Co-infections and multiple stressors in fish

16 Pág.Peer reviewe

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (–0.80%) and SF (–0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (–11.01 mL/m2 , p = 0.03) while for dp116 were correlated with decreased EF (–4.14%, p = Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD

Lo Scoglio del Tonno. La ceramica domestica di tipo egeo: produzioni locali e modelli egei

La ceramica domestica di uso comune da Scoglio del Tonno, i cui modelli richiamano affinità con quelli egei, è stata oggetto di indagine di analisi petrografia e chimica. I campioni sono stati selezionati sulla base di contenitori di modelli locali e modelli di uso comune di tipologia egea. Risultano non di produzione locale il piede di tripode tricostolato di tipologia rodiota e l’altro tripode con piede a stelo di tipologia egea, come due frammenti di contenitori da fuoco che non si riconoscono nelle produzioni locali. La presenza di tali importazione sottolinea un rapporto ed una funzione di presenza stabile sul territorio, non solo di approccio e scambio commerciale, della comunità micenea che si organizza con modalità diverse nell’arco di ca. tre secoli. E’ invece risultata di produzione locale, la ceramica grigia, i contenitori figulini torniti attribuibili alla seconda metà del XIII-XII sec. a.C. e due tripodi di tipologia egea

A case of rare meningioangiomatosis associated with cortical dysplasia

Meningioangiomatosis(MA) is a rare malformative or hamartomatous lesion involved in meninges and cortex. Although it was originally described in association with NF-2, recent studies have revealed that it occurs more frequently in sporadic form. The pathogenesis remains unclear. MA has distinct histological and biological features to meningioma(M) but their association(MA-M) isn’t unfrequent. Case report a 12-years-old male was referred to our paediatric division for a history of headhache associated to malformative lesions shown at a first radiological investigation (CT and MRI) done in other hospital when he was 6 years old. At that time, neurosurgeons recommended follow up program. The lesions haven’t change over the years, as shown at the follow-ups, however the persistence of headhache induced the family to request a second opinion. Our physical examination showed mental retardation. He had no family history or stigmata of NF2 and no seizure’s history, electroencephalography didn’t show anomalies. A head CT scan showed the presence of a right hyperdense single mass with gyriform signal pattern and clumped intralesional calcifications. MRI showed an intracranial mass measuring 2x3 × 2.5 cm located in the right posterior frontal cortex. The lesion was hyperintense on T2-weighted imaging and weakly hypointense on T1W1, with ring-like enhancement. MRI confirmed gyriform signal pattern associated to focal areas of cortical fronto-parietal dysplasia. The diagnosis of MA was made. Our patient didn’t present seizure and the lesions appeared stable compared with the previous MRI so, in compliance with the neurosurgeon’s advice, we established a long-term follow up program in association with symptomatic therapy for headhache. MA occurs mainly in children and younger adults with male predisposition, suffering from intractable seizure and less frequently headhache. Atypical symptoms included vomiting, diabetes insipidus, facial weakness, muscle atrophy and pain. MA is a single lesion usually stable or slowly growing. Imaging diagnoses for MA is difficult. The most common finding on CT is a round, single, hypodense mass with varying degrees of calcification. On MRI, the lesions seem confined to the cortex. On T1WI, MA shows a low or iso-intense signal, on T2WI lesions are more frequently hyperintense, but sometimes they can be hypointense. A gyriform signal pattern is common on either CT or MRI, typical of sporadic MA and it’s helpful to distinguish pure MA from MA-M

A case of short stature: a milder phenotypic spectrum of noonan syndrome?

