Phosphorylation of cardiac sodium channel at Ser571 anticipates manifestations of the aging myopathy.

Diastolic dysfunction and delayed ventricular repolarization are typically observed in the elderly, but whether these defects are intimately associated with the progressive manifestation of the aging myopathy remains to be determined. In this regard, aging in experimental animals is coupled with increased late Na+ current (INa,L) in cardiomyocytes, raising the possibility that INa,L conditions the modality of electrical recovery and myocardial relaxation of the aged heart. For this purpose, aging male and female wild-type (WT) C57Bl/6 mice were studied together with genetically engineered mice with phosphomimetic (gain of function, GoF) or ablated (loss of function, LoF) mutations of the sodium channel Nav1.5 at Ser571 associated with, respectively, increased and stabilized INa,L. At ∼18 mo of age, WT mice developed prolonged duration of the QT interval of the electrocardiogram and impaired diastolic left ventricular (LV) filling, defects that were reversed by INa,L inhibition. Prolonged repolarization and impaired LV filling occurred prematurely in adult (∼5 mo) GoF mutant mice, whereas these alterations were largely attenuated in aging LoF mutant animals. Ca2+ transient decay and kinetics of myocyte shortening/relengthening were delayed in aged (∼24 mo) WT myocytes, with respect to adult cells. In contrast, delayed Ca2+ transients and contractile dynamics occurred at adult stage in GoF myocytes and further deteriorated in old age. Conversely, myocyte mechanics were minimally affected in aging LoF cells. Collectively, these results document that Nav1.5 phosphorylation at Ser571 and the late Na+ current modulate the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction.NEW & NOTEWORTHY We have investigated the impact of the late Na current (INa,L) on cardiac and myocyte function with aging by using genetically engineered animals with enhanced or stabilized INa,L, due to phosphomimetic or phosphoablated mutations of Nav1.5. Our findings support the notion that phosphorylation of Nav1.5 at Ser571 prolongs myocardial repolarization and impairs diastolic function, contributing to the manifestations of the aging myopathy.

Exploring the Interplay between Complex Post-Traumatic Stress Disorder and Obsessive-Compulsive Disorder Severity: Implications for Clinical Practice.

Background and Objectives: Traumatic events adversely affect the clinical course of obsessive-compulsive disorder (OCD). Our study explores the correlation between prolonged interpersonal trauma and the severity of symptoms related to OCD and anxiety disorders. Materials and Methods: The study follows a cross-sectional and observational design, employing the International Trauma Questionnaire (ITQ) to examine areas linked to interpersonal trauma, the Hamilton Anxiety Rating Scale (HAM-A), and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to assess anxious and obsessive-compulsive symptoms, respectively. Descriptive analysis, analysis of variance (ANOVA), and logistic regression analyses were conducted. Results: We recruited 107 OCD-diagnosed patients, categorizing them into subgroups based on the presence or absence of complex post-traumatic stress disorder (cPTSD). The ANOVA revealed statistically significant differences between the two groups in the onset age of OCD (p = 0.083), psychiatric familial history (p = 0.023), HAM-A, and Y-BOCS (p < 0.0001). Logistic regression indicated a statistically significant association between the presence of cPTSD and Y-BOCS scores (p < 0.0001). Conclusions: The coexistence of cPTSD in OCD exacerbates obsessive-compulsive symptoms and increases the burden of anxiety. Further advancements in this field are crucial for mitigating the impact of early trauma on the trajectory of OCD and associated anxious symptoms.

Screening for Down syndrome in dichorionic twin pregnancies conceived by in vitro fertilization (IVF): a clinical pilot study to confirm the laboratory methods.

PURPOSE: The corrections necessary to estimate the risk for Down syndrome in twin pregnancies have been pointed out. We performed a nested controlled study to evaluate the validity of these corrections in dichorionic twins conceived by IVF. METHODS: Detailed clinical data was collected from the medical records. Twins were matched with a contemporaneous cohort of spontaneously conceived singleton pregnancies that serve as reference in a 1 to 4 ratio. All patients had their entire obstetrical care at our Hospital. The Student t-test was used for group comparisons and a p-value <0.05 was considered significant. RESULTS: Nineteen sets of normal twins concordant in size and with appropriate weight for gestational age were matched with 80 normal and mature newborns. Significant differences between groups were found for maternal age, gestational age at delivery and newborn weight (all p < 0.01). No statistical differences were noted for the levels of the biochemical markers expressed as multiples of the median. However, a 15 % closer approximation to the laboratory median for PAPP-A and a 10 % closer approximation to the laboratory median for free ß-hCG was evident in twins when compared to the reference group. CONCLUSIONS: These findings support the methods used to estimate the risk for Down syndrome in dichorionic twin pregnancies conceived after IVF. A future study with a larger sample size could confirm if the laboratory corrections done on the combined screening test improve the predictability of Down syndrome in dichorionic twin pregnancy conceived by IVF when compared to singleton pregnancies.

How effective are mood stabilizers in treating bipolar patients comorbid with cPTSD? Results from an observational study.

BACKGROUND: Multiple traumatic experiences, particularly in childhood, may predict and be a risk factor for the development of complex post-traumatic stress disorder (cPTSD). Unfortunately, individuals with bipolar disorder (BP) are more likely to have suffered traumatic events than the general population. Consequently, cPTSD could be comorbid with BD, and this may negatively affect psychopathological manifestations. To date, no one has explored whether such comorbidity also affects the response to treatment with mood stabilizers in BD patients. RESULTS: Here, a cross-sectional study was carried out by comparing the response to treatment, measured by the Alda scale, in a cohort of 344 patients diagnosed with BD type I and II, screened for the presence (or absence) of cPTSD using the International Trauma Questionnaire. The main result that emerged from the present study is the poorer response to mood stabilizers in BD patients with comorbid cPTSD compared with BD patients without cPTSD. CONCLUSIONS: The results collected suggest the need for an add-on therapy focused on trauma in BD patients. This could represent an area of future interest in clinical research, capable of leading to more precise and quicker diagnoses as well as suggesting better tailored and more effective treatments.

Unraveling the Complexity: Exploring the Intersection of Panic Disorder, Dissociation, and Complex Post-Traumatic Stress Disorder.

BACKGROUND: Patients with panic disorder (PD) may experience increased vulnerability to dissociative and anxious phenomena in the presence of repeated traumatic events, and these may be risk factors for the development of complex post-traumatic stress disorder (cPTSD). The present study aims to find out whether the presence of cPTSD exacerbates anxiety symptoms in patients suffering from panic disorder and whether this is specifically associated with the occurrence of dissociative symptoms. METHODS: One-hundred-and-seventy-three patients diagnosed with PD were recruited and divided into two groups based on the presence (or absence) of cPTSD using the International Trauma Questionnaire (ITQ) scale. Dissociative and anxious symptoms were assessed using the Cambridge Depersonalization Scale (CDS) and Hamilton Anxiety Scale (HAM-A), respectively. RESULTS: Significant differences in re-experienced PTSD (p < 0.001), PTSD avoidance (p < 0.001), PTSD hyperarousal (p < 0.001), and DSO dysregulation (p < 0.001) were found between the cPTSD-positive and cPTSD-negative groups. A statistically significant association between the presence of cPTSD and total scores on the HAM-A (p < 0.001) and CDS (p < 0.001) scales was found using regression analysis. CONCLUSIONS: This study highlights the potential link between dissociative symptoms and a more severe clinical course of anxiety-related conditions in patients with PD. Early intervention programs and prevention strategies are needed.

Hypoxia-inducible factor 1-α induces miR-210 in normoxic differentiating myoblasts.

