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1.
Artigo em Inglês | MEDLINE | ID: mdl-34619397

RESUMO

OBJECTIVES: During the COVID-19 pandemic, numerous cases of chilblains have been reported. However, in most cases, RT-PCR or serology did not confirm SARS-CoV-2 infection. Hypotheses have been raised about an interferon-mediated immunological response to SARS-CoV-2, leading to effective clearance of the SARS-CoV-2 without the involvement of humoral immunity. Our objective was to explore the association between chilblains and exposure to SARS-CoV-2. METHODS: In this multicentre case-control study, cases were the 102 individuals referred to five referral hospitals for chilblains occurring during the first lockdown (March to May 2020). Controls were recruited from healthy volunteers' files held by the same hospitals. All members of their households were included, resulting in 77 case households (262 individuals) and 74 control households (230 individuals). Household exposure to SARS-CoV-2 during the first lockdown was categorized as high, intermediate or low, using a pre-established algorithm based on individual data on symptoms, high-risk contacts, activities outside the home and RT-PCR testing. Participants were offered a SARS-CoV-2 serological test. RESULTS: After adjustment for age, the association between chilblains and viral exposure was estimated at OR 3.3, 95% CI (1.4-7.3) for an intermediate household exposure, and 6.9 (2.5-19.5) for a high household exposure to SARS-CoV-2. Out of 57 case households tested, six (11%) had positive serology for SARS-CoV-2, whereas all control households tested (n = 50) were seronegative (p = 0.03). The effect of potential misclassification on exposure has been assessed in a bias analysis. DISCUSSION: This case-control study demonstrates the association between chilblains occurring during the lockdown and household exposure to SARS-CoV-2.

2.
Physiol Plant ; 173(3): 1230-1243, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34342899

RESUMO

Understanding the molecular mechanisms that underlie cesium (Cs+ ) transport in plants is important to limit the entry of its radioisotopes from contaminated areas into the food chain. The potentially toxic element Cs+ , which is not involved in any biological process, is chemically closed to the macronutrient potassium (K+ ). Among the multiple K+ carriers, the high-affinity K+ transporters family HAK/KT/KUP is thought to be relevant in mediating opportunistic Cs+ transport. Of the 13 KUP identified in A. thaliana, only HAK5, the major contributor to root K+ acquisition under low K+ supply, has been functionally demonstrated to be involved in Cs+ uptake in planta. In the present study, we showed that accumulation of Cs+ increased by up to 30% in two A. thaliana mutant lines lacking KUP9 and grown under low K+ supply. Since further experiments revealed that Cs+ release from contaminated plants to the external medium is proportionally lower in the two kup9 mutant alleles, we proposed that KUP9 disruption could impair Cs+ efflux. By contrast, K+ status in kup9 mutants is not affected, suggesting that KUP9 disruption does not alter substantially K+ transport in experimental conditions used. The putative primary role of KUP9 in plants is further discussed.


Assuntos
Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Transporte Biológico , Césio/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Potássio/metabolismo
3.
Pediatr Dermatol ; 38(4): 864-867, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34152036

RESUMO

We report 20 newborns who developed, at a median age of 7 days, large abdominal patches of radially arranged purplish telangiectasia in a bilateral and symmetrical pattern in relation to the midline, creating a "butterfly wing" pattern. Clinical examination was normal in 13 newborns, six newborns had abdominal distention, and one newborn had poor weight gain due to inadequate breastfeeding. Most lesions spontaneously resolved within 3 months and did not reoccur for 19 newborns. Transient abdominal telangiectasia of the newborn (TATN) appears to be a distinctive entity that has not been previously described.


Assuntos
Abdome , Telangiectasia , Humanos , Recém-Nascido , Telangiectasia/diagnóstico
4.
Front Cell Dev Biol ; 9: 612581, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169069

RESUMO

Introduction: Pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder caused by pathogenic ABCC6 variants, is characterized by skin, ocular and cardiovascular (CV) symptoms. Due to striking phenotypic variability without genotype-phenotype correlations, modifier genes are thought to play a role in disease variability. In this study, we evaluated the collective modifying effect of rare variants on the cardiovascular phenotype of PXE. Materials and Methods: Mixed effects of rare variants were assessed by Whole Exome Sequencing in 11 PXE patients with an extreme CV phenotype (mild/severe). Statistical analysis (SKAT-O and C-alpha testing) was performed to identify new modifier genes for the CV PXE phenotype and enrichment analysis for genes significantly associated with the severe cohort was used to evaluate pathway and gene ontology features. Results Respectively 16 (SKAT-O) and 74 (C-alpha) genes were significantly associated to the severe cohort. Top significant genes could be stratified in 3 groups-calcium homeostasis, association with vascular disease and induction of apoptosis. Comparative analysis of both analyses led to prioritization of four genes (NLRP1, SELE, TRPV1, and CSF1R), all signaling through IL-1B. Conclusion This study explored for the first time the cumulative effect of rare variants on the severity of cardiovascular disease in PXE, leading to a panel of novel candidate modifier genes and disease pathways. Though further validation is essential, this panel may aid in risk stratification and genetic counseling of PXE patients and will help to gain new insights in the PXE pathophysiology.

5.
Am J Hum Genet ; 108(6): 1126-1137, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34010604

RESUMO

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.


Assuntos
Doenças Ósseas/etiologia , Doenças Cardiovasculares/etiologia , Doenças do Tecido Conjuntivo/etiologia , Imunidade Celular/imunologia , Mutação com Perda de Função , Perda de Heterozigosidade , beta Carioferinas/genética , Adolescente , Adulto , Animais , Doenças Ósseas/patologia , Doenças Cardiovasculares/patologia , Criança , Doenças do Tecido Conjuntivo/patologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem , Peixe-Zebra , beta Carioferinas/metabolismo
6.
Genet Med ; 23(9): 1604-1615, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34040193

RESUMO

PURPOSE: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature. METHODS: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival. RESULTS: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old. CONCLUSION: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.


Assuntos
Doença de Crohn , Úlcera da Perna , Deficiência de Prolidase , Criança , Pré-Escolar , Diagnóstico Tardio , Humanos , Fenótipo , Deficiência de Prolidase/diagnóstico , Deficiência de Prolidase/genética
7.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925341

RESUMO

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the "PXE gene" and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.


Assuntos
Calcificação Fisiológica/genética , Calcificação Fisiológica/fisiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , 5'-Nucleotidase/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Calcinose , Difosfatos/metabolismo , Proteínas Ligadas por GPI/genética , Humanos , Artropatias , Camundongos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Pseudoxantoma Elástico/genética , Pseudoxantoma Elástico/fisiopatologia , Pirofosfatases/genética , Pirofosfatases/metabolismo , Ratos , Calcificação Vascular , Doenças Vasculares
8.
J Clin Exp Neuropsychol ; 43(2): 163-175, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33685350

RESUMO

Introduction: Executive functions (EFs) impairment is common in children with neurofibromatosis type 1 (NF1), and could be a significant vulnerability associated with this medical disorder. However, we still know little about EFs in preschool NF1. Our study assessed EFs in NF1 children using performance-based tests and daily life questionnaires, which combined the views of parents and teachers.Method: Seven classic experimental tasks were used to evaluate EFs in 33 NF1 children aged 3 to 5 years old, and BRIEF-P questionnaires were completed by their parents and teachers. These children's performance was compared with a control group of 52 healthy children matched in age, gender and socio-cultural status.Results: NF1 children have significantly lower scores for 5 out of 7 executive tasks than control children and significantly higher levels of EF concerns in the parent and teacher BRIEF-P ratings. The correlations between performance-based tests and questionnaires are weak.Conclusions: Our results support an early executive dysfunction in NF1 children and call for early and systematic assessment of EFs. Both performance-based tests and questionnaires are complementary tools to investigate early EFs dysfunction in children with NF1.


Assuntos
Função Executiva , Neurofibromatose 1 , Criança , Pré-Escolar , Humanos , Neurofibromatose 1/complicações , Testes Neuropsicológicos , Pais , Inquéritos e Questionários
9.
Orphanet J Rare Dis ; 16(1): 71, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557904

RESUMO

Patients have been showing a growing interest in taking active participation in decision making, and having the opportunity to drive clinical investigation. This is more common for patients who have a rare disease than for those with more prevalent diseases. The EuroSoftCalc.Net COST Action, a group of clinicians and researchers involved in the dystrophic calcification process held a meeting in which three representatives of patients' associations, coming from Portugal, France and Spain, discussed the role of patients and their associations, namely in the Action, and also the main concerns in their countries. The disparities in health care between European Union countries with regard to connective tissue calcifying diseases, and the existing conflicts of interest, were a matter of debate during the meeting. As a consequence of the presentations and the debate that followed, it became clear that, despite their countries, the main concerns of the patients are identical, namely a lack of specific therapy and follow-up clinical guidelines, delays in the diagnosis, difficulties in getting members to enrol to associations, and/or difficulties with doctors' explanations for the diseases. The attendees also agreed that EuroSoftCalc.Net group should help to set up new associations where no Patient Associations presently exist, and, furthermore, should release diagnosis and follow-up guidelines, especially helpful in countries, and/or for diseases, where no multidisciplinary consultations are available.


Assuntos
Tecido Conjuntivo , União Europeia , França , Humanos , Portugal , Espanha
10.
Sci Rep ; 11(1): 3881, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594095

RESUMO

ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr-/- mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.

12.
J Surg Educ ; 78(2): 478-484, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32893155

RESUMO

OBJECTIVES: To determine whether immersive virtual patient simulation (IVPS) on the MedicActiv platform is influential in improving student academic performance in module validation tests. DESIGN: In this prospective randomized controlled study a comparison was made between IVPS training combined with regular faculty courses versus courses alone. The primary endpoint was module validation grades. Secondary endpoints were satisfaction scores (overall interest, ergonomics, realism, immersion, and training efficiency). SETTING: Angers School of Medicine, France. PARTICIPANTS: 2018 to 2019 class of fourth-year students, included on a voluntary basis. In the first semester 51 students were included, of whom 13 were excluded for lack of compliance (6 and 7 from the IVPS and control groups, respectively). In the second semester we included 57 students, of whom 10 were excluded for lack of compliance (2 and 8 from the IVPS and control groups, respectively). RESULTS: Mean age was 21 years (±0.8). There were 85 female and 23 male students. In the first semester mean grades were 13.4 ± 1.6 versus 11/.9 ± 2.4 in the IVPS and control groups, respectively (p = 0.038). In the second semester mean grades were 15.3 ± 2.5 versus 11.9 ± 3.6 in the IVPS and control groups, respectively p < 0.001. The entire study population was pooled (n = 85): mean grades were 14.5 ± 2.4 versus 11.9 ± 3 in the IVPS group and the control group, respectively, p < 0.001. The satisfaction questionnaire response rate was 54% (46/85). Score percentages ≥4 regarding overall interest, ergonomics, realism, immersion and training efficiency were 89%, 85%, 100%, 93%, and 93% respectively. CONCLUSIONS: Complementing conventional university education with simulation of virtual consultation cases on the MedicActiv platform improved student academic performance as compared with students studying regular courses. Students reported high levels of satisfaction with overall interest, ergonomics, realism, immersion and training efficiency on the MedicActiv platform.


Assuntos
Desempenho Acadêmico , Estudantes de Medicina , Adulto , Competência Clínica , Feminino , França , Humanos , Masculino , Simulação de Paciente , Estudos Prospectivos , Adulto Jovem
13.
Genet Med ; 23(1): 131-139, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873932

RESUMO

PURPOSE: Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting elastic fibers in the skin, eyes, and cardiovascular system. It is caused by biallelic pathogenic variants in the ABCC6 gene. To date, over 300 ABCC6 variants are associated with PXE, more than half being missense variants. Correct variant interpretation is essential for establishing a direct link between the variant and the patient's phenotype and has important implications for diagnosis and treatment. METHODS: We used a systematic approach for interpretation of 271 previously reported and 15 novel ABCC6 missense variants, based on the semiquantitative classification system Sherloc. RESULTS: Only 35% of variants were very likely to contribute directly to disease, in contrast to reported interpretations in ClinVar, while 59% of variants are currently of uncertain significance (VUS). Subclasses were created to distinguish VUS that are leaning toward likely benign or pathogenic, increasing the number of (likely) pathogenic ABCC6 missense variants to 47%. CONCLUSION: Besides highlighting discrepancies between the Sherloc, American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), ClinVar, and Leiden Open Variation Database (LOVD) classification, our results emphasize the need for segregation analysis, functional assays, and detailed evidence sharing in variant databases to reach a confident interpretation of ABCC6 missense variants and subsequent appropriate genetic and preconceptual counseling.


Assuntos
Pseudoxantoma Elástico , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Mutação de Sentido Incorreto , Fenótipo , Pseudoxantoma Elástico/diagnóstico , Pseudoxantoma Elástico/genética
14.
Int J Pharm ; 593: 120111, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33246045

RESUMO

Metastatic melanoma is a malignant tumor with a poor prognosis. Recent new therapeutics improved the survival of patients at a metastatic stage. However, the low response rate to immunotherapy, explained in part by resistance to apoptosis, needs to develop new strategies. The ferrocifen family represents promising bioorganometallic molecules for melanoma treatment since they show potent anticancer properties. The aim of this study is (i) to evaluate the benefits of a strategy involving encapsulated p722 in lipid nanocapsules (LNC) in B16F10 melanoma mice models and (ii) to compare the beneficial effects with an existing therapy such as anti-CTLA4 mAb. Interestingly, LNC-p722 induces a significant decrease of melanoma cell viability. In vivo data shows a significant improvement in the survival rate and a slower tumor growth with p722-loaded LNC in comparison with anti-CTLA4 mAb. Western blots confirm that LNC-p722 potentiates intrinsic apoptotic pathway. Treatment with LNC-p722 significantly activates CD8+ T lymphocytes compared to treatment with anti-CTLA4 mAb. This study uncovers a new therapeutic strategy with encapsulated p722 to prevent B16F10 melanoma growth and to improve survival of treated mice.


Assuntos
Melanoma , Nanocápsulas , Animais , Apoptose , Linfócitos T CD8-Positivos , Compostos Ferrosos , Humanos , Lipídeos , Melanoma/tratamento farmacológico , Camundongos , Nanocápsulas/uso terapêutico , Linfócitos T
15.
Front Cell Dev Biol ; 8: 573727, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363139

RESUMO

Epidemiological studies indicate that elevated alkaline phosphatase activity is associated with increased cardiovascular disease risk. Other epidemiological data demonstrate that mothers giving multiple childbirths (multipara) are also at increased risk of developing late-onset cardiovascular disease. We hypothesized that these two associations stem from a common cause, the insufficient plasma level of the ectopic mineralization inhibitor inorganic pyrophosphate, which is a substrate of alkaline phosphatase. As alkaline phosphatase activity is elevated in pregnancy, we hypothesized that pyrophosphate concentrations decrease gestationally, potentially leading to increased maternal vascular calcification and cardiovascular disease risk in multipara. We investigated plasma pyrophosphate kinetics pre- and postpartum in sheep and at term in humans and demonstrated its shortage in pregnancy, mirroring alkaline phosphatase activity. Next, we tested whether multiparity is associated with increased vascular calcification in pseudoxanthoma elasticum patients, characterized by low intrinsic plasma pyrophosphate levels. We demonstrated that these patients had increased vascular calcification when they give birth multiple times. We propose that transient shortages of pyrophosphate during repeated pregnancies might contribute to vascular calcification and multiparity-associated cardiovascular disease risk threatening hundreds of millions of healthy women worldwide. Future trials are needed to assess if gestational pyrophosphate supplementation might be a suitable prophylactic treatment to mitigate maternal cardiovascular disease risk in multiparous women.

16.
J Clin Med ; 9(11)2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33120982

RESUMO

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and ectopic calcification. There is growing evidence that vascular calcification is associated with inflammatory status and is enhanced by inflammatory cytokines. Since PXE has never been considered as an inflammatory condition, no incidence of chronic inflammation leading to calcification in PXE has been reported and should be investigated. In atherosclerosis and aortic stenosis, positron emission tomography combined with computed tomographic (PET-CT) imaging has demonstrated a correlation between inflammation and calcification. The purpose of this study was to assess skin/artery inflammation and calcification in PXE patients. Methods: 18F-FluroDeoxyGlucose (18F-FDG) and 18F-Sodium Fluoride (18F-NaF) PET-CT, CT-imaging and Pulse wave velocity (PWV) were used to determine skin/vascular inflammation, tissue calcification, arterial calcium score (CS) and stiffness, respectively. In addition, inorganic pyrophosphate, high-sensitive C-reactive protein and cytokines plasma levels were monitored. RESULTS: In 23 PXE patients, assessment of inflammation revealed significant 18F-FDG uptake in diseased skin areas contrary to normal regions, and exclusively in the proximal aorta contrary to the popliteal arteries. There was no correlation between 18F-FDG uptake and PWV in the aortic wall. Assessment of calcification demonstrated significant 18F-NaF uptake in diseased skin regions and in the proximal aorta and femoral arteries. 18F-NaF wall uptake correlated with CS in the femoral arteries, and aortic wall PWV. Multivariate analysis indicated that aortic wall 18F-NaF uptake is associated with diastolic blood pressure. There was no significant correlation between 18F-FDG and 18F-NaF uptake in any of the artery walls. CONCLUSION: In the present cross-sectional study, inflammation and calcification were not correlated. PXE would appear to more closely resemble a chronic disease model of ectopic calcification than an inflammatory condition. To assess early ectopic calcification in PXE patients, 18F-NaF-PET-CT may be more relevant than CT imaging. It potentially constitutes a biomarker for disease-modifying anti-calcifying drug assessment in PXE.

