Τετάρτη 1 Νοεμβρίου 2017
Anti-tumor immunity via the superoxide-eosinophil axis induced by a lipophilic component of Mycobacterium lipomannan
Abstract
Mycobacterium bovis Bacille Calmette–Guérin (BCG) has been shown to possess potent anti-tumor activity particularly in various animal models, while the cellular and molecular mechanisms underlying its activity are not well understood. We found that lipomannan (BCG-LM), a lipophilic component of the mycobacterial cell envelope, specifically inhibits tumor growth and induces the infiltration of eosinophils at local tumor invasion sites. In contrast, neither lipoarabinomannan (BCG-LAM) nor the cell wall of Mycobacterium bovis BCG (BCG-CW) exerted anti-tumor immunity. BCG-LM enhances cytotoxic activity of eosinophils via the increased production of superoxide. Global transcriptomic analyses of BCG-LM-pulsed dendritic cells identified C-C motif ligand (CCL) 5 as a crucial chemokine for the anti-tumor immunity induced by BCG-LM, indicating that CCL5 plays an important role for the accumulation of eosinophils in the tumor microenvironment. Furthermore, BCG-LM and memory Th2 cells exerted a synergetic effect on tumor progression by cooperatively enhancing the eosinophil function. Thus, this study revealed an un-identified BCG-LM-mediated anti-tumor mechanism via superoxide produced by infiltrated eosinophils in the tumor microenvironment. Since BCG-LM activates this unique pathway, it may have potent therapeutic potential as immune cell therapy for cancer patients.
Involvement of Zizimin2/3 in the age-related defect of peritoneal B-1a cells as a source of anti-bacterial IgM
Abstract
Zizimin2 (Ziz2), also known as dedicator of cytokinesis 11 (DOCK11), is a guanine nucleotide exchange factor that is predominantly expressed in lymphoid tissues. Recent findings demonstrated that Ziz2 is involved in the development of B cells, including germinal centre B cells and marginal zone B cells. However, limited information is currently available on the roles of Ziz2 in B-1 cells, a B-cell subset that resides in body cavities and contributes to protection against foreign pathogens in a T-cell-independent manner. We herein show that Ziz2 and its widely expressed isoform Ziz3 (also known as DOCK10) may be involved in defective production of anti-bacterial IgM by aged B-1a cells, a CD5+ subset of B-1 cells. Natural IgM against typical bacterial epitopes was defectively produced by peritoneal B-1a cells from aged mice. The down-regulation of Ziz2/3 in B-1a cells appeared to be responsible for this defective IgM production, as demonstrated by Ziz2/3 double-knockout mice. Mechanistically, lower levels of basal AKT phosphorylation did not allow for the differentiation of Ziz2/3-deficient B-1a cells into plasma cells. Defective production of anti-bacterial IgM was not fully rescued by immunization, resulting in slightly weaker protection in Ziz2/3-deficient mice. Thus, the down-regulation of Ziz2/3 in B-1a cells may at least partly account for defective protection in aged mice.Expression of KIR2DS1 does not significantly contribute to NK cell cytotoxicity in HLA-C1/C2 heterozygous haplotype B donors
Abstract
NK cells are functionally controlled by the killer immunoglobulin-like receptor (KIR) family that comprises inhibitory (iKIR) and activating (aKIR) members. Genetic association studies suggest that donors expressing aKIRs next to iKIRs will be superior donors in the setting of hematopoietic stem cell transplantation of patients with leukemia. However, contrary evidence states that aKIR expression may be irrelevant or even detrimental. Using a complex methodology incorporating KIR-Q-PCR, double fluorescence and viSNE analysis, we characterized subset distribution patterns and functionality in haplotype A donors which lack aKIRs and haplotype B donors that express a variety of B-specific genes. Here, we show that the alloreactive KIR2DS1+ NK cell subset in HLA-C1/C2 donors is highly responsive towards C2-expressing targets but quantitatively small and as such does not significantly contribute to cytotoxicity. Thus, we fail to find a direct link between haplotype allocation status and NK cell cytotoxicity at least in HLA-C1/C2 heterozygous donors.Hyperferritinemia and inflammation
Abstract
Understanding of ferritin biology has traditionally centered on its role in iron storage and homeostasis, with low ferritin levels indicative of deficiency and high levels indicative of primary or secondary hemochromatosis. However, further work has shown that iron, redox biology and inflammation are inexorably linked. During infection, increased ferritin levels represent an important host defense mechanism that deprives bacterial growth of iron and protects immune cell function. It may also be protective, limiting the production of free radicals and mediating immunomodulation. Additionally, hyperferritinemia is a key acute-phase reactants, used by clinicians as an indication for therapeutic intervention, aimed at controlling inflammation in high-risk patients. One school of thought maintains that hyperferritinemia is an 'innocent bystander' biomarker of uncontrolled inflammation that can be used to gauge effectiveness of intervention. Other schools of thought maintain that ferritin induction could be a protective negative regulatory loop. Others maintain that ferritin is a key mediator of immune dysregulation, especially in extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects. There is a clear need for further investigation of the role of ferritin in uncontrolled inflammatory conditions both as a biomarker and mediator of disease because its occurrence identifies patients with high mortality risk and its resolution predicts their improved survival.A clinical update on inflammasomopathies
Abstract
Inflammasomes are important elements of the innate immune defense. The most common autoinflammatory syndromes, as well a number of rare ones, are due to hereditary defects in the inflammasomes, hence are called inflammasomopathies. The recent clinical advances in these diseases will be reviewed, with special emphasis on reflecting the international collaborative work in the field. Recent recommendations for familial Mediterranean fever, cryopyrin-associated periodic syndromes and hyper-IgD syndrome/mevalonate kinase deficiency will be presented and diagnostics tests, treatment alternatives and follow-up recommendations will be summarized. The other rare inflammasomopathies will be briefly discussed based on clinical features; these diseases are pyogenic arthritis, pyoderma gangrenosum and acne, NLRC4-related macrophage-activation syndrome of enterocolitis, mutations in NLRP12 that cause hereditary periodic fever syndromes (familial cold inflammatory syndrome 2) and NLRP1-associated autoinflammation with arthritis and dyskeratosis.What are definitions of life good for? Transdisciplinary and other definitions in astrobiology
Abstract
The attempt to define life has gained new momentum in the wake of novel fields such as synthetic biology, astrobiology, and artificial life. In a series of articles, Cleland, Chyba, and Machery claim that definitions of life seek to provide necessary and sufficient conditions for applying the concept of life—something that such definitions cannot, and should not do. We argue that this criticism is largely unwarranted. Cleland, Chyba, and Machery approach definitions of life as classifying devices, thereby neglecting their other epistemic roles. We identify within the discussions of the nature and origin of life three other types of definitions: theoretical, transdisciplinary, and diagnostic definitions. The primary aim of these definitions is not to distinguish life from nonlife, although they can also be used for classificatory purposes. We focus on the definitions of life within the budding field of astrobiology, paying particular attention to transdisciplinary definitions, and diagnostic definitions in the search for biosignatures from other planets.
The coupling of taxonomy and function in microbiomes
Abstract
Microbiologists are transitioning from the study and characterization of individual strains or species to the profiling of whole microbiomes and microbial ecology. Equipped with high-throughput methods for studying the taxonomic and functional characteristics of diverse samples, they are just beginning to encounter the conceptual, theoretical, and experimental problems of comparing taxonomy to (micro-ecological) function, and extracting useful measures from such comparisons (i.e. diversity, stability, or "health"). Although still unresolved, these problems are well studied in macro-ecology (the ecology of non-microbes) and are reiterated here as an historical precautionary for microbial ecologists. Beyond expected and unresolved terminological vagueness, we argue that assessments and comparisons of taxonomic and functional profiles in micro-ecology suffer from theoretically unresolvable arbitrariness and ambiguities. We divide these into problems of scale, individuation, and commensurability. We argue that there is no technically/theoretically "correct" scale, individuation, or comparison of taxonomy and function, but there are nonetheless better and worse methodologies for profiling.
Methicillin resistant Staphylococcus aureus in minas frescal cheese: evaluation of classic enterotoxin genes, antimicrobial resistance and clonal diversity
Abstract
This study aimed to investigate classical enterotoxin (sea to see) and mecA genes, by polymerase chain reaction (PCR) and anitimicrobial susceptibility, by disc diffusion test of Staphylococcus aureus isolated from minas frescal cheese (MFC). All methicillin resistant S. aureus (MRSA) isolates were investigated for the presence of PVL genes and clonal diversity. Thirty-one S. aureus were isolated from four MFC samples. Seven (22.6%) S. aureus carried mecA gene and two of them carried enterotoxin genes seb/sec and sea/seb. Five (16.1%) S. aureus isolates showed induced resistance to clindamycin and nine (29%) were resistant to multiple antibiotics (MDR), among these, six were MRSA. No MRSA isolates presented the PVL genes. Four MRSA were grouped into three clones and three isolates were not typable by pulsed field gel electrophoresis (PFGE). MRSA isolates showed, by multilocus sequence typing (MLST), sequence types ST1, ST5, ST72 and ST4304 (new ST) and S. aureus protein A (spa type) t127, t568 and t2703. This data suggest MFC may constitute a risk to the consumer, because of its potential for staphylococcal food poisoning, however it might, also, become one of MRSA and MDR strains disseminator, including clones usually found in the hospital environment.Mutations de la préséniline dans la maladie de Dowling-Degos : lien avec l’occlusion folliculaire et avec la voie notch
Source:Annales de Dermatologie et de Vénéréologie
Author(s): O. Dereure
Polémiques sur la vitamine D
Source:Annales de Dermatologie et de Vénéréologie
Author(s): M.-T. Leccia
Nouveautés dans la prise en charge des épidermolyses bulleuses congénitales
Source:Annales de Dermatologie et de Vénéréologie
Author(s): D. Murrell
L’hyperplasie épithéliale verruqueuse du pénis
Source:Annales de Dermatologie et de Vénéréologie
Author(s): J.-N. Dauendorffer, B. Cavelier Balloy, M. Bagot, C. Renaud-Vilmer
The Influence of Home and School Environments on Children’s Diet and Physical Activity, and Body Mass Index: A Structural Equation Modelling Approach
Abstract
Introduction The home and school environments play important roles in influencing children's health behaviours. However, their simultaneous influence on childhood obesity has not yet been examined. We explore the relationship of the home and school environments with childhood obesity, to determine whether this relationship is mediated by children's fruit and vegetable intake and physical behaviours. Methods This study uses baseline data from 9 to 11 year old children, their parents and school principals (matched data n = 2466) from the Obesity Prevention and Lifestyle Project. Child-reported behaviours, parent-reported home environment and principal-reported school environment data were collected via questionnaires. Trained researchers measured children's height and weight, and Body Mass Index (BMI, kg/m2) was calculated. Structural equation modelling was used to assess the relationship of the home and school environments with children's fruit and vegetable intake, physical activity behaviours, and children's BMI. Result The home diet environment was positively associated with child diet (β = 0.18, p < 0.001). The home physical activity environment had the largest inverse association with BMI (β = − 0.11, p < 0.001), indirectly through child physical activity (β = 0.28 ,p < 0.001). Schools' healthy eating policy implementation was significantly associated with child diet (β = 0.52, p < 0.05), but physical activity policy was not associated with child activity (β = − 0.007, p > 0.05). The school environment was not associated with child BMI. Discussion The home environment had a stronger association with healthier child behaviours, compared to the school environment. These findings suggest that future childhood obesity interventions targeting healthier home environments and supporting parents can promote healthier child eating and physical activity behaviours.
Potentiation by potassium iodide reveals that the anionic porphyrin TPPS4 is a surprisingly effective photosensitizer for antimicrobial photodynamic inactivation
Publication date: Available online 31 October 2017
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Liyi Huang, Ahmed El-Hussein, Weijun Xuan, Michael R. Hamblin
We recently reported that addition of the non-toxic salt, potassium iodide can potentiate antimicrobial photodynamic inactivation of a broad-spectrum of microorganisms, producing many extra logs of killing. If the photosensitizer (PS) can bind to the microbial cells, then delivering light in the presence of KI produces short-lived reactive iodine species, while if the cells are added after light the killing is caused by molecular iodine produced as a result of singlet oxygen-mediated oxidation of iodide. In an attempt to show the importance of PS-bacterial binding, we compared two charged porphyrins, TPPS4 (thought to be anionic and not able to bind to Gram-negative bacteria) and TMPyP4 (considered cationic and well able to bind to bacteria). As expected TPPS4+light did not kill Gram-negative Escherichia coli, but surprisingly when 100mM KI was added, it was highly effective (eradication at 200nM+10J/cm2 of 415nm light). TPPS4 was more effective than TMPyP4 in eradicating the Gram-positive bacteria, methicillin-resistant Staphylococcus aureus and the fungal yeast Candida albicans (regardless of KI). TPPS4 was also highly active against E. coli after a centrifugation step when KI was added, suggesting that the supposedly anionic porphyrin bound to bacteria and Candida. This was confirmed by uptake experiments. We compared the phthalocyanine tetrasulfonate derivative (ClAlPCS4), which did not bind to bacteria or allow KI-mediated killing of E. coli after a spin, suggesting it was truly anionic. We conclude that TPPS4 behaves as if it has some cationic character in the presence of bacteria, which may be related to its delivery from suppliers in the form of a dihydrochloride salt.
UVR and PAR absorbing compounds of marine brown macroalgae along a latitudinal gradient of the Brazilian coast
Publication date: Available online 31 October 2017
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Caroline Schmitz, Fernanda Ramlov, Leidson Allan Ferreira de Lucena, Virgilio Uarrota, Manuela Bernardes Batista, Marina Nasri Sissini, Iara Oliveira, Bruno Briani de Paula, Cintia D.L. Martins, José Marcos de Castro Nunes, Leonardo Rörig, Paulo Antunes Horta, Félix L. Figueroa, Nathalie Korbee, Marcelo Maraschin, José Bonomi Barufi
Absorption spectra are indicative of biological sample chemical composition and can be used as a basis for the construction of descriptive and predictive models for biotechnological screening or assays. In marine algae, chemical composition can vary due to species-specific differences in biochemistry, as well as intra-specific responses to unique environmental variables. Different indices (UVCi, UVB+Ai and PARi) were proposed and calculated to evaluate how photoprotective compounds vary in 18 species of Phaeophyceae. In addition, they were correlated to abiotic factors. Through this technique, seven main peaks were detected in the absorbing spectra of marine brown algal extracts. The highest photoprotective indices values were found in species collected in tropical areas, where higher solar radiation is observed compared to the southern Brazilian coast. Considering additional abiotic factors, water temperature and nitrate concentration were negatively correlated with UV indices. PARi's indices were positively affected by nitrate. All species collected on the Brazilian coast have absorption peaks in the region of phenolic compounds and carotenoids, suggesting that tropical marine brown macroalgae may have developed an effective antioxidant defense system, suggesting adaptation to environments characterized by high solar radiation. UVR/PAR indices congregated essential information to possible future biotechnological screening, facilitating selection of high priority species or sites, fostering actions to enhance alternative sustainable management strategies of coastal environments.
The Prevalence of Periodontitis Is Increased in Psoriasis and Linked to Its Inverse Subtype
Periodontitis and psoriasis are suggested to be co-occurring, chronic inflammatory conditions with overlapping characteristics. However, respective evidence is rare and data on risk factors of periodontitis in psoriasis patients are minimal. The aim of this study was to expand the evidence of psoriasis-associated periodontitis and establish a potential risk profile for periodontitis. In total, data from 209 exacerbated psoriasis patients were retrospectively analyzed on recordings of periodontitis and compared with those of 91 patients with chronic spontaneous urticaria (CSU). Analysis showed a significantly increased prevalence of periodontitis in psoriasis compared to CSU patients with an odds ratio of 3.76 (95% CI = 1.60-10.27, p = 0.001). Within the psoriatic subtypes, the presence of the inverse type (affecting intertriginous body areas) was strongly linked to periodontitis with an odds ratio of 5.11 (95% CI = 1.36-20.38, p = 0.006). These results are enlarging the evidence for psoriasis-associated periodontitis and identify a link between the inverse type of psoriasis and periodontitis.
Skin Pharmacol Physiol 2017;30:324-328
Recycling drug screen repurposes hydroxyurea as a sensitizer of glioblastomas to temozolomide targeting de novo DNA synthesis, irrespective of molecular subtype
Abstract
Background
Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide; TMZ). The five-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through MGMT (O6-methylguanine DNA methyltransferase) promoter methylation status in the tumor. Methods
A drug screening aimed at evaluating the potential recycling and repurposing of known drugs was conducted in TMZ-resistant GBM cell lines and primary cultures of newly diagnosed GBM with different MGMT promoter methylation status, phenotypic/genotypic background and subtype, and validated with sphere formation, cell migration assays, and quantitative invasive orthotopic in vivo models. Results
We identified hydroxyurea (HU) synergized with TMZ in cells and in vivo models, irrespective of MGMT promoter methylation status, subtype, and/or stemness. HU acts specifically on the S-phase of the cell cycle by inhibiting the M2 unit of enzyme ribonucleotide reductase. Knockdown of this enzyme using RNA interference and other known chemical inhibitors exerted a similar effect to HU in combination with TMZ both in vitro and in vivo. Conclusions
We demonstrate preclinical efficacy of repurposing hydroxyurea in combination with TMZ for adjuvant glioblastoma therapy. This combination benefit is of direct clinical interest given the extensive use of TMZ and the associated problems with TMZ-related resistance and treatment failure.A Population-Based Study of Recurrent Symptomatic Bordetella pertussis Infections in Children in California, 2010–2015
Abstract
Background
Natural infection with Bordetella pertussis is thought to result in 4–20 years of immunity against subsequent symptomatic pertussis infection. However, these estimates are based on studies in unvaccinated or whole-cell pertussis–vaccinated children. We conducted a population-based study of pertussis infection and reinfection during a 5-year period in California in an cohort vaccinated exclusively with acellular pertussis (aP) vaccine. Methods
California surveillance data were reviewed to identify all children with 2 reported incidents of pertussis with symptom onset between 1 January 2010 and 31 December 2015. Case investigation reports were reviewed, and children with ≥2 episodes of symptomatic pertussis infection that met the case definition were included. Results
Of 26259 pertussis cases reported in children (aged <18 years), 27 children met the inclusion criteria. Recurrent cases occurred among children of all ages; 5 (19%) were <6 months of age at the time of their first illness. The time from initial infection to reinfection was <1 year in 11 (41%) cases. Twenty-one children (78%) had received ≥3 doses of diphtheria and tetanus toxoids and aP vaccine at the time of their first pertussis infection, 1 (4%) had received 1 dose, and 5 (19%) were unvaccinated. Conclusions
Recurrent cases of pertussis infection are extremely rare. Based on this surveillance data, approximately 0.1% of children who were infected with pertussis experienced a clinically significant second episode of pertussis within 4 years. More research is needed to understand the immune response to B. pertussis infection in children vaccinated with aP vaccines.Frequent undetected MRSA ward-based transmission linked to patient sharing between hospitals
Abstract
Background
Recent evidence suggests hospital transmission of methicillin-resistant Staphylococcus aureus (MRSA) is uncommon in UK centers that have implemented sustained infection control programmes. We investigated whether a healthcare-network analysis could shed light on transmission paths currently sustaining MRSA levels in UK hospitals. Methods
A cross-sectional observational study was performed in two NHS hospital groups and a general district hospital in South-East London. All MRSA patients identified at inpatient, outpatient and community settings between 1st November 2011 and 29th February 2012 were included. We identified genetically-defined MRSA transmission clusters in individual hospitals and across the healthcare-network, and examined genetic differentiation of ST22 MRSA isolates within and between hospitals and inpatient or outpatient and community settings, as informed by average and median pairwise single nucleotide polymorphisms (SNPs) and SNP-based proportions of nearly identical isolates ('I'). Results
248/610 (40.7%) MRSA patients were linked in 90 transmission-clusters, of which 27 spanned multiple hospitals. Analysis of a large 32 patient ST22-MRSA cluster showed that 26/32 patients (81·3%) had multiple contacts with one another during ward stays at any hospital. No residential, outpatient or significant community healthcare contacts were identified. Genetic differentiation between ST22 MRSA inpatient isolates from different hospitals was less than between inpatient isolates from the same hospitals (p ≤ 0.01). Conclusions
There is evidence of frequent ward-based transmission of MRSA brought about by frequent patient admissions to multiple hospitals. Limiting in-ward transmission requires sharing of MRSA-status data between hospitals.Plant-based chimeric HPV-virus-like particles bearing amyloid-β epitopes elicit antibodies able to recognize amyloid plaques in APP-tg mouse and Alzheimer’s disease brains
Abstract
The main amyloid-beta (Aβ) variants detected in the human brain are full-length Aβ1–40 and Aβ1–42 peptides; however, a significant proportion of AD brain Aβ consists also of N-terminal truncated/modified species. The majority of the previous immunotherapeutic strategies targeted the N-terminal immunodominant epitope of the full-length Aβ; however, most of the pathological N-truncated forms of Aβ lack this critical B cell epitope. Recently, virus-like particles (VLPs), self-assembled structures with highly ordered repetitive patterns on their surface and capable of inducing robust immune responses, were applied as a promising platform for various antigen expressions. In this study, we expressed in plants two chimeric HPV16 L1 capsid proteins obtained by introduction of the β-amyloid 11–28 epitope (Aβ 11–28) into the h4 helix or into the coil regions of the L1 protein. The Aβ 11–28 epitope was chosen because it is present in the full-length Aβ 1–42 as well as in the truncated/modified amyloid peptide species. After expression, we assembled the chimerical L1/Aβ 11–28 into a VLP in which the Aβ 11–28 epitope is exposed at very high density (360 times) on the surface of the VLP. The chimeric VLPs elicited in mice Aβ-specific antibodies binding to β-amyloid plaques in APP-tg mouse and AD brains. Our study is the first to demonstrate a successful production in plants and immunogenic properties in mice of chimeric HPV16 L1 VLPs bearing Aβ epitope that may be of potential relevance for the development of multivalent vaccines for a multifactorial disease such as AD.
Transcription Factors as Critical Players in Melanoma Invasiveness, Drug Resistance and Opportunities for Therapeutic Drug Development
Abstract
Resistance to targeted therapy in cancer is often coupled with the acquisition of a pro-invasive phenotype by tumors cells and a highly permissive tumor microenvironment promoting drug resistance. Transcription factors are frequently shown as major points of convergence of multiple dysregulated receptors and signaling pathways in cancer. Several transcription factors are now incriminated as drivers of both drug resistance and invasiveness. We focused this review on critical transcription factors playing a causal role in both the resistance to BRAF V600E targeted therapy and the pro-invasive behavior of melanoma cells. Simultaneous rewiring of pro-oncogenic signaling pathways, phenotype switching or phenotypic plasticity supporting pro-invasive/pro-metastatic behavior, actin remodeling, bidirectional interactions between tumor microenvironment and melanoma cells represent major challenges for overcoming resistance to BRAF V600E inhibitors (BRAFi) and will be discussed. Although it represents an underdeveloped area of translational investigation, inhibition of transcription factors may open new avenues to combat resistance to BRAFi.
This article is protected by copyright. All rights reserved.
PDCD1 Gene Polymorphisms as Regulators of T-Lymphocyte Activity in Cutaneous Melanoma Risk and Prognosis
Summary
This study aimed to evaluate whether PD1.1 (c.-606G>A), PD1 (c.627+252C>T), PD1.5 (c.804C>T) and PD1.9 (c.644C>T) single nucleotide polymorphisms of PDCD1 gene influence the risk, clinicopathological aspects and survival of cutaneous melanoma (CM). Individuals with phototype I or II and PD1 CC genotype were under 5.89-fold increased risk of developing CM. PD1.5 TT genotype increased PDCD1 expression (2.49 vs. 1.28 arbitrary units, P= 0.03) and PD1.5 CT or TT genotype and allele T increased PD1 expression in TCD4+ lymphocytes (16.6 vs. 12.5%, P= 0.01; 17.0 vs. 13.1%, P= 0.006). At 60 months of follow-up, short recurrence-free survival was seen in patients with PD1.1 AA genotype (33.3 vs. 71.8%, P= 0.03). Patients with PD1.1 AA and PD1.5 CC genotype had 4.21 and 2.62 more chances of presenting relapse and evolving death by disease in Cox analyses, respectively. Our data provides preliminary evidence that abnormalities in regulation of T-lymphocyte alter CM risk, clinical aspects and prognosis.
This article is protected by copyright. All rights reserved.
Τρίτη 31 Οκτωβρίου 2017
Clinicopathologic characteristics of early-onset Becker's nevus in Korean children and adolescents
Abstract
Background
Becker's nevus (BN) presents as a hairy patch or plaque with or without proliferation of the dermal smooth muscles. BN has been described as acquired as found in a similar entity, congenital smooth muscle hamartoma (CSMH). This study was aimed at evaluating the clinicopathological aspects of BN in Korean cases in differential diagnosis with CSMH.
Methods
We performed a retrospective study of 103 patients histopathologically diagnosed as having BN or CSMH. The cases included 40 cases diagnosed with BN or CSMH before the age of 10 years who had clinical monitoring and a second skin biopsy after puberty to determine the disease course.
Results
Among cases of children to adolescents (<18 years), we observed a slight male predominance. Among children aged <14 years, sex ratio converged at 1:1. Early-onset BN showed a female predominance and hyperpigmented skin lesions. All BN cases showed hyperpigmentation, and face and neck involvement tended to make severe cosmetic concerns. In contrast, hypertrichosis was more frequent in CSMH. Either skin-colored lesion or pseudo-Darier's sign was not seen in early-onset BN. BN showed less dermal smooth muscle than CSMH.
Conclusions
Androgens themselves do not seem to be related to the development of BN but play only an aggravating role especially in male patients. Considering high occurrence in exposed areas, BN may distress patients severely. As early laser treatment may be helpful in some patients with BN, early-onset BN in comparison to CSMH should be diagnosed appropriately.
Furuncular myiasis for the Western dermatologist: treatment in outpatient consultation
Abstract
Background
Furuncular myiasis is likely to be seen by Western dermatologists because of the increasing number of international travelers but remains unfamiliar to most of them, who tend to refer these patients to hospitals. Different treatments have been proposed, but many of them are not achievable in outpatient consultation.
Methods
We reported three typical cases of furuncular myiasis, according to each species involved, and proposed diagnostic and therapeutic guidelines for dermatologists in outpatient consultation.
Results
One patient, complaining of an inflammatory nodule of the leg with a central punctum, was diagnosed with Dermatobia hominis infection, after a forest walk in French Guiana. One woman returned from Senegal with a nodule of the left buttock. She had been infected by a Cordylobia anthropophaga larva after drying her underwear under a mango tree. One woman living in Cameroon presented with scalp nodules, pain, fatigue, and facial edema. She had been infected by more than 40 larvae of Cordylobia rodhaini after drying her sheets under a mango tree. Manual extraction ensured complete healing in the three patients. We used neither doppler ultrasound nor occlusive dressing. Diagnosis was immediately made thanks to the typical clinical stories.
Conclusions
The diagnosis of furuncular myiasis requires only clinical skills and basic knowledge of life cycles. The treatment varies slightly depending on the species involved but is achievable in outpatient consultation and does not require occlusive dressing.
Multiple epidermolytic acanthomas mimicking condyloma: a retrospective study of 8 cases
Abstract
Background
Epidermolytic acanthoma (EA) is an uncommon benign cutaneous lesion. Multiple epidermolytic acanthomas (multiple EAs) are rarely reported.
Methods
We retrospectively identified patients diagnosed with multiple EAs between 2005 and 2017 from our dermatopathology database and analyzed their clinical, pathological, and immunohistochemical features. We also evaluated the association of multiple EAs with human papillomavirus (HPV) infection.
Results
In total, eight patients (average age 51 years; 3 : 1 male predominance) with multiple EAs were found. All patients had lesions on the genitocrural area. The two most common clinical diagnoses were condyloma (5/8) and soft fibroma (3/8), which were predominantly skin-colored (5/8) or whitish (2/8). The lesions were less than 1 cm in diameter, and most (6/8) appeared to have a smooth surface. No molecular evidence suggesting HPV infection was found. Immunohistochemical staining showed low mitotic activity. The lesions were removed in one of two patients via cryotherapy, and one patient was treated with electrocauterization. The other five patients were followed without treatment.
Conclusion
The genital area was the most common location for multiple EAs, which was commonly misdiagnosed clinically as condyloma. Patients presenting with uniformly small-sized, skin-colored to whitish, smooth papular lesions in the genitalia should be carefully evaluated. The specific pathological features of epidermolytic hyperkeratosis are diagnostic, and the lesions can be observed without aggressive treatment after confirmed diagnosis.
A narrative review of dermatologic protocols for primary care medical service trips in Latin America and the Caribbean
Abstract
Background
Skin disorders are prevalent on primary care medical service trips in Latin America and the Caribbean and commonly include scabies, superficial mycoses, and pyoderma. There have been no previous attempts to describe protocols that international volunteer clinicians use in managing these patients. The purpose of this study was to collect North American clinical protocols used by sending organizations in their volunteer operations in Latin America and the Caribbean, summarize the most common pharmacologic and nonpharmacologic management strategies, and compare these to published international practice recommendations.
Methods
A systematic web search was used to identify North American medical service trip-sending organizations. Clinical protocols were downloaded from their websites, and organizations were directly contacted to request protocols that were not published online. The protocols obtained were summarized, analyzed thematically, and compared to existing international guidelines.
Results
Of 225 organizations contacted, 112 (49.8%) responded, and 31 of these (27.7%) claimed to possess protocols for their trips, of which 20 were obtained and analyzed. Ten (50%) protocols discussed scabies, eight (40%) discussed superficial mycoses, and five (25%) discussed pyoderma. The protocols discussed clinical assessment, pharmacologic and nonpharmacologic management with variable degrees of accuracy and thoroughness, and with important omissions when compared to international guidelines. None were the product of systematic literature searches, and most were not referenced.
Conclusions
To avoid ineffective treatment and related harms, context-specific clinical guidelines are needed for volunteer clinicians practicing in remote international settings, and such guidelines should be based on best evidence and stakeholder consensus.
Ethnic variations in the epidemiology of bullous pemphigoid in Israel
Abstract
Background
No ethnic or geographic predisposition to bullous pemphigoid (BP) was reported so far.
Objective
To evaluate trends in the incidence of BP in northern Israel, shedding light on differences between two distinct ethnic populations who inhabit the same region, namely Jews and Arabs.
Methods
Bullous pemphigoid incidence was retrospectively estimated from January 2000–December 2015 in two Israeli regions with a total population of 1.56 million inhabitants.
Results
A total of 287 new-onset BP patients (mean age: 77.6 ± 12.1) were identified. The incidence rate was 11.4 per million inhabitants per year (95% CI, 10.2–12.9). The crude incidence rate in Jews was 4.8-fold higher than that in Arabs (16.4 vs. 3.4 cases per million per year, respectively [P < 0.0001]). After adjusting for age, the discrepancy between the two populations diminished (11.7 vs. 8.9 cases per million per year, respectively) but remained statistically significant (P = 0.032). The incidence increased consistently from 7.6 cases per million per year in the calendar period 2000–2005 to 12.6 and 14.3 cases in 2006–2010 and 2011–2015, respectively (P < 0.0001). Bullous pemphigoid patients of Arab ancestry presented with the disease significantly earlier than Jews (69.5 ± 15.3 vs. 78.7 ± 11.1 years, respectively, P = 0.002).
Conclusions
The incidence of BP in northern Israel has increased in the last 16 years and is significantly higher among Jews compared to Arabs. The age of presentation is remarkably different between patients belonging to the two populations.
Cross-sectional study of Treponema pallidum PCR in diagnosis of primary and secondary syphilis
Abstract
Background
Syphilis remains a major challenge and a complex diagnosis. We aim to evaluate the role of polymerase chain reaction (PCR) in Treponema pallidum (Tp) detection in various types of biological samples in the diagnosis of early syphilis.
Methods
We conducted a cross-sectional study including all attendees of the STI clinic with clinical suspicion of early syphilis. One or more specimens for the detection of Tp by PCR testing were collected.
Results
The overall sensitivity of Tp PCR test was 82.61% (95% CI: 68.6–92.2%). Tp PCR test had sensitivity of 84.6% (95% CI: 54.6–98.1%) in primary syphilis cases and 81.8% (95% CI: 64.5–93%) in secondary syphilis cases. PCR test performance was independent of HIV status.
Conclusion
Tp PCR test is a fast and reliable method for the detection of Tp in skin lesions of early syphilis, and it is a powerful tool in clinical settings.
Prospective, pilot evaluation of the performance of nanofractional radiofrequency for improvement of skin texture via skin resurfacing
Summary
Background
The latest generation of radiofrequency, nanofractional radiofrequency, allows the heat energy to be delivered through the use of pins or needles as electrodes, facilitating increased efficacy and reduced pain, downtime, and side effects.
Objective
The objective of this prospective pilot clinical study was to evaluate the efficacy of nanofractional radiofrequency in skin resurfacing.
Methods and materials
Seventeen subjects were enrolled in the study, and each received three nanofractional radiofrequency (160-pin tip) treatments in the facial area at 3-week intervals. Follow-up visits were scheduled at 1 and 2 months after the final treatment. Clinical photography, patient, and investigator assessments were conducted during the treatment visits and follow-up.
Results
All subjects completed the study. At the 1- and 2-month follow-up, there was a moderate to significant improvement (2.6 and 3.5, respectively, P = .01) according to the investigator global esthetic improvement scale rating. Most subjects reported that they were satisfied or very satisfied with the outcome and level of comfort.
Conclusion
Nanofractional radiofrequency is a safe and effective strategy for improving texture, tone, and skin laxity with high patient satisfaction and tolerable safety profile.
Posicionamiento de la Academia Española de Dermatología y Venereología sobre la teledermatología
Publication date: Available online 31 October 2017
Source:Actas Dermo-Sifiliográficas
Author(s): D. Moreno-Ramírez, G. Romero-Aguilera, P. Pasquali, S. Vaño, L. Ríos-Buceta, J. Malvehy, L. Ferrándiz
Hemangioma microvenular: estudio morfológico de 3 casos
Publication date: Available online 31 October 2017
Source:Actas Dermo-Sifiliográficas
Author(s): A. Giacaman, L.J. del Pozo, A. Bauzá, C. Saus
Leishmaniasis mucocutánea en pacientes inmunocomprometidos: reporte de 4 casos autóctonos
Publication date: Available online 31 October 2017
Source:Actas Dermo-Sifiliográficas
Author(s): S. Habibi Naderizadeh, C. Valcárcel Sierra, L. Medrano Gallego, B.J. Flores Robles, L.G. Roustán-Gullón
Cyclin D1 promoter -56 and -54bp CpG un-methylation predicts invasive progression in arsenic-induced Bowen’s disease
Globally, hundreds of millions of people are under the challenge of environmental arsenic exposure (WHO 2008). Epidemiological studies have demonstrated that long-term exposure to arsenic is associated with an increased risk of malignant tumors in many organs, such as the skin, lung, and urinary bladder [1]. Arsenic-induced Bowen's disease (As-BD), an intraepidermal carcinoma, is the most prevalent arsenic-induced skin cancer [2–4]. As-BD lesions are able to progress to invasive squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in the skin [4–6].
US Food and Drug Administration Approval of Soft-Tissue Fillers
This systematic review examines the quality of evidence leading to US Food and Drug Administration approval of soft-tissue fillers.
The Impact and Influence of JAMA Facial Plastic Surgery
Meaningful and influential articles written by leading thought leaders in the field are the lifeblood of a journal. I am pleased to announce that the Impact Factor (IF) of JAMA Facial Plastic Surgery has reached a new high of 2.70 (up 58% from last year's IF of 1.74). This places our journal near the top of all journals in our comparative group of journals that publish similar content. Although this metric is imperfect, it is often recognized by the scientific and publishing community as one important measure of comparing journals in its scientific impact and influence. Recall that IF is calculated by counting all of the citations to every article published in a journal divided by the number of full-length articles (Original Investigations, Special Communications, Reviews) published in that journal during the 2 preceding years.
Safety and Efficacy of Bilateral Submental Cryolipolysis
This nonrandomized interventional cohort study investigates the safety and efficacy of cryolipolysis for reduction of lateral and central submental fat.
Capsular Contracture in Silicone Implant Rhinoplasty
This case series study examines the immunohistochemical features of capsular contracture in patients who have undergone silicone implant rhinoplasty.
Perceived Benefits of Facial Rejuvenation Beyond Restoring Youth
This survey study examines whether face-lift and upper facial rejuvenation surgery improve observer ratings of age, attractiveness, success, and health.
Emerging Goals in Aesthetic Medicine
I applaud Bater et al on their significant contribution in this issue of JAMA Facial Plastic Surgery to the growing body of literature further shaping and defining what the ultimate goal in aesthetic medicine is and should be. During the past decade, we have witnessed an evolution in aesthetic medicine, progressing from medieval standards of success defined by Eurocentrically oriented and canonized somatic ideals to a modern-day aspiration of enhanced social and psychological well-being. Let me be frank: those seeking cosmetic treatments are, at their core, desiring more than a straightened dorsum, a reduced cervical angle, or a projected mentum. They also—and perhaps more importantly—desire the self-satisfying and externally perceived benefits that result from the perception of idealized forms. It is the impression of beauty, whether elicited from the self, another, or both, from which our patients appreciate the aesthetic interventions we offer to them.
Association of Mental Health Status With Perception of Nasal Function
This cross-sectional study assesses the association of poor mental health with perception of nasal function.
A New Nasal Septum Splint
This Surgical Pearl describes a new type of splint designed to sit extremely caudally along the septum, to be left in place for 2 to 3 weeks postoperatively, and to replace other methods of posterior septal angle fixation to the nasal spine.
Neurovascular Characteristics of Facial Skin After Rhytidectomy
This study describes the change in epidermal nerve fibers, neurotransmitters, vasculature, and mast cells in facial skin following primary and revision face-lifts.
Duration of Facial Paralysis in Studies of Emotion and Well-Being—Reply
In Reply We appreciate Chaiet and Carpenter's thoughtful contribution regarding our recently published article "Association Among Facial Paralysis, Depression, and Quality of Life in Facial Plastic Surgery Patients."
Anatomy and Surgical Approaches to the Rabbit Nasal Septum
This ex vivo study examines the anatomy and approaches to rabbit septal surgery.
A Cautious but Optimistic Opinion of Submental Cryolipolysis
The increasing consumer demand for minimally invasive or noninvasive procedures has driven a burgeoning industry of technological advances that cater to this desire. Neck adiposity is an emerging area of interest, driven in large part by the US Food and Drug Administration's clearance of injectable deoxycholic acid in April 2015, along with a juggernaut of related marketing endeavors. As surgeons, we must always be wary of noninvasive methods that might make bold claims, using surgical methods of cervical fat reduction as the criterion standard by which to judge any new entrants into the competitive field. However, we must also embrace methods that may undoubtedly serve as adjuncts, alternatives, or replacements for surgical techniques when they are truly viable. With that spirit, I commend the article in this issue of JAMA Facial Plastic Surgery on submental cryolipolysis by Bernstein and Bloom, who have sought to quantifiably evaluate both the aesthetic improvement and the patients' subjective perception of their results and the nature of their experience. The article serves to expand the current limited body of literature exploring this new application of cryolipolysis.
Two-Dimensional Threshold for Perception of Artificial-Appearing Lips
This survey study characterizes the quantitative measurements for the perceptual threshold of artificial- and unnatural-appearing lips.
Don’t Miss the Fourth Dimension of the Nasal Airway
Nasal obstruction as a symptom is supposedly simple to grasp, with the nasal airway being easy to inspect and objective measures for both its resistance and diameter at hand. Because the nasal cavity is also amenable to enlargement through straightforward surgical procedures, a permanently blocked nose ought to be easy to fix. Yet, how often are physicians intrigued by patient dissatisfaction after surgery with what must be considered a success after nasal endoscopy? Little is known about the incidence of postoperative dissatisfaction after septoplasty, with no failures to be seen or measured. One reason for an incongruent appraisal of the outcome of surgery may be that reducing the cause of nasal obstruction or the sensation of nasal fullness to a septal deviation or mucosal edema and to swelling may be simplistic in light of the advances in our understanding of nasal pathologic conditions and mucosal neural regulation. Few studies have shown highly correlated associations of the sensation of nasal fullness with any of the objective parameters measured in routine clinical practice. The cause may be that the sensation of fullness is the computational end product of a complex neurologic integrative process. This process encompasses interoceptive sensation on the basis of the currently assessed severity relative to other competing sensory and emotional stimuli. Recollections of the difficulties experienced in breathing through the nose in the recent and more distant past also play a role. The sensation of fullness or blockage attributed to the nasal mucosa is a highly integrated interpretation of afferent information from multiple subsets of nociceptive and other neurons, with the perception of cooling during inspiration likely playing a central role.
Association of Diet With Skin Histological Features in UV-B–Exposed Mice
This animal model study examines the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation.
Nonsurgical Rhinoplasty
This Surgical Pearl demonstrates how fillers can be used to add volume to the soft tissues of the nose.
Association of Velopharyngeal Insufficiency With Quality of Life
This study uses the Velopharyngeal Insufficiency Effects on Life Outcomes instrument to assess the association of improved speech with quality of life in patients who underwent secondary speech surgery.
Negative and Positive Online Patient Reviews of Physicians
This study explores reasons for both excellent and poor patient reviews on websites rating physicians.
Patterns of Change in Facial Skeletal Aging
This case series study of 14 adults documents patterns of change in the facial skeleton and develops a methodology for measuring these changes.
Polyglutamine tracts as autophagy regulators
By Yoskaly Lazo-Fernandez, PhD
Polyglutamine tracts (polyQ tracts) are long chains of glutamine amino acidspresent in the sequence of many proteins. The length of polyQ tracts within proteins varies significantly as normal alleles of specific genes usually contain different number of the cytosine-adenine-guanine (CAG) nucleotide repeats1.
It has long been known that polyQ tracts play a role in the etiology of several inheritable neurodegenerative disorders, including spinocerebellar ataxia, and Huntington's disease2. These 'polyglutamine diseases' result from the excessive elongation of a polyQ tract in a particular gene which causes the resultant protein to become toxic. The toxicity of mutated polyQ tracts has been extensively studied and several explanatory hypotheses have been proposed: aggregation of polyQ tract proteins, transcriptional dysregulation, mitochondrial dysfunction, and impairment of both the ubiquitin-proteasome and autophagy-lysosome protein degradation systems.
Western blot analysis of Htt in four different lymphoblast HD cell lines extracts each expressing ~65 (mutant) and ~20 (normal) CAG repeats. Lanes 1-4 (A), HTT mAb clone 1A771 recognizes only the expanded or long form of Htt. (B), A different Htt antibody recognizing both normal and mutant Htt.
Interestingly, the physiological function of polyQ tracts in normal proteins remained unclear until very recently. This breakthrough has been published in a Nature paper3 that depicted very detailed and exhaustive studies performed by David Rubinsztein's group at the University of Cambridge in the UK. This group uncovered an interesting regulatory function of normal polyQ tract-containing protein ataxin 3 on autophagy.
In their experiments, Ashkenazi et al.3 explored whether the knockdown or overexpression of genes involved in polyQ diseases like ataxin 3 (related to spinocerebellar ataxia) and huntingtin (Huntington's disease) affected autophagosome formation, an essential step for proper autophagy function4. The knockdown of wild type ataxin 3 impaired autophagosome formation in different biological models including cultured mouse neurons and liver cells, as well as in immortalized human cultured cells. Conversely, the overexpression of ataxin 3 in the same models stimulated autophagosome formation. Most importantly, the authors identified the key component of autophagosome biogenesis that is affected by the modulation of ataxin 3 expression, beclin 1, which is a particularly important protein for the induction of autophagy after nutrient depletion4,5. Ataxin 3 was shown to be essential for the protection of beclin 1 from polyubiquitination and degradation, which made much sense since ataxin 3 is a deubiquitinating enzyme involved in the regulation of protein homeostasis. In fact, the polyQ tracts in ataxin 3 are necessary for its binding to and deubiquitination of beclin 1. Interestingly, longer polyQ tracts diminished the deubiquitinating activity of ataxin 3 and created a much stronger binding affinity of the mutated ataxin 3 to beclin 1. Longer polyQ tracts in huntingtin and other polyQ proteins also bonded strongly to beclin 1, leading to a competitive blockade of the functional interaction between wild type ataxin 3 and beclin 1, and thus resulting in excessive beclin 1 degradation and autophagy impairment.
Overall, this new study provides insight into the physiological function of normal polyQ tracts as binding domains to beclin 1, and therefore as regulators of autophagy. Also, this insight reveals a new integrative model by which mutated polyQ tract-containing proteins may cause disease. According to this new model, mutated polyQ tracts create a stronger than normal binding to beclin 1, which then blocks ataxin 3's binding and deubiquitination of beclin 1, causing beclin 1's excessive degradation. This sequence of events results in impaired basal levels of autophagy in polyQ disease patients which could explain the progressive toxic protein accumulation and aggregation observed in their neurons. Moreover, since impaired autophagy has been implicated in many chronic diseases like cancer and diabetes, perhaps the use of modulators targeting this new mechanism of autophagy regulation may provide alternative pharmacological treatments.
Learn more about autophagy regulation
References
- Rinaldi & Fischbeck. Pathological Mechanisms of Polyglutamine Diseases. Nature Education 8, (2015).
- Fan et al. Polyglutamine (PolyQ) Diseases: Genetics to Treatments. Cell Transplantation 23, 441–458(18)
- Ashkenazi et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108–111 (2017).
- Cohen-Kaplan, Livneh, Avni, Cohen-Rosenzweig & Ciechanover. The ubiquitin-proteasome system and autophagy: Coordinated and independent activities. The International Journal of Biochemistry & Cell Biology 79, 403–418 (2016).
- Kang, Zeh, Lotze & Tang. The Beclin 1 network regulates autophagy and apoptosis. Cell Death & Differentiation 18, 571–580 (2011).
Category:
Comparative Transcriptomics of Seasonal Phenotypic Flexibility in Two North American Songbirds
Abstract
Phenotypic flexibility allows organisms to reversibly alter their phenotypes to match the changing demands of seasonal environments. Because phenotypic flexibility is mediated, at least in part, by changes in gene regulation, comparative transcriptomic studies can provide insights into the mechanistic underpinnings of seasonal phenotypic flexibility, and the extent to which regulatory responses to changing seasons are conserved across species. To begin to address these questions, we sampled individuals of two resident North American songbird species, American goldfinch (Spinus tristis) and black-capped chickadee (Poecile atricapillus) in summer and winter to measure seasonal variation in pectoralis transcriptomic profiles and to identify conserved and species-specific elements of these seasonal profiles. We found that very few genes exhibited divergent responses to changes in season between species, and instead, a core set of over 1200 genes responded to season concordantly in both species. Moreover, several key metabolic pathways, regulatory networks, and gene functional classes were commonly recruited to induce seasonal phenotypic shifts in these species. The seasonal transcriptomic responses mirror winter increases in pectoralis mass and cellular metabolic intensity documented in previous studies of both species, suggesting that these seasonal phenotypic responses are due in part to changes in gene expression. Despite growing evidence of muscle nonshivering thermogenesis (NST) in young precocial birds, we did not find strong evidence of upregulation of genes putatively involved in NST during winter in either species, suggesting that seasonal modification of muscular NST is not a prominent contributor to winter increases in thermogenic capacity for adult passerine birds. Together, these results provide the first comprehensive overview of potential common regulatory mechanisms underlying seasonally flexible phenotypes in wild, free-ranging birds.Commentary on: Adipose-Derived Stem Cells in Aesthetic Surgery: A Mixed Methods Evaluation of the Current Clinical Trial, Intellectual Property, and Regulatory Landscape
Adipose-derived stem cells (ADSC) continue to incite controversy in the medical profession, are highly sought after by the public, incite excitement in commercial companies, and are seen as a lucrative income generator in clinics. This interesting analysis of ADSC registered trials as well as registered intellectual properties further illustrates these points.1
Sclerotherapy for Reticular Veins in the Lower Limbs
This randomized clinical trial compares sclerotherapy of reticular veins of the lower limb with 2% polidocanol diluted in 70% hypertonic glucose vs hypertonic glucose alone.
Prior Authorizations for Diagnostic Skin Biopsies
This Viewpoint outlines how managed care policies on prior authorization for diagnostic skin biopsies are affecting costs, access to care, and quality of care for patients.
Use of a Physician Extender and Dermatology Appointment Wait Times
This cross-sectional analysis of responses to a telephone algorithm finds that dermatology appointment wait times have doubled over the past decade and appointment wait time may have an influence on dermatology office management.
Descriptive Error in the Text
In the Original Investigation titled "Prevalence of Pubic Hair Grooming–Related Injuries and Identification of High-Risk Individuals in the United States," published online August 16, 2017, there was a descriptive error in the text. The term vagina was used rather than the more accurate labia majora in 4 instances. This article has been corrected online.
Nonhealing Leg Ulcer in a Middle-aged Indian Man
A middle-aged Indian man with multiple, ill-defined, hypopigmented, asymptomatic lesions on his face and scalp presents with a painful foot ulcer having well-defined margins and a yellowish slough that remained unhealed after 1 year. Treatment with rifampicin, dapsone, and clofazimine after an earlier diagnosis of multibacillary leprosy failed. What is your diagnosis?
Factors Associated With Chronic Urticaria in Children
This cohort study examined the resolution rate of chronic urticaria in children and whether there are biomarkers that can predict resolution.
Chronic Urticaria in Children
Six years ago, we reviewed what was then known about chronic urticaria (CU) in children. We came to the conclusion that many important and interesting questions were unanswered. These included, but were not limited to, how common chronic spontaneous urticaria (CSU) and inducible urticaria are in children, the clinical presentation, underlying causes, impact on everyday life of CU in children, and the natural course of pediatric CU. We also suggested strategies to address and answer these questions and encouraged further studies to do so.
Thyroid Function in Children With Alopecia Areata
This study characterizes thyroid function in children with alopecia areata to establish guidelines for thyroid dysfunction screening.
The Epidemic of Guns
The shooting in Las Vegas, Nevada, that left 59 people dead, 10 times that number wounded, and thousands of people with the psychological distress from being present at the scene during and after the massacre has once again raised the issue of what we as a nation can and should do about guns. The solution lies in not just focusing on Las Vegas and the hundreds of other mass shootings that have occurred in the United States in the last 14 months, but rather to underscore that on average almost 100 people die each day in the United States from gun violence. The 36 252 deaths from firearms in the United States in 2015 exceeded the number of deaths from motor vehicle traffic crashes that year (36 161). That same year, the US Centers for Disease Control and Prevention reported that 5 people died from terrorism. Since 1968, more individuals in the United States have died from gun violence than in battle during all the wars the country has fought since its inception.
Anesthesia Duration and Head and Neck Microvascular Reconstruction Complications
This study examines the association of anesthesia duration with complications after microvascular reconstruction of the head and neck.
Combining Rhinoplasty With Upper Lip–Lift Using a Single Incision Line
This Surgical Pearl describes a procedure that combines the columellar incision with the incision for the upper lip–lift, resulting in harmonious nasolabial proportions and a smaller surgical scar.
Outcomes of Buccinator Treatment With Botulinum Toxin in Facial Synkinesis
This cohort study evaluates outcomes for patients treated with botulinum toxin applied to the buccinator muscle in the setting of facial synkinesis.
Botulinum Neuromodulators in Facial Synkinesis Management
This randomized clinical trial evaluates the effectiveness of 3 commercially available botulinum toxin neuromodulators in the treatment of facial synkinesis.
THE NON-NEURONAL AND NON-MUSCULAR EFFECTS OF BOTULINUM TOXIN: A Graceful Opportunity for a Deadly Molecule to Treat a Human Disease in the Skin and Beyond
Abstract
There is growing evidence that botulinum neurotoxins (BoNTs) exhibit biological effects on various human cell types with a host of associated clinical implications. The BoNT receptors and intracellular targets are not unique for neurotransmission. They have been found in both neuronal and non-neuronal cells, but there are differences in the way BoNT binds to, and acts on neuronal vs. non-neuronal cells. The non-neuronal cells expressing one or more BoNT/A-binding proteins and/or cleavage target SNAP-25 include epidermal keratinocytes, mesenchymal stem cells from subcutaneous adipose, nasal mucosal cells, urothelial cells, intestinal epithelial cells, neutrophils, macrophages, and prostate, breast and alveolar epithelial cells, BoNT/A can also elicit specific biological effects in dermal fibroblasts, sebocytes and vascular endothelial cells. The reported non-traditional applications of BoNT in dermatologic conditions include hyperhidrosis, Hailey-Hailey disease, Darier disease, inversed psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenita, multiple eccrine hydrocystomas, eccrine angiomatous hamartoma, eccrine sweat gland nevi, congenital eccrine nevus, Raynaud phenomenon and cutaneous leiomyomas. Experimental studies demonstrated BoNT/A ability to protect skin flaps, facilitate wound healing, decrease thicknesses of hypertrophic scars, produce an anti-aging effect, and improve a mouse model of psoriasiform dermatitis. Furthermore, experimental studies also have revealed extracutaneous effects of BoNT arising from its anti-inflammatory and anti-cancer properties. Therefore, it is clear that BoNTs have a much wider zone of influence than originally understood, and that these ubiquitous events are based on individual cellular responses to the cholinergic impacts of BoNTs, which represents fertile grounds for future studies that are highly likely to result in impactful discoveries.
This article is protected by copyright. All rights reserved.
Incentivized goodness
Abstract
It will be argued that humans have a rational self-interest in voluntarily opting to subject themselves to moral bioenhancement. This interest is based on the fact that goodness appears to be conducive to happiness. Those who understand that will be more inclined to opt for safe and effective moral bioenhancement technologies that have the potential to augment our motivation to become better. The more people decide to follow this path, the likelier it is that states will adopt suitable policies that incentivize moral bioenhancement. Hence, goodness, happiness and state incentivized moral bioenhancement can operate in a circularly supportive fashion.
Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma Presenting with Vaginal Sloughing and Ulcerated Skin Nodule
Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma (NHL) with subtypes that can be distinguished on the basis of clinical, immunophenotypic, morphologic, and molecular characteristics. The genital tract as a primary site for NHL is very rare (1).
High calcium enhances the expression of double-stranded RNA sensors and antiviral activity in epidermal keratinocytes
Abstract
Double-stranded RNA (dsRNA) sensors including TLR3, MDA5, and RIG-I are expressed in epidermal keratinocytes, and play an important immunological role by enhancing various innate and adaptive immune responses. Although the role of elevated extracellular calcium concentration in keratinocyte differentiation is well understood, the effect of high calcium on dsRNA sensors is not well studied.
We investigated alterations in dsRNA sensor expression and antiviral activity induced by a high extracellular concentration of calcium in epidermal keratinocytes. Normal human epidermal keratinocytes (NHEKs) were stimulated with high calcium and/or synthetic dsRNA, poly (I:C). TLR3, IFIH1 (MDA5), and DDX58 (RIG-I) expression were measured via qPCR, and IFN-β and human beta defensin 2 (HBD2) levels were measured using ELISA. TLR3 localization was evaluated with immunocytofluorescence. Antiviral activity was quantified with virus plaque assays using herpes simplex virus type-1 (HSV-1). High calcium significantly upregulated mRNA expression of TLR3, IFIH1, and DDX58 in NHEKs. In addition, high calcium significantly enhanced poly (I:C)-induced anti-HSV-1 activity in NHEKs. The anti-viral molecule, HBD2 but not IFN-β induction by poly (I:C) was enhanced by high calcium.
Our findings indicate that high levels of extracellular calcium enhance the expression of dsRNA sensors and augment antiviral activity in epidermal keratinocytes.
This article is protected by copyright. All rights reserved.
Development of an asporogenic Bacillus cereus strain to improve keratinase production in exponential phase by switching sigmaH on and sigmaF off
Abstract
Many bacteria, including the genus Bacillus are able to produce proteases (keratinase). In Bacillus, proteases are produced in the stationary phase and initial stages of sporulation. Protease production is coordinated with sporulation in which expression of various genes by different sigma factors manages the transition from exponential to the stationary phase. In the present study the sigma-F gene of an indigenous Bacillus cereus strain, which is involved in transcription of maintaining sporulation genes was deleted. Meanwhil the sigma-H, which its product activates the genes that function in the zero phase of sporulation and inhibits suppression of protease production, and spo0B genes were expressed in the exponential phase under the control of a sucrose inducible promoter from Bacillus sacPA operon. For the first time, an asporogenic strain of B. cereus was generated that produced higher keratinase (390 U in compare to the 198 U of wild strain) and protease (450 U in compare to the 290 U of wild strain) activities in the exponential growth phase by induction with sucrose. The new strain is promising for production of keratinase for degradation of feather waste to produce feather meal for poultry feed and decrease environmental pollution of poultry industry.Hormonal contraceptives and risk of ischemic stroke in women with migraine: a consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC)
Several data indicate that migraine, especially migraine with aura, is associated with an increased risk of ischemic stroke and other vascular events. Of concern is whether the risk of ischemic stroke in migra...
Immunohistochemical markers informing the diagnosis of sebaceous carcinoma and its distinction from its mimics: Adipophilin and Factor XIIIa to the rescue?
In this issue of the Journal of Cutaneous Pathology, Tjarks et al. present a study that advances our understanding of the diagnosis of sebaceous neoplasms (in particular, sebaceous carcinoma) and the lesions that mimic them (1).
Calciphylaxis with Pseudoxanthoma Elasticum-like Changes: A Case Series
BACKGROUND
Calciphylaxis and pseudoxanthoma elasticum (PXE) are rare, clinically distinct, disorders that share a common feature of cutaneous calcification that vary widely in their cutaneous presentation.
METHODS
We conducted a descriptive, retrospective review of biopsy specimens collected over a two-year period. Only specimens with a histologic and clinical diagnosis of calciphylaxis were included in the review. Specimens were then histologically examined for features of pseudoxanthoma elasticum in the dermis and/or subcutaneous fat, utilizing hematoxylin and eosin staining. Von Kossa and Verhoeff-Van Gieson special stains were also performed to examine calcification and elastic fibers, respectively.
RESULTS
We reviewed 13 biopsy specimens from 9 patients with known clinical and histologic evidence of calciphylaxis, both uremic and non-uremic types. Upon reexamination, we found that 46.2% (n=6/13) of the specimens demonstrated concomitant PXE-like changes uniquely localized to the subcutaneous fat.
CONCLUSION
The presence of PXE-like changes in the subcutis may heighten suspicion for a diagnosis of calciphylaxis in the appropriate clinical setting and be helpful when classic histologic features are subtle or absent.
Folliculotropic mycosis fungoides presenting with a solitary lesion: clinicopathological features and long-term follow-up data in a series of nine cases
Folliculotropic mycosis fungoides (FMF) is a rare but distinct variant of mycosis fungoides (MF), histologically characterized by the presence of folliculotropic infiltrates, often with sparing of the epidermis, and clinically by the preferential involvement of the head and neck region.1
Me and I Are Not Friends, Just Aquaintances: on Thought Insertion and Self-Awareness
Abstract
A group of philosophers suggests that a sense of mineness intrinsically contained in the phenomenal structure of all conscious experiences is a necessary condition for a subject to become aware of himself as the subject of his experiences i.e. self-awareness. On this view, consciousness necessarily entails phenomenal self-awareness. This paper argues that cases of delusions of thought insertion undermine this claim and that such a phenomenal feature plays little role in accounting for the most minimal type of self-awareness entailed by phenomenal consciousness. First, I clarify the main view endorsing this claim i.e. the Self-Presentational View of Consciousness and formulate the challenge from thought insertion. After, I offer a systematic evaluation of all the strategies used by the advocates of this view to deal with this challenge. Finally, I conclude that most of these strategies are unsatisfactory for they rest in unwarranted premises, imprecisions about the agentive nature of cognitive experiences, and especially, lack of distinction between the different ways in which subjects can become aware of their own thoughts.
Testicular torsion and reperfusion: evidences for biochemical and molecular alterations
Abstract
This study was done in order to determine the molecular and biochemical alterations following testicular torsion (TT) and torsion-reperfusion (TR). For this purpose, 54 male Wistar rats were divided into five groups as control group (n = 6) and experimental group subjected to 1, 2, 4, and 8 h unilateral left torsion induction (n = 12 in each group). After induction of TT, testicular samples were collected from each group (n = 6), and the other six rats of each group underwent the same period of reperfusion after TT and then were sampled. Histological changes, the mRNA and protein expression of heat shock protein-70 (Hsp70), and caspase-3 were examined using reverse transcriptase-PCR (RT-PCR) and immunohistochemistry, respectively. Testicular total antioxidant capacity (TAC), glutathione peroxidase (GSH-px), and malondialdehyde (MDA) levels were evaluated. The mRNA damage and DNA fragmentation were assessed. The TT and TR significantly reduced differentiation and spermiogenesis indices (p < 0.05). The TT- and TR-induced groups exhibited a severe reduction in Hsp70 expression as well as remarkable enhancement in caspase-3 expression. The TAC and GSH-px levels were decreased and the MDA content was increased in TT- and TR-induced groups. Finally, the TT and TR enhanced mRNA damage and DNA fragmentation. The TT- and TR-induced damaging oxidative stress, diminished Hsp70 expression, and enhanced caspase-3 mRNA and protein levels result in apoptosis following 1, 2, and 4 h. Whereas, following 8 h, TT and TR initiate the necrosis by inducing energy depletion as well as severe mRNA damage.
Taking Multiple Exposure Into Account Can Improve Assessment of Chemical Risks
Abstract
During work, operators may be exposed to several chemicals simultaneously. Most exposure assessment approaches only determine exposure levels for each substance individually. However, such individual-substance approaches may not correctly estimate the toxicity of 'cocktails' of chemicals, as the toxicity of a cocktail may differ from the toxicity of substances on their own. This study presents an approach that can better take into account multiple exposure when assessing chemical risks. Almost 30000 work situations, monitored between 2005 and 2014 and recorded in two French databases, were analysed using MiXie software. The algorithms employed in MiXie can identify toxicological classes associated with several substances, based on the additivity of the selected effects of each substance. The results of our retrospective analysis show that MiXie was able to identify almost 20% more potentially hazardous situations than identified using a single-substance approach. It therefore appears essential to review the ways in which multiple exposure is taken into account during risk assessment.Seven years of clinical experience with the Yeast Traffic Light PNA FISH: assay performance and possible implications on antifungal therapy
Abstract
We evaluated the performance of Yeast Traffic Light PNA FISH (YTL PNA FISH) in identification of Candida spp. from blood cultures. A total of 200 new episodes of candidemia were analysed prospectively. The YTL PNA FISH results were reported to the clinicians and data on antifungal therapy was documented. In total, there were 164/200 (82%) positive blood culture bottles with monomicrobial growth. Coverage of monomicrobial yeasts was 150/164 (91.5%). YTL PNA FISH could identify 23/24 (95.8%) Candida spp. in bottles with concomitant growth of bacteria and one yeast. Growth of two or more different yeasts was observed in 12/200 (6%) blood culture bottles and the method could identify all yeasts in 8/12 (66.7%). Data on antifungal treatment was available for 181/200 patients (90.5%). In 132/137 (96.4%) samples from patients without antifungal treatment, YTL PNA FISH could identify the Candida spp. or gave a negative result for yeasts not included in panel, and based on the result guide appropriate antifungal therapy the same day when the blood culture bottle signaled positive. The present study shows that YTL PNA FISH is a rapid, reliable diagnostic method which significantly reduces time delay for choice of appropriate antifungal therapy for critically ill patients.
This article is protected by copyright. All rights reserved.
Undiagnosed Diabetes Mellitus in Community-Acquired Pneumonia: A Prospective Cohort Study
Abstract
Background
Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort. Methods
This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus. Results
Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35–4.45]), body mass index ≥25 kg/m2 (OR, 2.64 [95% CI, 1.48–4.72]), and hyperglycemia at admission (6–11 mM: OR, 2.93 [95% CI, 1.54–5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58–113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001). Conclusions
Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus.Δευτέρα 30 Οκτωβρίου 2017
Dermatological and environmental toxicological impact of the sunscreen ingredient oxybenzone/benzophenone-3
Summary
Oxybenzone (Benzophenone-3) is an emerging human and environmental contaminant used in sunscreens and personal care products to help minimize the damaging effects of ultraviolet radiation. The Center for Disease Control fourth national report on human exposure to environmental chemicals demonstrated that approximately 97% of the people tested have oxybenzone present in their urine, and independent scientists have reported various concentrations in waterways and fish worldwide. Oxybenzone can also react with chlorine, producing hazardous by-products that can concentrate in swimming pools and wastewater treatment plants. Moreover, adverse reactions could very well be increased by the closed loop of ingesting fish contaminated with oxybenzone and/or washing the ingredient off our bodies and having it return in drinking water as treatment plants do not effectively remove the chemical as part of their processing protocols. In humans, oxybenzone has been reported to produce contact and photocontact allergy reactions, implemented as a possible endocrine disruptor and has been linked to Hirschsprung's disease. Environmentally, oxybenzone has been shown to produce a variety of toxic reactions in coral and fish ranging from reef bleaching to mortality. Lastly, with the rise in skin cancer rates and the availability of more effective sunscreen actives such as micronized zinc oxide and titanium dioxide, serious doubts about the relative prevention benefit of personal care products containing oxybenzone must be raised and compared with the potential negative health and environmental effects caused by the accumulation of this and other chemicals in the ecosystem.
The pathogenesis of cutaneous squamous cell carcinoma in organ transplant recipients
Summary
The pathogenesis of keratinocyte carcinoma following organ transplantation is multifactorial, and recent evidence suggests a complex and often synergistic interplay between the carcinogenic effects of ultraviolet radiation, compromised immune surveillance, direct pro- and anticarcinogenic effects of drugs, oncogenic viruses (in particular, beta-genus human papillomaviruses) and host genetic susceptibility factors. We present an overview of those factors for which there is currently the most convincing evidence and highlight important gaps in our knowledge. In particular, a clear understanding of the interdependence and relative contributions of these co-factors is currently lacking, yet has important implications for rational development of clinically relevant biomarkers and targeted strategies for treatment and prevention of post-transplant keratinocyte cancers.
Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients
Summary
Although tremendous progress has been made in recent years in skin cancer care for organ transplant recipients, significant gaps remain in data-driven clinical guidelines, particularly for the treatment and prevention of cutaneous squamous cell carcinoma (cSCC), the most common malignancy among this population. In this review, we aim to summarize current knowledge around the management of cSCC and highlight the most significant gaps in knowledge that continue to pose challenges in the delivery of skin cancer care for organ transplant recipients. We suggest future directions for research that will bridge existing gaps and establish evidence-driven guidelines for primary prevention, screening and treatment of cSCC in this high-risk patient population.
TRPA1 channel participates in tacrolimus-induced pruritus in a chronic contact hypersensitivity murine model
Tacrolimus ointment (FK506), a calcineurin inhibitor, is a widely used topical medication in atopic dermatitis (AD) [1]. Although it is effective, pruritus and stinging sensation are common, particularly in AD patients [1]. Mediators of mast cells such as histamine have been suggested to be involved in the pathogenesis of tacrolimus-related pruritus by binding to the corresponding receptors on sensory nerve fibers [2]. Histamine acts on histamine receptors (HR) and activates the downstream transduction channel transient receptor potential V1 (TRPV1), which induces histamine-dependent pruritus [3].
Objective assessment of colonoscope manipulation skills in colonoscopy training
Abstract
Objective
Manipulation of the colonoscope is a technical challenge for novice clinicians which is best learned in a simulated environment. It involves the coordination of scope tip steering with scope insertion, using a rotated image as reference. The purpose of this work is to develop and validate a system which objectively assesses colonoscopy technical skills proficiency in an arbitrary training environment, allowing novices to assess their technical proficiency prior to real patient encounters.
Methods
We implemented a motion tracking setup to objectively analyze and assess the way operators perform colonoscopies, including an analysis of wrist and elbow joint motions. Subsequently, we conducted a validation study to verify whether our motion analysis could discriminate novice colonoscopists from experts. Participants navigated a wooden bench-top model using a standard colonoscope while their motions were tracked.
Results
The developed motion tracking setup allowed colonoscopists of varying levels of proficiency to have their colonoscope manipulation assessed, and was able to be operated by a trained non-technical operator. Novice operators had significantly greater median times (101.5 vs. 31.5 s) and number of hand movements (62.0 vs. 21.5) than experts. Experts, however, spent a significantly greater proportion of time in extreme ranges of wrist and elbow joint motion than novices.
Conclusion
We have developed and implemented a hand and joint motion analysis system that is able to discriminate novices from experts based on objective measures of motion. These metrics could, thus, serve as proxies for technical proficiency during training.
Releasing the “GENI”: integrating authentic microbial genomics research into the classroom through GENI-ACT
Abstract
The integration of genomics research into the undergraduate biology curriculum provides students with the opportunity to become familiar with bioinformatics tools and answer original research questions. Our purpose with this research project was to upscale the research experience through integration with classroom experience giving students access to authentic research projects. Students annotated 60 predicted ABC genes of Methanothermobacter thermautotrophicus and Methanobacterium sp. SWAN-1, and they were required to present a research poster to demonstrate their understanding of the project. During this research project a number of tests, assessments and surveys were conducted to assess familiarity with technical and conceptual understanding of genome annotation, satisfaction with annotation instruction, gain in bioinformatics research skills, scientific communications skills and increased student interest in research. We found that students gained significant skills in bioinformatics, specifically genome annotation skills and also gained confidence in their abilities to carry out scientific research. As a result of this authentic undergraduate research experience under-represented students were motivated to pursue future careers in STEM fields.Plasmids can transfer to Clostridium difficile CD37 and 630Δ erm both by a DNase resistant conjugation-like mechanism and a DNase sensitive mechanism
Abstract
Broad host range conjugative plasmids that replicate in Escherichia coli have been widely used to mobilise smaller replicons, bearing their cognate origin of transfer (oriT) into a variety of organisms that are less tractable genetically, such as Clostridium (Clostridioides) difficile. In this work we demonstrated that the oriT region of pMTL9301 (derived from RK2) is not required for transfer between E. coli and C. difficile strains 630Δerm and CD37 and that this oriT-independent transfer is abolished in the presence of DNase when CD37 is the recipient. Transfer to the 630Δerm strain is DNase resistant even without an obvious oriT, when E. coli CA434 is used as a donor and is sensitive to DNase when E. coli HB101 is the donor.Keeping education fresh—not just in microbiology
Abstract
Innovative practice from around the globe, addressing a range of recent educational themes and trends, was published in the FEMS Microbiology Letters virtual Thematic Issue 'Keeping Education Fresh' in October 2017. Its thought-provoking content is reviewed here to more directly facilitate reflections and discussions in the professional community. The focus is on best practice approaches when enhancing student engagement, how to adjust those to the diversity of learners, learning situations and infrastructures, and to a broad range of subjects. The need for authentic learning and to move away from didactic teaching is emphasized. The 'students as researchers' theme is featured e.g. in context of service learning. Creative approaches are presented such as using performing arts, popular culture and gamification. The development of interdisciplinary and intercultural competences, and the exploration of socioscientific themes and philosophical issues are considered. Revisions of curricula and programmes, reflective of educational advancements and sector drivers, are discussed from undergraduate to postgraduate and professional specialist level also in light of problem-based learning, interactive distance and on-campus learning, and even the legacy of Massive Open Online Courses. Such changes always require resources and skills, and carry risks. Yet, innovation is a risk worth taking to keep education fresh.
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Abstract Objectives To investigate factors related to reasoning skills in 434 school children aged 5–9 years. Methods The Leiter Interna...
