Internal Carotid Artery Occlusive Disease and Polymorphisms of Fractalkine Receptor CX3CR1

Background and Purpose— Fractalkine (FKN), a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1. The polymorphisms V249I and T280M affect receptor expression and function. The role of FKN in atherosclerosis has been recently demonstrated. The aim of this study was to investigate a possible association between CX3CR1 polymorphisms and increased risk of internal carotid artery (ICA) occlusive disease. Methods— We studied 108 patients consecutively recruited for ICA occlusive disease, 84 of whom underwent operation for carotid endarterectomy, and 204 subjects without ICA occlusive disease (controls). Polymorphic genotypes were determined by polymerase chain reaction and sequencing analysis. Results— The adjusted odds ratio (OR) associated with the presence of the M280 (TM+MM versus TT genotype) was 0.55 (95% CI: 0.29 to 0.99; P =0.037). Therefore, this allele is associated with a reduced risk of ICA occlusive disease. No significant differences were observed in I249 distribution. The frequency of I249 allele was significantly higher in cases of hard plaques, which are considered more stable than soft ones (OR: 0.38; 95% CI: 0.13 to 1.05; P =0.037). Multiple logistic regression analysis using the common risk factors and the I249 and M280 allele variants revealed that the M280 allele was an independent risk factor for ICA stenosis ( P =0.047). Conclusion— The results show that the CX3CR1 M280 is an independent genetic risk factor for ICA occlusive disease and that I249 is involved in the stability of carotid plaques. Even if obtained from a relatively limited patient series, these results might have relevant implications for treatment of ICA stenosis and possibly prevention of carotid related stroke. Further prospective cross-sectional studies are needed to confirm these results

Mitochondrial Complex I: Structural and functional aspects

AbstractThis review examines two aspects of the structure and function of mitochondrial Complex I (NADH Coenzyme Q oxidoreductase) that have become matter of recent debate. The supramolecular organization of Complex I and its structural relation with the remainder of the respiratory chain are uncertain. Although the random diffusion model [C.R. Hackenbrock, B. Chazotte, S.S. Gupte, The random collision model and a critical assessment of diffusion and collision in mitochondrial electron transport, J. Bioenerg. Biomembranes 18 (1986) 331–368] has been widely accepted, recent evidence suggests the presence of supramolecular aggregates. In particular, evidence for a Complex I–Complex III supercomplex stems from both structural and kinetic studies. Electron transfer in the supercomplex may occur by electron channelling through bound Coenzyme Q in equilibrium with the pool in the membrane lipids. The amount and nature of the lipids modify the aggregation state and there is evidence that lipid peroxidation induces supercomplex disaggregation. Another important aspect in Complex I is its capacity to reduce oxygen with formation of superoxide anion. The site of escape of the single electron is debated and either FMN, iron–sulphur clusters, and ubisemiquinone have been suggested. The finding in our laboratory that two classes of hydrophobic inhibitors have opposite effects on superoxide production favours an iron–sulphur cluster (presumably N2) is the direct oxygen reductant. The implications in human pathology of better knowledge on these aspects of Complex I structure and function are briefly discussed

The Epidemiology of Hypoparathyroidism in Italy: An 8-Year Register-Based Study

Hypoparathyroidism is a rare endocrine disorder, but few studies have focused on the epidemiology and hospital management of the disease and none has been performed in Italy. We investigated the prevalence of dif- ferent forms of hypoparathyroidism among hospitalized patients in Italy during an 8-year period. This study is designed as a retrospective register-based study. We retrieved data from the ‘‘Record of Hospital Discharge’’ (SDO) of the Italian Health Ministry, from the year 2006 to 2013 and analyzed the codes corresponding to hypoparathyroidism-related diagnoses. The inpatient prevalence of the disease was also calculated after excluding repeated hospitalizations. Overall, 27,692 hos- pitalization episodes for hypoparathyroidism were identi- fied during the entire period (72.2% in women and 27.8% in men; mean age 49.5 ± 22.9 years). The mean length of stay was 7.4 ± 9.8 days (25.9% of the episodes requiring less than 3 days of stay). The mean hospitalization rate for hypoparathyroidism was 5.9/100,000 inhabitants per year and there was a significant decrease during the period of 2006–2013 ( p \ 0.0001). The mean hospitalization rate for postsurgical hypoparathyroidism was 1.4/100,000 inhabi- tants per year and the trend showed a significant reduction during the years ( p \ 0.0001). The mean prevalence of hypoparathyroidism among inpatients was 5.3/100,000 inhabitants per year, and there was a significant decrease over the years ( p \ 0.0001). Hypoparathyroidism, partic- ularly the postsurgical form of the disease, is not an uncommon condition among hospitalized patients in Italy. We observed a tendency to a decrease in the frequency of hospitalization during the period 2006–201

Two-Phase Stefan Problem as the Limit Case of Two-Phase Stefan Problem with Kinetic Condition

AbstractBoth one-dimensional two-phase Stefan problem with the thermodynamic equilibrium condition u(R(t),t)=0 and with the kinetic rule uε(Rε(t),t)=εRε′(t) at the moving boundary are considered. We prove, when ε approaches zero, Rε(t) converges to R(t) in C1+δ/2[0,T] for any finite T>0, 0<δ<1

Nível de controle da asma em pacientes atendidos no serviço de atenção primária em um município do sudoeste da Bahia

