Novel contributions in canine craniometry : anatomic and radiographic measurements in newborn puppies

The largest differences in intraspecific head shape among the Carnivora order are to be found in dogs. Based on their skull morphotypes, dog breeds are currently classified as dolichocephalic, mesaticephalic and brachycephalic. Due to the fact that some breeds have not been yet defined, this classification is incomplete; moreover, multi-breed studies on the skull morphology of puppies have never been performed. The aim of this work was to verify (i) whether differences in the skull conformation of purebred puppies are already present within the first week of age; (ii) whether radiographic and anatomic measures could be considered interchangeable, and (iii) to possibly classify puppies from non-categorized breeds thanks to their radiographic cranial measurements using neural nets. One hundred and thirty-seven dead puppies aged 0-7 days were examined considering their anatomic and radiographic measures. All linear measures and anatomic indices significantly differed among brachycephalic and non-brachycephalic puppies. Radiographic indices, with the exception of CI, identified the three skull morphotypes (p<0.05, for all comparisons). Radiographic and anatomic measures proved to be non-interchangeable in newborn puppies. Finally, nineteen puppies belonging to 5 non-categorized breeds could be classified thanks to neural nets in the three skull morphotypes with different probability (P between 0,66 and 0,95)

An integrated approach to cardioprotection in lymphomas

In potentially curable cancers, long-term survival depends not only on the successful treatment of the malignancy but also on the risks associated with treatment-related toxicity, especially cardiotoxicity. Malignant lymphomas affect patients at any age, with acute and late toxicity risks that could have a severe effect on morbidity, mortality, and quality of life. Although our understanding of chemotherapy-associated and radiotherapy-associated cardiovascular disease has advanced considerably, new drugs with potential cardiotoxicity have been introduced for the treatment of lymphomas. In this Review, we summarise the mechanisms of treatment-related cardiac injury, available clinical data, and protocols for optimising cardioprotection in lymphomas. We discuss ongoing research strategies to advance our knowledge of the molecular basis of drug-induced and radiation-induced toxicity. Additionally, we emphasise the potential for personalised follow-up and early detection, including the role of biomarkers and novel diagnostic tests, highlighting the role of the cardio-oncology team

Meniscus maturation in the swine model: role of endostatin in cellular differentiation

The development of an engineered meniscus derives from the need to regenerate a tissue which is largely unable to self-repair with consequent loss of functionality. Hence a deeper knowledge of the native meniscus morphology and biomechanics in its different regions, including molecules involved in regulation of the maturation process, is essential. The meniscus is a complex tissue, displaying great regional variation in extracellular matrix components and in vascularization, as a result of several biomechanical stimuli. Its biochemical composition is modulated to adapt the tissue to the different functions that are required throughout growth, until a \u201cmature\u201d phase is reached in adulthood. The aim of this work is to evaluate the biological role of Endostatin in the regulation of angiogenesis as in the fibro-chondrogenic differentiation of neonatal meniscal cells in the pig. The swine is an attractive model for meniscal repair studies, as its knee joint is closely comparable to the human one in terms of anatomical structure, vascularization, and healing potential. Our preliminary data show that Endostatin contributes to the acquisition of chondrocyte phenotype in an undifferentiated but committed cellular population. Thus, a better understanding of the role of Endostatin in cell metabolism might lead to a deeper knowledge of the events regulating meniscus maturation. These findings may be crucial for the development of an engineered scaffold able to induce meniscal cell differentiation by releasing Endostatin-rich microspheres

Swine cortical and cancellous bone: histomorphometric and densitometric characterisation

