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Patients with history of atrial fibrillation (AF) undergoing mitral edge–to–edge repair procedure with Mitraclip tend to be relatively older, have more advanced valve disease, and suffer from more comorbidities than patients without AF [1;2]. Moreover, their all–cause mortality rate one year after the procedure and hospitalization rate for heart failure is higher than that of patients in sinus rhythm [3]. Therefore, managing patients with AF poses a greater challenge, and their prognosis is considerably worse. Improvement of mitral regurgitation following mitral edge–to–edge repair procedure with Mitraclip may reduce atrial volume overload positively impacting AF triggers. In this report, we present a case of spontaneous restoration of stable sinus rhythm in a patient with chronic AF undergoing mitral valve repair procedure with Mitraclip. The patient, 80 years old, underwent implantation of a clip on centro–lateral site of the mitral valve plane (A2–P2) with mild residual insufficiency and an optimal procedural result. The restoration of sinus rhythm, which occurred during the first hours after the procedure, proved to be stable at the 30th day control post–discharge. the indexed left atrial volume remained unchanged (LAVI 43–45 mL/m2). Literature on the frequency of spontaneous sinus rhythm restoration following edge–to–edge mitral repair with Mitraclip in patients with chronic AF is limited. In a sub–analysis of the COAPT study [4], in addition to the known benefits of the Mitraclip procedure, it was possible to highlight a significant reduction in the rate of stroke in patients with AF. This outcome could be attributed to the reduction of the AF burden associated with mitral valve insufficiency. More studies are although necessary to determine the procedure‘s impact in this specific clinical situation. Rreferences: [1] Velu JF, Am J Cardiol. 2017 Dec 1;120(11):2035–2040. [2] Saad AM, Catheter Cardiovasc Interv. 2021 May 1;97(6):1252–1256. [3] Shah S, Heart Fail Rev. 2021 May;26(3):531–543. [4] Gertz ZM, Circ Cardiovasc Interv. 2021 Apr;14(4):e010300.

Mechanical forces, acting on eukaryotic cells, are responsible for cell shape, cell proliferation, cell polarity, and cell differentiation thanks to two cells abilities known as mechanosensing and mechanotransduction. Mechanosensing consists of the ability of a cell to sense mechanical cues, while mechanotransduction is the capacity of a cell to respond to these signals by translating mechanical stimuli into biochemical ones. These signals propagate from the extracellular matrix to the nucleus with different well known physical connections, but how the mechanical signals are transduced into biochemical ones remains an open challenge. Recent findings showed that the cell-generated forces affect the translocation of transcription factors (TFs) from the cytoplasm to the nucleus. This mechanism is affected by the features of nuclear pore complexes. Owing to the complex patterns of strains and stresses of the nuclear envelope caused by cytoskeletal forces, it is likely that the morphology of NPC changes as cytoskeleton assemblies' change. This may ultimately affect molecular transport through the nucleus, hence altering cell functions. Among the various TFs, Yes-associated protein (YAP), which is typically involved in cell proliferation, survival, and differentiation, is able to activate specific pathways when entrapped into the cell nucleus. Here, starting from experimental results, we develop a multiscale finite element (FE) model aimed to simulate the macroscopic cell spreading and consequent changes in the cell mechanical behaviour to be related to the NPCs changes and YAP nuclear transport.

In the last few years, growing evidence indicate that gut miocrobiome is linked to irritable bowel syndrome (IBS) and atherosclerotic disorders. The effect on lipid metabolism seems to be one of the potential mechanisms by which gut microbiome might favour the atherosclerotic process. IBS is a functional bowel disorder defined by the presence of recurrent episodes of abdominal pain associated with altered bowel habits. In this retrospective study the effect of a novel nutraceutical compound, namely Triobiotix, on gastrointestinal symptoms in IBS patients has been evaluated. Effects on lipid profile have been also recorded. Triobiotix is a nutraceutical consisting of: maltodextrin; mineralized extract of Lithothamnion; Bioecolians® gluco–oligosaccharides; ferment mix; short–chain fructo–oligosaccharides powder. We analyzed the database of 40 Italian General Practitioners (GPs). A total of 587 patients with IBS and on Triobiotix were identified. Of these, in only 535 patients, a complete first and second control data was available. The primary endpoint of these analysis was to assess whether Triobiotix resulted in a reduction in pain and meteorism, thus resulting in a lesser intensity of the main gastrointestinal symptoms. Secondary endpoints were to look for significative changes in lab values of total cholesterol, triglycerides levels and glycaemia. Treatment with Triobiotix for four weeks resulted in a reduction in the frequency and intensity of bloating, abdominal pain, and tenesmus. Unexpectedly, at the T1 control, mean cholesterol values were significatively reduced compared to the TO evaluation. Triglycerides levels were also significantly decreased (186.37+66.4 vs. 176.13+67.9; p < 0.05). Our analysis showed an unexpected effect of this combination of micronutrients on lipid profile beyond IBS symptoms. However, further studies are needed to confirm this evidence and to evaluate the particular compound responsible of this effect. A goal of LDL–C less of 115mg/dL is desirable for patients at low to moderate CVR, a significative portion of population is far from this target. The discovery of novel micronutrients combinations with cholesterol lowering effects could be of great importance for the management of patients with low–moderate dyslipidaemia.

According to the latest ESC guidelines on CVD prevention (2021) arterial stiffness (AS) still has a role in predicting future CVD risk and defining patients’ CVD risk level. However, significative measurement difficulties make a widespread evaluation of the AS problematic, especially in the ambulatorial outpatient setting. The IMT measurement is no longer recommended in the CVD risk assessment due to lack of standardization in measurement protocol and low power to reclassify patients toward higher CV risk. Understanding the correlation between the structure and function of the large arteries can lead to an optimization of cardiovascular disease prevention strategies. At present, indices of arterial stiffness have not been associated with qualitative morphological characteristics of intima–media complex. The IM GSM is a relatively simple measurement that can be acquired during a carotid color–Doppler ultrasound exam. The aim of this study was to investigate the relationship between indices of arterial stiffness and echogenicity of intima media complex (IM GSM) of the common carotid arteries in subjects with arterial hypertension. In our study population of 421 hypertensive patients, subjects with IM GSM > 30 showed a significantly increased arterial stiffness and LVMI (P < 0.001). A weak positive correlation was found between IM GSM and SBP (r =0.35, P< 0.001), and duration of hypertension (r = 0.31, P < 0.01). Our study suggests that increased stiffness observed in hypertensives is associated with qualitative changes in carotid arterial wall.

Case Report A 42–year–old woman was carried to emergency room lamenting sudden memory loss. Her husband witnessed the onset of the episode. No recent head trauma was reported, blood pressure was under control. Anterograde and retrograde memory loss was present and confirmed by a neurologist. No other neurological signs were elicitable. Blood exams and toxicological analysis were negative. ECG, chest radiography, and cerebral TC showed no abnormalities. At physical examination a carotid bruit could be appreciated. The patient was asymptomatic. Subsequently an eco–colour–Doppler of carotid artery was performed showing a left common and internal carotid artery dissection. The diagnosis of ICA dissection was confirmed with a contrast CT furthermore excluding the coexistence of an aortic dissection. The anterograde amnesia resolved 15 h after the admission. A neurologist confirmed that the patient experimented an episode of transient global amnesia. After a vascular surgery consultation, a conservative treatment was deemed appropriate. After a 6 month follow up the patient didn’t complain of any other neurological symptom or sign. Transient global amnesia (TGA) is characterized by reversible anterograde and retrograde amnesia of sudden onset that resolves spontaneously within 24 h. The pathophysiological mechanisms underlying this puzzling neurological syndrome are yet not completely clarified. Some studies support an ischemic aetiology for TGA and cases of TGA following ICA–stenting or aortic dissection with involvement of the supra–aortic branches are reported in literature, thus supporting the hypothesis that a cause–effect relationship between ischemic pathologies of supra–aortic trunks and TGA might be present. In the case here presented, a Doppler ultrasound of carotid arteries performed in a patient presenting with TGA, asymptomatic for neck pain, led to a diagnosis of ICA dissection. In order to not miss a spontaneous ICA dissection as a rare ethology of TGA, we suggesto perform an eco–colour–Doppler of the epi–aortic vessels in patients affected by such amnesic syndrome.

In this article, we define a p-generalized modified error function as the solution to a non-linear ordinary differential equation of second order, with a Robin type boundary condition at x=0. We prove existence and uniqueness of a non-negative $C^{\infty}$ solution by using a fixed point argument. We show that the p-generalized modified error function converges to the p-modified error function defined as the solution to a similar problem with a Dirichlet boundary condition. In both problems, for p=1, the generalized modified error function and the modified error function are recovered. In addition, we analyze the existence and uniqueness of solution to a problem with a Neumann boundary condition.

A case of a 7-year-old girl finally diagnosed with Langerhans cell histiocytosis is presented. The differential diagnosis between Langerhans cell histiocytosis and chronic nonbacterial osteomyelitis is discussed.

The basement membrane (BM) is a thin specialized extracellular matrix that functions as a cellular anchorage site, a physical barrier and a signaling hub. While the literature on the biochemical composition and biological activity of the BM is extensive, the central importance of the physical properties of the BM, most notably its mechanical stiffness and topographical features, in regulating cellular function has only recently been recognized. In this Review, we focus on the biophysical attributes of the BM and their influence on cellular behavior. After a brief overview of the biochemical composition, assembly and function of the BM, we describe the mechanical properties and topographical structure of various BMs. We then focus specifically on the vascular BM as a nano- and micro-scale structured surface and review how its architecture can modulate endothelial cell structure and function. Finally, we discuss the pathological ramifications of the biophysical properties of the vascular BM and highlight the potential of mimicking BM topography to improve the design of implantable endovascular devices and advance the burgeoning field of vascular tissue engineering.

The mechanical interpretation of the plethora of factors that governs cellular localization of amyloid aggregates is crucial for planning novel therapeutical interventions in neurodegenerative diseases since these aggregates exert a primary role in the proteostasis machinery. The uptake of Cell Penetrating Peptides (CPPs) conjugated with different amyloid polypeptides occurs via different endocytic processes regulated by cytoskeleton organization and cell morphology. Herein, we deepened the internalization of an amyloid system in cells cultured on nanopatterned surfaces that represent a powerful tool to shape cell and regulate its contractility. We analyzed the behavior of an amyloid model system, employing NPM1264-277 sequence, covalently conjugated to Tat fragment 48-60 as CPP. To investigate its internalization mechanism, we followed the formation of aggregates on two kinds of substrates: a flat and a nanopatterned surface. Herein, investigations during time were carried out by employing both confocal and second harmonic generation (SHG) microscopies. We showed that modifications of cellular environment affect peptide localization, its cytoplasmic translocation and the size of amyloid aggregates.

The extracellular microenvironment proved to exert a potent regulatory effect over different aspects of Embryonic Stem Cells (ESCs) behavior. In particular, the employment of engineered culture surfaces aimed at modulating ESC self-organization resulted effective in directing ESCs toward specific fate decision. ESCs fluctuate among different levels of functional potency and in this context the Zscan4 gene marks the so-called "metastate," a cellular state in which ESCs retain both self-renewal and pluripotency capabilities. Here we investigated the impact of topographic cues on ESCs pluripotency, differentiation and organization capabilities. To this aim, we engineered culturing platforms of nanograted surfaces with different features size and we investigated their impact on ESCs multicellular organization and Zscan4 gene expression. We showed that the morphology of ESC-derived aggregates and Zscan4 expression are strictly intertwined. Our data suggest that ESC Zscan4 metastate can be promoted if the adhesive surface conditions guide cellular self-aggregation into 3D dome-like structure, in which both cell-material interactions and cell-cell contact are supportive for Zscan4 expression.

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In many cell types, shape and function are intertwined. In vivo, vascular endothelial cells (ECs) are typically elongated and aligned in the direction of blood flow; however, near branches and bifurcations where atherosclerosis develops, ECs are often cuboidal and have no preferred orientation. Thus, understanding the factors that regulate EC shape and alignment is important. In vitro , EC morphology and orientation are exquisitely sensitive to the composition and topography of the substrate on which the cells are cultured; however, the underlying mechanisms remain poorly understood. Different strategies of substrate patterning for regulating EC shape and orientation have been reported including adhesive motifs on planar surfaces and micro- or nano-scale gratings that provide substrate topography. Here, we explore how ECs perceive planar bio-adhesive versus microgrooved topographic surfaces having identical feature dimensions. We show that while the two types of patterned surfaces are equally effective in guiding and directing EC orientation, the cells are considerably more elongated on the planar patterned surfaces than on the microgrooved surfaces. We also demonstrate that the key factor that regulates cellular morphology is focal adhesion clustering which subsequently drives cytoskeletal organization. The present results promise to inform design strategies of novel surfaces for the improved performance of implantable cardiovascular devices.

Biochemical and biophysical stimuli of stem cell niches finely regulate the self-renewal/differentiation equilibrium. Replicating this in vitro is technically challenging, making the control of stem cell functions difficult. Cell derived matrices capture certain aspect of niches that influence fate decisions. Here aligned fibrous matrices synthesized by MC3T3 cells are produced and the role of matrix orientation and stiffness on the maintenance of stem cell characteristics and adipo- or osteo-genic differentiation of murine mesenchymal stem cells (mMSCs) is investigated. Decellularized matrices promoted mMSC proliferation. Fibrillar alignment and matrix stiffness work in concert in defining cell fate. Soft matrices preserve stemness, whereas stiff ones, in presence of biochemical supplements, promptly induce differentiation. Matrix alignment impacts the homogeneity of the cell population, i.e. soft aligned matrices ameliorate the spontaneous adipogenic differentiation, whereas stiff aligned matrices reduce cross-differentiation. We infer that mechanical signalling is a dominant factor in mMSC fate decision and the matrix alignment contributes to produce a more homogeneous environment, which results in a uniform response of cells to biophysical environment. Matrix thus produced can be obtained in vitro in a facile and consistent manner and can be used for homogeneous stem cell amplification or for mechanotransduction-related studies This article is protected by copyright. All rights reserved.

this file contains figures supporting the manuscript; .raw files contains manuscript dataset

Extracellular matrix assembly and composition influence the biological and mechanical functions of tissues. Developing strategies to control the spatial arrangement of cells and matrix is of central importance for tissue engineering-related approaches relying on self-assembling and scaffoldless processes. Literature reports demonstrated that signals patterned on material surfaces are able to control cell positioning and matrix orientation. However, the mechanisms underlying the interactions between material signals and the structure of the de novo synthesized matrix are far from being thoroughly understood. In this work, we investigated the ordering effect provided by nanoscale topographic patterns on the assembly of tissue sheets grown in vitro. We stimulated MC3T3-E1 preosteoblasts to produce and assemble a collagen-rich matrix on substrates displaying patterns with long- or short-range order. Then, we investigated microstructural features and mechanical properties of the tissue in uniaxial tension. Our results demonstrate that patterned material surfaces are able to control the initial organization of cells in close contact to the surface; then cell-generated contractile forces profoundly remodel tissue structure towards mechanically stable spatial patterns. Such a remodelling effect acts both locally, as it affects cell and nuclear shape and globally, by affecting the gross mechanical response of the tissue. Such an aspect of dynamic interplay between cells and the surrounding matrix must be taken into account when designing material platform for the in vitro generation of tissue with specific microstructural assemblies.

Material features proved to exert a potent influence on cell behaviour in terms of adhesion, migration and differentiation. In particular, biophysical and biochemical signals on material surfaces are able to affect focal adhesion distribution and cytoskeletal assemblies, which are known to regulate signalling pathways that ultimately influence cell fate and functions. However, a general, unifying model that correlates cytoskeletal-generated forces with genetic events has yet to be developed. Therefore, it is crucial to gain a better insight into the material-cytoskeleton crosstalk in order to design and fabricate biomaterials able to govern cell fate more accurately. In this work, we demonstrate that confining focal adhesion distribution and growth dramatically alters the cytoskeleton's structures and dynamics, which in turn dictate cellular and nuclear shape and polarization. MC3T3 preosteoblasts were cultivated on nanograted polydimethylsiloxane substrates and a thorough quantification – in static and dynamic modes – of the morphological and structural features of focal adhesions and cytoskeleton was performed. Nanoengineered surfaces provided well-defined zones for focal adhesions to form and grow. Unique cytoskeletal structures spontaneously assembled when focal adhesions were confined and, in fact, they proved to be very effective in deforming the nuclei. The results here presented provide elements to engineer surfaces apt to guide and control cell behaviour through the material-cytoskeleton-nucleus axis.

Video Objective Laparoscopic sacrocolpopexy (LSC) is known to achieve lower recurrence rates, shorter recovery time, and less dyspareunia. However, LSC is problematic because it requires specific laparoscopic skills and the laparoscopy takes longer than other competing operations. In this video, we present the surgical techniques for LSC we are using with a view to shortening operation times and reducing complications. We named this approach Time Sparing Sacrocolpexy (TSS) Design Prospective Clinical Trial Setting San Carlo di Nancy Hospital GVM Care & Research, Rome Patients: Ninety women with symptomatic stage 3 or greater POP underwent LSC in our hospital between November 2016 and January 2019. Interventions Ninety women with symptomatic stage 3 or greater POP underwent LSC in our hospital between November 2016 and January 2019. In the first 80 operations we followed the nerve-preserving technique described by Ercoli et al. in 2017. In the final 10 operations we modified the technique in order to reduce operative time. The main changes were: (1) Use of Bipolar loop to cut the cervix instead of the monopolar hook, (2) make a stitch on the meshes in order to reduce the time of introduction e positioning of them in the pelvis, (3) replacing part of the classic LSC stitches with (i) AbstackT fixations to fix meshes to the anterior and posterior vaginal wall, but maintaining nonabsorbable stitches at the urethrovesical junction, at the cervix, at the level of levator ani muscle and at the sacrum. Measurements and Main Results Operative Time. Intra and post operative related complications. The operation time decreased (around 40%) as the surgical technique improved through experience. No major intra- or postoperative complications occurred. Conclusion These modifications to the technique will help shorten operation times and reduce complications of LSC.

The Y-box binding protein 1 (YB-1) belongs to the cold-shock domain protein superfamily, one of the most evolutionarily conserved nucleic acid-binding proteins currently known. YB-1 performs a wide variety of cellular functions, including transcriptional and translational regulation, DNA repair, drug resistance, and stress responses to extracellular signals. Inasmuch as the level of YB-1 drastically increases in tumor cells, this protein is considered to be one of the most indicative markers of malignant tumors. Here, we present evidence that ΔNp63α, the predominant p63 protein isoform in squamous epithelia and YB-1, can physically interact. Into the nucleus, ΔNp63α and YB-1 cooperate in PI3KCA gene promoter activation. Moreover, ΔNp63α promotes YB-1 nuclear accumulation thereby reducing the amount of YB-1 bound to its target transcripts such as that encoding the SNAIL1 protein. Accordingly, ΔNp63α enforced expression was associated with a reduction of the level of SNAIL1, a potent inducer of epithelial to mesenchymal transition. Furthermore, ΔNp63α depletion causes morphological change and enhanced formation of actin stress fibers in squamous cancer cells. Mechanistic studies indicate that ΔNp63α affects cell movement and can reverse the increase of cell motility induced by YB-1 overexpression. These data thus suggest that ΔNp63α provides inhibitory signals for cell motility. Deficiency of ΔNp63α gene expression promotes cell mobilization, at least partially, through a YB-1-dependent mechanism.

This paper presents a variability study of several engineering properties of tire-derived aggregate based on a comprehensive literature survey of experimental test programs. The dry compacted unit weight, cohesion intercept, friction angle, constrained modulus, and modified secondary compression index were evaluated and compared to the engineering parameter variability of natural soils. A series of regression analyses were performed to investigate the presence and significance of scale-dependency. The results of the variability analysis indicate that unit weight has the lowest value of coefficient of variation (COV) whereas the shear strength parameters, constrained modulus, and compression index have COV values that are substantially higher. Regression analyses indicated that unit weight and constrained modulus showed the greatest sensitivity to changes in maximum tire particle size. A nonstatistical investigation was used to further investigate the variability and scale-dependency of the shear strength parameters. Using Mohr-Coulomb failure criterion and assuming that cohesion is negligible, the analysis showed a scale-independent relationship which is consistent with the statistical findings for cohesion and friction angle.

This paper examines immediate and time-dependent compression of tire derived aggregate (TDA) and TDA-soil composites. To accommodate large particle sizes, modified experimental devices were developed and used to test tire chips and tire shreds. Immediate compression of TDA, which results almost entirely from the reduction of pore volume, increases with TDA content and tire particle size. The secant constrained modulus ( Msec ) of TDA defined over the stress range of 0–50 kPa varied from a low of 255 kPa (100% tire shreds) to a high of 1,320 kPa (50% tire chips). A characteristic relationship between strain and time exists for TDA and TDA composites under one-dimensional confined compression. Time-dependent deformation is well described by the modified secondary compression index ( Cαe ) , which ranged from 0.0010 (50% tire chips) to 0.0074 (100% tire chips). Time-dependent deformation was inversely proportional to sand content, with the most significant changes resulting from the addition of 15% sand. Bot...

The biologica1 and mechanical functions of in-vitro generated tissues depend on the spatial arrangement of their microcostituents. Previous works, focused on controlling tissue structure by confining cells within mircogrooves or by mechanically stimulating cell-substrate constructs. However, ECM producing cells invariably migrate onto/within the substrate and the effect of migration on the dynamics of tissue assembly has not been thoroughly investigated. Recent studies started to unravel the interplay between the cytoskeleton machinery and collagen deposition. Our objective is to verify that spatial deposition of collagen is affected by ce11 migration: random migrating cells produce disordered tissues, whereas a polarized migration leads to an aligned tissue. To this aim, we used nanogrooved silicone substrates. MC3T3 cells were cultured on patterned or flat substrates (up to 4 weeks). Ce11 migration analysis was performed by time lapse microscopy of low density and high density cultures. Collagen was quantified by Sircol assay and its alignrnent was assessed by observing picrosirius stained tissues under polarized light. Microstructural analyses were performed using TEM and SEM. In the early stage of culture, MC3T3 are oriented and migrate predominantly along the nanogrooves. After one week, cells reach confluence, they are still aligned although they migrate more slowly. In contrast, no preferential direction of migratiodalignment is evident on flat substrates. At longer times, cells produce a dense multilayered collagen matrix, whose orientation is visible under polarized light. Fibres are coaligned with cells and the nanogrooves. Tissue grown on flat substrates shows local patches of cell/collagen coalignment although no macroscopic orientation is observable. These results suggest that collagen alignrnent can be controlled by guiding cells migration. The experimental setup might be a starting platform to explore different topographic patterns and to assess the optimal condition to generate tissues with predetermined orientation.

Topographic patterns are known to affect cellular processes such as adhesion, migration and differentiation. However, the optimal way to deliver topographic signals to provide cells with precise instructions has not been defined yet. In this work, we hypothesize that topographic patterns may be able to control the sensing and adhesion machinery of cells when their interval features are tuned on the characteristic lengths of filopodial probing and focal adhesions (FAs). Features separated by distance beyond the length of filopodia cannot be readily perceived; therefore, the formation of new adhesions is discouraged. If, however, topographic features are separated by a distance within the reach of filopodia extension, cells can establish contact between adjacent topographic islands. In the latter case, cell adhesion and polarization rely upon the growth of FAs occurring on a specific length scale that depends on the chemical properties of the surface. Topographic patterns and chemical properties may interfere with the growth of FAs, thus making adhesions unstable. To test this hypothesis, we fabricated different micropatterned surfaces displaying feature dimensions and adhesive properties able to interfere with the filopodial sensing and the adhesion maturation, selectively. Our data demonstrate that it is possible to exert a potent control on cell adhesion, elongation and migration by tuning topographic features’ dimensions and surface chemistry.

Two experiments investigated spontaneous class grouping behavior by human-enculturated and language-reared bonobos (Pan paniscus) and common chimpanzees (P. troglodytes). In experiment 1, three chimpanzees ranging in age from 6 to 18 years were presented with six objects. The objects embodied three conditions: additive, multiplicative and disjoint classes. All chimpanzees spontaneously produced single- and two-category classifying. In experiment 2, six chimpanzees ranging in age from 6 to 21 years were presented with 12 objects in the same class conditions. Chimpanzees mainly produced single-category classifying. Their two-category classifying was more rudimentary than that found in experiment 1. Chimpanzees did not produce any three-category classifying which would be necessary to construct the hierarchies that humans begin to construct during early childhood.

The development of spontaneous object manipulation in 5 chimpanzees (Pan troglodytes) from ages 15 to 54 months was investigated, focusing on formal properties of subjects’ acts and the objects they manipulated. Young chimpanzees’ manipulation progress from serial one-at-a-time acts on one object to parallel two-at-a-time acts on two or more objects. With age, simultaneous acts become increasingly transformational and identical or reciprocal to each other. Moreover, the class properties of objects manipulated simultaneously change. When presented with objects belonging to two different classes, subjects shift, with age, from manipulating different objects to manipulating identical or similar objects. In all these respects young chimpanzee’ development is similar to human infants’. In others it differs. Most especially, the onset age is later and the development is slower as well as less structurally complex.

Human infants’ developing manipulatory transformations involved in classifying objects from ages 6 to 24 months were investigated. Infants’ manipulations develop from predominantly serial one-at-a-time acts with one object to predominantly parallel two-at-a-time acts with two objects. This shift is marked by increasingly overt transformational consequences for the objects manipulated. When infants construct parallel transformations they are initially different. With age they are increasingly identical or reciprocal. Also during this age period, as the number of objects manipulated at the same time increases, so does the frequency with which infants coordinate them. At the same time, the kind of objects infants manipulate simultaneously changes. Six-month-olds manipulate different objects when acting on more than one object at a time. By age 12 months, infants switch to manipulating identical objects at the same time, indicating that they are beginning to construct identity classes. Since this development occurs about a half year before human infants develop any substantial naming behavior, the origins of classification cannot depend on this linguistic development

Aims Strategies to prevent adverse left ventricular (LV) remodelling after myocardial infarction have included several traditional approaches and novel cell-based or gene therapies. Delivery of growth factors in post-infarction heart failure has emerged as a valuable alternative strategy. Our aim was to investigate the effects of sequential release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) from biodegradable gelatin microspheres in experimental heart failure. Methods and results Gelatin hydrogel microspheres were known to guarantee a sustained release of encapsulated growth factors, characterized by an initial burst followed by a slower release. Rats with moderate myocardial infarction were randomized to receive empty microspheres (MI), microspheres loaded with IGF-1 or VEGF, or a combination thereof (DUAL). Myocardial injections of microspheres were performed at the time of surgery, and treatment lasted 4 weeks. Echocardiography, LV catheterization, morphometric histology and immunohistochemistry, and molecular assessment of downstream mediators [e.g. Akt, endothelial nitric oxide synthase (eNOS), and sarco/endoplasmic reticulum calcium ATPase-2 (SERCA-2)] were assessed at the end of the treatment period. Infarct sizes were 33 ± 2, 28 ± 4, 24 ± 3, and 16 ± 3% in the MI, IGF-1, VEGF, and DUAL groups, respectively. IGF-1 attenuated LV remodelling, improved LV systolic and diastolic function, increased myocyte size, and reduced apoptotic deaths, capillary loss, and indexes of inflammation. VEGF-treated animals displayed a marked myocardial neoangiogenesis that led to the formation of mature vessels if combined with IGF-1 delivery. Downstream effects of IGF-1 were principally mediated by the Akt–mTOR (mammalian target of rapamycin)-dependent pathway, and both growth factors, particularly VEGF, induced a robust and sustained increase of eNOS. Conclusion IGF-1 and VEGF exerted complementary therapeutic effects in post-infarction heart failure. Biodegradable gelatin microspheres provide sustained and controlled growth factor release locally, exposing myocardial tissue without the side effects of systemic administration.

We present an innovative and simple, soft UV lithographic method “FIll-Molding In Capillaries” (FIMIC) that combines soft lithography with capillary force driven filling of micro-channels to create smooth hydrogel substrates with a 2D micro-pattern on the surface. The lithographic procedure involves the molding of a polymer; in our case a bulk PEG-based hydrogel, via UV-curing from a microfabricated silicon master. The grooves of the created regular line pattern are consequently filled with a second hydrogel by capillary action. As a result, a smooth surface is obtained with a well-defined pattern design of the two different polymers on its surface. The FIMIC method is very versatile; the only prerequisite is that the second material is liquid before curing in order to enable the filling process. In this specific case we present the proof of principle of this method by applying two hydrogels which differ in their crosslinking density and therefore in their elasticity. Preliminary cell culture studies on the fabricated elasticity patterned hydrogels indicate the preferred adhesion of the cells to the stiffer regions of the substrates, which implies that the novel substrates are a very useful platform for systematic cell migration studies, e.g. more fundamental investigation of the concept of “durotaxis”.

Voiding dysfunction after incontinence surgery is a potential complication of all stress incontinence procedures. The term voiding dysfunction indicates from obstructive voiding symptoms up to complete urinary retention, requiring intermittent catheterization, and also includes irritative storage symptoms such as de novo urgency and detrusor overactivity. Of particular importance is the temporal relationship between symptoms and the previous surgical procedure, and although many different operations can result in voiding dysfunction, the most common cause remains attributable to hypersuspension of the urethra. The diagnosis of postoperative voiding dysfunction can be challenging. First of all surgeons must ask for an accurate history, in order to assess symptomatology and to carry out a physical examination. Further diagnosis could be done through urodynamics, but this is somewhat controversial: despite various proposed cut-off values, there are no absolute urodynamic criteria to define obstruction in women. Fortunately, most voiding dysfunction is transient and resolves spontaneously in a few days to weeks. Persistent voiding dysfunction (longer than 4 weeks) occurs in 5-20% after the Marshall-Marchetti-Krantz procedure, 4-22% after the Burch colposuspension, 5-7% after needle suspension, 4-10% after the pubovaginal sling procedure, and 2-4% after the trans-vaginal tape procedure. However, if symptoms persist, surgery is indicated. Several surgical approaches are described, including sling incision, sling lysis and formal urethrolysis, comprising vaginal and retropubic approach with or without graft interposition. In this article the procedures are described and the results of each type of urethrolysis are reported.