices have evolved in the context of therapeutic interventions for dystrophinopathy.
Feasibility of Formal Mindfulness-Based Stress-Resilience Training Among Surgery Interns
Authors: Carter C. Lebares, Amy O. Hershberger, Ekaterina V. Guvva, Aditi Desai, James Mitchell, Wen Shen, Linda M. Reilly, Kevin L. Delucchi, Patricia S. O’Sullivan, Nancy L. Ascher, Hobart W. Harris
Journal: JAMA Surgery (2018)

Among surgical trainees, burnout and distress are prevalent, but mindfulness has been shown to decrease the risk of depression, suicidal ideation, burnout, and overwhelming stress. In other high-stress populations, formal mindfulness training has been shown to improve mental health, yet this approach has not been tried in surgery.To test the feasibility and acceptability of modified Mindfulness-Based Stress Reduction (MBSR) training during surgical residency.A pilot randomized clinical trial of modified MBSR vs an active control was conducted with 21 surgical interns in a residency training program at a tertiary academic medical center, from April 30, 2016, to December 2017.Weekly 2-hour, modified MBSR classes and 20 minutes of suggested daily home practice over an 8-week period.Feasibility was assessed along 6 domains (demand, implementation, practicality, acceptability, adaptation, and integration), using focus groups, interviews, surveys, attendance, daily practice time, and subjective self-report of experience.Of the 21 residents included in the analysis, 13 were men (62%). Mean (SD [range]) age of the intervention group was 29.0 (2.4 [24-31]) years, and the mean (SD [range]) age of the control group was 27.4 (2.1 [27-33]) years. Formal stress-resilience training was feasible through cultivation of stakeholder support. Modified MBSR was acceptable as evidenced by no attrition; high attendance (12 of 96 absences [13%] in the intervention group and 11 of 72 absences [15%] in the control group); no significant difference in days per week practiced between groups; similar mean (SD) daily practice time between groups with significant differences only in week 1 (control, 28.15 [12.55] minutes; intervention, 15.47 [4.06] minutes; P = .02), week 2 (control, 23.89 [12.93] minutes; intervention, 12.61 [6.06] minutes; P = .03), and week 4 (control, 26.26 [13.12] minutes; intervention, 15.36 [6.13] minutes; P = .04); course satisfaction (based on interviews and focus group feedback); and posttraining-perceived credibility (control, 18.00 [4.24]; intervention, 20.00 [6.55]; P = .03). Mindfulness skills were integrated into personal and professional settings and the independent practice of mindfulness skills continued over 12 months of follow-up (mean days [SD] per week formal practice, 3 [1.0]).Formal MBSR training is feasible and acceptable to surgical interns at a tertiary academic center. Interns found the concepts and skills useful both personally and professionally and participation had no detrimental effect on their surgical training or patient care.ClinicalTrials.gov identifier: NCT03141190.
Epilepsy Profile in Infants with Congenital Zika Virus Infection
Authors: Hélio van der Linden, Maria D Carvalho, Vanessa van der Linden, Kalyne M Lacerda, André Pessoa, Mara L Carneiro, Marli T Cordeiro, Kette D Valente
Journal: New England Journal of Medicine (2018)

Seizures in Congenital Zika Virus Infection In this letter, aspects of epilepsy associated with congenital Zika virus infection are described.
Abstract 203: Measurement of Cardiac Function in a Porcine Model of Cardiac Arrest Due to Massive Exsanguination
Authors: John S Berry, Andriy I Batchinsky, Slava M Belenkiy, Corina Necsoiu, Chonna L Kendrick, Katherine M Ivey, Christopher E White, Stephen M Cohn, Jose Salinas, Todd E Rasmussen, Michael A Dubick, Leopoldo C Cancio
Journal: Circulation (2013)

