A solitary pink lesion: dermoscopy and RCM features of lichen planus

We present an unusual onset of cutaneous lichen planus (LP) in a middle-aged patient. The initial presentation as solitary, indolent pink lesion required further investigations to rule out malignancy, especially amelanotic melanoma. Dermoscopy and reflectance confocal microscopy findings were found to be helpful in our case in addressing the correct diagnosis

Malattia di Kyrle: eccezionale risposta all’isotretinoina orale

Si presenta il caso di una paziente di 51 anni, affetta da sindrome metabolica, spondiloartrite sieronegativa ed insufficienza renale cronica, afferente al servizio di dermatologia per la presenza di lesioni papulo-nodulari ipercheratosiche follicolari diffuse agli arti ed estremamente pruriginose. Tali lesioni, presenti da alcuni anni, erano state dapprima trattate con terapie topiche (steroidi, antibiotici, retinoidi ed emollienti) con scarso beneficio. A scopo diagnostico veniva eseguita una biopsia cutanea per esame istologico con esito di malattia di Kyrle. Veniva iniziato un ciclo di fototerapia con nb-UVB, poi sospeso per inefficacia. Anche la terapia con metotrexato, impostata per insoddisfacente controllo della patologia reumatologica, non mostrava alcun beneficio sulle manifestazioni cutanee. Veniva dunque intrapresa una terapia con isotretinoina orale 0,5 mg/Kg/die la quale dopo circa 1 anno ha permesso di ottenere una eccezionale e pressoché completa remissione del quadro cutaneo, in assenza di rilevanti effetti collaterali

Una storia di lesioni bollose di lunga durata

Si presenta il caso di una paziente di 33 anni di origine marocchina che riferiva fin dall’età infantile la comparsa al minimo traumatismo di multiple piccole lesioni bollose prevalentemente agli arti inferiori con saltuario coinvolgimento del cavo orale. In anamnesi ipertensione arteriosa in terapia farmacologica, un fratello di 47 anni con manifestazioni analoghe ed una sorella di 28 anni affetta da vitiligine, entrambi residenti nel paese di origine. All’esame obiettivo si osservavano molteplici esiti ipo- ed iper-pigmentati ed alcune aree disepitelizzate frammiste a lesioni crostose prevalentemente agli arti inferiori. Erano presenti, inoltre, alcune piccole bolle flaccide a contenuto siero-ematico alla pianta dei piedi ed un marcato diradamento dei capelli. Non era documentabile un interessamento delle mucose. Le indagini biochimiche, istologiche, immunologiche ed ultrastrutturali hanno portato ad una inconsueta diagnosi

SAÚDE COLETIVA INFORMA – CARTA DE DIREITO DOS USUÁRIOS DO SUS

A Carta dos Direitos dos Usuários do SUS é fruto de um trabalho cuidadoso, que visa garantir o acesso universal e igualitário às ações e serviços para promoção, proteção e recuperação da saúde. Com tantas mudanças sociais, econômicas e políticas acontecendo nos últimos anos no País, os usuários desconhecem a totalidade de seus direitos para usufruírem corretamente dos benefícios garantidos a eles. O documento, que tem como base seis princípios básicos de cidadania, caracteriza-se como uma importante ferramenta para que o cidadão conheça seus direitos e deveres no momento de procurar atendimento de saúde, tanto público quanto privado. Foi realizada uma pesquisa quantitativa por meio de coleta de dados com questionários nas Cidades de Herval d’Oeste e Joaçaba, entrevistando pessoas nas ruas e também dentro dos postos de saúde das Cidades. Alguns desses entrevistados foram filmados, e, então, foi produzido um vídeo para melhor entendimento do assunto proposto, explanando cada questão colocada na pesquisa em forma de telejornal; em cada questão citava-se um dos direitos contidos na carta para se observar se o usuário conhecia ou não esse direito. Infelizmente, os resultados da pesquisa evidenciaram que a maioria dos entrevistados não conhece todos os direitos oferecidos a eles, porém o ideal seria que a população tivesse plena ciência dessa Carta. Para o Conselho Nacional de Saúde, é importante que todos se apossem do conteúdo da Carta, elaborada com uma linguagem acessível, para, assim, permitir o debate e a apropriação dos direitos e deveres nela contidos por parte dos gestores, trabalhadores e usuários do SUS.Palavras-chave: Saúde pública. Direitos humanos. Sistema Único de Saúde

Presentazione dermoscopica atipica di lesioni non melanocitarie benigne: quale aiuto dal confocale?

Sono sempre più frequenti i report di lesioni cutanee benigne che simulano clinicamente il melanoma; in questi casi spesso mancano i criteri clinico-dermoscopici tipici. Abbiamo analizzato retrospettivamente in microscopia laser confocale (RCM) lesioni che presentassero in dermoscopia punteggio ≥1 alla revisited 7-point checklist, focalizzandoci su quelle prive di criteri melanocitari. Ogni caso è stato indagato quindi per la presenza di caratteristiche RCM non melanocitarie. La selezione ha permesso di raccogliere 117 lesioni a presentazione dermoscopica atipica, classificate al confocale come benigne (71 cheratosi seborroiche e 18 dermatofibromi), maligne (13 basaliomi e 2 spinaliomi), e “non specifiche” (13). Il valore K relativo al matching complessivo con l’istologia è risultato elevato (0.76); per cheratosi seborroiche e dermatofibromi la concordanza è risultata del 97% e 89% rispettivamente. I risultati ottenuti su un gruppo di lesioni di difficile inquadramento clinico, confermano l’utilità del confocale nella diagnosi differenziale non invasiva tra patologie benigne e maligne

Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening

Loss of FGFR4 promotes the malignant phenotype of PDAC

Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4 is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4 expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1 has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4 in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4 limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

BACKGROUND: Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. METHODS: For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. FINDINGS: We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. INTERPRETATION: We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec