AARS2-related ovarioleukodystrophy: Clinical and neuroimaging features of three new cases.

INTRODUCTION: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD), is the most frequent non-vascular adult-onset leukoencephalopathy. It is caused by autosomal dominant mutations in CSF1R gene. Recently, also autosomal recessive mutations in AARS2 gene were found to be the cause of an adult-onset leukodystrophy with axonal spheroids. Our aim was to achieve a genetic diagnosis in a cohort of CSF1R-negative patients, performing a sequence analysis of AARS2 gene. MATERIAL AND METHODS: AARS2 sequencing was performed in 38 CSF1R-negative patients with clinical and magnetic resonance imaging (MRI) findings of adult-onset leukoencephalopathy. RESULTS: Three patients carrying AARS2 compound heterozygous mutations have been found. All patients were female with ovarian failure and leukoencephalopathy. In 2 patients, MRI findings were consistent with previous reports while the third patient showed focal white matter (WM) lesions in the centrum semiovale and the corpus callosum in the absence of extensive involvement and rarefaction of the WM. MRI spectroscopy showed the presence of increased lactate in 2 patients, thus linking AARS2-related leukoencephalopathy with other mitochondrial leukoencephalopathies with high levels of cerebral lactate. CONCLUSION: We recommend screening for mutations in AARS2 gene in CSF1R-negative patients, also in the absence of a clear family history and peculiar MRI findings. Our results also suggest that findings of conventional MRI and MR spectroscopy may be useful in prompting the genetic screening.

A pilot study for development of a novel tool for clinical decision making to identify fallers among ophthalmic patients.

BACKGROUND: Falls in the elderly is a major problem. Although falls have a multifactorial etiology, a commonly cited cause of falls in older people is poor vision. This study proposes a method to discriminate fallers and non-fallers among ophthalmic patients, based on data-mining algorithms applied to health and socio-demographic information. METHODS: A group of 150 subjects aged 55 years and older, recruited at the Eye Clinic of the Second University of Naples, underwent a baseline ophthalmic examination and a standardized questionnaire, including lifestyles, general health, social engagement and eyesight problems. A subject who reported at least one fall within one year was considered as faller, otherwise as non-faller. Different tree-based data-mining algorithms (i.e., C4.5, Adaboost and Random Forest) were used to develop automatic classifiers and their performances were evaluated by assessing the receiver-operator characteristics curve estimated with the 10-fold-crossvalidation approach. RESULTS: The best predictive model, based on Random Forest, enabled to identify fallers with a sensitivity and specificity rate of 72.6% and 77.9%, respectively. The most informative variables were: intraocular pressure, best corrected visual acuity and the answers to the total difficulty score of the Activities of Daily Vision Scale (a questionnaire for the measurement of visual disability). CONCLUSIONS: The current study confirmed that some ophthalmic features (i.e. cataract surgery, lower intraocular pressure values) could be associated with a lower fall risk among visually impaired subjects. Finally, automatic analysis of a combination of visual function parameters (either self-evaluated either by ophthalmological tests) and other health information, by data-mining algorithms, could be a feasible tool for identifying fallers among ophthalmic patients.

Cloud-Based Smart Health Monitoring System for Automatic Cardiovascular and Fall Risk Assessment in Hypertensive Patients.

The aim of this paper is to describe the design and the preliminary validation of a platform developed to collect and automatically analyze biomedical signals for risk assessment of vascular events and falls in hypertensive patients. This m-health platform, based on cloud computing, was designed to be flexible, extensible, and transparent, and to provide proactive remote monitoring via data-mining functionalities. A retrospective study was conducted to train and test the platform. The developed system was able to predict a future vascular event within the next 12 months with an accuracy rate of 84 % and to identify fallers with an accuracy rate of 72 %. In an ongoing prospective trial, almost all the recruited patients accepted favorably the system with a limited rate of inadherences causing data losses (<20 %). The developed platform supported clinical decision by processing tele-monitored data and providing quick and accurate risk assessment of vascular events and falls.

[Perception of anxiety and learning difficulties according to the criteria of the family and teachers of children with Attention Deficit Hyperactivity Disorder]. / Percepción de la ansiedad y de las dificultades de aprendizaje según los criterios de la familia y de los profesores de niños con trastorno por déficit de atención e hiperactividad.

Both Attention Deficit Hyperactivity Disorder (ADHD) and anxiety are two of the disorders that are most evident in the infant-juvenile population and there is a correlation between the two, as shown in numerous studies. The combination of both disorders affects the child's teaching-learning processes, causing learning difficulties (LD). The aims of the present study were based on assessing the criteria evidenced by parents and teachers in children with ADHD to characterize the degree of adequacy of perception and to evaluate whether this is in line with reality or insufficient, whether there are differences in this perception between parents and teachers, and to analyze their awareness of the possible AD they may present, in order to provide appropriate guidelines for favourable intervention and evolution. The sample consisted of 137 subjects aged between 9 and 15 years with a Total IQ (TIQ) between 80 and 120. The instruments used were: the Wechsler Intelligence Scale for Children-V (WISCV), the State-Trait Anxiety Questionnaire for Children (STAI-C), the Child and Adolescent Assessment System (SENA) and the Inventory of Problems at School (IPE). As a result, it is observed that the anxiety perceived by these children is not related to the anxiety perceived by parents and teachers, although the latter do coincide in their assessment.

Tanto el Trastorno por Déficit de Atención e Hiperactividad (TDAH) como la ansiedad son dos de los trastornos que más se evidencian en la población infanto-juvenil existiendo una correlación entre ambos tal y como se recoge en numerosos estudios. La combinación de ambos trastornos afecta a los procesos de enseñanza-aprendizaje del niño provocando dificultades de aprendizaje (DA) en el mismo. Los objetivos del presente trabajo se basaron en valorar los criterios que evidencian padres y profesores en niños con TDAH para caracterizar el grado de adecuación de la percepción y evaluar si esta se ajusta a la realidad o es insuficiente, si existen diferencias en dicha percepción entre padres y docentes; analizar la conciencia que tienen sobre las posibles DA que puedan presentar, para así aportar orientaciones adecuadas que permitan una favorable intervención y evolución. La muestra se compone de 137 sujetos con edades comprendidas entre 9 y 15 años con un Coeficiente Intelectual Total (CIT) de entre 80 y 120. Los instrumentos que se utilizaron fueron: la escala de inteligencia de Wechsler para niños-V (WISC-V), el Cuestionario de Ansiedad Estado-Rasgo en Niños(STAI-C), el Sistema de Evaluación de Niños y Adolescentes(SENA) y el Inventario de Problemas en la Escuela (IPE). Como resultado se observa que la ansiedad percibida por estos niños no está relacionada con la que aprecian padres y profesores, sin embargo, estos últimos sí que coinciden en su apreciación.

Feedback-controlled laser ablation for cancer treatment: comparison of On-Off and PID control strategies.

Laser ablation is a rising technique used to induce a localized temperature increment for tumor ablation. The outcomes of the therapy depend on the tissue thermal history. Monitoring devices help to assess the tissue thermal response, and their combination with a control strategy can be used to promptly address unexpected temperature changes and thus reduce unwanted thermal effects. In this application, numerical simulations can drive the selection of the laser control settings (i.e., laser power and gain parameters) and allow evaluating the thermal effects of the control strategies. In this study, the influence of different control strategies (On-Off and PID-based controls) is quantified considering the treatment time and the thermal effect on the tissue. Finite element model-based simulations were implemented to model the laser-tissue interaction, the heat-transfer, and the consequent thermal damage in liver tissue with tumor. The laser power was modulated based on the temperature feedback provided within the tumor safety margin. Results show that the chosen control strategy does not have a major influence on the extent of thermal damage but on the treatment duration; the percentage of necrosis within the tumor domain is 100% with both strategies, while the treatment duration is 630 s and 786 s for On-Off and PID, respectively. The choice of the control strategy is a trade-off between treatment duration and unwanted temperature overshoot during closed-loop laser ablation. Clinical Relevance-This work establishes that different temperature-based control of the laser ablation procedure does not have a major influence on the extent of thermal damage but on the duration of treatment.

Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene.

Mutations in the FGD1 gene have been shown to cause Aarskog-Scott syndrome (AAS), or facio-digito-genital dysplasia (OMIM#305400), an X-linked disorder characterized by distinctive genital and skeletal developmental abnormalities with a broad spectrum of clinical phenotypes. To date, 20 distinct mutations have been reported, but little phenotypic data are available on patients with molecularly confirmed AAS. In the present study, we report on our experience of screening for mutations in the FGD1 gene in a cohort of 60 European patients with a clinically suspected diagnosis of AAS. We identified nine novel mutations in 11 patients (detection rate of 18.33%), including three missense mutations (p.R402Q; p.S558W; p.K748E), four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC), one in-frame deletion (c.2020_2022delGAG) and the first reported splice site mutation (c.1935+3A>C). A recurrent mutation (p.R656X) was detected in three independent families. We did not find any evidence for phenotype-genotype correlations between type and position of mutations and clinical features. In addition to the well-established phenotypic features of AAS, other clinical features are also reported and discussed.

Novel PTEN mutations in neurodevelopmental disorders and macrocephaly.

Somatic mutations of the phosphatase and tensin (PTEN) gene have been frequently detected in many types of human cancer. However, germline mutations can determine multiple hamartoma syndromes and, as more recently ascertained, syndromes clinically characterized by autism associated with macrocephaly. To determine whether germline mutations of PTEN may lead to different phenotypes, we screened all the nine exons of the PTEN gene in 40 patients with neurodevelopmental disorders, with or without features of autism spectrum disorder, associated with macrocephaly. Three novel de novo missense mutations were found (p.H118P, p.Y176C, p.N276S) in two severely mentally retarded patients with autism and in a subject with neurodevelopmental disorders without autistic features. Our results provide evidence that PTEN germline mutations may sustain a more wide phenotypical spectrum than previously suggested.

Percepción de la ansiedad y de las dificultades de aprendizaje según los criterios de la familia y de los profesores de niños con Trastorno por Déficit de Atención e Hiperactividad / Perception of anxiety and learning difficulties according to the criteria of the family and eachers of children with Attention Deficit Hyperactivity Disorder

Resumen Tanto el Trastorno por Déficit de Atención e Hiperactividad (TDAH) como la ansiedad son dos de los trastornos que más se evidencian en la población infanto-juvenil existiendo una correlación entre ambos tal y como se recoge en numerosos estudios. La combinación de ambos trastornos afecta a los procesos de enseñanza-aprendizaje del niño provocando dificultades de aprendizaje (DA) en el mismo. Los objetivos del presente trabajo se basaron en valorar los criterios que evidencian padres y profesores en niños con TDAH para caracterizar el grado de adecuación de la percepción y evaluar si esta se ajusta a la realidad o es insuficiente, si existen diferencias en dicha percepción entre padres y docentes; analizar la conciencia que tienen sobre las posibles DA que puedan presentar, para así aportar orientaciones adecuadas que permitan una favorable inter vención y evolución. La muestra se compone de 137 sujetos con edades comprendidas entre 9 y 15 años con un Coeficiente Intelectual Total (CIT) de entre 80 y 120. Los instrumentos que se utilizaron fueron: la escala de inteligencia de Wechsler para niños-V (WISC-V), el Cuestionario de Ansiedad Estado-Rasgo en Niños(STAI-C), el Sistema de Evaluación de Niños y Adolescentes(SENA) y el Inventario de Problemas en la Escuela (IPE). Como resultado se observa que la ansiedad percibida por estos niños no está relacionada con la que aprecian padres y profesores, sin embargo, estos últimos sí que coinciden en su apreciación.

Abstract Both Attention Deficit Hyperactivity Disorder (ADHD) and anxiety are two of the disorders that are most evident in the infant-juvenile population and there is a correlation between the two, as shown in numerous studies. The combination of both disorders affects the child's teaching-learning processes, causing learning difficulties (LD). The aims of the present study were based on assessing the criteria evidenced by parents and teachers in children with ADHD to characterize the degree of adequacy of perception and to evaluate whether this is in line with real ity or insufficient, whether there are differences in this perception between parents and teachers, and to analyze their awareness of the possible AD they may present, in order to provide appropriate guidelines for favourable intervention and evolution. The sample consisted of 137 subjects aged between 9 and 15 years with a Total IQ (TIQ) between 80 and 120. The instruments used were: the Wechsler Intelligence Scale for Children-V (WISC-V), the State-Trait Anxiety Questionnaire for Children (STAI-C), the Child and Adolescent Assessment System (SENA) and the Inventory of Problems at School (IPE). As a result, it is observed that the anxiety perceived by these children is not related to the anxiety perceived by parents and teachers, although the latter do coincide in their assessment.

Differential effect of adenosine on DNA synthesis in lymphoid and myeloid cell lines.

In this report, the effects of adenosine on the promyelocytic cell line HL-60 and on T-lymphocytic clones are compared. According to previous reports, adenosine induces a dose-dependent inhibition of DNA synthesis in T-lymphocytes. Conversely, adenosine dose-dependently enhances DNA synthesis in HL-60 cells, as documented with [3H]thymidine uptake studies and flow cytometric cell-cycle analysis. Unlike its effect on lymphocytes, the adenosine effect on HL-60 cells does not seem to be mediated by receptor binding, but it appears to be correlated with an intracellular mechanism following active uptake. Despite the different effects exerted by adenosine on lymphocytes and myeloid cells, a purinergic pathway appears to be more generally involved in the regulation of some phases of cell growth.

Standard versus trans-epithelial collagen cross-linking in keratoconus patients suitable for standard collagen cross-linking.

PURPOSE: Evaluating the clinical results of trans-epithelial collagen cross-linking (CXL) and standard CXL in patients with progressive keratoconus. METHODS: This prospective study comprised 20 eyes of 20 patients with progressive keratoconus. Ten eyes were treated by standard CXL and ten by trans-epithelial cross-linking (TE-CXL, epithelium on) with 1 year of follow-up. All patients underwent complete ophthalmologic testing that included pre- and postoperative uncorrected visual acuity, corrected visual acuity, spherical error, spherical equivalent, corneal astigmatism, simulated maximum, minimum, and average keratometry, coma and spherical aberration, optical pachymetry, and endothelial cell density. Intra-and postoperative complications were recorded. The solution used for standard CXL comprised riboflavin 0.1% and dextran 20.0% (Ricrolin), while the solution for TE-CXL (Ricrolin, TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with UV-X System at 3 mW/cm(2). RESULTS: In both the standard CXL group (ten patients, ten eyes; mean age, 30.4±7.3 years) and the TE-CXL group (ten patients, ten eyes; mean age, 28±3.8 years), uncorrected visual acuity and corrected visual acuity improved significantly after treatment. Furthermore, a significant improvement in topographic outcomes, spherical error, and spherical equivalent was observed in both groups at month 12 posttreatment. No significant variations were recorded in other parameters. No complications were noted. CONCLUSION: A 1-year follow-up showed stability of clinical and refractive outcomes after standard CXL and TE-CXL.

Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region.

Mutations in the ryanodine receptor type 1 (RYR1) gene are associated with Malignant Hyperthermia (MH) and Central Core Disease (CCD). We report here on the molecular analysis of the RYR1 gene in Italian families referred as potential cases of MH or in patients with CCD or multicore/minicore myopathy. Of a total of 20 individuals with mutations in the RYR1 gene, 14 were part of a group of 47 MH susceptible (MHS) patients, 4 of 34 individuals diagnosed as MH equivocal (MHE), and 2 were patients diagnosed with minicore myopathy and CCD, respectively. Mutations were found to segregate with the MHS or MHE phenotype within the families of the probands. A discordance between phenotype and genotype was observed in a family where a mutation detected in an MHS proband was also found in the father who had been diagnosed MH normal (MHN) at the IVCT. In addition to known mutations, seven novel mutations were found, five of which occurred in exons encoding the C-terminal region of RYR1. These results indicate that the C-terminal region of RYR1 represents an additional hot spot for mutations in patients with MH, similar to what has been reported for patients with CCD.

MECP2 mutation in male patients with non-specific X-linked mental retardation.

In contrast to the preponderance of affected males in families with X-linked mental retardation, Rett syndrome (RTT) is a neurological disorder occurring almost exclusively in females. The near complete absence of affected males in RTT families has been explained by the lethal effect of an X-linked gene mutation in hemizygous affected males. We report here on a novel mutation (A140V) in the MECP2 gene detected in one female with mild mental retardation. In a family study, the A140V mutation was found to segregate in the affected daughter and in four adult sons with severe mental retardation. These results indicate that MECP2 mutations are not necessarily lethal in males and that they can be causative of non-specific X-linked mental retardation.

A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome).

Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterised by short stature and multiple facial, limb and genital abnormalities. A gene, FGD1, altered in a patient with AAS phenotype, has been identified and found to encode a protein with homology to Rho/Rac guanine nucleotide exchange factors (Rho/Rac GEF). However, since this original report on identification of a mutated FGD1 gene in an AAS patient, no additional mutations in the FGD1 gene have been described. We analysed 13 independent patients with clinical diagnosis of AAS. One patient presented a mutation that results in a nucleotide change in exon 10 of the FGD1 gene (G2559>A) substituting a Gln for Arg in position 610. The mutation was found to segregate with the AAS phenotype in affected males and carrier females in the family of this patient. Interestingly, Arg-610 is located within one of the two pleckstrin homology (PH) domains of the FGD1 gene and it corresponds to a highly conserved residue which has been involved in InsP binding in PH domains of other proteins. The same residue is often mutated in the Bruton's tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia. The Arg610Gln mutation represents the first case of a mutation in the PH domain of the FGD1 gene and additional evidence that mutations in PH domains can be associated to human diseases.

Mutations in the glucose-6-phosphate transporter (G6PT) gene in patients with glycogen storage diseases type 1b and 1c.

Glycogen storage diseases type 1 (GSD 1) are a group of autosomal recessive disorders characterized by impairment of terminal steps of glycogenolysis and gluconeogenesis. Mutations of the glucose-6-phosphatase gene are responsible for the most frequent form of GSD 1, the subtype 1a, while mutations of the glucose-6-phosphate transporter gene (G6PT) have recently been shown to cause the non 1a forms of GSD, namely the 1b and 1c subtypes. Here, we report on the analysis by single-stranded conformation polymorphism (SSCP) and/or DNA sequencing of the exons of the G6PT in 14 patients diagnosed either as affected by the GSD 1b or 1c subtypes. Mutations in the G6PT gene were found in all patients. Four of the detected mutations were novel mutations, while the others were previously described. Our results confirm that the GSD 1b and 1c forms are due to mutations in the same gene, i.e. the G6PT gene. We also show that the same kind of mutation can be associated or not with evident clinical complications such as neutrophil impairment. Since no correlation between the type and position of the mutation and the severity of the disease was found, other unknown factors may cause the expression of symptoms, such as neutropenia, which dramatically influence the severity of the disease.

A Rett syndrome MECP2 mutation that causes mental retardation in men.

OBJECTIVE: To characterize the clinical features of a new type of X-linked mental retardation associated with MECP2 mutation in the index family. BACKGROUND: MECP2 mutations, originally described in a high percentage of patients with classic Rett syndrome, were considered lethal in men. The authors recently described a novel A140V MECP2 missense mutation in an Italian family with X-linked semidominant mental retardation. METHODS: The neurologic features of six symptomatic relatives (two women and four men) carrying the mutation were compiled. Laboratory investigations included EEG, EMG, conduction velocity (CV) of peripheral nerves, brain MRI, and (1)H-MR spectroscopy. RESULTS: Mental retardation and signs of neurologic impairment were present in all the affected members, but more pronounced in men. Neurologic features included slowly progressive spastic paraparesis/pyramidal signs (6/6), distal atrophy of the legs (6/6), ataxia (2/6), and postural tremor of the hands (3/6). Speech was preserved (6/6) but was dysarthric in the oldest brothers (2/6). Mild dysmorphic features were present in all cases. CONCLUSION: The neurologic disorder associated with A140V MECP2 mutation is not necessarily lethal in men, but they are more severely affected than women of the same family.

Autosomal recessive syndrome of growth and mental retardation, seizures, retinal abnormalities, and osteodysplasia with similarity to the Gurrieri syndrome.

We report on two sibs, brother and sister, with a multiple congenital anomaly/mental retardation syndrome consisting of severe growth and mental retardation, seizures, retinal abnormalities, osteodysplasia, brachydactyly, prognathism, and dental malocclusion. These clinical findings were present in both patients and seem to be consistent with the phenotype of the Gurrieri syndrome. The new features described in these sibs could expand the clinical spectrum of the Gurrieri syndrome and confirm the existence of this rare autosomal recessive condition.

Mosaicism for full mutation and normal-sized allele of the FMR1 gene: a new case.

The main mutation in fragile X patients is the expansion of the CGG repeat in the first exon of the FMR1 gene, associated with hypermethylation of the proximal CpG island. An increasing number of atypical cases have been reported showing the coexistence of full mutation and premutated or normal-sized alleles. These genotypes are more difficult to detect, and if a PCR strategy alone is adopted, they can be incorrectly identified. We report on a fragile X man with severe phenotype and mosaicism for full mutation and a (CGG)7 normal allele, the shortest fragment reported as yet in mosaics. This case of mosaicism, as other similar cases previously reported, suggests that the normal-length allele can derive from a deletion during the same early stage of development in which the full mutation expansion also arose.

Possible case of Pitt-Hopkins syndrome in sibs.

In this article, we describe two sibs, a brother and sister, with severe mental retardation and multiple congenital anomalies including "coarse" facial features, short stature, seizures, hypertrichosis, short great toes, and overbreathing. Comparison of these patients with previous reports suggests that they could represent the first familial cases of the Pitt-Hopkins syndrome. The recurrence in sibs within the same family supports autosomal recessive inheritance for the condition. Variable expression of the respiratory symptoms, which has not been reported earlier, is underlined.

Heparin inhibition of polymorphonuclear leukocyte activation in vitro. A possible pharmacological approach to granulocyte-mediated vascular damage.

The "in vitro" effects of heparin on different functions of human polymorphonuclear leukocytes were studied. Granulocyte aggregation, enzyme release induced by FMLP and zymosan-activated serum and superoxide anion and chemiluminescence generated by FMLP were assessed. Heparin (25-500 micrograms/ml) was able to inhibit in a dose-dependent way cellular aggregation and degranulation induced either by FMLP or by zymosan-activated serum. FMLP-dependent superoxide anion generation and chemiluminescence were specifically inhibited by heparin at the concentration of 25 micrograms/ml. Our results showed that heparin "in vitro" inhibits all the aspects of the functional and metabolic granulocyte activation. A possible protecting effect of the drug on leukocyte-mediated tissue injury and vascular damage is discussed.