A asma é uma manifestação crônica que afeta crianças e adultos e representa um problema de saúde pública mundial. Trata-se de uma doença inflamatória das vias aéreas, definida por aumentar a responsividade a estímulos sensíveis. É uma doença mais prevalente em crianças do sexo masculino e mulheres adultas. No Brasil, existem aproximadamente 20 milhões de asmáticos. Alguns fatores de risco são desencadeadores de crises asmáticas, incluindo tabagismo, comorbidades, mudanças climáticas e poluição. O presente trabalho teve como objetivo avaliar o nível de controle da asma em pacientes atendidos na atenção primária em um município do sudoeste da Bahia. Desta forma essa pesquisa trata-se de um estudo de caráter descritivo, com análise quantitativa, exploratória de campo, a fim de identificar o grau de adesão do tratamento farmacológico e não farmacológico dos pacientes asmáticos. Os resultados demonstraram que há boa adesão medicamentosa e não medicamentosa por parte dos asmáticos e que a rinite foi um fator relevante nos entrevistados, reafirmando a coexistência de ambas as patologias em sua maioria. O gênero mais afetado foi o sexo feminino. Os dados indicam a adequação do tratamento farmacológico e não farmacológico em pacientes atendidos na atenção primária de saúde do município

Phenotypic profiling of CD34⁺ cells by advanced flow cytometry improves diagnosis of juvenile myelomonocytic leukemia

Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) are currently well defined, however in some patients diagnosis still remains a challenge. Flow cytometry is a well established tool for diagnosis and follow-up of hematological malignancies, nevertheless it is not routinely used for JMML diagnosis. Herewith, we characterized the CD34+ hematopoietic precursor cells collected from 31 children with JMML using a combination of standardized EuroFlow antibody panels to assess the ability to discriminate JMML cells from normal/reactive bone marrow cell as controls (n=29) or from cells of children with other hematological diseases mimicking JMML (n=9). CD34+ precursors in JMML showed markedly reduced B-cell and erythroid-committed precursors compared to controls, whereas monocytic and CD7+ lymphoid precursors were significantly expanded. Moreover, aberrant immunophenotypes were consistently present in CD34+ precursors in JMML, while they were virtually absent in controls. Multivariate logistic regression analysis showed that combined assessment of the number of CD34+CD7+ lymphoid precursors and CD34+ aberrant precursors or erythroid precursors had a great potential in discriminating JMMLs versus controls. Importantly our scoring model allowed highly efficient discrimination of truly JMML versus patients with JMML-like diseases. In conclusion, we show for the first time that CD34+ precursors from JMML patients display a unique immunophenotypic profile which might contribute to a fast and accurate diagnosis of JMML worldwide by applying an easy to standardize single eight-color antibody combination.</p

Phenotypic profiling of CD34⁺ cells by advanced flow cytometry improves diagnosis of juvenile myelomonocytic leukemia

Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) are currently well defined, however in some patients diagnosis still remains a challenge. Flow cytometry is a well established tool for diagnosis and follow-up of hematological malignancies, nevertheless it is not routinely used for JMML diagnosis. Herewith, we characterized the CD34+ hematopoietic precursor cells collected from 31 children with JMML using a combination of standardized EuroFlow antibody panels to assess the ability to discriminate JMML cells from normal/reactive bone marrow cell as controls (n=29) or from cells of children with other hematological diseases mimicking JMML (n=9). CD34+ precursors in JMML showed markedly reduced B-cell and erythroid-committed precursors compared to controls, whereas monocytic and CD7+ lymphoid precursors were significantly expanded. Moreover, aberrant immunophenotypes were consistently present in CD34+ precursors in JMML, while they were virtually absent in controls. Multivariate logistic regression analysis showed that combined assessment of the number of CD34+CD7+ lymphoid precursors and CD34+ aberrant precursors or erythroid precursors had a great potential in discriminating JMMLs versus controls. Importantly our scoring model allowed highly efficient discrimination of truly JMML versus patients with JMML-like diseases. In conclusion, we show for the first time that CD34+ precursors from JMML patients display a unique immunophenotypic profile which might contribute to a fast and accurate diagnosis of JMML worldwide by applying an easy to standardize single eight-color antibody combination.</p

Polymorphism of the Fractalkine Receptor CX3CR1 and Systemic Sclerosis-associated Pulmonary Arterial Hypertension

Fractalkine (FKN) and its receptor CX3CR1 are critical mediators in the vascular and tissue damage of several chronic diseases, including systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH). Interestingly, the V249I and T280M genetic polymorphisms influence CX3CR1 expression and function. We investigated whether these polymorphisms are associated with PAH secondary to SSc. CX3CR1 genotypes were analyzed by PCR and sequencing in 76 patients with limited SSc and 204 healthy controls. PAH was defined by colorDoppler echocardiography. Homozygosity for 249II as well as the combined presence of 249II and 280MM were significantly more frequent in patients with SSc compared to controls (17 vs 6%, p = 0.0034 and 5 vs 1%, p = 0.0027, respectively). The 249I and 280M alleles were associated with PAH (odd ratio [OR] 2.2, 95% confidence interval [CI] 1.01-4.75, p = 0.028 and OR 7.37, 95%CI: 2.45-24.60, p = 0.0001, respectively). In conclusion, the increased frequencies of 249I and 280M CX3CR1 alleles in a subgroup of patients with SSc-associated PAH suggest a role for the fractalkine system in the pathogenesis of this condition. Further, the 249I allele might be associated with susceptibility to SSc

Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19

: Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy