Doublecortin mutation leads to persistent defects in the Golgi apparatus and mitochondria in adult hippocampal pyramidal cells.

Human doublecortin (DCX) mutations are associated with severe brain malformations leading to aberrant neuron positioning (heterotopia), intellectual disability and epilepsy. DCX is a microtubule-associated protein which plays a key role during neurodevelopment in neuronal migration and differentiation. Dcx knockout (KO) mice show disorganized hippocampal pyramidal neurons. The CA2/CA3 pyramidal cell layer is present as two abnormal layers and disorganized CA3 KO pyramidal neurons are also more excitable than wild-type (WT) cells. To further identify abnormalities, we characterized Dcx KO hippocampal neurons at subcellular, molecular and ultrastructural levels. Severe defects were observed in mitochondria, affecting number and distribution. Also, the Golgi apparatus was visibly abnormal, increased in volume and abnormally organized. Transcriptome analyses from laser microdissected hippocampal tissue at postnatal day 60 (P60) highlighted organelle abnormalities. Ultrastructural studies of CA3 cells performed in P60 (young adult) and > 9 months (mature) tissue showed that organelle defects are persistent throughout life. Locomotor activity and fear memory of young and mature adults were also abnormal: Dcx KO mice consistently performed less well than WT littermates, with defects becoming more severe with age. Thus, we show that disruption of a neurodevelopmentally-regulated gene can lead to permanent organelle anomalies contributing to abnormal adult behavior.

Clumsiness in fine motor tasks: evidence from the quantitative drawing evaluation of children with Down Syndrome.

INTRODUCTION: Drawing tests are commonly used for the clinical evaluation of cognitive capabilities in children with learning disabilities. We analysed quantitatively the drawings of children with Down Syndrome (DS) and of healthy, mental age-matched controls to characterise the features of fine motor skills in DS during a drawing task, with particular attention to clumsiness, a well-known feature of DS gross movements. METHODS: Twenty-three children with DS and 13 controls hand-copied the figures of a circle, a cross and a square on a sheet. An optoelectronic system allowed the acquisition of the three-dimensional track of the drawing. The participants' posture and upper limb movements were analysed as well. RESULTS: Results showed that the participants with DS tended to draw faster but with less accuracy than controls. DISCUSSION: While clumsiness in gross movements manifests mainly as slow, less efficient movements, it manifests as high velocity and inaccurate movements in fine motor tasks such as drawing.

Relationship between flat foot condition and gait pattern alterations in children with Down syndrome.

BACKGROUND: In patients with Down syndrome (DS) one of the most common abnormalities is flat foot which can interfere significantly with normal daily activities, such as gait. The aim of this study was to quantitatively assess the relationship between the flat foot and the gait alterations in DS children. METHOD: Twenty-nine patients with DS and 15 non-affected subjects were assessed using 3D Gait Analysis, using an optoelectronic system, force platforms and video recording. The degree of flat foot was assessed using the arch index and kinematic and kinetic parameters were identified and calculated from 3D Gait Analysis for each study participant. RESULTS: Data showed that ankle plantarflexion moment and ankle power during terminal stance were significant to differentiate the patients with and without flat feet: their peak values were significantly lower for the patients with flat foot. In addition, the research for correlation demonstrated that the higher the arch index value, the lower the peak of ankle moment and of the generated ankle power during terminal stance and the minimum of absorbed ankle power. CONCLUSIONS: Children with flat foot displayed a less functional gait pattern in terms of ankle kinetics than children without flat foot, suggesting that the presence of flat foot may lead to a weaker efficient walking. Then, the increasing flat foot tended to result in lower push-off ability, leading to a less functional walking.

The effects of low arched feet on foot rotation during gait in children with Down syndrome.

BACKGROUND: In children with Down syndrome (DS) hypotonia and ligament laxity are characteristic features which cause a number of orthopaedic issues, such as flat foot. The aim of this study was to determine if children with flat foot are characterised by an accentuated external foot rotation during walking. METHOD: Fifty-five children with DS and 15 typically developing children recruited as control group were assessed using three-dimensional gait analysis, using an optoelectronic system, force platforms and video recording. Parameters related to foot rotation were identified and calculated and the participants' foot morphology was assessed using the arch index. RESULTS: Data obtained in this study showed that while DS children without flat foot displayed the foot position on the transverse plane globally close to controls during the whole gait cycle, the DS children with flat foot were characterised by higher extra-rotation of the foot in comparison with those without flat foot and controls. CONCLUSIONS: Our results suggest that the presence of flatfoot lead the children with DS to extra-rotate their feet more than the children without flat foot. From a clinical point of view, these results could enhance the rehabilitative programmes in DS.

