Pediatric dermatofibromas: Truncal predominance in younger children.

Pediatric dermatofibromas are considered rare in young children and have not been well characterized, often misdiagnosed clinically. We performed a retrospective case series of children younger than 18 years with histopathologically diagnosed dermatofibromas at our institutions and evaluated age at onset and diagnosis, sex, lesion location, and size, associated symptoms, change over time, and pre-biopsy diagnosis. Overall, dermatofibromas were most common on the back and chest (20/53; 38%), followed by the legs (15/53; 28%) and arms (12/53; 23%) with the most common pre-biopsy diagnosis of "cyst" (23/53; 43%), followed by dermatofibroma (16/53; 30%), and pilomatricoma (12/53; 23%). Our study reinforces previous findings of truncal predominance of pediatric dermatofibromas, different from adults.

The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue.

Identifying molecular circuits that control adipose tissue macrophage (ATM) function is necessary to understand how ATMs contribute to tissue homeostasis and obesity-induced insulin resistance. In this study, we find that mice with a myeloid-specific knockout of the miR-23-27-24 clusters of microRNAs (miRNAs) gain less weight on a high-fat diet but exhibit worsened glucose and insulin tolerance. Analysis of ATMs from these mice shows selectively reduced numbers and proliferation of a recently reported subset of lipid-associated CD9+Trem2+ ATMs (lipid-associated macrophages [LAMs]). Leveraging the role of miRNAs to control networks of genes, we use RNA sequencing (RNA-seq), functional screens, and biochemical assays to identify candidate target transcripts that regulate proliferation-associated signaling. We determine that miR-23 directly targets the mRNA of Eif4ebp2, a gene that restricts protein synthesis and proliferation in macrophages. Altogether, our study demonstrates that control of proliferation of a protective subset of LAMs by noncoding RNAs contributes to protection against diet-induced obesity metabolic dysfunction.

Persistent Green-Blue Plaque in a Healthy Woman.

A woman in her 30s presents with a bruise on her hand with a blue-green plaque that appeared after a twisting injury to the affected hand. What is your diagnosis?

Navigating the initial diagnosis and management of adult IgA vasculitis: A review.

Background: IgA vasculitis in adults has not been thoroughly studied. This has left a practice gap related to the management and follow-up of a population that is at an increased risk of comorbidities and potentially poor outcomes. For this reason, it is important to synthesize evidence from the current literature because this can help direct the movement for more robust studies to clarify best practice recommendations. Objective: We sought to create a narrative review for the practicing dermatologist when diagnosing and leading the care of IgA vasculitis in adult patients. Methods: A broad literature search was performed with a focus on articles that were published after the introduction of the most updated European Alliance of Associations for Rheumatology/Pediatric Rheumatology International Trials Organization/Pediatric Rheumatology European Society criteria. Results: The characteristics and management guidelines for IgA vasculitis in adults have been refined, although more rigorous studies are needed to develop best practice recommendations. Limitations: Because of the lack of sufficient randomized controlled trials on IgA vasculitis in adults, this narrative review is composed of mostly observational, descriptive studies. Conclusion: Adults with IgA vasculitis are at an increased risk of complicated disease course, necessitating formal diagnostic assessment and clear-cut follow-up recommendations to manage and prevent poor health outcomes related to various comorbidities.

Allylic C-H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis.

Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines-a common motif in pharmaceuticals-remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal-catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z).

Publication Rate and Evidence-Based Evaluation of Abstracts Presented at the Annual Veterinary Orthopedic Society Conference.

OBJECTIVES: Scientific abstracts are a common method for disseminating new research. There is no information on the publication rate of orthopaedic surgery abstracts presented at the annual Veterinary Orthopedic Society (VOS) Conference. The objectives of this study were to document the publication rate, the publication timeline and the level of evidence (LoE) of abstracts presented at an annual orthopaedic meeting. STUDY DESIGN: All conference abstracts from the 2001 to 2014 annual VOS meeting were reviewed, and final publication was determined through a comprehensive bibliographic search. RESULTS: Over 14 conferences, 1,112 scientific abstracts were presented with an overall publication rate of 47%. The majority of abstracts had low LoE scores, and those abstracts were published less timely than ones with higher LoE scores. Once presented, most abstracts took 1 year to be submitted and 2 years to be published. Dog (45%) and ex vivo (19%) studies were the most common. Publication occurred most frequently in Veterinary Surgery (40%), Veterinary and Comparative Orthopaedics and Traumatology (17%) and the American Journal of Veterinary Research (12%). CONCLUSION: The publication rate for abstracts presented at the annual VOS meeting is lower than those from a more generalized veterinary surgery conference. Publication occurs most frequently in a select group of journals, and the subject matter is limited in scope with a focus on dog and ex vivo studies. Overall, most abstracts presented at VOS contain a lower LoE.