BACKGROUND Noonan syndrome (NS) is an autosomal dominant disorder characterised by genotypic and phenotypic variability. The prevalence and global frequency of NS at live birth almost all over the world has been reported as one in 1000–2500 individuals. Various symptoms have been reported for this abnormality such as short stature, unusual facial characteristics, congenital heart abnormalities, developmental complications, and an elevated tumour incidence rate. Short stature is its most striking manifestation. At birth, they are usually a normal length and weight, but growth slows over time. More than 90 mutations causing Noonan syndrome have been identified in the PTPN11 gene, which is involved in protein tyrosine phosphatase SHP-2 expression, on chromosome 12 (12q24), account for up to 50% of NS patients. CASE REPORT A 5,6 year old girl was admitted to our institute because of short stature. Paternal family history was positive for short stature. Prenatal chromosomal analysis showed that the fetus had a karyotype of 46 XX; t (10;12)(q24,3; q24,31). The same translocation was found in her father. Many genes are involved in these two chromosomal locations, such as PTPN11 gene. Examination at the admission revealed non dismorfic phenotype, and bot her height and weight were below the 3rd percentile compared to the normal peers. Bone age was delayed respect her chronological age (3 years vs 5,6 years). Laboratory tests revealed TSHlevels increased(8,73 µUI/ml; normal range 0,30–4,50 µUI/ml), fT4 levels within the normal range and ACTH levels decreased (4,8 pg/ml; normal ranges 7–51 pg/ml).Using GH stimulation testing with Arginine and Glucagon,GH deficiency was confirmed: peak GH levels were 2,08 ng/ml and 5,6 ng/ml, respectively. Therefore, recombinant human GH was introduced(0,8 mg/day for six days in a week). ConclutionS A diagnosis of NS should be kept in mind in all patients with short stature. The genetic aetiology may not be clinically apparent because the underlying monogenic cause is quite rare and lacks distinctive features, or the patient may represent a milder phenotypic spectrum of the disorder, without all of the characteristic features. A genetic approach to the diagnosis of short stature is necessary in selected patients who are more likely to have a genetic contributor to their short stature

Vitamin D status and seasonal variation in a pediatric population: Not enough even in summer?

The paper analyzes the results of a study monitoring the Vitamin D status and its seasonal level variation in a pediatric population. In particular, it is discussed whether the levels of Vitamin D could be considered sufficient in the children monitored by the study during the summer season

A case of unsuspected pulmonary emboli in child with lymphoma

Background Pulmonary embolism (PE) is a potentially lethal condition. Although it’s usually manifested with severe symptoms causing right ventricular dysfunction or haemodynamic instability, in case of partial arterial obstruction it can be asymptomatic. Cancer patients are at high risk of thromboembolic complications. The use of contrast-enhanced computerised tomography for cancer staging has documented a high incidence of asymptomatic PE. Case presentation We present a case of unsuspected PE in paediatric oncology patient. A 10-year-old boy presented with cervical and axillary lymph node swellings. No response to antibiotic therapy. Infectivological tests (mononucleosis, tuberculosis, toxoplasmosis…) were negative. Staging imaging revealed a positron emission tomography/computed tomography (PET-CT) avid anterior mediastinal lymph node. There weren’t liver, spleen and lung injury. Excisional biopsy of the lymph node was consistent with an anaplastic large cell lymphoma ALK+, t(2;5). After positioning of central venous catheter (CVC), the patient began treatment with chemotherapy with reduction of the lymphadenopathy. Subsequently, repositioning of CVC due to malfunction and displacement. After three months, he performed restaging; CT showed bilateral thromboembolism of the pulmonary arteries with partial obstruction. Echocardiogram showed a blood pressure’s increase in pulmonary artery (PAP 38 mmHg) but the child didn’t present respiratory and cardiac symptoms. Echo-color-doppler didn’t report venous thrombosis of the legs. Laboratory tests showed high platelet count. d-dimer levels and activated partial thromboplastin time value were increased. Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) were normal. The patient discontinued chemotherapy and started standard anticoagulant treatment. Two weeks later, CT and ultrasound controls displayed substantial reduction of the obstruction of the pulmonary arteries and decrease of PAP. Conclusions Thromboembolic complications are frequent in children with lymphoma. Often, routine thoracic MDCT examinations of paediatric oncology patients reveal cases of unsuspected PE. It is necessary to identify children at an increased risk for the development of PE to define an appropriate management. However, recent studies have showed that the lack of diagnosis and treatment do not have a negative influence on patient outcome