Propagation of extended fractures by local nucleation and rapid transverse expansion of crack-front distortion.

Fractures are ubiquitous and can lead to the catastrophic material failure of materials. Although fracturing in a two-dimensional plane is well understood, all fractures are extended in and propagate through three-dimensional space. Moreover, their behaviour is complex. Here we show that the forward propagation of a fracture front occurs through an initial rupture, nucleated at some localized position, followed by a very rapid transverse expansion at velocities as high as the Rayleigh-wave speed. We study fracturing in a circular geometry that achieves an uninterrupted extended fracture front and use a fluid to control the loading conditions that determine the amplitude of the forward jump. We find that this amplitude correlates with the transverse velocity. Dynamic rupture simulations capture the observations for only a high transverse velocity. These results highlight the importance of transverse dynamics in the forward propagation of an extended fracture.

Multiple primary melanomas: do they look the same?

BACKGROUND: A series of studies has investigated epidemiological, clinical and genetic characteristics of patients with multiple primary melanoma (MPM). However, comparison of the clinical and dermoscopic features of MPM within a given individual has been described only in case reports. OBJECTIVES: To describe the dermoscopic features of MPM for each given patient, and to evaluate the characteristics eventually associated with similar or dissimilar appearance. METHODS: From the databases of three skin-lesion clinics in the U.S.A., Italy and Spain we collected the dermoscopic images of melanomas in patients diagnosed with MPM. RESULTS: Among 58 patients with MPM, we found that 53% of patients had dermoscopically similar melanomas and 47% of patients had dermoscopically different melanomas. In older patients 59% of melanomas were dermoscopically similar vs. 47% in younger patients (P=0·377). Similar thickness was associated with the occurrence of dermoscopically similar melanomas (19/30 cases, 63%; P=0·039). Most (65%) of the synchronous lesions were similar, compared with 36% of nonsynchronous lesions (P=0·029), and most (69%) of the melanomas on sun-damaged skin were similar, vs. 37% of melanomas on nonsun-damaged skin (P=0·015; odds ratio 3·88, 95% confidence interval 1·11-13·98). The percentage of dermoscopically different melanomas was higher in patients with a family history of melanoma (67% vs. 48%). CONCLUSIONS: MPMs in a given patient have almost the same chance of looking dermoscopically similar or different. However, a subset of elderly patients with sun-damaged skin may present multiple, similar, thin melanomas characterized by pigment-network and regression structures.

Clinical, dermoscopic and reflectance confocal microscopy features of sebaceous neoplasms in Muir-Torre syndrome.

BACKGROUND: Muir-Torre syndrome (MTS) is an autosomal-dominant disorder characterized by the association of sebaceous tumors or keratoacanthomas with an early onset visceral cancer in the spectrum of Lynch syndrome. OBSERVATIONS: A total of 20 sebaceous tumors including 18 sebaceous adenoma and two sebaceomas of six patients with MTS were analysed. Two main clinico-dermoscopic features were observed: (1) clinically pink to white papules/nodules with a central crater, dermoscopically characterized by radially arranged, elongated crown vessels surrounding opaque structureless yellow areas at times covered by blood crusts (n = 13) and (2), clinically pink to yellow papules/nodules without a central crater, dermoscopically exhibiting a few, loosely arranged yellow comedo-like globules and branching arborizing vessels (n = 7). Confocal microscopy was available in three sebaceous adenomas and revealed a good histopathologic correlation; sebaceous lobules were composed by clusters of ovoid cells with dark nuclei and bright, highly refractile glistening cytoplasm. They were delimited by a rim of epithelial cells, corresponding to basaloid cells. CONCLUSIONS: A better characterization of clinical, dermoscopic and confocal microscopy features of sebaceous tumors may improve their recognition and consequently, aid to rise the suspect for MTS.

Quantitative 3D evaluation of step ascent and descent in individuals with Down syndrome--analysis of a daily challenging task.

BACKGROUND: Step ascent and descent can perturb stability increasing the incidence of falls, especially in older individuals with functional limitations and intellectual disabilities, such as those with Down syndrome (DS). The aim of this study was to investigate the biomechanics and motor coordination of step ascent and descent in adults with DS and compare them with a group of healthy individuals, considering movement kinematics and kinetics. METHOD: Fourteen adults with DS and 12 similarly aged adults without DS who were free of known motor problems were quantitatively assessed during ascending and descending a step using an optoelectronic system (BTS SMART-D), force platforms and video recording. Kinematic and kinetic parameters were identified and calculated for each study participant and comparisons were made between the DS and a control group (CG). RESULTS: Despite similar age ranges, subjects in the DS group performed the step ascent and descent movements slower, with longer duration and with a more accentuated range of motion of the trunk and of the ankle joint than those in the CG. Additionally, the double stance phase on the step was substantially longer in the DS group when represented as a percentage of the entire stepping sequence (ascent, double stance on the step and descent). In terms of kinetics, ground force platform data revealed that the DS subjects showed higher instability in the medio-lateral direction during double support phase than similarly aged CG subjects and cannot be attributed to age-associated changes in stability. CONCLUSIONS: These findings help to elucidate the complex biomechanical strategy of people with DS during a step ascent and descent movement task and may have a major role in the multidimensional evaluation and tailored management for them.

Regulation of microglia by neuromodulators: Modulations in major and minor modes.

Microglial cells, the brain resident macrophages, participate to brain development and function and help maintaining its homeostasis. To play these roles, they need to detect and adapt to modifications of their environment, including changes in the activity of neurons. The neuromodulators serotonin, dopamine, norepinephrine, acetylcholine and histamine are synthesized and released by specialized neurons to coordinate the activity of other neurons in different regions. In this review, we summarize the current evidence obtained in vitro or in vivo that neuromodulators act on microglia. On the short term, they can modify their motility, morphology and phagocytic activity; on the mid-long term they can modulate their transition between different immune activation states. Lastly, we review some recent data suggesting that these regulations of microglia by neuromodulators are involved in vivo in some aspects of central nervous system development, function and homeostasis.

Gait analysis and cerebral volumes in Down's syndrome.

The aim of this study was to look for a relationship between cerebral volumes computed using a voxel-based morphometry algorithm and walking patterns in individuals with Down's syndrome (DS), in order to investigate the origin of the motor problems in these subjects with a view to developing appropriate rehabilitation programmes. Nine children with DS underwent a gait analysis (GA) protocol that used a 3D motion analysis system, force plates and a video system, and magnetic resonance imaging (MRI). Analysis of GA graphs allowed a series of parameters to be defined and computed in order to quantify gait patterns. By combining some of the parameters it was possible to obtain a 3D description of gait in terms of distance from normal values. Finally, the results of cerebral volume analysis were compared with the gait patterns found. A strong relationship emerged between cerebellar vermis volume reduction and quality of gait and also between grey matter volume reduction of some cerebral areas and asymmetrical gait. An evaluation of high-level motor deficits, reflected in a lack or partial lack of proximal functions, is important in order to define a correct rehabilitation programme.

Abnormal expression of synaptic proteins and neurotrophin-3 in the Down syndrome mouse model Ts65Dn.

Down syndrome (DS) results from triplication of the whole or distal part of human chromosome 21. Persons with DS suffer from deficits in learning and memory and cognitive functions in general, and, starting from early development, their brains show dendritic and spine structural alterations and cell loss. These defects concern many cortical brain regions as well as the hippocampus, which is known to play a critical role in memory and cognition. Most of these abnormalities are reproduced in the mouse model Ts65Dn, which is partially trisomic for the mouse chromosome 16 that is homologous to a portion of human chromosome 21. Thus, Ts65Dn is widely utilized as an animal model of DS. To better understand the molecular defects underlying the cognitive and particularly the memory impairments of DS, we investigated whether the expression of several molecules known to play critical roles in long-term synaptic plasticity and long-term memory in a variety of species is dysregulated in either the neonatal brain or adult hippocampus of Ts65Dn mice. We found abnormal expression of the synaptic proteins synaptophysin, microtubule-associated protein 2 (MAP2) and cyclin-dependent kinase 5 (CDK5) and of the neurotrophin-3 (NT-3). Both the neonatal brain and adult hippocampus revealed significant abnormalities. These results suggest that a dysregulation in the expression of neurotrophins as well as proteins involved in synaptic development and plasticity may play a potential role in the neural pathology of DS in humans.

Holt-Oram syndrome associated with anomalies of the feet.

Holt-Oram syndrome (HOS) (OMIM 142900) is characterized by upper-extremity malformations involving the radial, thenar, or carpal bones and a personal and/or family history of congenital heart defects (CHDs). It is inherited in an autosomal dominant manner. The TBX5 gene located on chromosome 12 (12q24.1) is the only gene currently known to be associated with HOS and is associated with variable phenotypes. We report on the clinical and molecular characterization of a HOS family with three affected individuals and a novel mutation (Lys88ter). We discuss genotype-phenotype correlations, the presence of foot anomalies in one affected individual, and the role of atypical features in HOS differential diagnosis.

Melanoma epidemic across the millennium: time trends of cutaneous melanoma in Emilia-Romagna (Italy) from 1997 to 2004.

BACKGROUND: After a rapid increase in malignant melanoma (MM) incidence in the last decades, trends of the melanoma epidemic in the recent years seemed not homogeneous. OBJECTIVE: This study aimed at the monitoring of some epidemiological data referring to melanoma in a region of the Northern Italy during the past 8-year period. METHODS: All cases of melanoma, including also in situ lesions, diagnosed in Emilia-Romagna and San Marino State, with the exclusion of Cesena province, from 1997 to 2004 were recorded and the incidence of melanoma, adjusted for the European standard population by the direct method, was calculated. RESULTS: Mean standardized incidence was 9.7 for invasive MMs and 11.9, considering also in situ ones, showing an ascending trend with an increment of 3.3 new incident cases in 2004 compared with 1997. No differences in age distribution, gender and site were reported. Concerning tumour thickness, although a general ascending trend in all subtypes, only thin melanoma incidence significantly increased over the study period. CONCLUSIONS: Contrary to data from Northern European countries, melanoma incidence still showed an ascending trend in the Italian population of Emilia Romagna.

Detecting attention-deficit/hyperactivity disorder (ADHD) in adults with intellectual disability The use of Conners' Adult ADHD Rating Scales (CAARS).

There is an increasing interest in the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adulthood. It is also thought that ADHD is more prevalent in the field of intellectual disability (ID) than in the general population, but there are not many experimental studies. Since ADHD diagnosis in adults is more difficult, specific rating scales correlated to the main diagnostic systems have been created but have not been applied to people with ID. This work presents an application of an ADHD screening rating scale, the Conners' Adult ADHD Rating Scales (CAARS) screening version to 46 adults with ID. The resulting prevalence of "ADHD-positive" was 19.6%. These data are in accord with results reported in the general adult literature. Our data suggest that ID and attention disorders can co-occur. Therefore, not only can ADHD be a valid psychiatric diagnosis for a child with ID but for an adult with ID as well. The CAARS can be considered a useful clinical instrument to survey ADHD in ID.

Gait strategy of uninvolved limb in children with spastic hemiplegia.

AIM: The aim of this study is the gait pattern quantification in hemiplegic children with cerebral palsy using 3D Gait Analysis (GA), in order to distinguish kinematic and kinetic features of involved and uninvolved limbs. METHODS: Gait pattern of 28 hemiplegic children and 10 healthy children was quantified using GA. Spatial/temporal parameters, kinematic and kinetic parameters of the main joints of lower limbs were identified and calculated. RESULTS: In hemiplegic patients the gait pattern of uninvolved limbs was found to be different from those of involved limbs and of control group. The uninvolved limbs were characterized by significant longer stance phase, than involved limbs and healthy children. The main differences in kinematics were found at proximal joints: knee joint was more flexed than normality range during most of gait cycle and hip presented high flexion at the beginning of stance and in the swing phase. Ankle kinematics presented values closed to normative data, even if anomalous pattern was generally present. In term of ankle kinetics, excessive absorbed ankle power in the first phase of stance was found and ankle power generation revealed the mean value of its maximum to be closed to normative. CONCLUSION: Analysis of kinematic and kinetic parameters indicated that uninvolved limb of hemiplegic children generally presents a unique motor strategy, different from the involved limb and healthy group. Its gait pattern may be related to the search of a better stability in order to optimize gait and it may be a consequence of involved limb strategy due to the pathology.

The coefficient of friction in Parkinson's disease gait.

This study aimed to characterize the coefficient of friction (COF) curves of patients with Parkinson's disease (PD) during barefoot gait and to evaluate the relationships between this variable and functional scales. Twenty-two subjects with PD (ON phase of levodopa) and 22 healthy subjects participated in this study. The participants walked barefoot along a pathway that went over two force plates embedded in the floor of the data collection room. The instantaneous COF was calculated as the ratio between the horizontal and vertical components of the ground reaction forces. Two-sample t-tests applied to every 1% of the support phase of the COF curve were used to compare the groups and to identify the phases in which the two groups were different. Specifically, three COF areas were computed: Area 1 (for the loading response phase), Area 2 (for the midstance phase) and Area 3 (for the terminal stance phase). Pearson's tests were applied to assess the associations between the COF curve areas and the clinical scales. The subjects with PD exhibited lower COF values during the loading response and terminal stance phases and higher COF values during the mid-stance phase compared with the control group. A strong positive correlation was observed between Area 1 and the Timed Up and Go Test (90.3%). In conclusion, the patients' COFs exhibited patterns that were different from those of the control group. Moreover, during the loading response phase, these differences were well-correlated with the Timed Up and Go Test scale data; Timed Up and Go Test data can be used to identify the risk of falls among PD patients.

Robot-assisted gait training versus treadmill training in patients with Parkinson's disease: a kinematic evaluation with gait profile score.

The purpose of this study was to quantitatively compare the effects, on walking performance, of end-effector robotic rehabilitation locomotor training versus intensive training with a treadmill in Parkinson's disease (PD). Fifty patients with PD were randomly divided into two groups: 25 were assigned to the robot-assisted therapy group (RG) and 25 to the intensive treadmill therapy group (IG). They were evaluated with clinical examination and 3D quantitative gait analysis [gait profile score (GPS) and its constituent gait variable scores (GVSs) were calculated from gait analysis data] at the beginning (T0) and at the end (T1) of the treatment. In the RG no differences were found in the GPS, but there were significant improvements in some GVSs (Pelvic Obl and Hip Ab-Add). The IG showed no statistically significant changes in either GPS or GVSs. The end-effector robotic rehabilitation locomotor training improved gait kinematics and seems to be effective for rehabilitation in patients with mild PD.

Structural and functional relationships in 5'-nucleotidase from bull seminal plasma. A Fourier transform infrared study.

Fourier transform infrared spectroscopy (FTIR) was used to investigate the secondary structure of 5'-nucleotidase from bull seminal plasma (BSP). Spectra of protein in both D2O and H2O were analyzed by deconvolution and second derivative methods in order to observe the overlapping components of the amide I band. The protein, which is made up of two apparently identical subunits and which contains two zinc atoms, was studied in its native form, in the presence of dithiotreitol (DTT) and after removal of the two zinc atoms by means of nitrilotriacetic acid (NTA). Deconvolved and second derivative spectra of amide I band showed that the native protein contains mostly beta-sheet structure with a minor content of alpha-helix. The quantitative analysis of the amide I components was performed by a curve-fitting procedure which revealed 54% beta-sheet, 18% alpha-helix, 22% beta-turns and 6% unordered structure. The second derivative and deconvolved spectra of amide I band showed that no remarkable changes in the secondary structure of 5'-nucleotidase were induced by either DTT or NTA. These results were confirmed by the curve-fitting analysis where little or no changes occurred in the relative content of amide I components when the protein was treated with DTT or with NTA. Major changes, however, were observed in the thermal denaturation behavior of the protein. The native protein showed denaturation at temperatures between 70 and 75 degrees C, while the maximum of denaturation was observed between 65 and 70 degrees C and between 55 and 60 degrees C in the presence of NTA and DTT, respectively. The results obtained indicate that the two separate subunits of the protein have essentially the same secondary structure as that of the native enzyme.

Lipid-drug interaction: a structural analysis of pindolol effects on model membranes.

The ternary system constituted by distearoylphosphatidylcholine, pindolol (a vasodilator drug) and water has been investigated by using X-ray diffraction and calorimetric techniques. The structural modifications induced by the drug have been determined and a possible interaction model has been derived. In particular, the pindolol content-temperature dependent phase diagram shows the occurrence of two new phases: the first is an interdigitated gel, and the second is a lamellar structure presenting an unusual mixed disordered-ordered conformation of the hydrocarbon chains (L alpha beta). The comparative analysis of electron density profiles relative to the L alpha beta phase, reveals significant modifications in the paraffinic region of the lipid layer. In agreement with thermodynamic results, the structural data suggest that the drug induces a stiffening and a tightening of the hydrocarbon chains. Moreover, the hydrophilic properties of the membrane (particularly in P beta, and L alpha beta phases) present an evident dependence with the drug concentration.