Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome:phenotype comparison in two related syndromes

Background Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. Methods Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. Results Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. Conclusions Results show significant between and within syndrome variability. DifferentNFIXvariants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit

Further delineation of Malan syndrome

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall–Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only

Pharmacological action and therapeutic effects of glutathione on hypokinetic spermatozoa for enzymatic dependent pathologies and correlated genetic aspects

In this study, the pharmacologic substance reduced glutathione (GSH) was used in men with hypofertility problems linked to varicocele, in bulls with spermatozoa hypomobility due to varicocele, and in rabbits with dispermy caused by cryptorchidism. An efficacious therapeutic effect of increased motility of the spermatozoa was seen in subjects who were submitted to appropriate doses of glutathione I.M. GSH also showed some neutralizing effect on the catabolytes produced during spontaneous or induced peroxidation processes of the unsaturated lipids contained in the membranes of male germinal cells. The genetic aspects of the involved enzymes were also evaluated and the research was extended in vitro by incubating samples of spermatozoa with arachidonic acid homogenates, L-tryptophan, hematein, and with an addition of glutathione. The results showed that polynsaturated fatty acid metabolic substances (PUFA) play an important role in the acrosomal reaction of spermatozoa and that GSH has a determining role in increasing the motility of spermatozoa with consequent improved fertilization. The spermatozoa of bulls provided us with a valid model to study for the morphostructural, biochemical and pharmacological analyses of human spermatozoa

Pharmacological effects of melatonin on reproductive activity : experimental bioimplants with sustained-release polymeric systems

A vast literature documents the role of melatonin in human reproductive function including: a) the relation between melatonin and the menstrual cycle in relation to the peak time of luteinizing hormone in the middle of the cycle [1]; b) the varying concentrations of melatonin in the control of puberty [2]; c) the fewer conceptions in some artic populations where melatonin is connected significantly to seasonal photoperiodicity during the months of the polar nights [3]. The aim of this paper is to report our findings on the pharmacological action of this molecule on reproduction in which gonadal activity is clearly connected to photoperiodicity. We used polymer bioimplants programmed for the sustained release of melatonin for experimental gynecologic protocols. These implants had beneficial results with respect to the use of progestinics because melatonin allowed ovarian activity to be induced for at least two to three consecutive cycles with one single bioimplant. We thought it indispensable to use pharmacological systems with a sustained release because different preliminary tests showed that the half-life of melatonin is limited at maximum to two to three hours and, consequently, any other tested modalities of administration would not provide any appreciable results for our study. As a model for our research we used goats to administer melatonin via targeted programs since these animals clearly respond (even against the rule of the light/dark relation) in contrast to humans in whom response is less evident. For controls, after inserting bioimplants in the animals, we tested their efficiency in vitro and subsequently in vivo, evaluating blood parameters and pharmacological effects of melatonin occurring during the treatment. The final results proved to be interesting in relation to reproductive activity in that regular and programmed births were achieved

The safety of ketoprofen in different ages

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID), which acts by blocking cyclooxygenase (COX 1 and 2), an enzyme involved in the production of prostaglandins, messengers in the development of inflammation. All NSAIDs reduce signs of inflammation by blocking this enzyme and therefore prostaglandin production. In Calabria, 3.69% of adverse drug reactions (ADRs) reported in the National Network of Pharmacovigilance concerns the use of ketoprofen; only in one case in which the patient was under the age of 12 years, hospitalization was required for severe episode of pancreatitis. In Italy, Ketoprofen is the 6(th) drug for ADRs incidence (560 ADRs in the year 2012, of which, 31% are severe). Despite the high rate of spontaneous reporting, it must be considered that ketoprofen is one of the most used NSAIDs; therefore, as it happens for other commonly used drugs (eg, amoxicillin), the total number of ADRs should be related to the therapeutic use. However, it remains the problem of fragile patients (eg, children) and the safety of the drug in different ages. This paper presents a retrospective study on 2012 ADRs reviewing literature on the safety of ketoprofen in the elderly, children, and during pregnancy

A METHOD FOR VIRTUAL ANASTYLOSIS: THE CASE OF THE ARCH OF TITUS AT THE CIRCUS MAXIMUS IN ROME

This paper is the first report about the development of a methodology for the virtual Anastylosis of elements belonging to an archaeological site, based on the 3d modeling of fragments. This research is the result of the cooperation between Università Roma Tre, Dipartimento di Architettura and Sovrintendenza Capitolina ai Beni Culturali; several 3D survey, modeling, information systems and archaeology experts were involved. The purpose of the research was to study the complex and stratified site of the Arch of Titus at the Circus Maximus aiming, first of all, at completing the existing traditional graphic documentation using cataloguing and survey innovative methodologies, and, secondly, at supporting new proposals for the reconstruction and Anastylosis of the Arch itself. This tested methodology whose fundamental element is the three-dimensional textured model of each fragment, can also be used in other sites and contexts

A Method for virtual anastylosis: the case of the Arch of Titus at the Circus Maximus in Rome

This paper is the first report about the development of a methodology for the virtual Anastylosis of elements belonging to an archaeological site, based on the 3d modeling of fragments. This research is the result of the cooperation between Università Roma Tre, Dipartimento di Architettura and Sovrintendenza Capitolina ai Beni Culturali; several 3D survey, modeling, information systems and archaeology experts were involved. The purpose of the research was to study the complex and stratified site of the Arch of Titus at the Circus Maximus aiming, first of all, at completing the existing traditional graphic documentation using cataloguing and survey innovative methodologies, and, secondly, at supporting new proposals for the reconstruction and Anastylosis of the Arch itself. This tested methodology whose fundamental element is the three-dimensional textured model of each fragment, can also be used in other sites and contexts\"

Protease Nexin-1 affects the migration and invasion of C6 glioma cells through the regulation of urokinase Plasminogen Activator and Matrix Metalloproteinase-9/2

Protease Nexin-1 (PN-1) or Serpine2 is a physiological regulator of extracellular proteases as thrombin and urokinase (uPA) in the brain. Besides, PN-1 is also implicated in some human cancers and further identified as a substrate for Matrix Metalloproteinase (MMP)-9, a key enzyme in tumor invasiveness. Our aim was to study the role of PN-1 in the migration and invasive potential of glioma cells, using the rat C6 glioma cell line as stable clones transfected with pAVU6+27 vector expressing PN-1 short-hairpin RNA. We find that PN-1 knockdown enhanced the in vitro migration and invasiveness of C6 cells which also showed a strong gelatinolytic activity by in situ zymography. PN-1 silencing did not alter prothrombin whereas increased uPA, MMP-9 and MMP-2 expression levels and gelatinolytic activity in a conditioned medium from stable C6 cells. Selective inhibitors for MMP-9 (Inhibitor I), MMP-2 (Inhibitor III) or exogenous recombinant PN-1 added to the culture medium of C6 silenced cells restored either the migration and invasive ability or gelatinolytic activity thus validating the specificity of PN-1 silencing strategy. Phosphorylation levels of extracellular signal-related kinases (Erk1/2 and p38 MAPK) involved in MMP-9 and MMP-2 signaling were increased in PN-1 silenced cells. This study shows that PN-1 affects glioma cell migration and invasiveness through the regulation of uPA and MMP-9/2 expression levels which contribute to the degradation of extracellular matrix during tumor invasion