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Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

Purpose To evaluate if age, alcohol consumption, and body mass index (BMI) have synergistic effects on seminal quality, and to rank these factors based on their impact on semen. Methods Retrospective study of 9464 patients attending an andrology laboratory. Data on patients' age and daily alcohol intake were provided by the patients. BMI was recorded in the laboratory. Seminal parameters evaluated were volume, sperm concentration and total count, motility, morphology, viability, nuclear maturity, and membrane functional integrity. Results All the seminal parameters evaluated were affected by the synergistic interaction Age x BMI, suggesting that this combination is more potent in affecting semen quality. The variables sperm morphology and nuclear maturity seemed to be especially susceptible since they were affected by the three synergistic interactions. In the logistic regression analysis, age was the most powerful factor since it impacted first on five of the nine parameters, impacting mainly on sperm motility, viability, and morphology, with no effects on sperm count. On the contrary, BMI impacted first in sperm concentration and total sperm count; which was confirmed also by the logistic predictions analysis. Alcohol consumption impacted first on membrane functional integrity and nuclear maturity. A J-shaped association between BMI or alcohol consumption with semen quality was found in the multivariate analysis. Conclusion The factors considered in this study showed a synergistic negative impact on semen quality, being age and unhealthy weight the most important ones. Reducing the exposure to lifestyle risk factors may be promising for improving sperm quality in infertile patients.

Down syndrome (DS), the most common genetic cause of intellectual disability, is characterized by the triplication of chromosome 21. The triplication of the amyloid precursor protein gene, amyloid precursor protein (APP), is thought to be the underlying reason why Alzheimer's disease (AD) pathology develops in the DS brain with age. In this chapter, we explore the neuroinflammatory consequences of AD pathology in the brain, and how this may be unique in DS due to the triplication of immune-associated genes also located on chromosome 21.

Alzheimer’s disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 — a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses — in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins — including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) — and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01143-1.

Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In the present review, we highlight the physiological role of astrocytes in the CNS, including their communication with other cells in the brain. Furthermore, we discuss exciting findings and novel experimental approaches that elucidate the role of astrocytes in multiple neurological disorders.

Significance As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses, and the chronic inflammation mediated by inflammatory receptors represents a key mechanism by which amyloid-beta (Aβ) drives the development of cognitive decline in Alzheimer’s disease (AD). A crucial aspect of this process is a failure to resolve inflammation, which involves the suppression of inflammatory cell influx and the endocytosis of inflammatory receptors. We found that ablation of the endosomal adaptor target of Myb1 (TOM1) worsens neuroinflammation, impairs microglial phagocytosis, and significantly exacerbates amyloid deposition. Conversely, restoration of TOM1 reverses these effects and reduces Aβ pathology. These results highlight the importance of endosomal adaptors and their interaction with inflammatory receptors in the pathogenesis of AD., Defects in interleukin-1β (IL-1β)–mediated cellular responses contribute to Alzheimer’s disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1β inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1β receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.

Down syndrome (DS) is a form of accelerated aging, and people with DS are highly prone to aging-related conditions that include vascular and neurological disorders. Due to the overexpression of several genes on Chromosome 21, for example genes encoding amyloid precursor protein (APP), superoxide dismutase (SOD), and some of the interferon receptors, those with DS exhibit significant accumulation of amyloid, phospho-tau, oxidative stress, neuronal loss, and neuroinflammation in the brain as they age. In this review, we will summarize the major strides in this research field that have been made in the last few decades, as well as discuss where we are now, and which research areas are considered essential for the field in the future. We examine the scientific history of DS bridging these milestones in research to current efforts in the field. We extrapolate on comorbidities associated with this phenotype and highlight clinical networks in the USA and Europe pursuing clinical research, concluding with funding efforts and recent recommendations to the NIH regarding DS research.

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations remain unknown. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate high Gas6 levels in the serum of patients with neurological complications which correlated with downregulation of genes associated with the type I IFN responses as consequence of Socs1 upregulation. Gas6 gamma-carboxylation is essential for ZIKV replication in monocytes, the main source of this protein. Gas6 also facilitates ZIKV replication in adult immunocompetent mice enabled susceptibility to transplacental infection and congenital malformations. Our data thus indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

COVID-19 patients may exhibit neuropsychiatric and neurological symptoms. We found that anxiety and cognitive impairment are manifested by 28-56% of SARS-CoV-2-infected individuals with mild respiratory symptoms and are associated with altered cerebral cortical thickness. Using an independent cohort, we found histopathological signs of brain damage in 25% of individuals who died of COVID-19. All of the affected brain tissues exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Infection of neural stem cell-derived astrocytes changed energy metabolism, altered key proteins and metabolites used to fuel neurons and for biogenesis of neurotransmitters, and elicited a secretory phenotype that reduces neuronal viability. Our data support the model where SARS-CoV-2 reaches the brain, infects astrocytes and triggers neuropathological changes that contribute to the structural and functional alterations in the brain of COVID-19 patients.

Made available in DSpace on 2020-12-12T02:25:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-09-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Fundo de Apoio ao Ensino, à Pesquisa e Extensão, Universidade Estadual de Campinas Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19. Diabetic people with uncontrolled blood glucose levels have a greater risk to develop severe COVID-19 disease. Codo et al. show that elevated glucose levels and glycolysis promote SARS-CoV-2 (CoV-2) replication and cytokine production in monocytes through a mitochondrial ROS/hypoxia-inducible factor-1α dependent pathway, resulting in T cell dysfunction and epithelial cell death. Laboratory of Immunometabolism Department of Genetics Evolution Microbiology and Immunology Institute of Biology University of Campinas Department of Genetics Evolution Microbiology and Immunology Institute of Biology University of Campinas Department of Biochemistry and Tissue Biology Institute of Biology University of Campinas Department of Genetics at Ribeirao Preto Medical School University of Sao Paulo, Ribeirao Preto Department of Clinical and Toxicological analyses School of Pharmaceutical Sciences University of São Paulo Brazilian Biosciences National Laboratory (LNBio), Campinas Department of Animal Biology Institute of Biology University of Campinas, Campinas Department of Internal Medicine School of Medical Sciences University of Campinas, Campinas Department of Clinical Medicine School of Medical Sciences University of Campinas, Campinas Hematology and Hemotherapy Center University of Campinas, Campinas Obesity and Comorbidities Research Center (OCRC) University of Campinas Experimental Medicine Research Cluster (EMRC) University of Campinas Department of Structural and Functional Biology Institute of Biosciences São Paulo State University (UNESP), Botucatu D'Or Institute for Research and Education (IDOR) Instituto Nacional de Biomarcadores em Neuropsiquiatria Conselho Nacional de Desenvolvimento Científico e Tecnológico Department of Structural and Functional Biology Institute of Biosciences São Paulo State University (UNESP), Botucatu FAPESP: 20/04579-7 FAPESP: 2015/15626-8 FAPESP: 2016/18031-8 FAPESP: 2016/23328-0 FAPESP: 2017/01184-9 FAPESP: 2018/22505-0 FAPESP: 2019/00098-7 FAPESP: 2019/06372-3 FAPESP: 2020/04522-5 FAPESP: 2020/04558-0 FAPESP: 2020/04583-4 FAPESP: 2020/04746-0 FAPESP: 2020/04919-2 Fundo de Apoio ao Ensino, à Pesquisa e Extensão, Universidade Estadual de Campinas: 2274/20

Background In the last years, many health apps have been developed to support citizens' and patients' health management. Nevertheless, a thorough evaluation is necessary to support the decision to incorporate them into healthcare systems. Health technology assessment (HTA) could be considered a valid evaluation tool allowing considering different stakeholders' perspectives. This research aimed to look for studies that applied HTA to health apps and to analyze feasibility and limits of HTA in this field. Methods A systematic review was performed considering three databases, namely PubMed, Web of Science (WoS) and University of York-Centre for Reviews and Dissemination database. Being the topic of health app assessment new, articles were considered eligible if they assessed at least two of the domains of the HTA core model suggested by the European network for Health Technology Assessment (EUnetHTA). Furthermore, only articles published in English in the last 5 years were considered. Results A total of 850 articles were found: 383 articles from PubMed, 462 from WoS and 5 from York. After removing duplicates, 708 articles remained and 43 were eventually included after the screening process. Seven articles were focused on apps used by healthcare professionals, while 36 dealt with apps aimed to support patients. None of the papers explicitly mentioned HTA as assessment tool. Indeed, not all the domains of the HTA core model were assessed in any article. Apps' technical description, clinical effectiveness and social aspects were the domains considered more often. On the contrary, costs and economic evaluation was clearly faced by one article only. Conclusions Even though the scientific literature on health apps is growing, the adoption of standardized methods for their evaluation, such as HTA, is still scant. This might be due to peculiarities of health apps and points out the importance of adapting existing methods in order to let a thorough assessment possible.

The present updated systematic review and meta-analysis aims to summarize the evidence from published studies with low risk for any important bias (based on methodological quality assessment) investigating the potential associations of adiposity with sperm quality and reproductive hormones. We conducted a systematic search of the literature published in MEDLINE-PubMed and EMBASE through June 2019. Based on the criteria in our review, 169 eligible publications were used for data abstraction. Finally, 60 articles were included in the qualitative analysis and 28 in the quantitative analysis. Our systematic review results indicated that overweight and/or obesity were associated with low semen quality parameters (i.e., semen volume, sperm count and concentration, sperm vitality and normal morphology) and some specific reproductive hormones (e.g., inhibin B, total testosterone and sex hormone-binding globulin). Overweight and/or obesity were also positively associated with high estradiol concentrations. Meta-analysis indicated that overweight and/or obesity categories were associated with lower sperm quality (i.e., semen volume, sperm count and concentration, sperm vitality, total motility and normal morphology), and underweight category was likewise associated with low sperm normal morphology. In conclusion, our results suggest that maintaining a healthy body weight is important for increasing sperm quality parameters and potentially male fertility.

Down syndrome (DS), or trisomy 21, is the most common genetic cause of intellectual disability [...]

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

Funding Acknowledgements Nothing to declare OnBehalf None Background Peri-coronary fat attenuation index (pFAI) has emerged as a clinical marker of coronary inflammation, which is measurable from standard coronary CT angiography (CCTA). It compares well with gold-standard methods for the assessment of coronary inflammation and can predict future cardiovascular events. pFAI could prove invaluable to differentiate an inflammatory from noninflammatory coronary artery status, helping unravel the mechanisms subtending an event classified as myocardial infarction with nonobstructive coronary arteries (MINOCA) or Tako-Tsubo syndrome (TTs). Methods and Results Patients admitted with MINOCA and TTs diagnosis between 2011 and 2018, who had both CCTA and CMR performed during or shortly after the acute phase, were selected and pFAI measured in their index CCTA. pFAI was also measured in a control subjects who had CCTA for atypical chest pain work-up, no obstructive coronary artery disease found in their CCTA and no cardiac events at a minimum 2-year follow-up. In the n = 106 MINOCA/TTs patients selected, mean pFAI averaged for the 3 coronary arteries was -68.37 ± 8.29 vs -78.03 ± 6.20 in the n = 106 controls (p confirmed also when comparing mean pFAI in each single coronary artery between MINOCA/TTs and controls (p particular, were also more frequently found (p controls. Conclusions In MINOCA and TTs patients, CCTA is not only able to detect otherwise angiographically invisible atherosclerotic plaques, but its diagnostic yield can be further expanded using the simple off-line measurement of pFAI for the characterization of peri-coronary fat tissue. In MINOCA/TTs mean pFAI clearly demonstrates higher values in comparison with controls, a finding which has been previously associated with coronary artery inflammation. We speculate that this newly-available diagnostic tool in the future may help select patients for new therapies, for example therapies targeting coronary inflammation. I was able to build a table. Abstract 1176 Figure.

