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Background: Aesthetic neuromodulator injections of the upper face are frequently performed to temporarily block muscular actions of the periorbital muscles to ultimately reduce skin rhytids. However, the adverse event rate in the literature for toxin-induced blepharoptosis ranges from 0.51% to 5.4%., Objective: To identify access pathways by which injected neuromodulator product can travel from extra- to intra-orbital and therefore affect the levator palpebrae superioris muscle., Methods: Nine non-embalmed human body donors were investigated in this study with a mean age at death of 72.8 (16.1) years. The 18 supraorbital regions were injected in 28 times (14 for supratrochlear and 14 for supraorbital) with 0.5 cc, whereas eight cases (four for supratrochlear and four supraorbital) were injected with 0.1 cc of colored product. Anatomic dissections were conducted to identify structures stained by the injected color., Results: The results of this injection- and dissection-based study revealed that both the supratrochlear and the supraorbital neurovascular bundles are access pathways for injected neuromodulator products to reach the intra-orbital space and affect the levator palpebrea superioris muscle. Out of 36 conducted injection passes, seven (19.44%) resulted in affection of the sole elevator of the eyelid of which 100% occurred only at an injection volume of 0.5 cc and not at 0.1 cc., Conclusion: Clinically, the results indicate that a low injection volume, a superficial injection for the supraorbital location, and angling the needle tip away from the supratrochlear foramen (toward the contralateral temple) when targeting the corrugator supercilii muscles, can increase the safety profile of an aesthetic toxin glabellar treatment., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Synovial sarcoma (SynSa) is one of the most common translocation-related soft tissue sarcomas. Patients with metastatic SynSa have limited treatment options and a very poor prognosis. Several novel experimental therapies are currently being explored in clinical trials, including T cell-based therapies targeting cancer testis antigens such as New York esophageal squamous cell carcinoma 1 (NY-ESO-1) or melanoma-associated antigen A4 (MAGE-A4), and degraders targeting bromodomain-containing protein 9 (BRD9). Preclinical studies investigate inhibitors of Yes associated protein 1 (YAP1), transcriptional co-activator with PDZ-binding motif (TAZ) and inhibitors of chemokine receptor 4 (CXCR4)., Methods: We explored the immunohistochemical expression of these targets using a tissue microarray (TMA) constructed from 91 clinical SynSa samples and correlated these findings with corresponding clinicopathological data., Results: Expression of MAGE-A4 and NY-ESO-1 was found in 69 % and 56 % of the samples, respectively. NY-ESO-1 was statistically higher expressed in samples from metastatic lesions as compared to samples from primary tumors. Nuclear expression of YAP1 and TAZ was observed in 92 % and 51 % of the samples, respectively. CXCR4 was expressed in the majority of the samples (82 %). BRD9 was highly expressed in all specimens. No prognostic role could be identified for any of the investigated proteins., Conclusion: This study is a comprehensive study providing real-world data on the expression of several actionable proteins in a large proportion of SynSa samples. All evaluated markers were expressed in a clinically meaningful proportion of cases represented in our TMA, supporting the relevance of ongoing preclinical and clinical research with novel agents directed against these targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: The treatment of the medial infraorbital region also termed the tear trough has become increasingly popular by the use of soft tissue fillers in a minimally invasive approach using a cannula., Methods: A total of 246 tear troughs were injected and investigated originating from 123 study participants. The clinical outcome was evaluated 6 months after the treatment by independent observers based on standardized frontal images and the procedure was documented by ultrasound imaging., Results: On average, 0.26 (0.1) cc [range: 0.08-0.32] of soft tissue filler material was injected per tear trough. Tear trough depth was before the treatment rated as 2.12 (0.4), whereas after the treatment it was 1.15 (0.4) (p < 0.001). Hyperpigmentation score was 2.19 (0.4) before the treatment, whereas after the treatment it was 1.31 (0.5) (p < 0.001). Intraorbital fat pseudo-prolapse severity was rated before the treatment 1.88 (0.7), whereas it was rated after the treatment 1.14 (0.3) (p < 0.001). Wrinkle severity of the lower eyelid was rated before the treatment 1.51 (0.6), whereas it was rated after the treatment 1.12 (0.3) (p < 0.001)., Conclusion: The results of this retrospectively investigated case series revealed that the conducted injection technique for treating the tear trough for medial infraorbital hollowing with a cannula provided statistically significant clinical improvement with a limited adverse events profile. The technique utilized an injection approach which was perpendicularly oriented to the longitudinal axis of the tear trough thereby "bridging the gap instead of filling the entire valley.", (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Knowledge of anatomical variability is extremely important in order to better understand the etiology of pain, if present, or to avoid iatrogenic consequences. Sometimes the anatomical "anomalies" have the same anamnesis but different causes. For example, sciatic neuralgia may be caused by a herniated disc or it may have a different origin. The sciatic nerve (SN), also known as the ischial nerve, is the widest in the human body. This huge peripheral nerve originates from the roots of the lumbosacral plexus (L4-S3) and passes through the great sciatic foramen, under the piriformis muscle (PM). However, there is much variability in the pattern of SNs about the muscle, which has been known since the first half of the 20th century. In the present study, we describe six different case reports of anatomical variations of the SN and its interplay with the PM. The observations were made during dissection classes at the ICLO Teaching and Research Centre (Verona, Italy), on both male and female cadavers aged between 58 and 84 years. The SN was reported as a single and divided nerve into the tibial nerve (TN) and the common peroneal nerve (CPN), passing alone above, below, or between the PM. However, the two parts of the SN may also interact with the PM in different ways, adding to the anatomical variability. A thorough knowledge of the anatomical variations in any part of the human body is extremely important. The various techniques used, from imaging to autopsy or surgery, are also useful in the SN pathway. Thus, the anatomical features and the understanding of each variation are useful for a correct approach that can lead to an effective and correct treatment with a favorable outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Branca et al.)

All allergic responses to food indicate the failure of immunological tolerance, but it is unclear why cow's milk and egg (CME) allergies resolve more readily than reactivity to peanuts (PN). We sought to identify differences between PN and CME allergies through constitutive immune status and responses to cognate and non-cognate food antigens. Children with confirmed allergy to CME ( n = 6) and PN ( n = 18) and non-allergic (NA) ( n = 8) controls were studied. Constitutive secretion of cytokines was tested in plasma and unstimulated mononuclear cell (PBMNC) cultures. Blood dendritic cell (DC) subsets were analyzed alongside changes in phenotypes and soluble molecules in allergen-stimulated MNC cultures with or without cytokine neutralization. We observed that in allergic children, constitutively high plasma levels IL-1β, IL-2, IL-4, IL-5 and IL-10 but less IL-12p70 than in non-allergic children was accompanied by the spontaneous secretion of sCD23, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12p70, IFN-γ and TNF-α in MNC cultures. Furthermore, blood DC subset counts differed in food allergy. Antigen-presenting cell phenotypic abnormalities were accompanied by higher B and T cell percentages with more Bcl-2 within CD69 + subsets. Cells were generally refractory to antigenic stimulation in vitro, but IL-4 neutralization led to CD152 downregulation by CD4 + T cells from PN allergic children responding to PN allergens. Canonical discriminant analyses segregated non-allergic and allergic children by their cytokine secretion patterns, revealing differences and areas of overlap between PN and CME allergies. Despite an absence of recent allergen exposure, indication of in vivo activation, in vitro responses independent of challenging antigen and the presence of unusual costimulatory molecules suggest dysregulated immunity in food allergy. Most importantly, higher Bcl-2 content within key effector cells implies survival advantage with the potential to mount abnormal responses that may give rise to the manifestations of allergy. Here, we put forward the hypothesis that the lack of apoptosis of key immune cell types might be central to the development of food allergic reactions.

Anatomical variability in the human body is not as rare as was previously hypothesised. Indeed, as recently reviewed, the term 'norm' in anatomy can be considered an approximation. Thus, anatomical variations occur quite often, as largely demonstrated during non-invasive diagnosis, surgical intervention, or post mortem investigations. In the present study, we describe different anatomical variations in both the right and left lungs derived from cadavers of different ethnicities. The analysed organs were collected during dissection, and accessory lobes and fissures were observed in both the right and left lungs. Moreover, a horizontal fissure was missing from the right lung, resulting in only two lobes. Since lung anatomical variability is common in clinical practice and preclinical imaging studies can miss different morphologies, a deep and accurate knowledge of the anatomical variations of the lung is of extreme importance to avoid difficulties or changes during the surgical procedure., (© 2023 The Authors. Anatomia, Histologia, Embryologia published by Wiley-VCH GmbH.)

Background: Temporomandibular joint (TMJ) disorders, which affect millions of people worldwide, have multiple etiological factors that make an accurate diagnosis and effective treatments difficult. As a consequence, the gold standard diagnostic criteria for TMJ disorders remain elusive and often depend on subjective decisions., Aim: In this context, the lack of a non-invasive quantitative methodology capable of assessing the functional physiological state and, consequently, identifying risk indicators for the early diagnosis of TMJ disorders must be tackled and resolved., Methodology: In this work, we have studied the biomechanics and viscoelastic properties of the functional masticatory system by a non-invasive approach involving 52 healthy subjects, analysed by statistical-physics analysis applied to myotonic measurements on specific points of the masticatory system designing a TMJ network composed of 17 nodes and 20 links., Results: We find that the muscle tone and viscoelasticity of a specific cycle linking frontal, temporal, and mandibular nodes of the network play a prominent role in the physiological functionality of the system. At the same time, the functional state is characterised by a landscape of nearly degenerated levels of elasticity in all links of the network, making this parameter critically distributed and deviating from normal behaviour., Conclusions: Time evolution and dynamic correlations between biomechanics and viscoelastic parameters measured on the different cycles of the network provide a quantitative framework associated with the functional state of the masticatory system. Our results are expected to contribute to enriching the taxonomy of this system, primarily based on clinical observations, patient symptoms, and expert consensus.

Purpose: The standard treatment for chronic anal fissures that have failed non-operative management is lateral internal sphincterotomy. Surgery can cause de novo incontinence. Fissurectomy has been proposed as a sphincter/saving procedure, especially in the presence of a deep posterior pouch with or without a crypt infection. This study investigated whether fissurectomy offers a benefit in terms of de novo post-operative incontinence., Methods: Patients surgically managed with fissurectomy or lateral internal sphincterotomy for chronic anal fissures from 2013 to 2019 have been included. Healing rate, changes in continence and patient satisfaction were investigated at long-term follow-up., Results: One hundred twenty patients (55 females, 65 males) were analysed: 29 patients underwent fissurectomy and 91 lateral internal sphincterotomy. Mean follow-up was 55 months [confidence interval (CI) 5-116 months]. Both techniques showed some rate of de novo post-operative incontinence (> +3 Vaizey score points): 8.9% lateral internal sphincterotomy, 17.8% fissurectomy (p = 0.338). The mean Vaizey score in these patients was 10.37 [standard deviation (sd) 6.3] after lateral internal sphincterotomy (LIS) and 5.4 (sd 2.3) after fissurectomy Healing rate was 97.8% in the lateral internal sphincterotomy group and 75.8% in the fissurectomy group (p = 0.001). In the lateral internal sphincterotomy group, patients with de novo post-op incontinence showed a statistically significant lower satisfaction rate (9.2 ± 1.57 versus 6.13 ± 3; p = 0.023) while no differences were present in the fissurectomy group (8.87 ± 1.69 versus 7.4 ± 1.14; p = 0.077)., Conclusions: Lateral internal sphincterotomy is confirmed as the preferred technique in term of healing rate. Fissurectomy did not offer a lower rate of de novo post-operative incontinence, but resulted in lower Vaizey scores in patients in whom this occurred. Satisfaction was lower in patients suffering a de novo post-operative incontinence after lateral internal sphincterotomy., (© 2023. The Author(s).)

With the recent advances in medicine, human life expectancy is increasing; however, the extra years of life are not necessarily spent in good health or free from disability, resulting in a significantly higher incidence of age-associated pathologies. Among these disorders, neurodegenerative diseases have a significant impact. To this end, the presence of the protective blood-brain barrier (BBB) represents a formidable obstacle to the delivery of therapeutics. Thus, this makes it imperative to define strategies to bypass the BBB in order to successfully target the brain with the appropriate drugs. It has been demonstrated that targeting the BBB by ultrasound (US) can transiently make this anatomical barrier permeable and in so doing, allow the delivery of therapeutics. Thus, our aim was to carry out an in depth in vitro molecular and morphological study on the effects of US treatment on the BBB. The rat brain endothelial (RBE4) cell line was challenged with exposure to 12 MHz diagnostic US treatment for 10, 20, and 30 min. Cell viability assays, Western blotting analysis on the endoplasmic reticulum (ER), and oxidative stress marker evaluation were then performed, along with cytological and immunofluorescence staining, in order to evaluate the effects of US on the intercellular spaces and tight junction distribution of the brain endothelial cells. We observed that the US treatment exerted no toxic effects on either RBE4 cell viability or the upregulation/dislocation of the ER and oxidative stress marker (GRP78 and cytochrome C, respectively). Further, we observed that the application of US induced an increase in the intercellular spaces, as shown by Papanicolaou staining, mainly due to the altered distribution of the tight junction protein zonula occludens -1 (ZO-1). This latter US-dependent effect was transient and disappeared 20 min after the removal of the stimulus. In conclusion, our results show that US induces a transient alteration of the BBB, without altering the intracellular signaling pathways such as the ER and oxidative stress that could potentially be toxic for endothelial cells. These results suggested that US treatment could represent a potential strategy for improving drug delivery to the brain.