MicroRNA-210 (miR-210) induction is a virtually constant feature of the hypoxic response in both normal and transformed cells, regulating several key aspects of cardiovascular diseases and cancer. We found that miR-210 was induced in normoxic myoblasts upon myogenic differentiation both in vitro and in vivo. miR-210 transcription was activated in an hypoxia-inducible factor 1-α (Hif1a)-dependent manner, and chromatin immunoprecipitation experiments show that Hif1a bound to the miR-210 promoter only in differentiated myotubes. Accordingly, luciferase reporter assays demonstrated the functional relevance of the Hif1a binding site for miR-210 promoter activation in differentiating myoblasts. To investigate the functional relevance of increased miR-210 levels in differentiated myofibers, we blocked miR-210 with complementary locked nucleic acid oligonucleotides (anti-miR-210). We found that C2C12 myoblast cell line differentiation was largely unaffected by anti-miR-210. Likewise, miR-210 inhibition did not affect skeletal muscle regeneration following cardiotoxin damage. However, we found that miR-210 blockade greatly increased myotube sensitivity to oxidative stress and mitochondrial dysfunction. In conclusion, miR-210 is induced in normoxic myofibers, playing a cytoprotective role.

Knockdown of cyclin-dependent kinase inhibitors induces cardiomyocyte re-entry in the cell cycle.

Proliferation of mammalian cardiomyocytes stops rapidly after birth and injured hearts do not regenerate adequately. High cyclin-dependent kinase inhibitor (CKI) levels have been observed in cardiomyocytes, but their role in maintaining cardiomyocytes in a post-mitotic state is still unknown. In this report, it was investigated whether CKI knockdown by RNA interference induced cardiomyocyte proliferation. We found that triple transfection with p21(Waf1), p27(Kip1), and p57(Kip2) siRNAs induced both neonatal and adult cardiomyocyte to enter S phase and increased the nuclei/cardiomyocyte ratio; furthermore, a subpopulation of cardiomyocytes progressed beyond karyokynesis, as assessed by the detection of mid-body structures and by straight cardiomyocyte counting. Intriguingly, cardiomyocyte proliferation occurred in the absence of overt DNA damage and aberrant mitotic figures. Finally, CKI knockdown and DNA synthesis reactivation correlated with a dramatic change in adult cardiomyocyte morphology that may be a prerequisite for cell division. In conclusion, CKI expression plays an active role in maintaining cardiomyocyte withdrawal from the cell cycle.

Heart Rate Variability Reveals Altered Autonomic Regulation in Response to Myocardial Infarction in Experimental Animals.

The analysis of beating rate provides information on the modulatory action of the autonomic nervous system on the heart, which mediates adjustments of cardiac function to meet hemodynamic requirements. In patients with myocardial infarction, alterations of heart rate variability (HRV) have been correlated to the occurrence of arrhythmic events and all-cause mortality. In the current study, we tested whether experimental rodent models of myocardial infarction recapitulate dynamics of heart rate variability observed in humans, and constitute valid platforms for understanding mechanisms linking autonomic function to the development and manifestation of cardiovascular conditions. For this purpose, HRV was evaluated in two engineered mouse lines using electrocardiograms collected in the conscious, restrained state, using a tunnel device. Measurements were obtained in naïve mice and animals at 3-∼28 days following myocardial infarction, induced by permanent coronary artery ligation. Two mouse lines with inbred and hybrid genetic background and, respectively, homozygous (Homo) and heterozygous (Het) for the MerCreMer transgene, were employed. In the naïve state, Het female and male mice presented prolonged RR interval duration (∼9%) and a ∼4-fold increased short- and long-term RR interval variability, with respect to sex-matched Homo mice. These differences were abrogated by pharmacological interventions inhibiting the sympathetic and parasympathetic axes. At 3-∼14 days after myocardial infarction, RR interval duration increased in Homo mice, but was not affected in Het animals. In contrast, Homo mice had minor modifications in HRV parameters, whereas substantial (> 50%) reduction of short- and long-term RR interval variation occurred in Het mice. Interestingly, ex vivo studies in isolated organs documented that intrinsic RR interval duration increased in infarcted vs. non-infarcted Homo and Het hearts, whereas RR interval variation was not affected. In conclusion, our study documents that, as observed in humans, myocardial infarction in rodents is associated with alterations in heart rhythm dynamics consistent with sympathoexcitation and parasympathetic withdrawal. Moreover, we report that mouse strain is an important variable when evaluating autonomic function via the analysis of HRV.