Current methods for assessing circulating tumor cells (CTC) in blood focus on capture and enumeration with epithelial markers that provide little information about the aggressive and invasive potential of CTC. As a result, valuable knowledge that improves monitoring of cancer recurrence and metastasis is lacking. To provide actionable information on CTC, we developed a CTC identification method based on detection of the second subunit of Chaperonin Containing TCP1 (CCT2). CCT is a macromolecular protein folding complex composed of eight subunits (CCT1-8) that drives expression of many tumorigenic factors. Bioinformatic analysis in multiple cancers, such as breast cancer, revealed increased gene expression in tumor tissue compared to normal tissue for CCT1-8 (p< 0.0001), with the largest differences observed in CCT2 and CCT3. Genomic alteration of CCT2 inversely correlated with cancer patient survival, and depletion of CCT2 prevented growth of murine breast tumors. In a correlative study of blood and tumor tissues from metastatic breast cancer patients, high CTC counts positively correlated with detectable CCT2 in tumor tissues. These results support CCT2 as a possible marker for CTC. To determine this, antibodies to CCT2 were validated for use in the CellSearch System (CSS), currently the only FDA approved CTC enrichment platform, and tested with breast cancer cells spiked into healthy human blood. Recovery using CCT2 for identification, led to increased collection up to 6% of spiked breast cancer cells that would have been lost by standard CTC classification using cytokeratin (CK). With prognostic thresholds around 3-5 CTC/tube of blood, increased detection of even 1-2 more CTC can be significant for assessing patients' risks. Analysis in an open software program called ACCEPT (Automated CTC Classification, Enumeration and PhenoTyping) confirmed that the majority of recovered spiked cancer cells expressed CCT2. Flow cytometry analysis of spiked cancer cells confirmed that CCT2+ enriched cells expressed cancer markers CD44 or estrogen receptor (ER). These results show that the addition of CCT2 staining to a CTC detection protocol has positive implications for enumeration of CTC from blood, such as increased detection of CTC with low expression of epithelial markers. This experiment was repeated using small cell lung cancer cell lines with similar results. The combined bioinformatics, histologic and experimental results indicate that identification of CCT2-expressing CTC can be incorporated into CTC detection platforms to monitor those patients with a heightened risk for cancer recurrence or metastasis. Citation Format: Amanda Cox, Ana Martini, Eunkyung Lee, Rebecca Moroose, Amr Khaled, Annette R. Khaled. Using chaperonin containing TCP1 as a marker to track clinically relevant circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2601.

Spinal cord injury (SCI) is a devastating neurologic disorder with significant impacts on quality of life, life expectancy, and economic burden. Although there are no fully restorative treatments yet available, several animal and small-scale clinical studies have highlighted the therapeutic potential of cellular interventions for SCI. Mesenchymal stem cells (MSCs)-which are conventionally isolated from the bone marrow-recently emerged as promising candidates for treating SCI and have been shown to provide trophic support, ameliorate inflammatory responses, and reduce cell death following the mechanical trauma. Here we evaluated the human skin as an alternative source of adult MSCs suitable for autologous cell transplantation strategies for SCI. We showed that human skin-derived MSCs (hSD-MSCs) express a range of neural markers under standard culture conditions and are able to survive and respond to neurogenic stimulation in vitro. In addition, using histological analysis and behavioral assessment, we demonstrated as a proof-of-principle that hSD-MSC transplantation reduces the severity of tissue loss and facilitates locomotor recovery in a rat model of SCI. Altogether, the study provides further characterization of skin-derived MSC cultures and indicates that the human skin may represent an attractive source for cell-based therapies for SCI and other neurological disorders. Further investigation is needed to elucidate the mechanisms by which hSD-MSCs elicit tissue repair and/or locomotor recovery.

Background Nevi of special sites display aberrant clinical and histologic features that can be difficult to distinguish from melanoma, leading to unnecessarily high rates of excision with poor cosmetic or functional results. Dermoscopy can improve clinical assessment of melanocytic lesions by visualizing morphologic structures beyond the epidermis. Objective We sought to assess the value of specific dermoscopic features for diagnosing melanocytic neoplasms arising on the breast area in females. Methods In this retrospective cohort study, we collected clinical and dermoscopic information for 104 nevi and 13 melanomas removed from the breast, chest, and areola, and evaluated the diagnostic performance of each dermoscopic feature. Results Melanomas from the breast area were larger ( P = .0175) than nevi and occurred in older women ( P = .0117). Irregular blotches, nonuniform radial streaks, blue-gray veil, and regression were highly specific for melanoma, whereas atypical network and irregular dots and globules had low to moderate specificity. Limitations This study was retrospective with a small sample size. Conclusion Compared to melanocytic neoplasms from other sites, atypical network and irregular dots and globules were poor indicators for breast melanoma. Irregular blotches, nonuniform radial streaks, blue-gray veil, and regression were highly specific and should heighten clinical suspicion for melanoma arising on the breast.

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

Background Dermoscopy allows for visualization of morphologic structures beyond the epidermis, including features that may indicate early malignant transformation. However, dermoscopic features are rarely considered during routine histologic sectioning, and areas of clinical concern may be missed during microscopic evaluation. Objective We assessed the diagnostic impact of a dermoscopy-guided micropunch score for the evaluation of melanocytic lesions. Methods In this case-control study, we evaluated 150 scored melanocytic lesions. Original tissue specimens were reprocessed to create a control group, in which a new score was introduced elsewhere in the lesion to guide an alternative plane of section. Slides were reviewed in a randomized, double-blinded manner to assess histologic features and render a diagnosis. Dermoscopy was also reviewed. Results The proportion of cases with a higher grade in the original, dermoscopy-guided section was statistically significant. Four invasive melanomas were exclusively identified using the scoring protocol. The presence of regression structures, negative pigment network, radial streaming or pseudopods, and irregular blotches were highly specific for a higher diagnostic grade. Limitations This study is retrospective and reprocessing tissue does not perfectly mimic routine sectioning. Conclusion Dermoscopy can identify important, histologically high-grade areas, and this information can be used to optimize the sectioning of melanocytic neoplasms.

Mitogen-activated protein kinases (MAPKs) have been implicated in central nervous system injuries, yet the roles within neurodegeneration following spinal cord injury (SCI) still remain partially elucidated. We aimed to investigate the changes in expression of the three MAPKs following SCI and the role of spinal c-jun-NH2-terminal kinase (JNK) in motor impairment following the lesion. SCI induced at the T9 level resulted in enhanced expression of phosphorylated MAPKs shortly after trauma. SCI increased spinal cord myeloperoxidase levels, indicating a local neutrophil infiltration, and elevated the number of spinal apoptotic cells. Intrathecal administration of a specific inhibitor of JNK phosphorylation, SP600125, given at 1 and 4h after SCI, reduced the p-JNK expression, the number of spinal apoptotic cells and many of the histological signs of spinal injury. Notably, restoration of locomotor performance was clearly ameliorated by SP600125 treatment. Altogether, the results demonstrate that SCI induces activation of spinal MAPKs and that JNK plays a major role in mediating the deleterious consequences of spinal injury, not only at the spinal level, but also those regarding locomotor function. Therefore, inhibition of JNK activation in the spinal cord shortly after trauma might constitute a feasible therapeutic strategy for the functional recovery from SCI.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

Spinal cord injury (SCI) is a devastating neurologic disorder that often inflicts neuropathic pain, which further impacts negatively on the patient's quality of life. Endothelin peptides, which exert their effects via endothelin A (ETAR) and endothelin B (ETBR) receptors, can contribute to sensory changes associated with inflammatory and neuropathic pain, but their role in nociception following SCI is unknown. At different time points after subjecting male Wistar rats to surgery for compression-induced T10 level SCI, the spinal cord levels of ETAR and ETBR were assessed by Western blot and immunohistochemistry, and the corresponding mRNAs by real-time PCR, alongside recordings of behavioural responses to mechanical stimulation of the hind paws with von Frey hairs. SCI was associated with development of hind paw mechanical allodynia from day 14 onwards, and up-regulation of ETAR and ETBR mRNA in the spinal cord and dorsal root ganglia, and of ETAR protein in the spinal cord. SCI increased ETAR protein expression in spinal grey matter. Treatment on day 21 after surgery with the ETAR selective antagonist BQ-123 (40 and 90 pmol, intrathecally) or the dual ETAR/ETBR antagonist bosentan (30 and 100mg/kg, orally) transiently reduced SCI-induced mechanical allodynia, but the ETBR antagonist BQ-788 was ineffective. Altogether, these data show that SCI upregulates ETAR expression in the spinal cord, which appears to contribute to the hind paw mechanical allodynia associated with this condition. Therapies directed towards blockade of spinal ETAR may hold potential to limit SCI-induced neuropathic pain.

Background: Genetic counselling and testing (GCT) for hereditary breast and ovarian cancer (BOC) has become a standard option in BOC care in Europe allowing for prognostic information on the individual risk for disease onset/ relapse as well as on treatment options comprising prophylactic surgery or surveillance programs. However, data on the psychosocial long-term consequences is limited, especially in high-risk counsellees opting against genetic testing. We aimed at investigating the long-term psychosocial consequences of GCT for hereditary BOC in all counsellees irrespective of their decision after counselling. Patients and Methods: Counsellees for BOC with and without a previous disease who had undergone genetic counselling at Innsbruck Medical University between 2011 and 2014 were asked to participate in a cross-sectional Patient Reported Outcome (PRO) assessment (incl. Multidimensional Impact of Cancer Risk Assessment, Genetic counseling satisfaction scale, Satisfaction with Decision Scale, Breast Cancer Heredity Knowledge Scale, Hospital Anxiety and Depression Scale/ HADS, Short Form 12 Health Survey, Cancer Worry Scale/ CWS) targeting on psychological distress, cancer worry, patient knowledge and patient satisfaction with genetic counselling and decisions by means of an anonymous mail survey. Subsequent decisions for vs. against genetic testing and if eligible, for surveillance vs. prophylactic surgery were also assessed. A reference sample of BC survivors was recruited at the outpatient unit. Results: An overall sample of 137 counselees was included in the analysis (67.9% decided to undergo genetic testing for a HCPS, 22.6% decided not to be tested, 9.5% were still uncertain about their decision). 22.6% of counsellees experienced clinically relevant levels of anxiety and 9.8% scored above the cut-off for clinically relevant depression according to the HADS. Mean CWS score was 11 (SD 3.6, 3-24). Counsellees did not differ from breast cancer survivors regarding anxiety and depression according to the HADS (depression: p Conclusion: Our results indicate that genetic counselling for BOC has no overall deleterious psychosocial consequences in long-term. Levels of depression and anxiety were comparable to those of the general population, while distress levels did not differ from those of breast cancer survivors without a hereditary BOC predisposition. The overall satisfaction with counselling as well as the certainty with decisions on testing and related medical interventions are highly predictive for the long-term satisfaction with decisions. Hence, genetic counselling should focus on supporting counsellees in forming clear decisions and include identifying counsellees with increased cared needs in this regard by means of PRO assessment in follow-up. Citation Format: Hubalek M, Sztankay M, Meraner V, Martini C, Sperner-Unterweger B, Weber I, Morscher R, Zschocke J, Egle D, Dünser M, Oberguggenberger A. Long-term psychosocial consequences and counsellees' satisfaction after genetic counselling for hereditary breast- and ovarian cancer - A patient reported outcome study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-22.

Background:Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with higher risk of cardiovascular events and metabolic syndrome. The inflammation not only accelerates atherosclerosis, but also may influence cardiovascular (CV) risk factors such as lipid profile, blood pressure and insulin resistance. Lipid profile has previously been studied in PsA, however this association is still controversial.Objectives:To study the frequency of altered lipid profile in patients with PsA and its association with disease activity.Methods:We studied all the patients with diagnosis of PsA who consecutively attended to Rheumatology Unit at Cordoba Hospital from July 2018 to December 2019. PsA was diagnosed according CASPAR criteria. Clinical and laboratory data were collected. The activity of the disease was evaluated by PASI, MDA and DAPSA. Quantitative variables will be expressed in median and 1st and 3rd interquartile; qualitative variables expressed in frequency and percentage. Correlation analysis was calculated using Spearman’s rank correlation coefficient. PResults:42 PsA patients were included. Mean age was 56 years old (47.25-62.75) and 54.76% were female (n=23). 92.86% (n=39) of the patients had plaque Psoriasis and 87.8% (n=36) had peripheral joint involvement.Frequency of comorbidities in PsA are shown in Graphic 1. 31 (73.8%) of the patients were treated with topical therapy, 3 (7.14%) with phototherapy, 31 (73.8%) with Methotrexate and 17 (41.46%) with biologics and JAK inhibitor. Activity Disease Index and Lipid profile are shown in Table 1 and 2.There was not association between Apo B/Apo A coefficient with DAPSA (rho=0.013; p=0.940) and MDA (rho=-0.029; p=0.867).Conclusion:In spite of the presence of cardiovascular factors in the majority of PsA patients, lipid profile is not correlated with disease activity in this population.References:[1]Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasis is associated with clinically significant cardiovascular risk: A Danish nationwide cohort study. J Intern Med 2011;270:147-57.[2]Mallbris, L., Ritchlin, C.T., Ståhle, M. “Metabolic disorders in patients with psoriasis and psoriatic arthritis.” Curr RheumatolRep.8(5): 355–363. 2006[3]Ng CY, Tzeng I-S, Liu S-H, Chang Y-C, Huang Y-H. Metabolic parameters in psoriatic patients treated with interleukin-12/23 blockade (Ustekinumab). J Dermatol 2018; 45:309–313[4]Kaur S, Kingo K, Zilmer M. Psoriasis and cardiovascular risk – do promising new biomarkers have clinical impact? Mediators Inflamm 2017; 2017: 7279818[5]Gentile M, Peluso R, Di Minno MN, et al. Association between small dense LDL and sub-clinical atherosclerosis in patients with psoriatic arthritis. ClinRheumatol 2016; 35: 2023-9.Graphic 1.Comorbidities in PsATable. 1.Activity Disease Index in PsAACTIVITY INDEXn=42DAPSA14.45 (9.72-23.92)DAPSA≤4 REMISSION3>4 y ≤14 low disease activity16>14 y ≤28 moderate disease activity17>28 high disease activity3cDAPSA14.00 (8.00-23.00)/41*MDA9 (25)/36PASI2.20 (0.20-6.80)/41**Expressed in median and interquartiles.Qualitative variables expressed in frequency and percentage.Table. 2.Lipid Profile in PsA patients.Cholesterol (mg/dl)194.5 (164.8-218.2)HDL (mg/dl)48.00 (37.00-57.00)LDL (mg/dl)114.5 (78.5-140.8)TG (mg/dl)139.50 (89.25-191.20)Expressed in median and interquartiles.Disclosure of Interests:None declared

The purpose of this study was to evaluate the intragestational role of ghrelin in offspring development and reproductive programming in a mouse model of ghrelin imbalance during pregnancy. Female mice were injected with ghrelin (supraphysiological levels: 4 nmol/animal/day), antagonist (endogenous ghrelin inhibition with (D-Lys3)GHRP-6, 6 nmol/animal/day) or vehicle (control = normal ghrelin levels) throughout the pregnancy. Parameters evaluated in litters were growth, physical, neurobiological and sexual development and, at adulthood, reproductive function. Litter size and initial weight did not vary between treatments. Male pups from dams treated with ghrelin showed higher body weight increase until adulthood (31.7 ± 0.8 vs control = 29.7 ± 0.7, n = 11-14 litters/treatment; P < 0.05). Postnatal physical and neurobiological development was not modified by treatments. The antagonist accelerated male puberty onset, evidenced as earlier testis descent and increased relative testicular weight (antagonist = 0.5 ± 0.0% vs ghrelin = 0.4 ± 0.0% and control = 0.4 ± 0.0%, n = 5-10 litters/treatment; P < 0.05). At adulthood, these males exhibited lower relative testicular weight and reduced sperm motility (63.9 ± 3.6% vs control = 70.9 ± 3.3 and ghrelin = 75.6 ± 3.0, n = 13-15 animals; P < 0.05), without changes in plasma testosterone or fertility. Female pups intragestationally exposed to the antagonist showed earlier vaginal opening (statistically significant only at Day 25) and higher ovarian volume (antagonist = 1085.7 ± 64.0 mm3 vs ghrelin = 663.3 ± 102.8 mm3 and control = 512.3 ± 116.4 mm3; n = 4-6 animals/treatment; P < 0.05), indicating earlier sexual maturation. At adulthood, these females and those exposed to ghrelin showed a tendency to higher percentages of embryo loss and/or foetal atrophy. In conclusion, ghrelin participates in reproductive foetal programming: Alterations in ghrelin activity during pregnancy modified body weight increase and anticipated puberty onset, exerting (or tending to) negative effects on adult reproductive function. Fil: Torres, Pedro Javier. Universidad Nacional de Córdoba. Secretaria de Ciencia y Tecnología; Argentina Fil: Luque, Eugenia Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Ponzio, Marina Flavia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Cantarelli, Verónica Inés. Ministerio de Ciencia, Tecnología e Innovación Productiva. Agencia Nacional de Promoción Científica y Tecnológica. Fondo para la Investigación Científica y Tecnológica; Argentina Fil: Diez, Marcela. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Figueroa, S.. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina Fil: Vincenti, Laura María. Universidad Nacional de Córdoba. Facultad de Medicina; Argentina Fil: Carlini, Valeria Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Martini, Ana Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina

Alzheimer's disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.

Background The influence of pregnancy on the development, progression, and prognosis of melanoma is controversial. Objective We sought to compare clinical characteristics, histologic features, and proliferative activity in pregnancy-associated melanoma (PAM) and melanoma in nonpregnant women of reproductive age (non-PAM). Methods In this retrospective cohort study, we reviewed medical records and pathology reports from women given a diagnosis of melanoma between 2006 and 2015. We also examined tumor proliferation rates using mitotic count and 2 immunohistochemical markers of proliferation, phosphohistone H3 and Ki-67. Results In 50 PAM and 122 non-PAM cases, a diagnosis of melanoma in situ was associated with PAM. Among invasive melanomas, there was no difference in proliferative activity between groups. Pregnancy status was also not associated with age at diagnosis, tumor site, Breslow depth, Clark level, ulceration, or overall stage. Limitations This was a retrospective study with a small sample size of mostly patients with early-stage melanoma. Conclusions In our study of primarily early-stage melanoma, pregnancy did not have a significant impact on tumor proliferation. Particularly for patients given a diagnosis of stage I melanoma who are undergoing close surveillance, a history of PAM should not outweigh traditional factors, such as advanced maternal age, in planning future pregnancies.

Social robotics strives to create robots that enable social interactions similar to those experienced between two humans with the goal to increase performance in human-robot interaction (HRI). This is often achieved by designing robots that create an illusion of intentionality either through biologically inspired design or functional design in which the agent mirrors the cognitive or physical aspects of a human. The current study focused on functionally inspired design with the intent to learn what minimal features need to be included in the physical design of a social robot in order for it to appear as an intentional agent. Two groups of three and four participants respectively were lead through a design thinking workshop in which they brainstormed and ranked the physical features and expected interactions of social and non-social robots. They were asked to sketch ideal and minimum versions of each type of robot which were then evaluated on the degree to which different mental states were attributed to the robot (as only an intentional agent can have a mind and therefore mental states). Results showed that the minimum features required for participants to attribute mental states to a robot include an emotive head with eyes and a mouth. This minimal feature set can be utilized by social roboticists to aid in future designs in order to save both time and monetary resources.

BACKGROUND: Shiny white streaks (SWSs) are best visualized with polarized dermoscopy and correlate with dermal fibroplasia histopathologically. SWSs have been described at higher frequencies in melanomas than in benign nevi. OBJECTIVE: We assessed the diagnostic value of different patterns of SWSs and their histologic correlate in melanocytic lesions. METHODS: Polarized dermoscopic images of 1507 histopathologically diagnosed melanocytic neoplasms were analyzed for presence and pattern of SWSs. Histology was also reviewed for correlation. RESULTS: Among 1507 melanocytic neoplasms, SWSs were observed in 31 of 144 melanomas (22%) and 22 of 1363 benign neoplasms (1.6%) (P < .001). The sensitivity and specificity of SWSs for melanoma were 22% and 98%, respectively. Diffuse SWSs exhibited the greatest diagnostic value for melanoma, with sensitivity of 11.8% and specificity of 99.5%. Focal central and peripheral SWSs were comparable in diagnostic significance. The presence of SWSs was highly uncommon in dysplastic nevi, whereas in certain benign subgroups of nevi such as Spitz nevi and atypical genital special site nevi, SWSs were not uncommon. Diffuse SWSs correlated with greater breadth of deep fibroplasia than focal SWSs (P = .009), and SWSs correlated with greater Breslow depth among melanomas (P = .007). LIMITATIONS: This study was retrospective. CONCLUSION: Polarized dermoscopy is a valuable diagnostic tool in the identification of SWSs, a feature that is highly specific for melanoma.

Prototyping is a quick and effective way to facilitate iterative conceptual design, and allows user experience researchers to test the user experience of early conceptual designs. The current study compared usability testing that was supported by traditional paper prototyping methods with testing that was supported by a new iPhone software application called Prototyping on Paper (POP). POP supports testing and development by allowing uploaded images to be linked together to form virtual interactive prototypes. Usability testing was carried out on an actual smartphone product that is currently under development called ‘Fleet,’ a product that provides travelers with crowd-sourced information about commercial air travel. Data from the user testing showed that participants slightly preferred interacting with POP in comparison with traditional paper prototyping, but no reliable differences were found in terms of user performance. Test facilitators also showed no reliable preference between the two techniques. The increased level of interactivity POP offers and its ability to better model actual interactions on a mobile device makes it a novel prototyping technique for smartphone applications that should be considered by usability experts.

Researchers who employ traditional laboratory task-set switching paradigms often assume that their participants are using only one strategy to complete switch moves. In the current study, we hypothesized that real world task-set switching behaviors are facilitated by multiple processing strategies, including fast “heuristic” strategies that are employed when switching is routine, and slower “reasoned” strategies that are used less often when heuristic strategies fail. In this study, 151 undergraduate students from George Mason University volunteered to complete the Youmans Cognitive Flexibility Assessment (YCFA), a computer-based, reactive task-set switching paradigm that takes the form of a simple puzzle game. Participants’ reaction time data suggests that they tried to utilize both heuristic and reasoned strategies to make task-set switches, and that they only used reasoned strategies when heuristic strategies failed. The data also revealed that participants quickly abandoned reasoned strategies when heuristic strategies once again become successful. We conclude by providing some guidance for system designers regarding the speed with which humans who are employing reasoned approaches to task-set switching will abandon them once heuristic approaches again become successful, and by discussing the implications of our findings for safe system design.

There is accumulating evidence that substance P released from peripheral sensory neurons participates in inflammatory and neuropathic pain. In this study it was investigated the ability of substance P to induce orofacial nociception and thermal and mechanical hyperalgesia, as well as the role of NK1 receptors on models of orofacial inflammatory and neuropathic pain. Substance P injected into the upper lip at 1, 10 and 100 μg/50 μL failed to induce nociceptive behavior. Also, substance P (0.1-10 μg/50 μL) injected into the upper lip did not evoke orofacial cold hyperalgesia and when injected at 1 μg/50 μL did not induce mechanical hyperalgesia. However, substance P at this latter dose induced orofacial heat hyperalgesia, which was reduced by the pre-treatment of rats with a non-peptide NK1 receptor antagonist (SR140333B, 3mg/kg). Systemic treatment with SR140333B (3 mg/kg) also reduced carrageenan-induced heat hyperalgesia, but did not exert any influence on carrageenan-induced cold hyperalgesia. Blockade of NK1 receptors with SR140333B also reduced by about 50% both phases of the formalin response evaluated in the orofacial region. Moreover, heat, but not cold or mechanical, hyperalgesia induced by constriction of the infraorbital nerve, a model of trigeminal neuropathic pain, was abolished by pretreatment with SR140333B. Considering that substance P was peripherally injected (i.e. upper lip) and the NK1 antagonist used lacks the ability to cross the blood-brain-barrier, our results demonstrate that the peripheral SP/NK1 system participates in the heat hyperalgesia associated with inflammation or nerve injury and in the persistent pain evoked by formalin in the orofacial region.

Our study demonstrates the repeated isolation of vaccine-derived Newcastle disease viruses from different species of wild birds across four continents from 1997 through 2014. The data indicate that at least 17 species from ten avian orders occupying different habitats excrete vaccine-derived Newcastle disease viruses. The most frequently reported isolates were detected among individuals in the order Columbiformes (n = 23), followed in frequency by the order Anseriformes (n = 13). Samples were isolated from both free-ranging (n = 47) and wild birds kept in captivity (n = 7). The number of recovered vaccine-derived viruses corresponded with the most widely utilized vaccines, LaSota (n = 28) and Hitchner B1 (n = 19). Other detected vaccine-derived viruses resembled the PHY-LMV2 and V4 vaccines, with five and two cases, respectively. These results and the ubiquitous and synanthropic nature of wild pigeons highlight their potential role as indicator species for the presence of Newcastle disease virus of low virulence in the environment. The reverse spillover of live agents from domestic animals to wildlife as a result of the expansion of livestock industries employing massive amounts of live virus vaccines represent an underappreciated and poorly studied effect of human activity on wildlife.

More than 1 million patients with melanoma in the United States are at risk to develop a second primary melanoma. Early detection of melanoma improves survival. Patients with melanoma may be able to self-manage care with their skin-check partners ("partners") and alert the physician when a concerning lesion is identified, thus providing an important adjunct to yearly skin examinations by a physician.To evaluate the effect of a structured skin self-examination (SSE) intervention for patients with melanoma and their partners ("dyads") on SSE performance and the detection of new melanomas by the dyad or the physician.Randomized clinical trial with 24-month follow-up assessments. Patients with stage 0 to IIB melanoma and their skin-check partners participated from June 6, 2011, to April 24, 2015.Dyads of patients and their partners were randomly assigned to receive the skills training intervention or customary care (control group).The main outcome was frequency of SSE performance. The secondary outcome was detection of a new or recurrent melanoma by the dyad or physician. The tertiary outcome was the number of unscheduled physician appointments for concerning lesions.The study cohort comprised 494 participants. The patient population was 51.2% (253 of 494) female and had a mean (SD) age of 55 (10) years. Patients in the intervention arms had significantly increased SSEs with their partners at 4, 12, and 24 months (P .001 for all) compared with the control group (mean differences, 1.57 [95% CI, 1.29-1.85], 0.72 [95% CI, 0.39-1.06], and 0.94 [95% CI, 0.58-1.30], respectively). Patients in the intervention arms identified new melanomas more than those in the control group (χ21 = 28.77, P .01 [n = 51 melanomas in situ] and χ21 = 6.43, P .05 [n = 18 invasive melanomas]) and did not increase physician visits.Patients with melanoma and their partners reliably performed SSE after participating in a structured skills training program lasting approximately 30 minutes, with reinforcement every 4 months by the study dermatologist. Accurate SSE by those at risk to develop melanoma may enhance early detection and relieve some of the burden on health services to provide continuing follow-up to a growing population of eligible patients.clinicaltrials.gov Identifier: NCT01432860.

Background Clinical and histopathologic assessment of pigmented skin lesions remains challenging even for experts. Differentiated and accurate noninvasive diagnostic modalities are highly desirable. Objective We sought to provide clinicians with such a tool. Methods A 2-gene classification method based on LINC00518 and preferentially expressed antigen in melanoma (PRAME) gene expression was evaluated and validated in 555 pigmented lesions (157 training and 398 validation samples) obtained noninvasively via adhesive patch biopsy. Results were compared with standard histopathologic assessment in lesions with a consensus diagnosis among 3 experienced dermatopathologists. Results In 398 validation samples (87 melanomas and 311 nonmelanomas), LINC00518 and/or PRAME detection appropriately differentiated melanoma from nonmelanoma samples with a sensitivity of 91% and a specificity of 69%. We established LINC00518 and PRAME in both adhesive patch melanoma samples and underlying formalin fixed paraffin embedded (FFPE) samples of surgically excised primary melanomas and in melanoma lymph node metastases. Limitations This technology cannot be used on mucous membranes, palms of hands, and soles of feet. Conclusions This noninvasive 2-gene pigmented lesion assay classifies pigmented lesions into melanoma and nonmelanoma groups and may serve as a tool to help with diagnostic challenges that may be inherently linked to the visual image and pattern recognition approach.