UN CASO PRESSANTE DI LEISHMANIOSI

P.A., 7 anni 9 mesi, da 5 giorni astenia, febbre e addominalgie successive a trauma accidentale. Condotta in PS, vengono eseguiti esami ematici e TAC addome con riscontro di epatomegalia e splenomegalia (dl circa 30 cm). La piccola viene trasferita presso la U.O.C. di Chirurgia Pediatrica nel sospetto di rottura splenica. In tale sede, esclusa l’ipotesi chirurgica, per il riscontro di pancitopenia (GB 1570/ mcl, Hb 6 gr/dl, PLT 50.000/mcl) si inviava la paziente presso la nostra U.O.C. di Oncoematologia Pediatrica. All’ingresso in reparto la piccola presentava febbre (TC 38,8°C) e astenia. L’emocromo confermava la pancitopenia, l’ETG addome la splenomegalia (dl 25 cm). Si eseguiva aspirato midollare con evidenza di numerosi parassiti negli istiociti. L’esame sierologico è risultato positivo per leishmaniosi viscerale, (L. infantum, sierologia positiva:1/2560 (IFI)). Ha quindi iniziato trattamento con Ambisome (AmB, 3mg/kg per 5 gg) con miglioramento generale e riduzione della splenomegalia. Al gg+7 dalla terapia, comparsa di stato di incoscienza, areflessia, sguardo lateralizzato con pupille normoreagenti. All’EEG: “crisi subentranti con clonie oculari a dx>sn, talora suppresion burst”. Esegue RMN encefalo: “aree di alterato segnale che coinvolgono le regioni cerebrali parieto-occipitali ed il ponte: quadro suggestivo di Posterior Reversible Syndrome (PRES).” Trasferita in Rianimazione, ha iniziato terapia con IgHD e desametasone con miglioramento progressivo fino alla risoluzione dei segni clinici e dell’imaging. Nonostante la mancata somministrazione della 6° dose di AmB prevista al gg+10, si è assistito alla guarigione completa della parassitosi. La PRES è stata attribuita a tossicità farmacologica da Ambisome, antimicotico a veicolo liposomico, Nelle regioni del Mediterraneo, è il farmaco di scelta per il trattamento della Leishmaniosi viscerale, con efficace risposta e capacità di impedire recidive parassitarie. Tuttavia, l’Ambisome può causare disfunzioni renali, ipokaliemia, febbre e raramente una leucoencefalopatia, talora progressiva e fatale. Tale neurotossicità, dose correlata, è secondaria al legame del farmaco con la mielina, che provoca un aumento della permeabilità di membrana e dispersione delle componenti intracellulari. In conclusione, questo caso evidenzia l’importanza di tre elementi fondamentali nel percorso diagnostico- terapeutico della leishmaniosi viscerale in soggetti di età evolutiva: 1) la diagnosi differenziale con condizioni associate ad importante splenomegalia e simile presentazione clinica (ie: leucemie, linfomi, anemia emolitica, malaria, febbre tifoide, tubercolosi miliare, endocardite batterica, brucellosi, ipertensione portale); 2) un attento monitoraggio nella gestione terapeutica, tenendo presente i costi-benefici di un adeguato trattamento, anche se potenzialmente tossico; 3) l’accurata identificazione dell’agente eziologico, di grande importanza nel trattamento farmacologico perché specie diverse che infettano lo stesso tessuto possono presentare differente suscettibilità ad un determinato farmaco. Bibliografia 1. Sato M, Hirayanagi K, Makioka K, Ikeda Y. Reversal of leukoencephalopathy induced by liposomal amphotericin B in a patient with cryptococcal meningitis. J Neurol Sci. 2015 Mar 15;350(1-2):118-9. 2. di Martino L, Davidson RN, Giacchino R, Scotti S, Raimondi F, Castagnola E, Tasso L, Cascio A, Gradoni L, Gramiccia M, Pettoello-Mantovani M, Bryceson AD. Treatment of visceral leishmaniasis in children with liposomal amphotericin B. J Pediatr. 1997 Aug;131(2):271-7. 3. Antonini G, Morino S, Fiorelli M, Fazi P, Ceschin V, Petti C. Reversal of encephalopathy during treatment with amphotericin-B. J Neurol Sci. 1996 Dec;144(1-2):212-3