How Owners of Epileptic Dogs Living in Italy Evaluate Their Quality of Life and That of Their Pet: A Survey Study.

Epilepsy is the most common chronic neurological disorder of dogs and requires a substantial commitment by the pet owner. The aim of this study was to evaluate how Italian owners of epileptic dogs receiving long-term treatment perceived their own quality of life (QoL) and that of their pet, using a list of key questions. A questionnaire was sent to owners of dogs affected by recurrent seizures and treated with antiepileptic drugs for at least three months. The questions included signalment, medical history and physical, social and psychological aspects associated with managing an epileptic dog. Eighty complete questionnaires were obtained. Most owners surveyed had a positive opinion on their dog's QoL and they did not believe that commitment to managing their animals was a limitation of QoL. Dog QoL, seizure, frequency and severity were considered the most important factors in evaluating the efficacy of the antiepileptic treatment. The evaluation of the different aspects of QoL can help veterinary professionals understand the need for correct and exhaustive information provided to owners and the development of therapeutic plans and follow up, corresponding to the needs of dogs and owners.

Migalastat Treatment in a Kidney-Transplanted Patient with Fabry Disease and N215S Mutation: The First Case Report.

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity and, consequently, to glycosphingolipid accumulation in a wide variety of cells. Fabry disease due to N215S (c.644A>G, p.Asn215Ser) missense mutation usually results in a late-onset phenotype presenting with isolated cardiac involvement. We herein present the case of a patient with N215S mutation with cardiac involvement, namely left ventricular hypertrophy and ventricular arrhythmias, and end-stage renal disease requiring kidney transplantation. To the best of our knowledge, this is the first report of a kidney-transplanted Fabry patient treated with oral pharmacologic chaperone migalastat.

Myalgia, Obtundity and Fever in a Patient with a Prosthesis.

OBJECTIVE: We describe a rare case of group G streptococcus (GGS) sepsis complicated by bacterial toxin myopathy. CASE: A 65-year-old man, with a history of infection of his shoulder prosthesis, presented with multiorgan failure and notable myalgia likely caused by toxins. The patient was treated successfully with antibiotics and prosthesis removal. CONCLUSION: This case suggests infection by GGS should be considered in a patient presenting with myalgia associated with sepsis. LEARNING POINTS: Infection by GGS should be considered in a patient presenting with myalgia associated with sepsis.The differential diagnosis in this case included a neurological condition (meningitis or atypical Guillain-Barré syndrome) and sepsis with myopathy induced by bacterial toxins.Group G streptococcus (GGS) infection in a prosthetic shoulder was successfully treated with antibiotics and prosthesis removal.

Homeodomain-interacting protein kinase-2 restrains cytosolic phospholipase A2-dependent prostaglandin E2 generation in human colorectal cancer cells.

PURPOSE: Homeodomain-interacting protein kinase-2 (HIPK2), a corepressor for homeodomain transcription factors, is a multifunctional kinase whose role in tumor cell survival is not completely clarified. We addressed whether HIPK2 restrains colon tumorigenesis by turning off cytosolic phospholipase A2 (cPLA2)-dependent prostaglandin E2 (PGE2) generation in the light of overwhelming evidence suggesting the contribution of this prostanoid in a variety of cancers. EXPERIMENTAL DESIGN: In the human colorectal cancer cell line, RKO, we studied the effect of RNA interference for HIPK2 (HIPK2i) on prostanoid biosynthesis, both in the absence and in the presence of the cPLA2 inhibitor arachidonyl trifluoromethyl ketone. We evaluated the role of HIPK2 in the cPLA2 gene regulation by reverse transcriptase-PCR, transcriptional activity, and chromatin immunoprecipitation analyses. The involvement of HIPK2 in tumorigenicity in vivo was studied by tumor growth of HIPK2i cells in nude mice. We compared the gene expression of HIPK2 and cPLA2 in human colorectal cancer specimens by reverse transcriptase-PCR. RESULTS: HIPK2 silencing was associated with rousing PGE2 biosynthesis that was profoundly suppressed by the cPLA2 inhibitor. HIPK2 overexpression, along with histone deacetylase-1, inhibited the cPLA2-luc promoter that is strongly acetylated in HIPK2i cells. The tumors derived from HIPK2i cells injected in nude mice showed noticeably increased growth compared with parental cells. HIPK2 mRNA levels were significantly higher in colorectal cancers of patients with familial adenomatous polyposis, which showed undetectable cPLA2 levels compared with sporadic colorectal cancer expressing cPLA2. CONCLUSIONS: Our findings reveal the novel mechanism of HIPK2 to restrain progression of human colon tumorigenesis, at least in part, by turning off cPLA2-dependent PGE2 generation.

Oxidative Stress-Induced miR-200c Disrupts the Regulatory Loop Among SIRT1, FOXO1, and eNOS.

AIMS: Reactive oxygen species (ROS) play a pivotal role in different pathologic conditions, including ischemia, diabetes, and aging. We previously showed that ROS enhance miR-200c expression, causing endothelial cell (EC) apoptosis and senescence. Herein, we dissect the interaction among miR-200c and three strictly related proteins that modulate EC function and ROS production: sirtuin 1 (SIRT1), endothelial nitric oxide synthase (eNOS), and forkhead box O1 (FOXO1). Moreover, the role of miR-200c on ROS modulation was also investigated. RESULTS: We demonstrated that miR-200c directly targets SIRT1, eNOS, and FOXO1; via this mechanism, miR-200c decreased NO and increased the acetylation of SIRT1 targets, that is, FOXO1 and p53. FOXO1 acetylation inhibited its transcriptional activity on target genes, that is, SIRT1 and the ROS scavengers, catalase and manganese superoxide dismutase. In keeping, miR-200c increased ROS production and induced p66Shc protein phosphorylation in Ser-36; this mechanism upregulated ROS and inhibited FOXO1 transcription, reinforcing this molecular circuitry. These in vitro results were validated in three in vivo models of oxidative stress, that is, human skin fibroblasts from old donors, femoral arteries from old mice, and a murine model of hindlimb ischemia. In all cases, miR-200c was higher versus control and its targets, that is, SIRT1, eNOS, and FOXO1, were downmodulated. In the mouse hindlimb ischemia model, anti-miR-200c treatment rescued these targets and improved limb perfusion. Innovation and Conclusion: miR-200c disrupts SIRT1/FOXO1/eNOS regulatory loop. This event promotes ROS production and decreases NO, contributing to endothelial dysfunction under conditions of increased oxidative stress such as aging and ischemia. Antioxid. Redox Signal. 27, 328-344.

HIPK2 contributes to PCAF-mediated p53 acetylation and selective transactivation of p21Waf1 after nonapoptotic DNA damage.

The p53 tumor suppressor gene is activated in response to DNA damage resulting in either growth arrest or apoptosis. We previously demonstrated the specific involvement of homeodomain interacting protein-kinase 2 (HIPK2), a nuclear serine/threonine kinase, in inducing p53-dependent apoptosis through selective p53 phosphorylation at serine 46 after severe genotoxic damage. Here we show that HIPK2 contributes to p53 regulation, independently from serine 46 phosphorylation upon nonapoptotic DNA damage such as that induced by cytostatic doses of cisplatin. We show that HIPK2 depletion by RNA interference inhibits p53 binding to the p21Waf1 promoter affecting its p53-induced transactivation thereby allowing cell proliferation. We found that nonapoptotic DNA damage induces p53 acetylation mediated by the HAT protein PCAF and this p53 post-translational modification is abolished by HIPK2 depletion. In this regard, we found that HIPK2 cooperates with PCAF to induce selectively p53 transcriptional activity toward the p21Waf1 promoter while depletion of either HIPK2 or PCAF abolished this function. These data show that HIPK2 regulates the p53 growth arrest function through its PCAF-mediated acetylation.

HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function.

The p53 oncosuppressor protein is subject to negative regulation by MDM2, which efficiently inhibits its activity through an autoregulatory loop. In response to stress, however, p53 undergoes post-translational modifications that allow the protein to escape MDM2 control, accumulate, and become active. Recent studies have shown that, following DNA damage, the HIPK2 serine/threonine kinase binds and phosphorylates p53, inducing p53 transcriptional activity and apoptotic function. Here, we investigated the role of HIPK2 in the activation of p53 in the presence of MDM2. We found that HIPK2 rescues p53 transcriptional activity overcoming MDM2 inhibition, and that restoration of this p53 function induces apoptosis. Recovery of p53-dependent apoptosis is achieved by preventing p53 nuclear export and ubiquitination mediated by MDM2 in vitro and in vivo following genotoxic stress. These results shed new light on the mechanisms by which the HIPK2/p53 pathway promotes apoptosis and suppression of tumorigenesis.

HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations.

We address here the involvement of the homeodomain-interacting protein kinase 2 (HIPK2)/p53 complex on MDM2 regulation following apoptotic DNA damage. Our results provide a plausible transcriptional (p53-dependent) and posttranscriptional (p53-independent) double mechanism by which HIPK2 accomplishes MDM2 downmodulation. First, in wtp53-carrying cells HIPK2-dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level. Secondly, HIPK2 interacts with MDM2 in vitro and in vivo and promotes MDM2 nuclear export and proteasomal degradation, in p53-null cellular context. This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro. In response to DNA damage, depletion of HIPK2 by RNA-interference abolishes MDM2 protein degradation. We propose that HIPK2 contributes to drug-induced modulation of MDM2 activity at transcriptional (through p53Ser46 phosphorylation) and posttranscriptional (through p53-independent subcellular re-localization and proteasomal degradation) levels.

RelB/p52-mediated NF-κB signaling alters histone acetylation to increase the abundance of corticotropin-releasing hormone in human placenta.

Corticotropin-releasing hormone (CRH) produced in the placenta may be part of a clock that regulates the length of human gestation. Maternal plasma CRH abundance exponentially increases as pregnancy advances. Glucocorticoid stimulates CRH expression in full-term human placenta by promoting noncanonical (RelB/p52 heterodimer-mediated) nuclear factor κB (NF-κB) pathway activity. Using dexamethasone to mimic glucocorticoid exposure, we found that an epigenetic switch mediated the glucocorticoid-induced expression of CRH as gestation advances. The amount of acetylated histone H3 lysine 9 (H3K9) associated with the CRH promoter was greater in cytotrophoblasts from full-term placenta than in those from midterm placenta. Knocking down the lysine acetyltransferase CBP reduced H3K9 histone acetylation and prevented dexamethasone-induced CRH expression. Unexpectedly, knocking down the histone deacetylase HDAC1 or pharmacologically inhibiting type I and II HDACs also decreased the expression of CRH yet increased the acetylation of H3K9 and other histone regions. Both CBP and HDAC1 bound at the CRH promoter in a complex with the RelB/p52 heterodimer in a mutually dependent manner; knocking down any one factor in the complex prevented binding of the others as well as the dexamethasone-induced CRH expression. Our results suggest that glucocorticoids induce a transcription complex consisting of RelB/p52, CBP, and HDAC1 that triggers a dynamic acetylation-mediated epigenetic change to induce CRH expression in full-term human placenta.

Hypoxia-induced miR-210 modulates tissue response to acute peripheral ischemia.

