Erythropoietin and the heart: facts and perspectives.

EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio-renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases. © The Authors Journal compilation © 2011 Biochemical Society

Geo-Climatic Changes and Apomixis as Major Drivers of Diversification in the Mediterranean Sea Lavenders (Limonium Mill.)

The Mediterranean realm, comprising the Mediterranean and Macaronesian regions, has long been recognized as one of the world’s biodiversity hotspots, owing to its remarkable species richness and endemism. Several hypotheses on biotic and abiotic drivers of species diversification in the region have been often proposed but rarely tested in an explicit phylogenetic framework. Here, we investigate the impact of both species-intrinsic and -extrinsic factors on diversification in the species-rich, cosmopolitan Limonium, an angiosperm genus with center of diversity in the Mediterranean. First, we infer and time-calibrate the largest Limonium phylogeny to date. We then estimate ancestral ranges and diversification dynamics at both global and regional scales. At the global scale, we test whether the identified shifts in diversification rates are linked to specific geological and/or climatic events in the Mediterranean area and/or asexual reproduction (apomixis). Our results support a late Paleogene origin in the proto-Mediterranean area for Limonium, followed by extensive in situ diversification in the Mediterranean region during the late Miocene, Pliocene, and Pleistocene. We found significant increases of diversification rates in the “Mediterranean lineage” associated with the Messinian Salinity Crisis, onset of Mediterranean climate, Plio-Pleistocene sea-level fluctuations, and apomixis. Additionally, the Euro-Mediterranean area acted as the major source of species dispersals to the surrounding areas. At the regional scale, we infer the biogeographic origins of insular endemics in the oceanic archipelagos of Macaronesia, and test whether woodiness in the Canarian Nobiles clade is a derived trait linked to insular life and a biotic driver of diversification. We find that Limonium species diversity on the Canary Islands and Cape Verde archipelagos is the product of multiple colonization events followed by in situ diversification, and that woodiness of the Canarian endemics is indeed a derived trait but is not associated with a significant shift to higher diversification rates. Our study expands knowledge on how the interaction between abiotic and biotic drivers shape the uneven distribution of species diversity across taxonomic and geographical scales.info:eu-repo/semantics/publishedVersio

Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: Novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy

Epidermolysis bullosa simplex (EBS) with cardiomyopathy (EBS-KLHL24) is an EBS subtype caused by dominantly inherited, gain-of-function mutations in the gene encoding for the ubiquitin-ligase KLHL24, which addresses specific proteins to proteasomal degradation. EBS-KLHL24 patients are born with extensive denuded skin areas and skin fragility. Whilst skin fragility rapidly ameliorates, atrophy and scarring develop over time, accompanied by life-threatening cardiomyopathy. To date, pathogenetic mechanisms underlying such a unique disease phenotype are not fully characterized. The basal keratin 14 (K14) has been indicated as a KLHL24 substrate in keratinocytes. However, EBS-KLHL24 pathobiology cannot be determined by the mutation-enhanced disruption of K14 alone, as K14 is similarly expressed in foetal and postnatal epidermis and its protein levels are preserved both in vivo and in vitro disease models. In this study, we focused on foetal keratins as additional KLHL24 substrates. We showed that K7, K8, K17 and K18 protein levels are markedly reduced via proteasome degradation in normal foetal keratinocytes transduced with the mutant KLHL24 protein (Delta N28-KLHL24) as compared to control cells expressing the wild-type form. In addition, heat stress led to keratin network defects and decreased resilience in Delta N28-KLHL24 cells. The KLHL24-mediated degradation of foetal keratins could contribute to congenital skin defects in EBS-KLHL24. Furthermore, we observed that primary keratinocytes from EBS-KLHL24 patients undergo accelerated clonal conversion with reduced colony forming efficiency (CFE) and early replicative senescence. Finally, our findings pointed out a reduced CFE in Delta N28-KLHL24-transduced foetal keratinocytes as compared to controls, suggesting that mutant KLHL24 contributes to patients' keratinocyte clonogenicity impairment

Detection of butterfly fractures of long bones through multi-slice computed tomography and micro-computed tomography

: Motor-vehicle accidents often result in lower limb injuries with biosseous fractures. The present study aimed at comparing multi-slice computed tomography (MS-CT), micro-computed tomography (micro-CT) and external fractography for the analyses of experimentally produced biosseus leg fractures. Briefly, 48 human legs amputated for medical reasons were defleshed and then experimentally fractured using a 3-point dynamic bending model (70,6 J of impact energy at the middle of the anterior surface of the tibia) producing 38 biosseous and 10 mono-osseous fractures with a total of 86 fractured bones. External fractography detected 63 (73,2%) "butterfly" fractures (24 (27,9%) complete and 39 (45,3%) incomplete), 14 (16,3%) "oblique" fractures, 6 (7,0%) "comminuted" fractures and 3 (3,5%) "transverse" fractures. Forty-three (43) of the 48 included legs displayed at least one butterfly fracture located at the tibia or fibula. MS-CT correctly detected and classified 16 complete and 20 incomplete butterfly fractures, failing to properly classify 27 fractures; 19 of these misclassifications led to an interpretative error on the trauma direction (i.e., 16 incomplete butterfly fractures classified as oblique fractures and 3 incomplete butterfly fractures classified as transverse). Micro-CT correctly detected and classified 22 complete and 37 incomplete butterfly fractures, failing to properly classify 4 fractures; two of these misclassifications led to an interpretative error on the trauma direction (i.e., two incomplete butterfly fractures classified as oblique fractures). Although further studies evaluating a wider number of fractures and fracture patterns are required to drive any definitive conclusions, this preliminary experimental investigation showed that MS-CT and micro-CT represent useful tools for reconstructing the morphology of leg fractures and could be crucial for trauma analysis in the forensic context. MS-CT could be used as a screening tool, micro-CT as second level analysis and external/internal fractography as third level, confirmatory analysis

Kidney Biopsy and Immuno-Rheumatological Diseases: A Retrospective and Observational Study

Renal involvement is a common occurrence in patients with immuno-rheumatological diseases (IRDs). Several instances of glomerulonephritis (GN) occur in the setting of IRD and complicate the clinical course of an underlying condition. The aim of this study was to observe the spectrum of nephropathies according to age, kidney function, history of IRD at the time of biopsy, and histopathological kidney diagnosis. We evaluated data relating to 699 consecutive kidney native biopsies (female 52.1%) with a median age of 48 years (IQR 34–62) performed in adult patients collected over 15 years. The study population was divided into three groups: patients with kidney histological findings correlated to underlying IRD (Group 1), patients with kidney histological findings not correlated to underlying IRD (Group 2), and patients with kidney histological findings compatible with “de novo” IRD (absent in personal medical history) (Group 3). Kidney involvement related to IRD was found in 25.2% of patients. Group 1 was mostly represented by lupus nephritis (76.6%), with a younger age than Group 3 (p < 0.001) and by a higher percentage of females than other groups (p < 0.001). Group 3 was the most represented by microscopic polyangiitis (50.8%) when compared with the other two groups (p < 0.001). Acute nephritic syndrome (p < 0.001), acute kidney injury (AKI), and abnormal urinalysis (p < 0.001) were more represented in Group 3 than the other groups. In conclusion, IRDs are characterized by different clinical presentations and heterogeneous histological findings. Kidney biopsy remains fundamental to achieving the correct diagnosis and starting targeted therapy

differential tbxa2 receptor transcript stability is dependent on the c924t polymorphism

Abstract Background In order to better characterize the molecular mechanisms involved in processing mutated transcripts, we investigated the post-transcriptional role of the C924T polymorphism (rs4523) located in the 3′ region of the TBXA2R gene. Methods and Results Experiments of dose response with Actinomycin D on MEG-01 human cell line showed a significant decrease on cell viability that was more evident on cells treated for 24 h. In addition, we showed that treatments with 5–10 μM, 15 μM and 20 μM of actinomycin D reduced cell viability by 44%, 72% and 75%, respectively, compared to the control group. Conversely, the samples treated with 1 μM of actinomycin D did not show significant difference on cell viability as compared to the control group. Analysis of the steady state mRNA level of TBXA2R by qRT-PCR evidenced an increase in mRNA stability for the wild type (C) compared to the mutant (T) allele. Furthermore, the expression levels of TBXA2R on wild type (CC) and mutant type (TT) patients, based on C924T polymorphism, were analyzed. The wild type showed a higher expression of TBXA2 receptor also with two different degrees of glycosylation (55 and 64 kDa), when compared to the mutant. These observations correlated with platelet aggregation, which was reduced in TT, independently of the platelet aggregation stimuli. Conclusions The instability of the TBXA2R transcript and the lack of effect on platelet aggregation might suggest a protective role for the TBXA2R TT genotype against atherothrombosis and its complications in high-risk aspirin-treated patients

Feeding and smoking habits as cumulative risk factors for early childhood caries in toddlers, after adjustment for several behavioral determinants: a retrospective study

Background: Several maternal health determinants during the first period of life of the child, as feeding practice, smoking habit and socio-economic level, are involved in early childhood health problems, as caries development. The potential associations among early childhood caries, feeding practices, maternal and environmental smoking exposure, Socio-Economic Status (SES) and several behavioral determinants were investigated. Methods: Italian toddlers (n = 2395) aged 24–30 months were recruited and information on feeding practices, sweet dietary habit, maternal smoking habit, SES, and fluoride supplementation in the first year of life was obtained throughout a questionnaire administered to mothers. Caries lesions in toddlers were identified in visual/tactile examinations and classified using the International Caries Detection and Assessment System (ICDAS). Associations between toddlers’ caries data and mothers’ questionnaire data were assessed using chi-squared test. Ordinal logistic regression was used to analyze associations among caries severity level (ICDAS score), behavioral factors and SES (using mean housing price per square meter as a proxy). Results: Caries prevalence and severity levels were significantly lower in toddlers who were exclusively breastfed and those who received mixed feeding with a moderate–high breast milk component, compared with toddlers who received low mixed feeding and those exclusively fed with formula (p &lt; 0.01). No moderate and high caries severity levels were observed in an exclusively breastfed children. High caries severity levels were significantly associated with sweet beverages (p &lt; 0.04) and SES (p &lt; 0.01). Toddlers whose mothers smoked five or more cigarettes/day during pregnancy showed a higher caries severity level (p &lt; 0.01) respect to those whose mothers did not smoke. Environmental exposure to smoke during the first year of life was also significantly associated with caries severity (odds ratio =7.14, 95% confidence interval = 6.07-7.28). No association was observed between caries severity level and fluoride supplementation. More than 50% of toddlers belonging to families with a low SES, showed moderate or high severity caries levels (p &lt; 0.01). Conclusions: Higher caries severity levels were observed in toddlers fed with infant formula and exposed to smoke during pregnancy living in area with a low mean housing price per square meter.</br

Massive stars in the Cl 1813-178 Cluster. An episode of massive star formation in the W33 complex

Young massive (M >10^4 Msun) stellar clusters are a good laboratory to study the evolution of massive stars. Only a dozen of such clusters are known in the Galaxy. Here we report about a new young massive stellar cluster in the Milky Way. Near-infrared medium-resolution spectroscopy with UIST on the UKIRT telescope and NIRSPEC on the Keck telescope, and X-ray observations with the Chandra and XMM satellites, of the Cl 1813-178 cluster confirm a large number of massive stars. We detected 1 red supergiant, 2 Wolf-Rayet stars, 1 candidate luminous blue variable, 2 OIf, and 19 OB stars. Among the latter, twelve are likely supergiants, four giants, and the faintest three dwarf stars. We detected post-main sequence stars with masses between 25 and 100 Msun. A population with age of 4-4.5 Myr and a mass of ~10000 Msun can reproduce such a mixture of massive evolved stars. This massive stellar cluster is the first detection of a cluster in the W33 complex. Six supernova remnants and several other candidate clusters are found in the direction of the same complex.Comment: 11 Figures. Accepted for publication in Ap

Safety and efficacy of direct-acting antivirals in transfusion-dependent thalassemic patients with chronic hepatitis C

Background: Hepatitis C virus (HCV) infection is a major cause of liver-related morbidity and mortality among thalassemic patients. New treatments based on direct-acting antivirals (DAAs) are highly effective and well-tolerated by patients; nonetheless, they have not been studied in thalassemic populations. In this study, we evaluated the safety and efficacy of these treatments in a cohort of Sardinian thalassemic patients with chronic HCV infection. Methods: We consecutively recruited thalassemic patients with HCV infection, who were eligible for DAA therapy at 3 liver units. Different drug combinations, depending on HCV genotype and hepatic disease severity, were used according to the current guidelines. Sustained virological response was assessed at 12 weeks posttreatment. Data regarding the side effects and transfusion requirements were also collected. Results: We recruited 49 patients, including 29 males (59.2%), with the mean age of 43 years (genotype 1, 55.1%). Twenty-one (42.9%) patients had a history of interferon-based treatment. Cirrhosis was detected in 28 (57.1%) patients; only 1 patient had ascites and hypoalbuminemia (Child-Pugh B7). On the other hand, 35 (71.4%) patients received a sofosbuvir-based regimen. Ribavirin treatment was reported in 26 (53.1%) cases. All the patients were followed-up for at least 12 weeks after therapy, and sustained virological response was observed in 98% of the patients. No treatment discontinuation was required due to adverse events. The most common side effects included fatigue (24.5%), headache (10.2%), and anaemia (77%), requiring further blood transfusion in patients receiving ribavirin. Conclusions: This prospective study showed that DAAs are safe and effective agents in thalassemic patients with advanced liver fibrosis, regardless of previous antiviral treatment responses