Background: While extremity hemorrhage can be stymied with a well placed tourniquet, vascular injury within the thorax and abdomen is not amenable to direct compression. Uncontrolled, noncompressible torso hemorrhage (NCTH) and the resultant cardiac arrest (CA) may account for up to 80% of preventable deaths in combat. We developed a porcine model of CA to test novel surgical interventions and are reporting measures of cardiovascular function during a simulated NCTH. Methods: Ten anesthetized Yorkshire pigs underwent tracheostomy, arterial and central line placement. Animals were awakened and sedated with midazolam titrated to a bispectral index of 75 ± 5. Spontaneously breathing, the animals were subjected to a computerized hemorrhage of 80% total blood volume (TBVH) over 20 minutes or until death, defined as mean arterial pressure (MAP)=0 mmHg and etCO2&lt;10. During hemorrhage, if minute ventilation decreased 25% from baseline (BL) for &gt;20 seconds, volume control ventilation was initiated. The Millar MPVS Ultra system continuously collected left ventricular (LV) and descending aortic pressures, as well as LV volume data via indwelling catheters. A repeated measures one-way ANOVA with Tukey’s procedure was performed on data collected at BL, 25%, 44%, 62% TBV hemorrhage, and CA, defined as a MAP&lt;20 mmHg. Data are presented as means±SEM. Results: Weight was 63.8±2.8kg. TBVH at CA was 2941±130ml (71.0±1.5%). Time to CA was 18:22±00:40min. In Table 1, * denotes a significant change (p&lt;0.05) in a variable from previous hemorrhage phase as marked by #. Conclusions: We developed a porcine model of CA secondary to exsanguination. We found that despite decreasing left ventricular volumes and pressures, cardiac contractility and conduction system function were maintained throughout hemorrhage. This suggests that lifesaving interventions (such as endovascular aortic balloon occlusion and extracorporeal life support) may be possible despite profound hypovolemia.
Case 27-2018: A 3-Year-Old Boy with Seizures
Authors: Mark P. Gorman, Grace Y. Gombolay, William A. Mehan, Ronald L. Thibert
Journal: New England Journal of Medicine (2018)

A 3-year-old boy was admitted to the hospital because of a seizure. Decreased language output, lethargy, mood lability, unsteady gait, and abnormal movements developed. CSF analysis revealed lymphocytic pleocytosis. A diagnosis and management decisions were made.
Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease
Authors: Andrew J. Muir, Cynthia Levy, Harry L.A. Janssen, Aldo J. Montano‐Loza, Mitchell L. Shiffman, Stephen Caldwell, Velimir Luketic, Dora Ding, Catherine Jia, Bryan J. McColgan, John G. McHutchison, G. Mani Subramanian, Robert P. Myers, Michael Manns, Roger Chapman, Nezam H. Afdhal, Zachary Goodman, Bertus Eksteen, Christopher L. Bowlus
Journal: Hepatology (2018)

Lysyl oxidase like‐2 (LOXL2) plays a central role in fibrogenesis and is elevated in the serum and liver of patients with primary sclerosing cholangitis (PSC). We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody directed against LOXL2, in patients with PSC. Patients with compensated liver disease caused by PSC were randomized 1:1:1 to receive weekly subcutaneous injections of simtuzumab 75 mg, simtuzumab 125 mg, or placebo for 96 weeks. The primary efficacy endpoint was mean change in hepatic collagen content assessed by morphometry between baseline and week 96. Additional endpoints included change in Ishak fibrosis stage and the frequency of PSC‐related clinical events. Overall, 234 patients were randomized and started treatment. At week 96, the mean change from baseline in hepatic collagen content was –0.5% for patients receiving simtuzumab 75 mg ( P = 0.73 versus placebo), +0.5% for patients receiving simtuzumab 125 mg ( P = 0.33 versus placebo), and 0.0 for patients receiving placebo. Compared with placebo, neither dose of simtuzumab led to significant reductions in Ishak fibrosis stage, progression to cirrhosis, or frequency of clinical events. Overall, 80 (34%) patients had fibrosis progression and 47 (20%) experienced PSC‐related clinical events. In a multivariate model of baseline factors, PSC‐related clinical events were more frequent in patients with advanced fibrosis (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.02‐4.06; P = 0.045), higher alkaline phosphatase (HR per 10 U/L, 1.01; 95% CI, 1.00‐1.02; P = 0.015), and higher enhanced liver fibrosis score (HR per unit, 1.26; 95% CI, 0.98‐1.61; P = 0.073). Overall, rates of adverse events and laboratory abnormalities were similar between groups. Conclusion: Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC.
Time of Day Affects Eosinophil Biomarkers in Asthma: Implications for Diagnosis and Treatment
Authors: Hannah J. Durrington, Gael O. Gioan-Tavernier, Robert J. Maidstone, Karolina Krakowiak, Andrew S. I. Loudon, John F. Blaikley, Stephen J. Fowler, Dave Singh, Angela Simpson, David W. Ray
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors
Authors: Jolanda Brummelman, Emilia M.C. Mazza, Giorgia Alvisi, Federico S. Colombo, Andrea Grilli, Joanna Mikulak, Domenico Mavilio, Marco Alloisio, Francesco Ferrari, Egesta Lopci, Pierluigi Novellis, Giulia Veronesi, Enrico Lugli
Journal: The Journal of Experimental Medicine (2018)