PKCδ Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function.

Angiotensin II (AngII) and the mineralocorticoid receptor (MR) ligand aldosterone both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling. We previously demonstrated that AngII activates MR-mediated gene transcription in human vascular smooth muscle cells (SMCs), yet the mechanism and the impact on SMC function are unknown. Using an MR-responsive element-driven transcriptional reporter assay, we confirm that AngII induces MR transcriptional activity in vascular SMCs and endothelial cells, but not in Cos1 or human embryonic kidney-293 cells. AngII activation of MR was blocked by the MR antagonist spironolactone or eplerenone and the protein kinase C-δ (PKCδ) inhibitor rottlerin, implicating both in the mechanism. Similarly, small interfering RNA knockdown of PKCδ in SMCs prevented AngII-mediated MR activation, whereas knocking down of MR blocked both aldosterone- and AngII-induced MR function. Coimmunoprecipitation studies reveal that endogenous MR and PKCδ form a complex in SMCs that is enhanced by AngII treatment in association with increased serine phosphorylation of the MR N terminus. AngII increased mRNA expression of the SMC-MR target gene, FKBP51, via an MR-responsive element in intron 5 of the FKBP51 gene. The impact of AngII on FKBP51 reporter activity and gene expression in SMCs was inhibited by spironolactone and rottlerin. Finally, the AngII-induced increase in SMC number was also blocked by the MR antagonist spironolactone and the PKCδ inhibitor rottlerin. These data demonstrate that AngII activates MR transcriptional regulatory activity, target gene regulation, and SMC proliferation in a PKCδ-dependent manner. This new mechanism may contribute to synergy between MR and AngII in driving SMC dysfunction and to the cardiovascular benefits of MR and AngII receptor blockade in humans.

T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma.

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease-negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

Outcome in lacunar stroke: A cohort study.

OBJECTIVES: We evaluated a prospective cohort of 150 patients under observation in our centre for lacunar strokes. The purpose of this study was to evaluate the outcome at time of discharge and 6 months after lacunar stroke, as well as the correlation with cardiovascular risk factors and selected biochemical parameters already evaluated on admission. Focus was to identify possible prognostic factors, which might be targeted through appropriate intervention concentrating on reduction in the incidence and impact of early clinical deterioration. METHODS: 150 patients with a lacunar stroke were included in the present study. A clinical 6-month follow-up was available for 98.7% of the patients. Infarcts were classified by size, shape and location. RESULTS: The most important predictors of high NIHSS score at time of discharge resulted NIHSS on admission (P < .001), leukocytosis (P = .013), in-hospital infections (P = .016) and size of lacunae (P = .005). Similarly, the most important predictors of poor outcome 6 months later were NIHSS on admission (P = .01), leukocytosis (P = .014), elevated CRP (P = .019), in addition to pre-admission Rankin (P < .001). CONCLUSION: Although infections are not causatively related to lacunar strokes, their prompt recognition and early treatment, control of inflammatory markers and fever are most important in influencing functional outcome in lacunar stroke.

Design, Synthesis, and Application of Chiral C2 -Symmetric Spiroketal-Containing Ligands in Transition-Metal Catalysis.

We present an expedient and economical route to a new spiroketal-based C2 -symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium-catalyzed hydroarylations (up to 95 % ee), palladium-catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium-catalyzed Heck couplings (up to 94 % ee), and rhodium-catalyzed dehydroalanine hydrogenation (up to 93 % ee).

Diabetes-Related Cardiac Dysfunction.

The proposal that diabetes plays a role in the development of heart failure is supported by the increased risk associated with this disease, even after correcting for all other known risk factors. However, the precise mechanisms contributing to the condition referred to as diabetic cardiomyopathy have remained elusive, as does defining the disease itself. Decades of study have defined numerous potential factors that each contribute to disease susceptibility, progression, and severity. Many recent detailed reviews have been published on mechanisms involving insulin resistance, dysregulation of microRNAs, and increased reactive oxygen species, as well as causes including both modifiable and non-modifiable risk factors. As such, the focus of the current review is to highlight aspects of each of these topics and to provide specific examples of recent advances in each area.

