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Huntington's disease (HD) is a fatal neurodegenerative disorder with no effective cure currently available. Over the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingosine-1-phosphate (S1P) has been reported in multiple disease settings, including human postmortem brains from HD patients. In this study, we investigate the potential therapeutic effect of the inhibition of S1P degradative enzyme SGPL1, by the chronic administration of the 2-acetyl-5-tetrahydroxybutyl imidazole (THI) inhibitor. We show that THI mitigated motor dysfunctions in both mouse and fly models of HD. The compound evoked the activation of pro-survival pathways, normalized levels of brain-derived neurotrophic factor, preserved white matter integrity, and stimulated synaptic functions in HD mice. Metabolically, THI restored normal levels of hexosylceramides and stimulated the autophagic and lysosomal machinery, facilitating the reduction of nuclear inclusions of both wild-type and mutant huntingtin proteins.

The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.

We analyze surface texturing induced by femtosecond laser irradiation of a silicon target at high repetition rates. The features of the produced surface structures in ablative conditions, i.e. at fluences larger than the ablation threshold, are investigated as a function of number of pulses and pulse energy, for various repetition rates, in the range 10 Hz–200 kHz. Our experimental findings highlight a significant influence of the pulse repetition rate on both surface texture and crater size produced by irradiation with a fixed sequence of N laser pulses. This effect is ascribed to plume shielding occurring at repetition rates larger than ≈10 kHz.

Background Chronic subdural hematoma associated with dural calcifications in previously pediatric shunted patients is a rare condition. The inner dural membrane opening can lead to progressive brain herniation into the subdural space due to brain reexpansion. Case Description A 15-year-old boy, previously shunted at birth for congenital hydrocephalus, presented with a giant chronic right hemispheric subdural hematoma. After 2 surgical procedures in which the subdural calcified neomembrane was opened and a subdural shunt was implanted, he developed a cortical brain herniation into the subdural space, resulting in brain ischemia and upper limb weakness and vomiting. The final surgical treatment consisted of an extensive wide peeling of visceral calcified membrane mutually to programmable valve placement along the subduroperitoneal shunt, in order to create a positive gradient between the subdural space and the ventricles. The patient experienced a prompt clinical improvement. Conclusions This case illustrates a rare complication of the treatment of a chronic subdural hematoma caused by insufficient opening of the calcified inner mambrane of the hematoma and encouraged by gradient pressure between the ventricular and subdural compartments. To avoid this complication, it is preferable to not open a thick, calcified, unelastic inner membrane. However, in case of lack of clinical and radiologic improvement, it may become necessary to open it: a wide opening should be attempted, in order to prevent brain strangulation.

Backgrounds Infant-directed speech (IDS) is part of an interactive loop that plays an important role in infants’ cognitive and social development. The use of IDS is universal and is composed of linguistic and emotional components. However, whether the emotional component has similar acoustics characteristics has not been studied automatically. Methods We performed a cross-cultural study using automatic social signal processing techniques (SSP) to compare IDS across languages. Our speech corpus consisted of audio-recorded vocalizations from parents during interactions with their infant between the ages of 4 and 18 months. It included 6 databases of five languages: English, French, Hebrew (two databases: mothers/fathers), Italian, and Brazilian Portuguese. We used an automatic classifier that exploits the acoustic characteristics of speech and machine learning methods (Support Vector Machines, SVM) to distinguish emotional IDS and non-emotional IDS. Results Automated classification of emotional IDS was possible for all languages and speakers (father and mother). The uni-language condition (classifier trained and tested in the same language) produced moderate to excellent classification results, all of which were significantly different from chance (P Conclusion The automated classification of emotional and non-emotional components of IDS is possible based on the acoustic characteristics regardless of the language. The results found in the cross-over condition support the hypothesis that the emotional component shares similar acoustic characteristics across languages.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits caused by the loss of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA). However, clinical data revealed that not only the dopaminergic system is affected in PD. Postmortem studies showed degeneration of noradrenergic cells in the locus coeruleus (LC) to an even greater extent than that observed in the SN/VTA. Pharmacological models support the concept that modification of noradrenergic transmission can influence the PD-like phenotype induced by neurotoxins. Nevertheless, there are no existing data on animal models regarding the distant impact of noradrenergic degeneration on intact SN/VTA neurons. The aim of this study was to create a transgenic mouse model with endogenously evoked progressive degeneration restricted to noradrenergic neurons and investigate its long-term impact on the dopaminergic system. To this end, we selectively ablated the transcription initiation factor-IA (TIF-IA) in neurons expressing dopamine β-hydroxylase (DBH) by the Cre-loxP system. This mutation mimics a condition of nucleolar stress affecting neuronal survival. TIF-IA

A neutron irradiation facility based on four 241Am–Be sources, each one with an activity of 111 GBq, placed in Plexiglas pipes inside a tank filled with water used both as a moderator and a biological shielding, has been realized at the Engineering Department of Palermo University. In view of its use as a testing tool in various research activities, a characterisation of the irradiator has been carried out through the determination of neutron and gamma-ray flux profiles, the evaluation of the thermal to total neutron flux percentage ratio and of the epithermal neutron shaping factor. To this aim, results of a Monte Carlo (MCNP5 code) simulation based on a previously validated source model have been compared with the experimental results obtained from TLD dosimeters and activated gold foils. Experimental values show a good agreement with MCNP5 evaluations, highlighting a gradually decreasing of dose values as a function of the distance from the lying plane of sources. Maximum values of experimental neutron fluxes have been found to be (3.73 ± 0.38) × 104 cm−2 s−1 (thermal) and (2.13 ± 0.25) × 104 cm−2 s−1 (epithermal and fast), with a percentage of 64% of thermal to total neutron flux and epithermal neutron shaping factor equal to −0.16 ± 0.04. Both neutron and gamma fluxes for the most used positions inside the irradiation channel can then be provided and the main parameters for any irradiation plane can be easily established.

Survival, reproduction and detection rates may vary greatly amongst individuals. Failure to account for this variation results in biased inferences about age effects and population size. However, individual variation is not normally considered in population viability analysis, potentially leading to misleading projections for small populations. We present a novel data-augmentation approach for incorporating individual variation in rates in integrated population models. By adding rows to survival and reproduction matrices for hypothetical individuals in both the past and future, inferences about individual variation derived from Bayesian hierarchical modelling are propagated into population projections. We apply this method to a small reintroduced population of hihi (Notiomystis cincta) at Bushy Park, New Zealand, where individuals vary greatly in reproductive success, longevity and detection probability, and ongoing management decisions depend on modelling projections. We compare the results to those from an alternative model that ignores individual variation but incorporates sex and age effects. The modelling confirmed pronounced individual variation in all rates, and greatly altered their interpretation. Estimated survival and reproduction rates of average individuals became much lower and apparent age effects disappeared. In addition, the estimated proportion of fledglings produced by unmonitored females dropped from 23% to 9%. Incorporation of individual variation in the integrated population model resulted in more optimistic population projections over the next four years although the difference was minor in relation to the 95% prediction limits. The methodology presented has broad potential for assessing whether population projections used to guide management of small populations are sensitive to individual variation.

Endogenous recruitment of circulating angiogenic cells (CACs) is an emerging strategy to induce angiogenesis within a defect site, and multiple recent strategies have deployed soluble protein releasing biomaterials for this purpose. However, the way in which the design of biomaterials affects CAC recruitment and invasion are poorly understood. Here we used an enhanced-throughput cell invasion assay to systematically examine the effects of biomaterial design on CAC recruitment. The screens co-optimized hydrogel presentation of a stromal-derived factor-1α (SDF-1α) gradient, hydrogel degradability, and hydrogel stiffness for maximal CAC invasion. We also examined the specificity of this invasion by assessing dermal fibroblast, mesenchymal stem cell, and lymphocyte invasion individually and in co-culture with CACs to identify hydrogels specific to CAC invasion. These screens suggested a subset of MMP-degradable hydrogels presenting a specific range of SDF-1α gradient slopes that induced specific invasion of CACs, and we posit that the design parameters of this subset of hydrogels may serve as instructive templates for the future design of biomaterials to specifically recruit CACs. We also posit that this design concept may be applied more broadly in that it may be possible to utilize these specific subsets of biomaterials as “filters” to control which types of cell populations invade into and populate the biomaterial. Statement of Significance The recruitment of specific cell types for cell-based therapies in vivo is of great interest to the regenerative medicine community. Circulating angiogenic cells (CACs), CD133+ cells derived from the blood stream, are of particular interest for induction of angiogenesis in ischemic tissues, and recent studies utilizing soluble-factor releasing biomaterials to recruit these cells in vivo show great promise. However, these studies are largely “proof of concept” and are not systematic in nature. Thus, little is currently known about how biomaterial design affects the recruitment of CACs. In the present work, we use a high throughput cell invasion screening platform to systematically examine the effects of biomaterial design on circulating angiogenic cell (CAC) recruitment, and we successfully screened 263 conditions at 3 replicates each. Our results identify a particular subset of conditions that robustly recruit CACs. Additionally, we found that these conditions also specifically recruited CACs and excluded the other tested cells types of dermal fibroblasts, mesenchymal stem cells, and lymphocytes. This suggests an intriguing new role for biomaterials as “filters” to control the types of cells that invade and populate that biomaterial.

The incidence of fractures of the humerus has increased exponentially in recent years. The most used classifications for humerus fracture are morphological (Neer), biological (AO/ASIF) and descriptive (Hertel). The types of surgical treatment for humerus fracture include prosthetic replacement and synthesis using different devices, including the Tension Guide Fixator (TGF), Gex-Fix. External fixation for displaced proximal humeral fractures avoids dissection and soft tissue stripping and has been reported by some authors to be associated with higher union rates, a lower incidence of avascular necrosis, less scarring of the scapulohumeral interface, and faster rehabilitation compared with open reduction and internal fixation. Other authors have reported that external fixation does not ensure acceptable reduction and fracture stability, particularly in patients with osteoporosis. The external fixation technique involves the introduction of Steinmann's pin to keep manual reduction, the introduction of two K-wires in the humeral head, the removal of the Steinmann's pin, and the introduction of two fiches on the humeral shaft. Hub connectors are mounted on the wires and on the chips to connect the outer bar and tensioning system. A total of 84 patients aged 42–84 years with proximal end humeral fractures (66% had two-part fractures) were treated with Fixator TGF in this study from December 2007 to June 2012. The postoperative recovery was earlier and the active-assisted motion was less painful than has been reported with other surgical techniques. The TGF was removed without anaesthesia at the outpatient clinic at a mean of 7 weeks (range 5–8 weeks) after surgery, and there was no loss of reduction or secondary displacement after removal. These results, after five years of experience, confirm that the best indication for this fixator is two- or three-part fractures because the device enables early active mobilisation. The limitations of this fixator are evident in fractures in which closed reduction is not possible and in three-part fractures with varus displacement because the TGF has less stability than other systems, such as the plate or cage. The short learning curve, reduced surgical time and risk, and low cost encourage the use of this technique.

Yearly, in Europe, more than 1 million tonnes of plastic materials are used in agricultural activities. Among the possible applications, plastic films for protected cultivation practices are highly used worldwide because of the significant advantage deriving from the shortening of the growing period. However, in the absence of a correct policy disposal of plastic films, environmental degradation could take place with serious ecological and economic consequences. In this study, a geographical information system (GIS) - based model to locate and quantify the yearly amount of agricultural plastic waste (APW) coming from crop-shelter coverage used in greenhouses system was put forward and was applied in a study area located in southern Italy, highly characterised by protected cultivation practices. Firstly, the areas with the highest density of crop shelters were mapped, then a suitable index to determine APW amount was computed and applied to obtain heat maps related to covering plastic films. Finally, sensitivity analyses were carried out by varying thickness, lifetime, and density of the covering films of the greenhouses, located in the considered samples. The index ranged between 976 kg ha−1yr−1and, 2484 kg ha−1yr−1. The results showed that the density of greenhouses and tunnels-greenhouses is still elevated nearby the coastline, highlighting that the guidelines of the territorial plan of the Province of Ragusa concerning the displacement of protected crops from the coast to the internal rural areas were disregarded. Moreover, the GIS-based model results could provide basic information for the analysis of the environmental impact due to transportation of APW. Therefore, these results could offer a suitable tool to improve the correct disposal management of covering plastic films and the related recycle policy.

The ability to locally deliver bioactive molecules to distinct regions of the skeleton may provide a novel means by which to treat osteomyelitis,improve bone healing, or accelerate growth. In this manuscript we demonstrate that biologically active molecules can be released from bioabsorbable membranes and have a local effect on the skeleton. Herein, we introduce a mineral-coated poly-e-caprolactone film capable of binding and releasing HGH and TGF-β1both in vitro and in vivo. These mineral coated membranes loaded with either HGH or TGF-β1 were surgically placed underneath the periosteum, and multiple effects on neighboring osseous tissue, periosteal tissue, and local bone marrow cellularity were observed. Importantly, the observed effects in the presence of HGH orTGF-β1 were distinct from sham surgeries and implanted mineral-coated poly-e-caprolactone films without these growth factors. Such results suggest that HGH and TGF-β1 released from the mineral-coated films are indeed bioactive in vivo and are exerting localized effects on the skeleton. We posit that this work represents the first step towards the development of technologies to locally affect the skeleton, and that further studies to develop therapeutic applications and optimize these systems can now be pursued.

The effects of room temperature γ-ray irradiation up to a dose of ∼1300 kGy are investigated by Electron paramagnetic resonance (EPR) measurements in amorphous silicon dioxide (a-SiO2) produced by a sol-gel synthesis method that introduces O{triple bond, long}Si{single bond}Si{triple bond, long}O oxygen deficiency. We have found that exposure to radiation generates the Eγ′ center with the same spectral features found in high purity commercial a-SiO2. The maximum concentration of defects induced in this sol-gel material indicates that its resistance to radiation is comparable to that of synthetic fused a-SiO2. The concentration of Eγ′ center increases with irradiation, featuring a sublinear dose dependence up to the highest investigated dose and showing no saturation effects. This defect generation process suggests that the chemically induced precursor influences the mechanisms of Eγ′ center generation. © 2007 Elsevier B.V. All rights reserved.