Introduction: Swine bone morphology, composition and remodelling are similar to humans\u2019, therefore they are considered good models in bone-related research. They have been used for several studies involving bone growth, bone and cartilage fractures and femoral head osteonecrosis. Nevertheless, the literature about pig normal bone features is incomplete. This work aims to fill the literature gaps on the microarchitecture and Bone Mineral Density (BMD) of swine femoral diaphysis and distal epiphysis and tibial plateau and diaphysis. Materials and methods: Five hind limbs were collected from slaughtered 80-100 kg pigs. Microscopic analysis of cortical and cancellous bone from middle/distal femur and proximal/middle tibia was performed to determine basic histomorphometric parameters at different sites. Dual-energy X-Rays Absorptiometry was also employed to evaluate BMD. ANOVA and correlation between BMD, bone area (BA) and cortical thickness were performed. Results and discussion: Diaphyseal cortical bone was mostly plexiform both in the tibia and the femur; primary/secondary osteons without clear organization were also found. Mean values for bone area, bone perimeter, trabecular width, number and separation and BMD at different anatomical sites were defined. No significant difference was found for these values at different anatomical sites. BMD proved to be positively correlated with cortical thickness (r=0,80; p<0,01). Despite the small sample size, these results seem homogeneous. They could therefore represent reference values for normal bone parameters in pigs. Applied anatomy and regenerative medicine, in fact, demand very precise information about bone micromorphology, composition and density to provide reliable indication in bone substitutes building. Moreover, since the interpretation of bone abnormalities is based on mastering normal bone characteristics, the definition of reference parameters is mandatory to avoid misinterpretation and allow comparative evaluation. Conclusion: The results of this study, although preliminary, may be considered a dependable starting point for the definition of normal bone features in pigs

Ultrastructural and matrix evaluation of morpho-functional age-related changes in dog meniscus

Menisci are essential structures for the knee joint. Different attempts were made trying to replace or regenerate the meniscus after its tear, but the perfect solution is still far away. A better knowledge of the physiologic development of this structure through time could be useful to understand its behavior in the light of the tissue bio-engineering. In this study, the changes in canine meniscal morphology were evaluated to assess how it varies among diverse age stages. The fibers arrangement and matrix deposition in canine menisci from neonatal (died at birth), 10-days, 30-days and adult dogs, dead for causes not related to the present study, were evaluated by means of histochemistry (safranin-O and Sirius red staining), polarized light microscopy, immunofluorescence (collagen I and II) and Scanning Electron Microscopy (SEM). Moreover, quantitative measurements of glycosaminoglycans (GAGs), DNA and GAGs/DNA ratio were performed. The \u201cknotty\u201d structure of neonatal meniscus is probably due to balls of collagen fibres that are not completely stretched until the 30-days stage (Fig 1). The stretching of the fibres starts from the inner portion that is probably the first and the most compressed zone. Safranin-O staining shows how matrix composition vary during growth. Neonatal meniscus is characterized by a huge number of elongated cells (fibroblast-like) and GAGs, features that characterized a still afunctional tissue. With growth, more and more cells assumed a rounded shape. The end-point of the maturation process is represented by the adult meniscus: it is characterized by almost only rounded cells (fibro-chondrocyte-like), in small number, and surrounded by matrix (Fig 1). Nevertheless, 10-30 days interval could be considered the starting point of the meniscus specialization and maturation. Fibres arrangement starts like balls of collagen fibres that follow a disorganized pattern in the neonatal meniscus (Fig 1). In 10-days meniscus, these balls of fibres tend to disappear starting from the meniscus\u2019 inner portion, in association with an initial organization of the fibres according to the longitudinal and radial axes of the meniscus. The organization of fibres network is almost complete at 30-days of life, when all the fibres follow the two main axes of the meniscus and show a well-organized disposition, as seen in adult meniscus. Through the double immunofluorescence it is possible to recognized different aspect of maturation (Fig 3). Neonatal meniscus shows almost only collagen type I fibres. Collagen type I and II co-expression starts at 10 days (yellow) and become more evident in 30-days meniscus in which even a differentiation of the inner and the outer zone starts. The same differentiation persist in adult meniscus that is characterized by a frankly fibro-chondrocitic-like cellular phenotype. Biochemical analysis confirmed that cellularity decrease over the time starting from neonatal to adult (Fig 3). The same decreasing trend is observed in GAGs deposition. Even if 30-days meniscus present a lot of common characteristics with the adult one, the GAGs/DNA ratios show how the latter is the only that present a maturely functional tissue in which a small number of cells is able to produce a matrix rich of GAGs. Meniscal structure changes during growth. The starting point is represented by the neonatal tissue, rich of immature cells and with poor expression of matrix components. The end-point is the adult tissue, characterized by phenotypically mature cells, which assure a functional matrix deposition. Ten-thirty days interval seems to be the turning point of this developmental process. This work highlights how dog meniscal structure changes its morphology among different age stages; this fact may suggest a role of the biomechanical forces, physiologically acting on meniscus, in the development of its ultimate shape and functions. The knowledge of the developmental process of a structure has a capital importance to comprehend its physiologic anatomy and function

Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).CONCLUSIONS:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active

Definitions and pathophysiology of vasoplegic shock.

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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