Diabetes-Related Cardiac Dysfunction

The proposal that diabetes plays a role in the development of heart failure is supported by the increased risk associated with this disease, even after correcting for all other known risk factors. However, the precise mechanisms contributing to the condition referred to as diabetic cardiomyopathy have remained elusive, as does defining the disease itself. Decades of study have defined numerous potential factors that each contribute to disease susceptibility, progression, and severity. Many recent detailed reviews have been published on mechanisms involving insulin resistance, dysregulation of microRNAs, and increased reactive oxygen species, as well as causes including both modifiable and non-modifiable risk factors. As such, the focus of the current review is to highlight aspects of each of these topics and to provide specific examples of recent advances in each area.

Early effect of dalfampridine in patients with MS: A multi-instrumental approach to better investigate responsiveness.

BACKGROUND: 4-aminopyridine (4-AP) is a potassium-channel blocker able to enhance walking speed in MS improving the action potentials of demyelinated axons on which internodal potassium channels are exposed. OBJECTIVE: to study early 4-AP effect with clinical, subjective, neurophysiological and neuroradiological tools. METHODS: Clinical (Timed 25-Foot Walk - T25FW, Timed Up-And-Go - TUG), subjective (MS Walking Scale-12 - MSWS-12), neurophysiological (Motor Evoked Potentials - MEPs) and imaging (Diffusion Tensor Imaging - DTI) evaluations were performed before (T0) and after (T1) 14days of 4-AP treatment. MEPs were recorded from Abductor Hallucis of both legs. A Tract-Based-Spatial-Statistics (TBSS) was performed on DTI. RESULTS: We found a significant difference between T0 and T1 for T25FW, TUG, MSWS-12 (p≤0.001) in the whole patients' sample (23 subjects, median EDSS 6.0) and decrease of Central Motor Conduction Time and increase of mean Amplitude (Amp) at T1 (p=0.008 and p=0.006). We also recorded a significant difference of T25FW, TUG, MSWS-12 and Amp in clinical responder (CR) patients (CR: amelioration >20% at T25FW). TBSS showed a significant Mean and Radial Diffusivity reduction in the corticospinal tracts (p<0.05) of the whole group of patients; this reduction was also found in the CR subgroup. CONCLUSION: Neurophysiological and neuroradiological parameters were modified in MS patients treated with 4-AP, and most of them reported a subjective improvement of their motor performances after treatment. The use of clinical, subjective, neurophysiological and neuroradiological tools could help to better explore MS patients responsiveness to 4-AP.

T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma.

Therapies with novel mechanisms of action are needed for multiple myeloma (MM). B-cell maturation antigen (BCMA) is expressed in most cases of MM. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells in this dose-escalation trial. Among the 6 patients treated on the lowest 2 dose levels, limited antimyeloma activity and mild toxicity occurred. On the third dose level, 1 patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9 × 10(6) CAR(+) T cells/kg body weight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM, making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's MM entered a stringent complete remission that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. This patient is in an ongoing very good partial remission. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients had prolonged cytopenias. Our findings demonstrate antimyeloma activity of CAR-BCMA T cells. This trial was registered to www.clinicaltrials.gov as #NCT02215967.

Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease.

PURPOSE: Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. METHODS: We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient's alloHSCT donor. RESULTS: Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease-negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels. CONCLUSION: Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.

Development and validation of the multiple sclerosis questionnaire for the evaluation of job difficulties (MSQ-Job).

OBJECTIVE: Multiple sclerosis (MS) affects young adults of working age. Difficulties in work-related activities are usually ascribed to MS symptoms, while the impact of workplace features is underestimated. This article presents the Multiple Sclerosis Questionnaire for Job Difficulties (MSQ-Job), designed to assess working difficulties due to MS symptoms and workplace features. METHODS: A sample of employed MS patients completed the MSQ-Job, the WHO-Disability Assessment Schedule (WHODAS 2.0) and the 54-items MS Quality of Life Questionnaires (MSQOL-54); the expanded disability status scale (EDSS) was used to define MS severity. Factor structure was evaluated using principal component extraction and Oblimin rotation; internal consistency was assessed with Cronbach's alpha; construct and discriminant validity using t-test (EDSS 0-2 vs >2; patients self-reporting need for support vs patients reporting no needs; full-time vs part-time employees); and Pearson's correlation with WHODAS 2.0 and MSQOL-54. RESULTS: The MSQ-Job is a 42-item questionnaire with six scales and an overall factor. Scores range on a 0-100 scale (higher scores indicate more and more severe difficulties); patients with EDSS>2 and self-reporting support needs had worse scores than those with EDSS 0-2 and without needs. Correlations with WHODAS 2.0 and MSQOL-54 were generally significant (P < 0.0007) and below 0.70. CONCLUSIONS: The MSQ-Job jointly measures the impact of respondents' symptoms and workplace features on work activities and enables to assess the effects of clinical and occupational interventions and better describe the impact of MS indirect costs.

Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.

Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity.