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Background and purpose: Ataxia‐telangiectasia (A‐T) is a rare neurodegenerative disease, due to A‐T mutated (ATM) gene mutations, which typically presents with signs of progressive neurological dysfunction, cerebellar ataxia and uncoordinated movements. A‐T severely affects patients’ quality of life. Successful treatment options are still not available. The aim of this multicenter study, performed with a blind evaluation procedure, was to define the minimal effective dosage of oral betamethasone, thus preventing the occurrence of side effects. Methods: Nine A‐T patients were enrolled to receive betamethasone at increasing dosages of 0.001, 0.005 and 0.01 mg/kg/day. Neurological assessment and the evaluation of quality of life were performed through the Scale for the Assessment and Rating of Ataxia and the Italian version of the Childhood Health Assessment Questionnaire (CHAQ) at each time‐point. The drug safety profile was evaluated. Patients were categorized as responders, partial responders and non‐responders. Results: Four of nine patients had a benefit at a dose of 0.005 mg/kg/day of oral betamethasone. Using the higher dosage, only one additional patient had a positive response. Conversely, a daily dose of 0.001 mg/kg was ineffective. A correlation between the serum adrenocorticotropic hormone levels and the clinical response was observed. Five of 30 CHAQ items improved in four patients. Conclusions: These data suggest that a short‐term betamethasone oral treatment, at a daily dosage of 0.005 mg/kg, is effective in some patients. Pre‐existing risk factors for side effects should be taken into account before therapy. [ABSTRACT FROM AUTHOR]

Background and purpose: Ataxia‐telangiectasia (A‐T) is a rare neurodegenerative disease, due to A‐T mutated (ATM) gene mutations, which typically presents with signs of progressive neurological dysfunction, cerebellar ataxia and uncoordinated movements. A‐T severely affects patients’ quality of life. Successful treatment options are still not available. The aim of this multicenter study, performed with a blind evaluation procedure, was to define the minimal effective dosage of oral betamethasone, thus preventing the occurrence of side effects. Methods: Nine A‐T patients were enrolled to receive betamethasone at increasing dosages of 0.001, 0.005 and 0.01 mg/kg/day. Neurological assessment and the evaluation of quality of life were performed through the Scale for the Assessment and Rating of Ataxia and the Italian version of the Childhood Health Assessment Questionnaire (CHAQ) at each time‐point. The drug safety profile was evaluated. Patients were categorized as responders, partial responders and non‐responders. Results: Four of nine patients had a benefit at a dose of 0.005 mg/kg/day of oral betamethasone. Using the higher dosage, only one additional patient had a positive response. Conversely, a daily dose of 0.001 mg/kg was ineffective. A correlation between the serum adrenocorticotropic hormone levels and the clinical response was observed. Five of 30 CHAQ items improved in four patients. Conclusions: These data suggest that a short‐term betamethasone oral treatment, at a daily dosage of 0.005 mg/kg, is effective in some patients. Pre‐existing risk factors for side effects should be taken into account before therapy. [ABSTRACT FROM AUTHOR]

The erythrocyte skeleton plays an essential role in determining the shape and deformability of the red cell. Disruption of the interaction between components of the red cell membrane skeleton may cause loss of structural and functional integrity of the membrane. Several observations based on studies in vitro strongly suggest that phosphorylation may modify interactions between proteins, leading to a reduced affinity. In particular, increased phosphorylation of beta-spectrin decreases membrane mechanical stability. In order to investigate the presence of membrane protein defects we investigated the erythrocyte membrane protein composition and phosphorylation in 22 children with leukemia at diagnosis and during the remission phase. Sixteen children had acute lymphoblastic leukemia (ALL), three had chronic myeloid leukemia (CML) and three had acute myeloid leukemia (AML). Ten patients (eight ALL and two CML) displayed elliptocytosis and poikilocytosis, an increase of spectrin dimers (41.8 +/- 15.6) and an enhanced phosphorylation of beta-spectrin (108 +/- 15%) at diagnosis. These alterations disappeared during the remission phase. This is the first demonstration of a reversible erythrocyte membrane alteration in leukemia. Since the beta-spectrin phosphate sites are located near the C-terminal region and close to the head of the beta-chain that is involved in dimer-dimer interaction, we supposed that the beta-chain phosphorylation has an effect upon the interactions between spectrin dimers, ie the tetramerization process. The weakening of this process should be responsible for the presence of elliptocytes and poikilocytes as reported in hereditary elliptocytosis and pyropoikilocytosis. [ABSTRACT FROM AUTHOR]

We report an analysis of the stretching peak appearing in the IR experimental spectra of liquid water. In the literature, ATR-IR spectroscopic measurements were repeatedly performed in a wide range of temperature and gave rise to a lively debate among scientists. In particular a two components model related to H-bond complexes of different strength have been proposed in order to justify the existence of two types of molecules as it appears from the spectroscopic data. At the opposite, Molecular Dynamics simulations support a multistate (continuum) system of H-bond having different strength giving rise to a (locally) tetrahedral description of liquid water. We will show that liquid water is a quantum two-level system according to the predictions of Quantum Electrodynamics (QED) and that several features (the asymmetric band profile, the existence of an isosbestic point and the modifications of the vibrational stretching band with the temperature) cannot be fully justified in the realm of a classical picture. In particular the differences of energy and entropy between the two phases are estimated from the experimental data and compared with the prediction of QED showing a remarkable agreement. The behaviour of water near hydrophilic surfaces is also discussed and several feature of the so-called "Exclusion Zone" observed by several authors are evaluated according to the two level system model. [ABSTRACT FROM AUTHOR]

By resorting to measurements of physically characterizing observables of water samples perturbed by the presence of Nafion and by iterative filtration processes, we discuss their scale free, self-similar fractal properties. By use of algebraic methods, the isomorphism is proved between such self-similarity features and the deformed coherent state formalism. [ABSTRACT FROM AUTHOR]

Adults with normal glucose tolerance (NGT) but exaggerated plasma glucose excursion at 1 h (1HPG) following the oral glucose tolerance test (OGTT) have significantly higher risk of developing impaired glucose tolerance (IGT) or diabetes. Aim of the study will be to characterize the metabolic phenotype of NGT obese youth according to values of 1HPG. To accomplish this aim, obese patients ( N = 1,454; 761 men; 79 IGT; BMI z-score 2.56 ± 0.16 SDS; age 11 ± 0.7 years) from two data sets were analyzed. In all patients, empirical parameters of insulin metabolism were calculated in fasting condition and following an OGTT (1.75 mg of glucose per kilogram/body weight). Receiver-operating characteristic (ROC) analysis was performed in the first group (training set, N = 920) to establish the cutoff value of 1HPG best identifying IGT. The second set (validation set, N = 534) served to verify the goodness of the model and the identified cutoff values. 1HPG ≥ 132.5 mg/dl identified IGT with 80.8% sensitivity and 74.3% specificity in the training set (AUC 0.855, 95% CI 0.808-0.902, p < 0.0001), and 70.3% sensitivity and 80% specificity in the validation set (AUC 0.81, 95% CI 0.713-0.907, p < 0.0001), respectively. NGT patients with 1HPG ≥ 132.5 mg/dl had a metabolic phenotype (triglycerides, insulin action, and secretion) that was in between those of NGT patients with 1HPG below the threshold and IGT patients ( p < 0.0001 for all the comparisons). 1HPG ≥ 132.5 mg/dl seems to be associated with increased metabolic risk in obese youth, identifying patients with lower insulin sensitivity, early secretion, and higher total insulin secretion than in obese mates with lower 1HPG. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (A-T) is a non-curable neurodegenerative disorder, associated with progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, predisposition to cancer and radiosensitivity. A recent study documented improvement in neurological symptoms after a short-term therapy with betamethasone in patients with A-T. Aim of this study was to evaluate the minimum therapeutically effective dosage of betamethasone on neurological symptoms of A-T. Six responsive patients with A-T, received two 20-day cycles of oral betamethasone at 0.01 and 0.03 mg/kg/day (10% and 30% of the previously used full dosage), each followed by a 20-day washout period. Clinical and laboratory evaluations were carried out at T0 and at the end of each cycle. Neurological assessment was performed through the Scale for the Assessment and Rating of Ataxia (SARA). The glucocorticoid-induced leucine zipper (GILZ) and glucocorticoid receptor (GR) RNA expression were evaluated before and during the trial through real-time PCR. SARA scores significantly improved in all patients at the dosage of 0.03 mg/kg/day. In particular, three patients exhibited an improvement in 5/8 variables and two patients of 7 and 8 variables, respectively. Furthermore, the clinical improvement was already evident after the lower dosage. The basal GILZ and GR RNA expression were significantly lower in patients than in controls. GILZ expression increased in all patients after the beginning of the therapy, whereas no correlation between GR and the response was found. Our data indicate that betamethasone is effective in A-T at a minimal dosage and that GILZ may be a useful biomarker of the clinical response. This study provides Class IIIA evidence that betamethasone at very low dosage is effective in improving neurological signs of patients affected with ataxia-telangiectasia. [ABSTRACT FROM AUTHOR]

We show that in nonlinear systems dynamical order can be reached through the flows of matter, energy, and information, which can be non uniformly spread over the organism due to self-trapping induced by the correlated coherence domains of interfacial water. Endogenous electromagnetic field is self trapped in these domains and forms the dynamical pathways as wave-guides, along which these flows can occur via soliton mechanisms. Solitons in the pathways can be stimulated either by intrinsic dynamics or by external stimuli and can be visualized in the infrared range as bright or dark solitons. The formation of such pathways is the consequence of coherence-non coherence transitions occurring in the biological cycle of the organism. A rational therapy appears then to be the induction of conditions for soliton existence necessary for maintaining the coherence of the system. [ABSTRACT FROM AUTHOR]

N-acylethanolamines, which include the endocannabinoid anandamide and the cannabinoid receptor-inactive saturated compounds N-palmitoyl ethanolamine and N-stearoyl ethanolamine, are ethanolamines of long-chain fatty acids degraded by fatty acid amide hydrolase (FAAH) known to accumulate in degenerating tissues and cells. Whilst much evidence supports a protective anti-inflammatory role of both anandamide and N-palmitoyl ethanolamine, very little information is available with regard to the bioactivity of N-stearoyl ethanolamine. Employing a murine model of passive IgE-induced cutaneous anaphylaxis, we have found that N-stearoyl ethanolamine is endowed with marked anti-inflammatory properties in vivo, supporting the hypothesis that endogenous N-stearoyl ethanolamine is, in analogy to N-palmitoyl ethanolamine, a bioactive signalling lipid capable of downregulating allergic inflammation in the skin. This effect, although mimicked by synthetic, non-selective, CB1/CB2 receptor agonists, such as WIN55, 212-2, was not sensitive to CB1 or CB2 receptor antagonists, but rather was fully reversed by capsazepine, a competitive antagonist of the TRPV1 receptor. Moreover, CB1 receptor antagonists, although effective in antagonising the WIN55,212-2-induced hypothermia, did not reduce the anti-inflammatory effect of WIN55,212-2, whilst CB2 receptor antagonists, per se inactive, potentiated the WIN55,212-2 effect, suggesting an involvement of non-CB1/CB2 receptors in the anti-inflammatory action of WIN55,212-2. All this, together with demonstration of FAAH as a major regulator of the in vivo concentrations of saturated N-stearoyl ethanolamine, in addition to N-palmitoyl ethanolamine, raise the speculation that pharmacological treatments with saturated N-acylethanolamines such as N-stearoyl ethanolamine, or alternatively FAAH inhibitors able to increase their local concentration, rather than selective CB receptor agonists, might be of promising therapeutic benefit in reducing allergic inflammation in the skin. [ABSTRACT FROM AUTHOR]

A recent clinical observation reported on a dramatic improvement of neurological symptoms following short-term betamethasone administration in a child affected with ataxia-teleangiectasia (A-T). The aim of this study was to extend this observation to additional A-T patients followed at a single Immunodeficiency Center. Six consecutive patients (three males; mean age 16.3 years, range 5–30 years) were enrolled into this monocentric before–after trial. A cycle of oral betamethasone at the dosage of 0.1 mg/kg/day was administered for 10 days. The neurological evaluation was performed through the Scale for the Assessment and Rating of Ataxia. Overall, five of the six patients exhibited a clear amelioration of the neurological performances. Only in two patients, a slight amelioration persisted 7 days after the therapy withdrawal, whilst in the other patients the score reached approximately the pre-treatment value at the end of the therapy. Twenty-eight of the 46 evaluated neurological items (60%) improved during therapy. The speech disturbance, finger chase and nose–finger test showed the more significant improvement. The clinical amelioration was inversely correlated with the level of cerebellum atrophy, as revealed by the magnetic resonance. Our data indicate that neurological signs in A-T are susceptible of beneficial pharmacological intervention even years after the disease onset. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the prevalence of functional gastrointestinal disorders (FGIDs) in children with migraine headache and the effects of flunarizine on gastrointestinal manifestations. We studied 50 migrainous children (mean age 8.63 years). The clinical pattern and the diagnosis of FGIDs were obtained from structured questionnaires. All subjects underwent measurement of total gastric emptying time (TGEt) performed by real-time ultrasonography of the gastric antrum at baseline (T0). In the second part of the study, we evaluated 10 migrainous children (mean age 9.8 years) with associated FGIDs. In these 10 patients, repeated TGEt evaluation together with a detailed symptom history was obtained after 1 (T1) and 2 months (T2) of treatment with flunarizine. Control groups were composed of 10 migrainous children without FGIDs (mean age 9.2 years) and nine sex- and age-matched healthy children. Gastrointestinal disorders were present in 70% of the patients. Migrainous children with FGIDs had significantly ( P < 0.01) more prolonged TGEt than subjects without FGIDs. Prior to therapy, all migrainous children with FGIDs had prolongation of TGEt compared with controls ( P < 0.05). Patients on flunarizine had a significant decrease in TGEt at both 1 ( P < 0.01) and 2 months ( P = 0.002) of therapy. The mean frequency of abdominal pain per month was significantly ( P < 0.001) reduced at T1 compared with T0. The mean frequency of vomiting per month was significantly decreased at T1 ( P < 0.05) and even more so at T2 ( P < 0.01). Finally, the mean frequency of headache per month was significantly reduced only at T2 ( P < 0.05), whereas the mean duration of headache was significantly decreased at T1 ( P < 0.01) with no difference between T1 and T2. Most children with migraine report FGIDs, associated with a delayed gastric emptying. Flunarizine decreases the frequency and duration of migrainous episodes as well as the gastrointestinal symptoms. [ABSTRACT FROM AUTHOR]

Presents the first pediatric case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) associated with a fatal hemophagocytic lymphohistiocytosis (HLH). Development of weakness of the lower limbs in the context of a picture of infectious mononucleosis and Epstein-Barr virus infection; Finding of a compound heterozygosity for two mutations in the perforin gene.

Glasses are known to possess some puzzling features among condensed matter systems, as shown by the Kauzmann paradox. We show that if the coherent interaction mechanisms of Quantum Electrodynamics are taken into account, glasses are nothing but molecular liquids in which a large fraction of the molecules enter a collective, coherent state. In this conceptual framework the temperature of glass formation can be identified with the temperature at which the non-coherent fraction vanishes. Using a recently developed treatment of liquid water where QED interactions are not neglected, we suggest a possible interpretation of the surprising finding of two low-temperature water amorphs and of their phase-transition. [ABSTRACT FROM AUTHOR]

BACKGROUND: Melanocortin-4 receptor (MC4R) mutations have been reported as the most common single genetic cause of obesity in some populations and it has been suggested that they may be responsible for more than 4% of early-onset obesity. OBJECTIVES: To verify the presence of mutations of the MC4R coding region in children from southern Italy with early-onset obesity. SUBJECTS AND METHODS: Two-hundred and eight unrelated obese children and adolescents were included in the study. The average age at obesity onset was 4.5±2.6y. MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC). Automatic sequencing of PCR products of all individuals that showed an aberrant SSCP and/or DHPLC pattern was performed. RESULTS: One novel missense mutation and one previously described polymorphism (Vall03lle) were identified. The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI) = 35 kg/m²) who has been obese since she was 8 y old. The mutation co-segregated with the obesity phenotype for over three generations and was not found in the control population. CONCLUSIONS: Our data show MC4R obesity causing mutations in less than 0.5% of the patients (ie 1 out of 208 patients) and therefore indicate a low prevalence of MC4R variants in the obese population from southern Italy. The specific genetic background of the Mediterranean population could make it difficult for MC4R mutations to produce an essentially polygenic trait such as common obesity, at least during childhood. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although linkage studies strongly suggest that proopiomelanocortin (POMC) alterations could play a role in the genetic predisposition to obesity, systematic POMC mutational analysis did not completely confirm this hypothesis. OBJECTIVES: To verify the presence of mutations of the POMC coding region in Italian children with very early onset obesity. SUBJECTS AND METHODS: Eighty seven unrelated Italian obese children and adolescents were studied. Mean age at obesity onset was 4.7 ± 2.5y. The POMC gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern. RESULTS: Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the POMC signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-proopiomelanocortin signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the β-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than obese subjects homozyous for the POMC wild-type allele. CONCLUSIONS: Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-proopiomelanocortin into the endoplasmic reticulum and, therefore, can be implicated in obesity. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between obesity and POMC. [ABSTRACT FROM AUTHOR]

Explains an approach to the dynamical evolution of a waveguide laser which goes beyond the Maxwell-Bloch equations. Theory of a simple waveguide laser; Phase of the matter quantum field that describes the atomic systems; Effects of dephasing of the electromagnetic laser field.

A Leu34Phe mutation in the cocaine- and amphetamine-regulated transcript (CART) gene has been associated with severe early-onset obesity in an affected family. It has been shown that, in a cell culture system, the mutation resulted in altered CART peptide levels, and animal studies suggest that CART is involved in anxiety as well. The availability of the affected family allowed for testing of anxiety and other traits in humans carrying a mutation in CART gene. This study shows that a small group of adolescents with the mutation exhibit higher anxiety and depression scores than control subjects. Depression and Anxiety 23:90–92, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about CART, a regulated neuropeptide that plays a role in many physiological processes including stress, reward and reinforcement and feeding, published online on August 24, 2004.

Background and purpose: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by alterations of the A-T mutated (ATM) gene. Although A-T is a noncurable disease, we, previously, documented a clear improvement of cerebellar functions during a short-term betamethasone trial. The aim of this study was to define the underlying biochemical mechanism. Methods: In six A-T patients receiving a short-term steroid therapy, intracellular glutathione (GSH) levels were evaluated with a colorimetric assay. The lipid peroxidation level and reactive oxygen species (ROS) production were evaluated using commercial assays. All the parameters were compared with the improvement of cerebellar functions expressed as delta (Δ) of the Scale for the Assessment and Rating of Ataxia (SARA). Results: We observed an inverse correlation between Δ SARA and the severity of cerebellar atrophy and between the latter and basal GSH values. Four of the five patients with the highest Δ SARA also had the highest GSH values. Moreover, even though basal ROS values were comparable in patients and controls, in the only patient studied at different time-points of therapy, a remarkable reduction in ROS levels was documented. Conclusion: We suggest that antioxidative mechanisms play a role in favouring the improvement of cerebellar functions observed in A-T patients receiving a short-term betamethasone trial. [ABSTRACT FROM AUTHOR]

Abstract: The first passage times for the formation of the first nucleus of three deposits (α-PbO2, Ag and Hg) on a carbon microelectrode disk of area=5×10−7 cm2 are compared with the models of such processes. It is shown that the interpretation of the data requires us to assume that nucleation starts with the formation of incoherent clusters. The transition to spontaneous crystal growth is suggested to be the consequence of the development of coherence domains in the electrodeposit. [Copyright &y& Elsevier]

The electrolytic insertion of hydrogen into Pd79.5Rh20.5 (at.%) alloy from acid and alkaline electrolytes was investigated in the temperature range 25–95 °C. It was found that, at 25 °C, the alloy can be loaded up to hydrogen to metal (H/M) ratios (0.90 in acid, 0.95 in alkaline electrolytes) comparable to those achieved by H2 pressures above 108 Pa. The desorption isotherm of β hydride obtained in 0.5 M H2SO4 at 25 °C and the thermal decomposition of this phase do not differ greatly from the expectations of the thermodynamics of the Pd80Rh20 system. At temperatures above 25 °C, high H/M ratios (from 0.95 to 0.93) and the unpredicted thermal stability of the β hydride phase were found only after cathodic loading in alkaline electrolytes. The phenomenon is explained by co-deposition of hydrogen and alkali metal on the alloy, which partially hinders the exit of loaded hydrogen. [Copyright &y& Elsevier]

Abstract: We characterise the fluctuations in the observation of the first passage times for the formation of the first nucleus by the variance of the observations. It is shown that the variance is much smaller than that predicted on the basis of the presently accepted approach which has been used to explain nucleation phenomena; this effect is regarded as an indication that the thermal noise in the interfacial region is much lower than expected. [Copyright &y& Elsevier]

Limb girdle muscular dystrophy 2A (LGMD2A), caused by calpain 3 deficiency, is currently diagnosed through the immunodetection of muscle protein by Western blot (WB) analysis . However, WB may provide normal results in patients with LGMD2A. The case of a female (3y 6mo of age) is described. She was found to be affected by asymptomatic hypercreatine-kinaesaemia during routine biochemical analysis at 10 months of age and had developed myopathic signs at the last neurological assessment. The WB of muscle biopsy performed at 28 months of age showed a normal quantity and pattern of bands for calpain 3. Despite this finding, on molecular analysis she was found to be a compound heterozygote for two mutations of the calpain 3 (CAPN3) gene (R110X and G222R). Autocatalytic activity assay showed a loss of function of calpain 3. This is the first genetically confirmed case of very early onset calpainopathy with a normal amount of protein at WB. Molecular analysis is also suggested in very young patients with normal WB. [ABSTRACT FROM AUTHOR]

A quiz concerning the diagnosis of haemorrhagic gastritis in a neurologically impaired boy is presented.

Primary autosomal recessive microcephaly ( MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing ( WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c. 2953A>G; pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism ( PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction. [ABSTRACT FROM AUTHOR]

Summary: Background: The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver‐derived triglyceride‐rich lipoproteins. Objectives: The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. Methods: We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3 I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. Results: The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low‐density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non‐high‐density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8–39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. Conclusion: Although the TMS6SF2 E167K variant predisposes the obese children to non‐alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health. [ABSTRACT FROM AUTHOR]

On March 2020, COVID-19 has been declared as a pandemic emergency by World Health Organization (WHO). One paediatric patient had asthma (7%) and another patient had celiac disease and allergy. Twenty-three patients were adults with age ranging from 35 to 72 years, eight patients (35%) were male and 15 (65%) female, 12/23 (52%) had no previous disease. [Extracted from the article]

The article presents a study which shows that patients affected by dent disease 2 could be predisposed to hidradenitis suppurativa (HS). Topics include the lesions started as ‘blind' deep inflammatory nodules and subsequently developed into abscesses, and the primum movens in the HS pathophysiological mechanism is stated to be occlusion followed by inflammation of the hair follicle.

Objectives: To investigate whether the functional variant Q63R of the cannabinoid 2 (CB2) receptor is associated with susceptibility to oligo/poly-articular juvenile idiopathic arthritis (JIA) and with its clinical features. Method: A total of 171 Italian children with oligoarticular/rheumatoid factor negative poly-articular JIA and 600 healthy controls were enrolled in the study and genotyped. Results: A significant difference in genotype distribution of the CB2 Q63R variant ( CNR2 rs35761398) between oligo/poly-articular JIA patients and controls was found ( p = 0.001). The R63 variant was associated with increased rates of relapse ( p = 0.0001). Conclusions: This study indicates that the CB2 receptor contributes to susceptibility to oligo/polyarticular JIA and to the severity of its clinical course. [ABSTRACT FROM AUTHOR]

What is already known about this subject Fasting triglycerides above 1.17 mmol/L have been shown to be useful to select obese children and adolescents who may present impaired glucose tolerance in a Canadian cohort., Fasting plasma glucose is associated with the risk to present impaired glucose tolerance in several cohorts of obese children and adolescents., What this study adds When applied to Italian cohorts of obese children and adolescents, the triglycerides cut-off of 1.17 mmol/L has similar validity as in the Canadian cohort to select patients who may present impaired glucose tolerance., Fasting plasma glucose and fasting triglycerides can be combined to obtain an accurate criterion to select obese children and adolescents who may present impaired glucose tolerance., Objectives We aimed to validate fasting triglycerides > 1.17 mmol L−1, a criterion recently proposed for selecting obese children at risk of impaired glucose tolerance ( IGT), and to assess whether the accuracy of triglycerides ( TG) can be improved by the use of other variables. Methods We studied an Italian cohort of 817 obese children and adolescents (8-18.4 years) who underwent clinical examination, fasting blood analysis and the oral glucose tolerance test ( OGTT). The discriminative properties of TG > 1.17 mmol L−1 were assessed and compared with those observed in a Canadian cohort from which this criterion was derived: 71.4 [57.8-85.1]% sensitivity and 64.1 [57.7-70.4]% specificity. The possible contribution of other variables was evaluated by assessing the net reclassification improvement ( NRI), i.e., the net increase in the percentage of subjects correctly classified. Results Thirty-nine children (4.7%) had IGT. The 1.17 mmol L−1 TG threshold showed 66.6 [51.8-81.4]% sensitivity and 68.2 [64.9-71.5]% specificity, thus successfully validated. Fasting plasma glucose ( FPG) was independently associated with IGT (odds ratio = 3.86 [2.09-7.14], P < 0.001), besides TG. The bivariate criterion of TG ≥ 1.13 mmol L−1 plus FPG ≥ 4.44 mmol L−1 had a 69.2 [54.7-83.7]% sensitivity and a 78.2 [76.8-79.6]% specificity, thus displaying a 12.6% NRI ( P < 0.001) compared with TG>1.17 mmol L−1. Conclusions TG > 1.17 mmol L−1 is a useful criterion to detect roughly 66% of obese children with IGT through OGTT performed in about 33% of all obese children. However, the ' TG≥1.13 mmol L−1 plus FPG≥4.44 mmol L−1' criterion improved discrimination accuracy, leading to the possibility of detecting even more than 66% of obese children with IGT though limiting OGTT to just 25% of all obese children. [ABSTRACT FROM AUTHOR]

The patatin-like phospholipase domain-containing 3 gene ( PNPLA3) and the apolipoprotein C3 gene ( APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C ( n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M ( P = 0.034) and p.148M/M ( P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis ( P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes ( P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis. [ABSTRACT FROM AUTHOR]

We recently described the neuroimaging and clinical findings in 6 children with cerebellar clefts and proposed that they result from disruptive changes following prenatal cerebellar hemorrhage. We now report an additional series of 9 patients analyzing the clinical and neuroimaging findings. The clefts were located in the left cerebellar hemisphere in 5 cases, in the right in 3, and bilaterally in one child who had bilateral cerebellar hemorrhages as a preterm infant at 30 weeks gestation. In one patient born at 24 weeks of gestation a unilateral cerebellar hemorrhage has been found at the age of 4 months. Other findings included disordered alignment of the folia and fissures, an irregular gray/white matter junction, and abnormal arborization of the white matter in all cases. Supratentorial abnormalities were found in 4 cases. All but 2 patients were born at term. We confirm the distinct neuroimaging pattern of cerebellar clefts. Considering the documented fetal cerebellar hemorrhage in our first series, we postulate that cerebellar clefts usually represent residual disruptive changes after a prenatal cerebellar hemorrhage. Exceptionally, as now documented in 2 patients, cerebellar clefts can be found after neonatal cerebellar hemorrhages in preterm infants. The short-term outcome in these children was variable. [ABSTRACT FROM AUTHOR]

Background : Drug-resistant mutants may emerge in patients with chronic hepatitis B receiving lamivudine therapy. Aim : To evaluate whether different viral mutational patterns may be associated with clinical reactivation during lamivudine treatment in patients with chronic B hepatitis. Methods : Eight anti-hepatitis B e-positive patients with (group A) and 14 patients without clinical exacerbation (five anti-hepatitis B e-positive, group B1; nine hepatitis B e antigen-positive, group B2) during lamivudine treatment were investigated. Results : ‘Polymerase region’: M204V/I variants were found in all group A patients, but in none of group B1 ( P = 0.0007) and in four of nine of group B2 (44%; P = 0.02) patients. The L180M substitution was detected in four of eight (50%) of group A and in none of groups B1 and B2. ‘Core promoter’: the double basic core promoter (A1762T/G1764A) variant was detected in seven of eight (87%) of group A and in one of five (20%; P = 0.03) of group B1 and one of nine (11%; P = 0.002) of group B2 patients. ‘Precore’: the G1896A stop codon mutation was present in seven of eight (87%) of group A and in zero of five ( P = 0.004) of group B1 and one of nine (11%; P = 0.002) of group B2. Conclusions : Different mutational patterns were observed in the lamivudine-treated patients with and without exacerbation. There was an association of the basic core promoter and stop codon mutations with lamivudine resistance in patients with disease exacerbation. [ABSTRACT FROM AUTHOR]

BACKGROUND: The management of subclinical hypothyroidism (SH) is still controversial, as the benefit to risk ratio of prolonged L-thyroxine therapy is not clear cut. Some authors have shown abnormalities of myocardial function and structure in adults with SH, which could be reversed by L-thyroxine therapy. As SH frequently affects children with Down's syndrome (DS), and almost one half of these are affected by congenital heart disease, a concomitant SH related impairment of cardiac function might further compromise their clinical condition. AIMS: To establish whether SH influences myocardial structure and function in children with DS. METHODS: Sixteen children with DS and untreated SH and 25 matched euthyroid controls with DS underwent echocardiographic analysis of left ventricular mechanics and tissue characterisation. RESULTS: None of the 16 patients had myocardial impairment. CONCLUSION: Results suggest that children with DS who have SH are not at risk of cardiac disease. Clinicians should consider these data in the management of SH, as the benefit to risk ratio of prolonged L-thyroxine therapy is not clear cut. [ABSTRACT FROM AUTHOR]

We analysed the hepatitis B virus (HBV) core-promoter (CP) and precore (PC) regions before, during and after interferon treatment in young Caucasian cancer survivors who had acquired HBV infection during chemotherapy for malignancies. Fourteen patients with chronic hepatitis B [hepatitis B e antigen (HBeAg) /HBV-DNA positive] received α-2a interferon (IFN), 5 MU/m2 t.i.w. for 12 months. HBV CP and PC region sequences were analysed following polymerase chain reaction (PCR) amplification. Sera from responders were studied at: T0 (before starting IFN), T1 [at alanine aminotransferase (ALT) peak preceding HBeAg seroconversion], T2 (at ALT normalization), T3 (at end of IFN) and T4 (at one year after IFN) and in nonresponders at time points T0 , T3 and T4 . Amplified HBV-DNA was cloned and sequenced automatically. Six of 14 patients (43%) responded to IFN treatment. Five of the six (83%) responders displayed the double CP mutation A1762T/G1764A always in association with a T1753C change. None of the nonresponders showed these mutations at any time point. The G1896A change creating the PC stop codon mutation was never detected in any of the patients. In our cancer survivors, IFN-induced HBeAg/anti-HBe seroconversion appeared to correlate with CP mutations and was not influenced by previous chemotherapy. These mutations in addition to low HBV DNA levels and elevated ALT can be considered favourable factors of response to IFN-induced anti-HBe seroconversion. [ABSTRACT FROM AUTHOR]

Cocaine- and amphetamine-regulated transcript (CART) inhibits feeding and induces the expression of c-Fos in hypothalamic areas implicated in appetite regulation. Furthermore, the CART peptide is found in neurons regulating sympathetic outflow, which in turn play an integral role in regulating body temperature and energy expenditure. The CART gene was screened by single-strand conformation polymorphism and automatic sequencing in 130 (72 girls) unrelated obese Italian children and adolescents. Their Z-scores (mean +/- SD) of relative to BMI percentiles was 3.9 +/- 1.8, and the average age at obesity onset was 4.7 +/- 2.6 years. Two previously described silent polymorphisms were found in the 3' untranslated region: an adenine deletion at position 1457 in 9 patients (allele frequency 0.035) and an A/G substitution at position 1475 in 11 patients (allele frequency 0.042). We found no difference between the obese patients heterozygous for one of these polymorphisms and those patients homozygous for the wild allele with respect to their age of obesity onset, BMI Z-scores, and leptin levels. A missense mutation of G729C resulting in the substitution of Leu with Phe at codon 34, within the NH2-terminal CART region, has been detected in the heterozygous state in a 10-year-old obese boy who has been obese since the age of 2 years. The patient belongs to a large family of obese subjects. The mutation cosegregated with the severe obesity phenotype over three generations and was not found in the control population. Resting metabolic rates were lower than expected in the propositus (-14%) and his mother (-16%), who carried the mutation. Leucine at codon 34, conserved in this position in the human and in the rat sequences, immediately precedes a couple of lysine residues that may well represent a dibasic processing site. The Leu34Phe mutation might alter the susceptibility to proteolysis of this potential processing site, likely altering the CART effect on thermogenesis and energy expenditure. [ABSTRACT FROM AUTHOR]

Congenital dyserythropoietic anaemia type II (CDA II) is the most common congenital dyserythropoietic anaemia. CDA II is frequently misdiagnosed as Hereditary Spherocytosis (HS) due to the presence of mild chronic haemolytic anaemia with splenomegaly, increased osmotic fragility, and presence of microspherocytes. Accurate diagnosis of CDA II is important to prevent severe iron overload. Erythrocyte and reticulocyte indices were assessed in 10 patients from six families with CDA II, 18 patients from eight families with HS, and 50 normal controls. Characteristic increases in distribution width were present in CDA II for cell volume (RDW, anisocytosis) and in HS for cell haemoglobin concentration (HDW, anisochromia), resulting in an RDW/HDW ratio which was significantly greater in CDA than HS (P < 0.0002). A cut-off value for RDW/HDW of 5.34 resulted in 89% sensitivity and 70% specificity in distinguishing CDA II from HS. Distribution width for cell haemoglobin content of reticulocytes (CHDWr) was characteristically increased in CDA II, resulting in a CHDW/CHDWr ratio significantly lower in CDA II than HS (P < 0.0002). A cut-off value of 0.98 provided 89% sensitivity and 80% specificity in distinguishing CDA II from HS. These differences in distribution widths of flow-cytometric parameters of reticulocytes and mature erythrocytes reflect the different pathogeneses of the two diseases and are helpful for the differential diagnosis of these two conditions. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 3-year-old boy who was admitted at Ospedale Bambino Gesu Hospital in Rome, Italy due to hypocortisolism and early-onset severe obesity. The patient had a history of hypoglycaemia days after his birth. Results from sequencing analysis of the patient revealed a homozygous single substitution C20CT, indicating a presence of a stop codon Gln68X. The case illustrates the combined effect of hair pigmentation of the Agouti inverse agonism.

Iron deficiency has been linked to obesity. Hepcidin is the main regulator of iron homeostasis and is higher in obese children compared to controls. To gain insight into the link between obesity and hepcidin, we performed an intervention study in 15 obese children. These children were subjected to a 6-month weight loss program and underwent physical examination and iron status and absorption as well as hepcidin, interleukin-6 and leptin serum levels evaluation at baseline and after the weight loss program. After the program all children reduced their body mass index standard deviation score (BMI SDS) of at least 0.5. We observed a significant decrease in hepcidin (P=0.003) and leptin levels (P=0.005), and a significant increase in iron absorption (P=0.02). A direct correlation between the measure of hepcidin and leptin reduction was observed and this correlation appeared significant (r2=0.33, P=0.003) when adjusted for interleukin-6 and BMI SDS variations. In conclusion, we have shown that, in obese children, BMI reduction is associated with hepcidin reduction, potentially improving iron status and absorption. Implications of these findings could be considered in the management of obese children with poor iron status. [ABSTRACT FROM AUTHOR]

Impaired glucose tolerance (IGT) is a strong risk factor for Type 2 diabetes and cardiovascular disease. The aim of this study was to validate and implement a previously published fasting predictive tool for IGT in obese children: TG>1.17mmol /L, which showed a 71.4[57.8–85.1]% sensitivity and a 64.1[57.7–70.4]% specificity in 259 obese Canadian children. The possible contribution of other metabolic variables was evaluated by assessing the net reclassification improvement (NRI). 817 Italian obese children (8–18.4 years) were recruited and underwent fasting blood analysis and oral glucose tolerance test (OGTT). Thirty-nine children (4.7%) had IGT. The 1.17mmol/L TG threshold showed 66.6 [51.8–81.4]% sensitivity and 68.2 [64.9–71.5]% specificity, thus successfully validated. Fasting plasma glucose (FPG) was independently associated with IGT (OR=3.86 [2.09–7.14], P <0.001), besides TG. The bivariate criterion of TG>1.13mmol/L plus FPG>4.44mmol/L had a 69.2[54.7–83.7]% sensitivity and a 78.2[76.8–79.6]% specificity, thus displaying a 12.6% NRI (P <0.001) compared with TG>1.17mmol/L. TG>1.17mmol/L is a useful criterion to detect roughly 66% of obese children with IGT through OGTT performed in about 33% of all obese children. However, the ‘TG>1.13mmol/L plus FPG>4.44 mmol/L’ criterion allows for detecting even more than 66% of obese children with IGT, though limiting OGTT to just 25% of all obese children. [Copyright &y& Elsevier]