Introduction: For many years, anatomical studies have been conducted with a shattered view of the body. Although the study of the different apparatuses provides a systemic view of the human body, the reconstruction of the complex network of anatomical structures is crucial for the understanding of structural and functional integration., Aim: We used network analysis to investigate the connection between the whole-body osteo-myofascial structures of the human musculoskeletal system., Materials and Methods: The musculoskeletal network was performed using the aNETomy ® anatomical network with the implementation of the open-source software Cytoscape for data entry., Results: The initial graph was applied with a network consisting of 2298 body parts (nodes) and 7294 links, representing the musculoskeletal system. Considering the same weighted and unweighted osteo-myofascial network, a different distribution was obtained, suggesting both a topological organization and functional behavior of the network structure., Conclusions: Overall, we provide a deeply detailed anatomical network map of the whole-body musculoskeletal system that can be a useful tool for the comprehensive understanding of every single structure within the complex morphological organization, which could be of particular interest in the study of rehabilitation of movement dysfunctions.

Cadmium (Cd) is a well-known occupational and environmental pollutant worldwide, and its toxicity is widely recognised. Cd is reported to increase the permeability of the blood-brain barrier (BBB) and to penetrate and accumulate in the brain. Although many lines of evidence show that Cd toxicity is induced by different mechanisms, one of the best known is the Cd-dependent production of reactive oxygen species (ROS). Zinc is a trace element known as coenzyme and cofactor for many antioxidant proteins, such as metallothioneins and superoxide dismutase enzymes. To date, very little is known about the role of Zn in preventing Cd-induced blood-brain barrier (BBB) alterations. The goal of this study was to test the Zn antioxidant capacity against Cd-dependent alterations in a rat brain endothelial cell line (RBE4), as an in vitro model for BBB. In order to mimic acute Cd poisoning, RBE4 cells were treated with CdCl 2 30 µM for 24 h. The protective role of ZnCl 2 (50 µM) was revealed by evaluating the cell viability, reactive oxygen species (ROS) quantification, cytochrome C distribution, and the superoxide dismutase (SOD) protein activity. Additionally, the effectiveness of Zn in counteracting the Cd-induced damage was investigated by evaluating the expression levels of proteins already known to be involved in the Cd signalling pathway, such as GRP78 (an endoplasmic reticulum (ER) stress protein), caspase3 pro- and cleaved forms, and BAX. Finally, we evaluated if Zn was able to attenuate the alterations of zonula occludens-1 (ZO-1), one of the tight-junction (TJ) proteins involved in the formation of the BBB. Our data clearly demonstrate that Zn, by protecting from the SOD activity impairment induced by Cd, is able to prevent the triggering of the Cd-dependent signalling pathway that leads to ZO-1 dislocation and downregulation, and BBB damage.

Adjuvant treatment with Imatinib is the standard of care for high-risk resected GISTs. Imatinib is known to have an impact on bone mineral density in patients affected by chronic myeloid leukemia, however this effect has never been investigated in GISTs. We retrospectively evaluated, on CT scans, the effect of adjuvant Imatinib (400 mg/die) on bone mineral density and muscle composition in 14 patients with surgically resected GISTs and in a control group of 8 patients who did not received any treatment. The effect of bone and muscle composition on Imatinib-tolerance was assessed as well. Overall patients receiving Imatinib experienced an increase in bone mineral density during treatment (p = 0.021); with higher increase in patients with basal values < 120 mg/cm 3 (p = 0.002). No changes were observed in the control group (p = 0.918). Skeletal muscle index and lean body mass did not change over time during Imatinib therapy; however, patients with lower lean body mass and lower body mass index experienced more grade 3 treatment related toxicities (p = 0.024 and p = 0.014 respectively). We also found a non-significant trend between basal BMD and grade 3 toxicities (p = 0.060)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background : The "classic" thyroid gland arterial vascularization takes into account two superior thyroid arteries (STA), two inferior thyroid arteries (ITA) and, occasionally, a thyroid ima artery (TIMA). The present review focuses on exploring the available data concerning thyroid gland arterial vascularization and its variations. Methods : Here, we analysed 49 articles from the last century, ranging from case reports to reviews concerning cadaver dissection classes, surgical intervention, and non-invasive techniques as well. Results : The harvested data clearly highlighted that: (i) the STA originates predominantly from the external carotid artery; (ii) the ITA is a branch of the thyrocervical trunk; and (iii) the TIMA is a very uncommon variant predominantly occurring to compensate for ITA absence. Conclusion : A systematic review of a highly vascularized organ is of great relevance during surgical intervention and, thus, the knowledge of normal anatomy and its modification is essential both for fact-finding and in surgery.

Background: Adult-type soft tissue sarcomas (STSs) are rare tumors representing about 1% of all adult malignant tumors. Their extreme histological heterogeneity places them among the most challenging fields of diagnostic pathology. The variability of clinical and prognostic presentation between the various histotypes reflects the different management that should be followed on a case-by-case basis. These features make STSs the case in point of how important it is a centralized and multidisciplinary approach., Summary: Surgery represents the mainstay in the treatment of localized STSs. Recently, more and more studies are making efforts to understand what the contribution of chemotherapy and radiotherapy with neoadjuvant and adjuvant intent may be both in unselected and selected histological subgroups. In fact, despite the improvement in overall survival seen in the past few years thanks to the adoption of a more radical surgical approach, mortality remains relatively high and the 5-year overall survival is around 65%., Key Messages: In this review, we comment upon the treatment of localized STSs of the extremity, trunk wall, and retroperitoneum and how surgery, radiotherapy, and chemotherapy can be integrated with each other and individually tailored. Nomograms can assist clinicians in this complex therapeutic decision-making process, through the identification of patients at higher risk of death or disease relapse., (© 2022 S. Karger AG, Basel.)

Oxaliplatin is a third-generation chemotherapy drug mainly used for colorectal cancer treatment. However, it is also known to trigger neuropathy whose underlying neurobiological mechanisms are still under investigation and currently available treatments show limited efficacy. It is now established that neurons are not the only cell type involved in chronic pain and that glial cells, mainly astrocytes and microglia, are involved in the initiation and maintenance of neuropathy. Among all the pathogenetic factors involved in neuropathic pain, an oxaliplatin-dependent oxidative stress plays a predominant role. In our study, the antioxidant properties of magnesium (Mg), manganese (Mn) and zinc (Zn) salts were evaluated in order to counteract microglial activation induced by oxaliplatin. The antioxidant efficacy of these metals was evaluated by the means of molecular and morphological assays on the BV-2 microglial cell line. Our data clearly show that Mg, Mn and Zn are able to prevent oxaliplatin-dependent microglial alterations by reducing both oxidative and endoplasmic reticulum stress.

In recent years, alcohol abuse has dramatically grown with deleterious consequence for people's health and, in turn, for health care costs. It has been demonstrated, in humans and animals, that alcohol intoxication induces neuroinflammation and neurodegeneration thus leading to brain impairments. Furthermore, it has been shown that alcohol consumption is able to impair the blood-brain barrier (BBB), but the molecular mechanisms underlining this detrimental effect have not been fully elucidated. For this reason, in this study we investigated the effects of alcohol exposure on a rat brain endothelial (RBE4) cell line, as an in vitro-validated model of brain microvascular endothelial cells. To assess whether alcohol caused a concentration-related response, the cells were treated at different times with increasing concentrations (10-1713 mM) of ethyl alcohol (EtOH). Microscopic and molecular techniques, such as cell viability assay, immunofluorescence and Western blotting, were used to examine the mechanisms involved in alcohol-induced brain endothelial cell alterations including tight junction distribution, apoptosis, and reactive oxygen species production. Our findings clearly demonstrate that alcohol causes the formation of gaps between cells by tight junction disassembly, triggered by the endoplasmic reticulum and oxidative stress, highlighted by GRP78 chaperone upregulation and increase in reactive oxygen species production, respectively. The results from this study shed light on the mechanisms underlying alcohol-induced blood-brain barrier dysfunction and a better understanding of these processes will allow us to take advantage of developing new therapeutic strategies in order to prevent the deleterious effects of alcohol.

Hyaluronic acid fillers indisputably represent an important tool for face rejuvenation and volume restoration. The temporal area has recently been considered as a potential site of injection. As it happens in the middle face and in other regions of the face, the temporal fossa changes according to the aging process. In a young person, the temple profile has a fullness aspect, and this contributes to giving the face a beautiful and healthy appearance. With age, the loss of volume leads the bone prominences to be visible. The aim of this article is to classify the temporal fossa atrophy and get better into the anatomy, identifying the ideal plane to inject in, through the use of a safe and reliable technique. Cadaver dissections have been performed to specifically describe the anatomy of the temple layer by layer. The authors' preferred technique, called interfascial by cannula implantation, is discussed. All the treated patients reported a good improvement by survey according to the Global Aesthetic Improvement Scale scale. No major complications were detected. No ecchymosis neither swelling were documented. Although further studies are necessary to broaden the casuistry and better verify the potentiality of this technique, the authors do believe that it could be considered a very reliable procedure with pretty consistent results, if supported by an adequate and imperative anatomical knowledge., Competing Interests: Disclosure: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Cadmium (Cd), a category I human carcinogen, is a well-known widespread environmental pollutant. Chronic Cd exposure affects different organs and tissues, such as the central nervous system (CNS), and its deleterious effects can be linked to indirect reactive oxygen species (ROS) generation. Since Cd is predominantly present in +2 oxidation state, it can interplay with a plethora of channels and transporters in the cell membrane surface in order to enter the cells. Mitochondrial dysfunction, ROS production, glutathione depletion and lipid peroxidation are reviewed in order to better characterize the Cd-elicited molecular pathways. Furthermore, Cd effects on different CNS cell types have been highlighted to better elucidate its role in neurodegenerative disorders. Indeed, Cd can increase blood-brain barrier (BBB) permeability and promotes Cd entry that, in turn, stimulates pericytes in maintaining the BBB open. Once inside the CNS, Cd acts on glial cells (astrocytes, microglia, oligodendrocytes) triggering a pro-inflammatory cascade that accounts for the Cd deleterious effects and neurons inducing the destruction of synaptic branches.

Although modern anatomy is commonly retained to begin in the XVI century, the roots of anatomical study in the Western world may be identified beforehand. An anatomical practice was present in the Western world well before the Middle Ages, starting in ancient Greece. Hippocrates of Cos (V-IV centuries B.C.) provided descriptions of the heart and vessels, and the so-called "Hippocratic Corpus" largely deals with anatomy. Aristotle of Stagira (IV century B.C.) was one of the first well-known scholars of the past to perform dissections of animals. The anatomical interest of Aristotle contained a "physiological" background too, since he was convinced that all parts of human organisms had one or more specific functions. Galen of Pergamum (II century A.D.) was the performer of hundreds of dissections of animals, and he described a great number of anatomical parts of apes, dogs, goats and pigs. The anatomical system of Galen became a gold standard for medicine for more than a thousand years, and in the Middle Ages (V-XV centuries A.D.) the human anatomy that was taught and acquired in European universities remained based on Galenic anatomy. In conclusion, Greek-speaking scholars between the IV century B.C. and the II century A.D. set the basis for the systematic dissection of animals and the comparative investigation of animal anatomical findings. These scholars also began to study the structures of the human body, interestingly taking into account the relationship between the macroscopical morphology of observed structures and their more evident functions. (www.actabiomedica.it).

Cadmium (Cd) is a highly toxic environmental pollutant released from the smelting and refining of metals and cigarette smoking. Oral exposure to cadmium may result in adverse effects on a number of tissues, including the central nervous system (CNS). In fact, its toxicity has been related to neurological disorders, as well as neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Under normal conditions, Cd barely reaches the brain in adults because of the presence of the blood-brain barrier (BBB); however, it has been demonstrated that Cd-dependent BBB alteration contributes to pathogenesis of neurodegeneration. However, the mechanism underlying Cd-dependent BBB alteration remain obscure. Here, we investigated the signaling pathway of Cd-induced tight junction (TJ), F-actin, and vimentin protein disassembly in a rat brain endothelial cell line (RBE4). RBE4 cells treated with 10 μM cadmium chloride (CdCl 2 ) showed a dose- and time-dependent significant increase in reactive oxygen species (ROS) production. This phenomenon was coincident with the alteration of the TJ zonula occludens-1 (ZO-1), F-actin, and vimentin proteins. The Cd-dependent ROS increase elicited the upregulation of GRP78 expression levels, a chaperone involved in endoplasmic reticulum (ER) stress that induces caspase-3 activation. Further signal profiling by the pannexin-1 (PANX1) specific inhibitor 10 Panx revealed a PANX1-independent increase in ATP spillage in Cd-treated endothelial cells. Our results point out that a ROS-dependent ER stress-mediated signaling pathway involving caspase-3 activation and ATP release is behind the BBB morphological alterations induced by Cd.

Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer. Despite its beneficial effects in tumor reduction, the most prevalent side-effect of oxaliplatin treatment is a chemotherapy-induced neuropathy that frequently forces to discontinue the therapy. Indeed, along with direct damage to peripheral nerves, the chemotherapy-related neurotoxicity involves also the central nervous system (CNS) as demonstrated by pain chronicity and cognitive impairment (also known as chemobrain), a newly described pharmacological side effect. The presence of the blood brain barrier (BBB) is instrumental in preventing the entry of the drug into the CNS; here we tested the hypothesis that oxaliplatin might enter the endothelial cells of the BBB vessels and trigger a signaling pathway that induce the disassembly of the tight junctions, the critical components of the BBB integrity. By using a rat brain endothelial cell line (RBE4) we investigated the signaling pathway that ensued the entry of oxaliplatin within the cell. We found that the administration of 10 μM oxaliplatin for 8 and 16 h induced alterations of the tight junction (TJs) proteins zonula occludens-1 (ZO-1) and of F-actin, thus highlighting BBB alteration. Furthermore, we reported that intracellular oxaliplatin rapidly induced increased levels of reactive oxygen species and endoplasmic reticulum stress, assessed by the evaluation of glucose-regulated protein GRP78 expression levels. These events were accompanied by activation of caspase-3 that led to extracellular ATP release. These findings suggested a possible novel mechanism of action for oxaliplatin toxicity that could explain, at least in part, the chemotherapy-related central effects., Competing Interests: CONFLICTS OF INTEREST All authors declare that there are no conflicts of interest to disclose.

Cadmium (Cd), a worldwide occupational pollutant, is an extremely toxic heavy metal, capable of damaging several organs, including the brain. Its toxicity has been related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The neurotoxic potential of Cd has been attributed to the changes induced in the brain enzyme network involved in counteracting oxidative stress. On the other hand, it is also known that trace elements, such as zinc (Zn) and selenium (Se), required for optimal brain functions, appears to have beneficial effects on the prevention of Cd intoxication. Based on this protective effect of Zn and Se, we aimed to investigate whether these elements could protect neuronal cells from Cd-induced excitotoxicity. The experiments, firstly carried out on SH-SY5Y catecholaminergic neuroblastoma cell line, demonstrated that the treatment with 10 μM cadmium chloride (CdCl 2 ) for 24 h caused significant modifications both in terms of oxidative stress and neuronal sprouting, triggered by endoplasmic reticulum (ER) stress. The evaluation of the effectiveness of 50 μM of zinc chloride (ZnCl 2 ) and 100 nM sodium selenite (Na 2 SeO 3 ) treatments showed that both elements were able to attenuate the Cd-dependent neurotoxicity. However, considering that following induction with retinoic acid (RA), the neuroblastoma cell line undergoes differentiation into a cholinergic neurons, our second aim was to verify the zinc and selenium efficacy also in this neuronal phenotype. Our data clearly demonstrated that, while zinc played a crucial role on neuroprotection against Cd-induced neurotoxicity independently from the cellular phenotype, selenium is ineffective in differentiated cholinergic cells, supporting the notion that the molecular events occurring in differentiated SH-SY5Y cells are critical for the response to specific stimuli., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: Regular and structured physical activity is known to be effective in preventing and/or reducing the physical and mental decline associated with aging. Indeed, such usefulness of physical activity has been associated with the concept of "successful aging". The aim of the present study was to evaluate the possible physical and cognitive effects deriving from the practice of Dancesport in comparison with the participation in adapted physical activity (APA) programs and sedentarity., Methods: A total of 150 healthy older adults were enrolled, consisting of three groups: 1) Dancesport (non-competitive Latin American and Standard dancers); 2) APA (subjects practicing a multicomponent training program adapted to elderly); 3) control (sedentary subjects). All participants were assessed with cognitive computerized tests and underwent motor tests (Tinetti Test [TT] and Sit and Reach [SR] Test), and filled out a questionnaire to evaluate leisure cognitive activities and Short Form-12 (SF-12) questionnaire to assess quality of life., Results: Subjects practicing Dancesport and APA performed significantly better in all proposed tests than sedentary subjects. In particular, dancers reported better scores in both cognitive and motor tests as well as in SF-12 compared to APA., Conclusion: Given its peculiar characteristics, Dancesport represents a feasible, attractive and alternative physical activity to preserve cognitive and physical functions during aging. Increased self-esteem, social contact and psychophysical wellness significantly ameliorate the quality of life during aging.

Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin-induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH-SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA-GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co-cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce the dual effect of reduction of oxaliplatin-induced neurotoxicity, together with possible synergism in the overall anticancer effect.

Growing evidence has shown the promise of mesenchymal stromal cells (MSCs) for the treatment of cutaneous wound healing. We have previously demonstrated that MSCs seeded on an artificial dermal matrix, Integra (Integra Lifesciences Corp., Plainsboro, NJ) enriched with platelet-rich plasma (Ematrix) have enhanced proliferative potential in vitro as compared with those cultured on the scaffold alone. In this study, we extended the experimentation by evaluating the efficacy of the MSCs seeded scaffolds in the healing of skin wounds in an animal model in vivo. It was found that the presence of MSCs within the scaffolds greatly ameliorated the quality of regenerated skin, reduced collagen deposition, enhanced reepithelization, increased neo-angiogenesis, and promoted a greater return of hair follicles and sebaceous glands. The mechanisms involved in these beneficial effects were likely related to the ability of MSCs to release paracrine factors modulating the wound healing response. MSC-seeded scaffolds, in fact, up-regulated matrix metalloproteinase 9 expression in the extracellular matrix and enhanced the recruitment of endogenous progenitors during tissue repair. In conclusion, the results of this study provide evidence that the treatment with MSC-seeded scaffolds of cutaneous wounds contributes to the recreation of a suitable microenvironment for promoting tissue repair/regeneration at the implantation sites., (© 2014 The Authors. Wound Repair and Regeneration published by . Wiley Periodicals, Inc. on behalf of The Wound Healing Society.)

Objective: It is well known that limited joint mobility of the ankle and foot level, impaired muscular performance and reduced gait speed are risk factors for ulceration in diabetic foot. The aim of this study was to evaluate the effect of an experimental protocol of exercise therapy on joint mobility, muscular strength and gait speed in a group of long-term diabetic subjects., Methods: The protocol consisted of a 12-week supervised training program; both joint mobility and muscular strength at the ankle were measured before and after exercise therapy respectively by an inclinometer and isometric dynamometers in 26 diabetic subjects and compared to 17 healthy controls., Results: Ankle joint mobility of plantar flexion was reduced about 36% and dorsal flexion by about 23% in diabetic subjects compared to controls (p < 0.001), but significantly increased after exercise therapy (p < 0.001 for both). Ankle muscular strength in plantar flexion was reduced by about 51% and in dorsal flexion by 30% in diabetic patients compared to controls, but these also significantly increased after exercise therapy (p < 0.001). Consequently, patients' walking speed increased after exercise therapy by 0.28 m/s (p < 0.001)., Conclusion: A 12-week supervised program of exercise therapy significantly improves joint mobility, muscular performance and walking speed in diabetic patients--thus limiting one of the pathogenic factors of diabetic foot and potentially preventing disability.