Background Spinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. Here, we have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI. Methods Spinal hemisection at T10 was carried out in adult male CD1 mice and Wistar rats. To test if LXA4 can reduce neuroinflammation and neuropathic pain, each animal received two intrathecal injections of LXA4 (300 pmol) or vehicle at 4 and 24 h after SCI. Sensitivity to mechanical stimulation of the hind paws was evaluated using von Frey monofilaments, and neuroinflammation was tested by measuring the mRNA and/or protein expression levels of glial markers and cytokines in the spinal cord samples after SCI. Also, microglia cultures prepared from murine cortical tissue were used to assess the direct effects of LXA4 on microglial activation and release of pro-inflammatory TNF-α. Results LXA4 treatment caused significant reductions in the intensity of mechanical pain hypersensitivity and spinal expression levels of microglial markers and pro-inflammatory cytokines induced by SCI, when compared to rodents receiving control vehicle injections. Notably, the increased expressions of the microglial marker IBA-1 and of the pro-inflammatory cytokine TNF-α were the most affected by the LXA4 treatment. Furthermore, cortical microglial cultures expressed ALX/FPR2 receptors for LXA4 and displayed potentially anti-inflammatory responses upon challenge with LXA4. Conclusions Collectively, our results suggest that LXA4 can effectively modulate microglial activation and TNF-α release through ALX/FPR2 receptors, ultimately reducing neuropathic pain in rodents after spinal cord hemisection. The dual anti-inflammatory and analgesic properties of LXA4, allied to its endogenous nature and safety profile, may render this lipid mediator as new therapeutic approach for treating various neuroinflammatory disorders and chronic pain with only limited side effects. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0540-8) contains supplementary material, which is available to authorized users.

To increase adherence to cancer management guidelines, the Commission on Cancer (CoC) developed and approved five melanoma quality measures in 2015. Our objectives were to evaluate formally the national performance of these melanoma measures and to examine patient, tumor, and hospital characteristics associated with adherence. From the National Cancer Data Base (2012), patients with invasive, nonmetastatic melanoma were identified. Inclusion and exclusion criteria were based on the CoC definition for each measure. Patient-level and hospital-level adherence rates were calculated for the five measures. A hospital was deemed “compliant” if it met the CoC standard, which requires 80 % of patients to receive the measure-specific recommended care. Patient, tumor, and hospital characteristics potentially associated with higher likelihood of adherence at the patient-level were estimated using hierarchical random-effects logistic regression models. A total of 31,598 patients from 1343 hospitals were examined. Patient-level adherence rates varied from 31.6 % (Measure 5: ≥10 axillary lymph nodes removed/examined) to 72.6 % (Measure 1: sentinel lymph node biopsy (SLNB) appropriateness measure). Hospital-level adherence rates, ranged from 19.3 % of hospitals (N = 538 hospitals for Measure 5) to 44.8 % of hospitals (N = 1090 hospitals for Measure 3: completion lymph node dissection after positive SLNB). No hospital-level factors (e.g., teaching status) were consistently associated with better adherence. National adherence rates to the five new CoC melanoma quality metrics are low, and most hospitals would not meet the CoC requirement of 80 % adherence. Feedback for performance of these measures to hospitals, decisions support tools, and educational initiatives are needed to improve guideline adherence.

Background and Purpose Kinin B1 and B2 receptors have been implicated in physiological and pathological conditions of the urinary bladder. However, their role in overactive urinary bladder (OAB) syndrome following spinal cord injury (SCI) remains elusive. Experimental Approach We investigated the role of kinin B1 and B2 receptors in OAB after SCI in rats. Key Results SCI was associated with a marked inflammatory response and functional changes in the urinary bladder. SCI resulted in an up-regulation of B1 receptor mRNA in the urinary bladder, dorsal root ganglion and spinal cord, as well as in B1 protein in the urinary bladder and B1 and B2 receptor protein in spinal cord. Interestingly, both B1 and B2 protein expression were similarly distributed in detrusor muscle and urothelium of animals with SCI. In vitro stimulation of urinary bladder with the selective B1 or B2 agonist elicited a higher concentration-response curve in the SCI urinary bladder than in naive or sham urinary bladders. Cystometry revealed that treatment of SCI animals with the B2 selective antagonist icatibant reduced the amplitude and number of non-voiding contractions (NVCs). The B1 antagonist des-Arg9-[Leu8]-bradykinin reduced the number of NVCs while the non-peptide B1 antagonist SSR240612 reduced the number of NVCs, the urinary bladder capacity and increased the voiding efficiency and voided volume. Conclusions and Implications Taken together, these data show the important roles of B1 and B2 receptors in OAB following SCI in rats and suggest that blockade of these receptors could be a potential therapeutic target for controlling OAB.

Background Early diagnosis of melanoma remains of paramount importance, because it has been widely demonstrated that survival is strongly related to Breslow thickness. Several studies have shown that dermatoscopy improves accuracy in the diagnosis of melanoma. Although histopathology is considered the gold standard to differentiate melanoma from nevi, there are some cases of melanoma in which the histopathologic features are less than definitive. It has also been demonstrated that fluorescence in situ hybridization can be used to differentiate melanomas from nevi based on chromosomal copy number aberrations. Objective In this study we present a case series to demonstrate the value of combining fluorescence in situ hybridization and dermatoscopy/clinical history to enhance diagnostic capability for selected cases of early melanoma. Methods Cases were identified that had dermatoscopic findings or clinical history highly suggestive of melanoma and fluorescence in situ hybridization evaluation positive for melanoma, but histopathologic features that were less than definitive. Two dermatopathologists performed independent histologic analysis of specimens and two dermatologists experienced in dermatoscopy reviewed dermatoscopic and clinical data. Results Nine cases meeting inclusion criteria were identified. In 6 cases the histologic differential diagnosis was dysplastic nevus versus early melanoma whereas in 3 cases the differential diagnosis included Spitz nevus versus early melanoma. Limitations Limitations of this study include restrictive inclusion criteria and study design restricted to a case series. Conclusion This exploratory study demonstrates that in a subset of early melanoma cases, combining multiple diagnostic modalities such as dermatoscopy and molecular techniques with histology enhances detection of early melanoma.