AIMS: Peripheral artery disease is caused by the restriction or occlusion of arteries supplying the leg. Better understanding of the molecular mechanisms underpinning tissue response to ischemia is urgently needed to improve therapeutic options. The aim of this study is to investigate hypoxia-induced miR-210 regulation and its role in a mouse model of hindlimb ischemia. RESULTS: miR-210 expression was induced by femoral artery dissection. To study the role of miR-210, its function was inhibited by the systemic administration of a miR-210 complementary locked nucleic acid (LNA)-oligonucleotide (anti-miR-210). In the ischemic skeletal muscle, anti-miR-210 caused a marked decrease of miR-210 compared with LNA-scramble control, while miR-210 target expression increased accordingly. Histological evaluation of acute tissue damage showed that miR-210 inhibition increased both apoptosis at 1 day and necrosis at 3 days. Capillary density decrease caused by ischemia was significantly more pronounced in anti-miR-210-treated mice; residual limb perfusion decreased accordingly. To investigate the molecular mechanisms underpinning the increased damage triggered by miR-210 blockade, we tested the impact of anti-miR-210 treatment on the transcriptome. Gene expression analysis highlighted the deregulation of mitochondrial function and redox balance. Accordingly, oxidative damage was more severe in the ischemic limb of anti-miR-210-treated mice and miR-210 inhibition increased oxidative metabolism. Further, oxidative-stress resistant p66(Shc)-null mice displayed decreased tissue damage following ischemia. INNOVATION: This study identifies miR-210 as a crucial element in the adaptive mechanisms to acute peripheral ischemia. CONCLUSIONS: The physiopathological significance of miR-210 is context dependent. In the ischemic skeletal muscle it seems to be cytoprotective, regulating oxidative metabolism and oxidative stress.

Severe Kawasaki disease in a 3-month-old patient: a case report.

BACKGROUND: Kawasaki disease is a multi-system vasculitis which usually occurs in children under 5 years of age. In infants under three months of age, it is very rare and usually associated with a high incidence of incomplete or atypical forms, often unresponsive to treatment. This condition increases the risk of cardiovascular complications such as coronary artery aneurysms. CASE PRESENTATION: We describe a 3-month-old infant who developed early and severe aneurysms in three coronary arteries despite a timely administration of intravenous immunoglobulins, followed by three days of intravenous methylprednisolone. CONCLUSION: This case report underlines that the development of coronary artery aneurysm correlates with a delayed diagnosis and treatment, incomplete or atypical forms of the disease, and additionally the severity of clinical presentation, especially in cases of very young infants below 3 months of age. Our case is notable because of the very young age of the patient, the severity of clinical presentation with an early development of coronary artery aneurysms and the unresponsiveness to the therapy.

Urticaria and anaphylaxis in a child after inhalation of lentil vapours: a case report and literature review.

BACKGROUND: Among legumes, lentils seem to be the most common legume implicated in pediatric allergic reactions in the Mediterranean area and India, and usually they start early in life, below 4 years of age. CASE REPORT: A 22 -month-old child was admitted to our Pediatric Department for anaphylaxis and urticaria. At the age of 9 months she presented a first episode of angioedema and laryngeal obstruction, due to a second assumption of lentils in her diet. At admission we performed routine analyses that were all in the normal range, except for the dosage of specific IgE, that revealed a positive result for lentils. Prick tests too were positive for lentils, while they were all negative for other main food allergens. The child also performed a prick by prick that gave the same positive result (with a wheal of 8 mm of diameter). The child had not previously eaten lentils and other legumes, but her pathological anamnesis highlighted that the allergic reaction appeared soon after the inhalation of cooking lentil vapours when the child entered the kitchen Therefore a diagnosis of lentils vapours allergy was made. CONCLUSIONS: Our case shows the peculiarity of a very early onset. In literature there are no data on episodes of anaphylaxis in so young children, considering that our child was already on lentils exclusion diet. Therefore a diet of exclusion does not absolutely preserve patients from allergic reactions, that can develop also after their cooking steams inhalation.