Background: Overall, the comparative data available on the timing of metopic suture closure in present-day and fossil members of human lineage, as well as great apes, seem to indicate that human brain evolution occurred within a complex network of fetopelvic constraints, which required modification of frontal neurocranial ossification patterns, involving delayed fusion of the metopic suture. It is very interesting that the recent sequencing of the Neanderthal genome has revealed signs of positive selection in the modern human variant of the RUNX2 gene, which is known to affect metopic suture fusion in addition to being essential for osteoblast development and proper bone formation. It is possible that an evolutionary change in RUNX2, affecting aspects of the morphology of the upper body and cranium, was of importance in the origin of modern humans. Thus, to contribute to a better understanding of the molecular evolution of this gene probably implicated in human evolution, we performed a comparative bioinformatic analysis of the coding sequences of RUNX2 in Homo sapiens and other non-human Primates., Results: We found amino-acid sequence differences between RUNX2 protein isoforms of Homo sapiens and the other Primates examined, that might have important implications for the timing of metopic suture closure., Conclusions: Further studies are needed to clear the potential distinct developmental roles of different species-specific RUNX2 N-terminal isoforms. Meantime, our bioinformatic analysis, regarding expression of the RUNX2 gene in Homo sapiens and other non-human Primates, has provided a contribution to this important issue of human evolution.

Quality by Design (QbD) is a new paradigm of quality to be applied to pharmaceutical products and processes, recently encouraged by International Conference on Harmonisation guidelines. In this paper QbD approach was applied to the development of a CE method for the simultaneous assay of metformin hydrochloride (MET) and its main impurities. QbD strategy was focused on electrophoretic process understanding, and the analytical method was thoroughly evaluated by applying risk assessment and chemometric tools. Method scouting allowed CD-CZE based on the addition of carboxymethyl-β-CD to Britton-Robinson acidic buffer to be chosen as operative mode. Seven critical process parameters (CPPs) were selected, related to capillary, injection, BGE and instrumental settings. The effect of the different levels of the CPPs on critical quality attributes (CQAs), e.g. critical resolution values and analysis time, was evaluated in a screening study. Response surface methodology led to draw contour plots and sweet spot plots. The definition of design space was accomplished by applying Monte-Carlo simulations, thus identifying by risk of failure maps a multivariate zone where the CQAs fulfilled the requirements with a selected probability. Finally, a control strategy was designed and the method was applied to a real sample of MET tablets., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Grafting fetal striatal cells into the brain of Huntington's disease (HD) patients has raised certain expectations in the past decade as an effective cell-based-therapy for this devastating condition. We argue that the first requirement for successful transplantation is defining the window of plasticity for the striatum during development when the progenitor cells, isolated from their environment, are able to maintain regional-specific-identity and to respond appropriately to cues. The primary cell culture from human fetal striatal primordium described here consists of a mixed population of neural stem cells, neuronal-restricted progenitors and striatal neurons. These cells express trophic factors, such as BDNF and FGF2. We show that these neurotrophins maintain cell plasticity, inducing the expression of neuronal precursor markers and cell adhesion molecules, as well as promoting neurogenesis, migration and survival. We propose that BDNF and FGF2 play an important autocrine-paracrine role during early striatum development in vivo and that their release by fetal striatal grafts may be relevant in the setting of HD cell therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Polymerized resin-based materials are successfully utilized in medical applications. One draw- back is the release of monomers from the matrix due to an incomplete polymerization or degradation processes. Released monomers can diffuse in the systemic circulation and induceadverse effects to biological tissues. Although there are many hypotheses about the induction of cell death by resin monomers, the underlying mechanisms are still under discussion. The aim of the study was to investigate the morphological modifications in human gingival fibroblasts exposed to 2-hydroxy-ethyl methacrylate (HEMA) to better elucidate the mechanism of cell death induced by resin monomers. Primary cultures of gingival fibroblasts were exposed to 3mM HEMA for 24 h, 72 h, 96 h. Morphological investigations were performed by scanning and transmission electron microscopy, while western blot for caspase-3 was carried out to ver- ify apoptosis. Electron microscopy images showed deep changes in the cell surface and cyto- plasm after 72 h and 96 h of HEMA treatment. Autophagic vesicles were easily observed just after 24 h. Cleaved caspase-3 was detected after 72 h of treatment. These findings suggest that resin based materials induced cell death by the cooperation of apoptosis and autophagy mecha- nisms. The understanding of these mechanisms will lead to the development of smart biomate- rials without or with low adverse effects.

Together with race, stature and age, sex is a main component of the biological identity. Thanks to its proportional correlation with parts of the human body, sex can be evaluated form the skeleton. The most accurate approach to determine sex by bone size is based on os coxae or skull. After natural disaster their presence can never be guaranteed, therefore the development of methods of sex determination using other skeletal elements can result crucial. Herein, sexual dimorphism in the human scapula is used to develop a two-variable discriminant function for sex estimation. We have enrolled 100 males and 100 females who underwent thoracic CT scan evaluation and we have estimated two scapular diameters. The estimation has been carried out by analyzing images of the scapulae of each patient after three dimensional post-processing reconstructions. The two-variable function allows to obtain an overall accuracy of 88% on the calibration sample. Furthermore, we have employed the mentioned function on a collection of 10 individual test sample from the collection of the "Museo di Anatomia Umana di Firenze" of the Università degli Studi di Firenze; sex has been correctly predicted on 9 skeletons.

This study demonstrates the existence of a linear correlation between Body Mass Index (BMI) and waist circumference in Italian school aged children and suggests an indirect method (from weight and height) to estimate waist circumference, whose increase may be indicative for the diagnosis of the metabolic syndrome., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Natural surfactant combined with beclomethasone decreases pulmonary oxidative stress in preterm lambs with respiratory distress syndrome (RDS)., Objectives: To test the hypothesis that this occurs through a decrease in pulmonary inflammation., Methods: Preterm lambs received 200 mg/kg of natural surfactant or 200 mg/kg of natural surfactant combined with 400 or 800 μg/kg of beclomethasone. Interleukin 8 (IL-8) and macrophage migration inhibitory factor (MIF) were assayed in bronchial aspirate samples and lung mechanics were evaluated., Results: IL-8 increased in all the groups, but the increase was lower in the groups treated with surfactant plus 400 and 800 μg/kg of beclomethasone. MIF decreased in the surfactant group, did not vary in the surfactant plus 400 μg/kg beclomethasone group, and decreased in the surfactant plus 800 μg/kg beclomethasone group. MIF concentration was higher in the surfactant plus 800 μg/kg beclomethasone group than in the other groups., Conclusions: Natural surfactant combined with beclomethasone at 800 μg/kg is effective in reducing lung inflammation in an animal model of RDS, thus explaining the associated decrease in lung oxidative stress. The increase in MIF in animals treated with surfactant plus 800 μg/kg of beclomethasone might be an important maturative and protective factor for neonatal lungs., (Copyright © 2011 S. Karger AG, Basel.)

The 17th century was characterized by a real revolution in the field of scientific research due to the introduction of the experimental method, promoted by Galileo Galilei who was the most representative scientist of this period. Therefore, medical disciplines, particularly Anatomy, underwent innovative and deep changes shattering traditional culture and representing the background for the modern science. In this fermenting period, Tuscany played a significant role since numerous distinguished scientists were gathered by Medici Grand Dukes (especially Ferdinando the 2nd and Cosimo the 3rd) at Pisa University and at their court in Florence. Among them, it must be mentioned Giovanni Alfonso Borelli, creator of iathromechanics, Marcello Malpighi, founder of microscopic Anatomy, Francesco Redi, who denied the insect spontaneous generation, Nils Steensen who continued in Florence his anatomical studies on lymph nodes and salivary glands while setting also the bases of modern geology. Moreover, at the end of the 17th century, the anatomical wax modelling techniques arose and developed in Florence thanks to the work of Gaetano Zumbo (or Zummo), capable of creating some real masterpieces, still very well preserved and collected in the Museum of Natural Sciences "La Specola".

We performed a randomized study in preterm lambs to assess the hypothesis that the treatment with natural surfactant combined with beclomethasone might decrease pulmonary oxidative stress in an animal model of respiratory distress syndrome (RDS). Animals received 200 mg/kg of porcine natural surfactant or 200 mg/kg of natural surfactant combined with 400 or 800 microg/kg of beclomethasone. Lung tissue oxidation was studied by measuring total hydroperoxide (TH), advanced oxidation protein products (AOPP), and non-protein bound iron (NPBI) in bronchial aspirate samples. In addition, lung mechanics was evaluated. TH was lower in the groups treated with surfactant plus 400 or 800 microg/kg of beclomethasone than in the surfactant group; AOPP was lower in the group treated with surfactant plus 800 microg/kg of beclomethasone than in the other groups; NPBI was similar in all groups. Surfactant treatment was followed by a sustained improvement of tidal volume (TV) and airway resistance, while dynamic compliance did not vary. However, the mean airway pressure needed to obtain similar values of TV was lower in the group treated with surfactant plus 800 microg/kg of beclomethasone than in other groups. We concluded that natural surfactant combined with beclomethasone at 800 microg/kg is effective in reducing the oxidative lung stress and improving the respiratory function in an animal model of RDS.

It was the aim of this pilot study to investigate effects of motor activity on psychosocial and functional-physical conditions (using an assisted multidimensional questionnaire) of 53 (39 female, 14 male) free living elderly and old subjects in Florence, Italy. In addition, ADL (test of Activities of Daily Living) and Pfeiffer test (short portable mental status questionnaire) were applied to test autonomy of everyday life and presence of intellectual disturbance of organic origin. Motor activity appeared to influence significantly psychosocial and functional-physical conditions, i. e. motor activity was significantly correlated with subjective feeling of autonomy and independence, and with the variable to have hobbies, as well as with good posture and walking. From ADL and Pfeiffer tests resulted absence of respective pathologies.

Membrane-cytoskeleton interaction regulates transmembrane currents through stretch-activated channels (SACs); however, the mechanisms involved have not been tested in living cells. We combined atomic force microscopy, confocal immunofluorescence, and patch-clamp analysis to show that stress fibers (SFs) in C2C12 myoblasts behave as cables that, tensed by myosin II motor, activate SACs by modifying the topography and the viscoelastic (Young's modulus and hysteresis) and electrical passive (membrane capacitance, C(m)) properties of the cell surface. Stimulation with sphingosine 1-phosphate to elicit SF formation, the inhibition of Rho-dependent SF formation by Y-27632 and of myosin II-driven SF contraction by blebbistatin, showed that not SF polymerization alone but the generation of tensional forces by SF contraction were involved in the stiffness response of the cell surface. Notably, this event was associated with a significant reduction in the amplitude of the cytoskeleton-mediated corrugations in the cell surface topography, suggesting a contribution of SF contraction to plasma membrane stretching. Moreover, C(m), used as an index of cell surface area, showed a linear inverse relationship with cell stiffness, indicating participation of the actin cytoskeleton in plasma membrane remodeling and the ability of SF formation to cause internalization of plasma membrane patches to reduce C(m) and increase membrane tension. SF contraction also increased hysteresis. Together, these data provide the first experimental evidence for a crucial role of SF contraction in SAC activation. The related changes in cell viscosity may prevent SAC from abnormal activation.

Our aim was to evaluate if the combined inhalation of both nitric oxide (iNO) and aerosolized prostacyclin or iNO and adrenomedullin (ADM) is more effective in lowering pulmonary arterial pressure (PAP) and improving oxygenation than nitric oxide alone in an animal model with pulmonary hypertension (PH). Moreover, we studied the effect on pulmonary mechanics, surfactant activity, and pulmonary oxidative stress of the different treatments. Twenty-eight piglets with acute lung injury induced by lung lavages with saline were randomized to receive nitric oxide, nitric oxide plus prostacyclin, nitric oxide plus ADM or saline, after. Dynamic compliance, tidal volume, and airway resistance were measured. Lung tissue oxidation was evaluated by measuring total hydroperoxide and advanced oxidation protein products in bronchial aspirate samples. Surface surfactant activity was studied using Capillary Surfactometer. Inhaled nitric oxide combined with prostacyclin or ADM was more effective than nitric oxide alone in lowering PAP and improving oxygenation. Nitric oxide alone or combined increased lung compliance and tidal volume, and decreased airway resistance. No effects on surfactant surface activity and lung tissue oxidation were observed. The treatment with nitric oxide alone or combined with prostacyclin or ADM were effective in decreasing mean PAP and improving oxygenation in a piglet model of PH. However, nitric oxide plus prostacyclin and nitric oxide plus ADM were more effective than nitric oxide alone. The combination of aerosolized prostacyclin and ADM with nitric oxide might have a role in the treatment of infants with PH refractory to nitric oxide alone., ((c) 2007 Wiley-Liss, Inc.)

The life, activity and specimens of Girolamo Segato (Sospirolo 1792--Firenze 1836), as well as the mystery still surrounding his petrifaction method are outlined in this paper with the aim of shedding some light on one of the most controversial naturalists of the 19th century. Even if after his death many preparations became scattered or even destroyed, the greatest nucleus of them is now collected and exhibited in the Museum of the Department of Anatomy in Florence. Special attention has been given to the description of one of the most famous "pieces", a female head, recently added to the collection, coming from Museo Civico of Belluno. This sample, submitted to conventional Rx analysis and CT Scan Tomography, displays an outstanding injection of the thinnest peripheral blood vessels.

NAPOR-3 is a central nervous system RNA binding protein that is associated with downstream mRNA targets and has been demonstrated to be selectively overexpressed during apoptotic cell death. In this study, we first examined the regional distribution of NAPOR-3 mRNA in the adult rat brain by in situ hybridization: the transcript was abundantly expressed in many brain regions, mostly in gray matter, including the CA1-CA4 regions and dentate gyrus of the hippocampus, the piriform cortex and the cerebellar granule cell layer. We then investigated the role of NAPOR-3 in neuronal cell death by monitoring its mRNA and protein expression levels using semiquantitative RT-PCR and Western blotting, respectively. NAPOR-3 was overexpressed in rat organotypic slices exposed to staurosporine and to oxygen-glucose deprivation (OGD), an in vitro model of apoptotic cerebral ischemia, but not when exposed to glutamate toxicity. Our results also demonstrate that NAPOR-3 gene overexpression is an early step in the chain of signaling events leading to apoptosis, taking place upstream of caspase-3 activation. Finally, antisense-mediated downregulation of NAPOR-3 gene expression protected hippocampal cultures against OGD-induced apoptosis and prevented caspase-3 activation. Our results demonstrate that NAPOR-3 gene overexpression is necessary for the execution of OGD-induced programmed cell death.

Sphingosine-1-phosphate (S1P) is a lipid mediator, which affects many essential processes such as cell proliferation, differentiation and contraction in many cell types. We have previously demonstrated that the lipid mediator elicits Ca(2+) transients in a myoblastic cell line (C2C12) by interacting with its specific receptors (S1PR(s)). In the present study, we wanted to correlate the Ca(2+) response with activation of myoblastic cell contractility. C2C12 cells were first investigated for the expression and cellular organization of cytoskeletal proteins by immunoconfocal microscopy. We found that myoblasts exhibited a quite immature cytoskeleton, with filamentous actin dispersed as a web-like structure within the cytoplasm. To evaluate intracellular Ca(2+) mobilization, the cells were loaded with a fluorescent Ca(2+) indicator (Fluo-3), stimulated with S1P and simultaneously observed with differential interference contrast and fluorescence optics. Exogenous S1P-induced myoblastic cell contraction was temporally unrelated to S1P-induced intracellular Ca(2+) increase; cell contraction occurred within 5-8 s from stimulation, whereas intracellular Ca(2+) increase was evident only after 15-25 s. To support the Ca(2+) independence of myoblastic cell contraction, the cells were pretreated with a Ca(2+) chelator, BAPTA/AM, prior to stimulation with S1P. In these experimental conditions, the myoblasts were still able to contract, whereas the S1P-induced Ca(2+) transients were completely abolished. On the contrary, when C2C12 cells were induced to differentiate into skeletal myotubes, they responded to S1P with a rapid cell contraction concurrent with an increase in the intracellular Ca(2+). These data suggest that Ca(2+)-independent mechanism of cell contraction may be replaced by Ca(2+)-dependent ones during skeletal muscle differentiation., (Copyright 2004 S. Karger AG, Basel.)

To investigate the effects of physical activity not only on morphometric left ventricular parameters, but also on the abdominal aorta diameter and on blood pressure, we enrolled 100 healthy subjects, 50 males and 50 females, aged between 63 and 91 years (mean 73.3 +/- s.d. 7.7), each divided into two subgroups, sedentary and non sedentary, come to our observation for a diagnostic screening. For each subject an Echography was performed, by using an Acuson 128XP10 apparatus, equipped with a 2 MHz phased array probe, both for the study of the heart and for the study of the abdominal aorta. Then, all the subjects underwent 24 hours blood pressure monitoring by using a P6 Delmar apparatus in order to get mean systolic and diastolic blood pressure. Diastolic blood pressure was significantly related to physical activity (sedentary > non sedentary, P < 0.01), while systolic blood pressure was not; left ventricle and abdominal aorta diameters were both significantly related to sex (males > females, P < 0.001), but left ventricle diameter was significantly related to diastolic blood pressure (P < 0.01), while abdominal aorta diameter was significantly related to systolic blood pressure (P < 0.001). Our data suggest that physical activity might be strongly recommended to control blood pressure.

Chronic injuries of the locomotor apparatus represent the main cause of drop-out among top level gymnasts. The aim of the present paper was to verify whether the postural control, investigated by using an integrated approach and accordingly optimized, could be an effective tool for the secondary prevention of training-related disorders of the locomotor apparatus, in a cohort of 20 young female athletes practicing rythmic gymnastic at top level. After a preliminary medical consultation all the subjects underwent a static and dynamic baropodometric test, an ophtalmological and a dental screening. Then athletes were given prescriptions based upon the results of the above named examination. After 6 months, symptoms were completely disappeared in 80% and remarkably improved in 20%, and at baropodometric test, the contact duration as well as the contact surface, the max and mean contact pressure were significantly increased in all the athletes. Our data show that the proposed integrated approach is actually an effective tool for the secondary prevention of training related disorders of the locomotor apparatus.

Several papers have shown that in young people sports activity is associated with a higher prevalence of cardiac valves incompetence, that can be detected, though to a lesser extent, even in healthy subjects randomly selected from the population. Aim of the present study was to analyse the effects of physical activity not only in young subjects but even in the elderly, with particular reference to valve competence, by using the Echo-Color-Doppler. The study cohort was represented by 80 healthy young subjects, 40 men and 40 women, aged between 20 and 25 years, each group subdivided into two subgroups, sedentary and non sedentary, and 80 healthy elderly subjects, 40 men and 40 women, aged between 65 and 91 years, again divided into sedentary and non sedentary. Valve incompetence was more frequent in the elderly if compared to young subjects (P<0.001) and in non sedentary if compared to sedentary subjects (P<0.01), while no significant difference was found between males and females. Worth of interest the fact that in young subjects valve incompetence was more frequent in non sedentary if compared to sedentary subjects (P<0.001), while in the elderly no significant difference was found between sedentary and non sedentary subjects. This original datum may be explained both by the natural higher prevalence of valve incompetence in the elderly, and by the kind of physical activity usually performed by the elderly, i.e. endurance activity.