17.
Lasers Med Sci ; 35(8): 1821-1830, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32372237

RESUMO

Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up.


Assuntos
Microscopia Óptica não Linear/métodos , Pseudoxantoma Elástico/diagnóstico por imagem , Pele/diagnóstico por imagem , Estudos de Casos e Controles , Colágeno/metabolismo , Tecido Conjuntivo/patologia , Elastina/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pseudoxantoma Elástico/metabolismo , Pseudoxantoma Elástico/patologia , Pele/metabolismo , Pele/patologia
18.
Am J Hum Genet ; 106(6): 893-904, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32386558

RESUMO

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.


Assuntos
Ciliopatias/genética , Ciliopatias/patologia , Genes Dominantes/genética , Cinesina/genética , Mutação , Retina/patologia , Sequência de Aminoácidos , Animais , Gatos , Pré-Escolar , Cílios/patologia , Feminino , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Cinesina/química , Cinesina/metabolismo , Larva , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Células Fotorreceptoras/metabolismo , Retina/citologia , Retina/crescimento & desenvolvimento , Retina/metabolismo , Rodopsina/metabolismo , Adulto Jovem , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
19.
Sci Rep ; 10(1): 7912, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404941

RESUMO

We acquired depth-resolved light scattering measurements from the retinas of triple transgenic Alzheimer's Disease (3xTg-AD) mice and wild type (WT) age-matched controls using co-registered angle-resolved low-coherence interferometry (a/LCI) and optical coherence tomography (OCT). Angle-resolved light scattering measurements were acquired from the nerve fiber layer, outer plexiform layer, and retinal pigmented epithelium using image guidance and segmented thicknesses provided by co-registered OCT B-scans. Analysis of the OCT images showed a statistically significant thinning of the nerve fiber layer in AD mouse retinas compared to WT controls. The a/LCI scattering measurements provided complementary information that distinguishes AD mice by quantitatively characterizing tissue heterogeneity. The AD mouse retinas demonstrated higher mean and variance in nerve fiber layer light scattering intensity compared to WT controls. Further, the difference in tissue heterogeneity was observed through short-range spatial correlations that show greater slopes at all layers of interest for AD mouse retinas compared to WT controls. A greater slope indicates a faster loss of spatial correlation, suggesting a loss of tissue self-similarity characteristic of heterogeneity consistent with AD pathology. Use of this combined modality introduces unique tissue texture characterization to complement development of future AD biomarker analysis.


Assuntos
Doença de Alzheimer/patologia , Retina/diagnóstico por imagem , Retina/patologia , Tomografia de Coerência Óptica , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Imunofluorescência , Processamento de Imagem Assistida por Computador/métodos , Camundongos , Camundongos Transgênicos , Retina/metabolismo , Processamento de Sinais Assistido por Computador , Tomografia de Coerência Óptica/métodos
20.
Clin Genet ; 98(1): 74-79, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32270475

RESUMO

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive ectopic mineralization disorder, characterized by skin, eye and cardiovascular symptoms. The most devastating ocular complication is choroidal neovascularization, which is thought to be mediated by vascular endothelial growth factor (VEGF) signaling, a molecule encoded by the VEGFA gene. As early detection and treatment is essential to preserve vision, prioritization of patients at risk is crucial, but impossible because of wide phenotypic variability and a lack of genotype-phenotype correlations for PXE. This study aimed to validate the previously suggested association of five single nucleotide VEGFA variants (rs13207351, rs833061, rs699947, rs25648 and rs1413711) with a severe PXE retinopathy in an independent cohort. Direct Sanger sequencing was performed in 100 PXE patients, with a mild (56) or severe (44) PXE retinopathy. The inclusion criteria for severe retinopathy were a unilateral best-corrected visual acuity of <5/10 and/or the need for anti-angiogenic treatment. We found a significant association of three of five variants and borderline missed significance for one. These data further suggest the VEGFA gene to be a modifier gene for the PXE retinopathy. Hereby, we provide the necessary evidence to implement these variants in ocular risk stratification and individualized patient follow-up.


Assuntos
Marcadores Genéticos/genética , Polimorfismo de Nucleotídeo Único/genética , Pseudoxantoma Elástico/genética , Doenças Retinianas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neovascularização de Coroide/genética , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pele/patologia , Adulto Jovem
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