CD8+ T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined. By high-dimensional single cell analysis of millions of CD8+ T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood. Besides exhausted and activated cells, we identified CXCR5+ TIM-3– CD8+ T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome. Ex vivo, CXCR5+ TIM-3– CD8+ T cells displayed enhanced self-renewal and multipotency compared with more differentiated subsets and were largely polyfunctional. Analysis of inhibitory and costimulatory receptors revealed PD-1, TIGIT, and CD27 as possible targets of immunotherapy. We thus demonstrate a hierarchy of differentiation in the context of T cell exhaustion in human cancer similar to that of chronically infected mice, which is further shown to disappear with disease progression.
Program Director and Resident Perspectives on New Parent Leave in Dermatology Residency
Authors: Lia E. Gracey, Morgan Cronin, Kanade Shinkai, Erin F. Mathes
Journal: JAMA Dermatology (2018)

crossover study of aprepitant for the treatment of pruritus in patients with Sézary syndrome.The data do not support the efficacy of aprepitant as an antipruritic agent in patients with Sézary syndrome.This is in contrast to at least 7 case series that have reported an improvement in symptoms in a total of 17 patients with Sézary syndrome or mycosis fungoides. [1]][3][4][5] This study has limitations.Although the study was randomized, blinded, and placebo controlled, the sample size was small including only 5 patients.Because pruritus can vary in patients with Sézary syndrome due to changes in disease activity and external factors such as ambient temperature and humidity, we cannot exclude the impact of these factors on the scoring of pruritus by visual analog scale.We dosed aprepitant daily for 1 week, and we cannot exclude the possibility that the results would have been different if we had used intermittent dosing.In conclusion, in patients with Sézary syndrome, aprepitant treatment may not improve pruritus as reported in previous retrospective observational studies.The unexpected observation
Psychosocial factors in low back pain: letting go of our misconceptions can help management
Authors: Mary O’Keeffe, Steven Z George, Peter B O’Sullivan, Kieran O’Sullivan
Journal: British Journal of Sports Medicine (2018)

The Lancet low back pain (LBP) series1 highlighted the important role of psychosocial factors in LBP and its associated disability. It is worth reflecting on what psychosocial factors are, and are not, in order to optimise management.

Not all psychosocial factors are indicative of a mental health disorder which requires assessment and treatment by a dedicated mental health provider. For example, fear of movement is NOT necessarily a mental health disorder unless the individual meets the criteria for phobic disorder. While we need to competently identify patients with comorbid mental health disorders, such cases are the exception, not the rule. As such, many psychosocial factors (eg, fear of movement, distress about scan findings, depression related to a loss of valued activities, anxiety about the future, social stress) can be within the scope of musculoskeletal clinicians.

We contend that the way we have categorised interventions for LBP into ‘physical’ or ‘psychological’ has created boundaries for what clinicians deem to be within their scope.2 We …
Abstract 16553: FAST Kinase Domain Containing Protein 1 Prevents Myocardial Infarction Induced Rupture
Authors: Kurt D Marshall, Rajika Roy, Maike Krenz, Christopher P Baines
Journal: Circulation (2016)

We have previously identified the mitochondrial protein FAST Kinase Domain containing protein 1 (FASTKD1) as a novel cyclophilin-D binding protein, that protects cells from oxidative stress induced cell death in vitro. However, the role of FASTKD1 in the myocardium in vivo is unknown. Therefore we developed cardiac myocyte specific FASTKD1 transgenic mice to test the effects of this protein on myocardial infarction (MI). Three independent lines of mice with cardiac myocyte specific overexpression of FASTKD1 to varying degrees were generated. These mice displayed normal cardiac morphology and function at the gross and microscopic levels. Isolated cardiac mitochondria from all transgenic mouse lines showed normal mitochondrial function, ATP levels, and mitochondrial permeability transition pore activity. Mice from the highest expressing line were subjected to 8-weeks of permanent coronary ligation. However, approximately 40% of non-transgenic mice underwent left ventricular free wall rupture within the firs...
Tumor hypoxia directed multimodal nanotherapy for overcoming drug resistance in renal cell carcinoma and reprogramming macrophages
Authors: Hashem O. Alsaab, Samaresh Sau, Rami M. Alzhrani, Vino T. Cheriyan, Lisa A. Polin, Ulka Vaishampayan, Arun K. Rishi, Arun K. Iyer
Journal: Biomaterials (2018)
Comparability of Early Dynamic and Conventional Static Imaging With 18F-Fluorocholine PET/CT in a Patient With Primary Hyperparathyroidism
Authors: Meghana Prabhu, Garima Kumari, Nishikant Avinash Damle, Geetanjali Arora, Madhavi Tripathi, Chandrasekhar Bal, Praveen Kumar, Rajeev Kumar
Journal: Clinical Nuclear Medicine (2018)

Recent studies have established the superiority of FCH PET/CT over MIBI scan in accurate preoperative localization of parathyroid adenomas. In this patient, we compared both early dynamic and conventional static imaging to see if early imaging could suffice. We describe a 15-year-old boy with primary hyperparathyroidism, in whom early dynamic FCH PET/CT was performed for 15 minutes after injection, followed by conventional static image at 60 minutes. Early dynamic images accurately localized the parathyroid adenoma. Also, higher SUVmax was observed on dynamic imaging when compared with conventional static images, but parathyroid-to-thyroid ratio was higher in the latter.
Imaging Brain Metastasis Patients With 18F-(2S,4R)-4-Fluoroglutamine
Authors: Xiaoxia Xu, Hua Zhu, Fei Liu, Yan Zhang, Jianhua Yang, Lifang Zhang, Lin Zhu, Nan Li, Hank F. Kung, Zhi Yang
Journal: Clinical Nuclear Medicine (2018)

Purpose There is a need for an alternative PET probe, which does not show normal brain tissue uptake in the evaluation of metastasis to the brain. Therefore, we investigate the feasibility of 18 F-labeled glutamine analog, 18 F-(2S,4 R )-4-fluoroglutamine ( 18 F-FGln), as a new metabolic probe to detect brain metastasis. Methods Patients (7 men and 7 women; age, 25–67 years) with suspected brain metastasis were enrolled for this study. All patients were imaged first with 18 F-FGln PET (3 patients for 1-hour dynamic whole-body PET/CT scans, and 11 patients for static whole-body scans at 30 ± 10 minutes after injection), followed by a whole-body 18 F-FDG PET performed in the same week. The characteristics of 18 F-FGln PET imaging in brain metastasis patients were compared with that of 18 F-FDG PET and/or contrast-enhanced MRI patient-by-patient. A composite of all functional and anatomic imaging studies served as the imaging comparator. Results Initial study in 3 patients using 1-hour dynamic scan showed that 30 ± 10 minutes after injection is optimal for identifying brain metastasis with a high-contrast ratio. All patients were positive for brain metastasis on this studies that demonstrated 38 lesions in 6 anatomic regions on the imaging comparator. The per-lesion detection rates for 18 F-FGln PET and 18 F-FDG PET were 81.6% and 36.8%, respectively. The average tumor-to-normal brain ratio of 18 F-FGln PET was significantly better than that of 18 F-FDG PET in all patients (4.97 ± 2.23 vs 1.22 ± 0.69, P &lt; 0.05). Furthermore, our results suggest that 18 F-FGln uptake in brain metastasis appeared to be independent of tumor size and peripheral edema. In addition, in 14 brain metastatic lesions visualized by both 18 F-FDG PET and 18 F-FGln PET imaging, a positive correlation of SUV max was observed ( r = 0.780, P &lt; 0.01). As to the extracranial metastasis, both tracers showed a concordant increased radioactive uptake except in liver and bone. Conclusions The initial imaging of 18 F-FGln presenting a promising new PET radiotracer for patients with brain metastasis and its utility in the liver and bone metastatic lesions may require more caution due to uptake in normal structures.
Differences between epidermal growth factor receptor mutation status and clinic and radiologic features in metastatic lung adenocancer pati̇ents treated with erlotinib.
Authors: Metin Ozkan, Ender Dogan, Ozlem Canoz, Teoman Sakalar, Sumeyra Derin, Oktay Bozkurt, Mevlude Inanc
Journal: Journal of Clinical Oncology (2018)

e21217 Background: Epidermal growth factor receptor (EGFR) mutation positive and negative nonsmall cell lung cancer patients have some differences. EGFR positive nonsmall cell lung cancer patients are predominantly female and nonsmokers. But radiological differences between EGFR positive and negative tumors are still not stratified. We aimed to evaluate radiological and clinical differences according to EGFR mutation status in patients diagnosed metastatic lung adenocancer treated with erlotinib. Methods: We retrospectively reviewed metastatic lung adenocancer patients and included patients who treated erlotinib. We divided into two groups according to EGFR mutation status. We noted radiological tumor characteristics. We compared EGFR positive patients with negative patients according to radiological features. We used Chi square testing method for this issue. Results: We included 30 patients to the study. Fourteen patients were EGFR positive and 16 was negative. Ten patients had exon 19 mutation and 4 patients had exon 21 mutation. In EGFR positive group, eleven of them female and three of them male. In EGFR negatıve group six of them were female and ten of them were male. The median age was 69 in EGFR mutant and 56 in EGFR nonmutant group. Eigthy five percent of patiens were nonsmoker in EGFR positive group and fifty percent of patients were nonsmoker in EGFR negative group. Tumor diameter was 40 mm in EGFR mutant and 30 mm in non mutant group. There were pleura effusion in 7 patients (%50) in EGFR mutant and in 2 (%12)patients in nonmutant group (p = 0.04) . There were lymphangitis carcinomatosa in 4 patients (%40) in EGFR mutant and in 5 (%45) patients in nonmutant group (p = 0.59) Conclusions: Our study demonstrated that pleural effusion was more common in EGFR mutant lung adenocancer patients.