Deletion of gene coding for mitochondrial citrate carrier in C. elegans impairs the acetylcholine synthesis

The mitochondrial citrate carrier (CIC) encoded by the SLC25A1 gene, catalyzes the export of citrate from mitochondria to the cytosol where it is broken into acetyl-CoA and oxaloacetate. Acetyl-CoA can be used as building block for de novo synthesis of fatty acids or, in motoneurons, can be condensed to choline to give acetylcholine. Pathogenic SLC25A1 variants were identified in several patients (1, 2) that suffered from a severe neurodevelopmental syndrome (1) and CIC deficiency has been classified as an inborn disorder of metabolism (OMIM: 615182) whose hallmark is combined D-2- and L-2-hydroxyglutaric aciduria (2). More recently we reported a novel homozygous mutation in the SLC25A1 gene in an affected sib pair. Both patients presented with myasthenia and impaired neuromuscular junction (NMJ) transmission whilst no neurodevelopment disorder has been observed (3). Interestingly, the identified mutation in sib pair caused a milder activity impairment than the previously reported mutations suggesting a fundamental role of CIC in neuromuscular transmission whose defect was previously masked by the harsher phenotypes. Signal transmission at Neuromuscular junction (NMJ) relies on massive synthesis in motor neurons of acetylcholine. While the choline can be recycled after neurotransmitter release and breakdown in the synaptic cleft, the acetylCoA must be continuously generated by oxidative metabolism in mitochondria. Knocking down the SLC25A1 orthologues by injection of antisense morpholino oligonucleotides in zebrafish embryos showed short and erratic outgrowth of motor axons toward muscle fiber at NMJ suggesting that transmission impairment could be related to pre-synaptic nerve terminal abnormalities. Using the CRISPR/CAS9 approach we obtained stable lines of Caenorhabditis elegans knocked-out in the SLC25A1 ortholog that showed resistance to levamisole, a nicotinic acetylcholine receptor agonist, that causes continued stimulation of the worm muscles, leading to paralysis. This phenotype was, at least in part, rescued by the expression of wild-type SLC25A1 under the control of a neuron-specific promoter, strongly pointing towards an underlying pre-synaptic defect. qPCR analysis showed an up-regulation of genes involved in presynaptic acetylcholine biosynthesis and its release in the synaptic cleft, and a down-regulation of acetylcholine esterase. Furthermore, the amount of acetylcholine is decreased by about 50% in KO strain. Lipidomic analysis by mass spectrometry (HILIC-ESI-FTMS) showed no gross defect in lipogenesis. Altogether these data demonstrate a conserved role of CIC in neuromuscular transmission. Furthermore, our results validate the worm C. elegans as an animal model suitable for further study of the molecular and cellular underpinnings of the NMJ transmission defect associated to CIC deficiency 1. Edvardson et al. 2013 J Med Genet 50:240-5 2. Nota et al. 2013 Am J Hum Genet 92:627-31 3. Chaouch et al. 2014 J Neuromuscul Dis 1:75-9

Food intake in obese children and adolescents at higher risk for metabolic syndrome

The paper presents and discusses a study regarding the food intake in a population of obese children and adolescents who have been classified at high risk for metabolic syndrom