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The pathological aggregation of tau plays an important role in Alzheimer's disease and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies o disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies, we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTO-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.

The purpose of this report was to describe an uncommon congenital anomaly in a dog. An 8-year-old, mixed-breed, male dog, was referred because of progressive difficulties on defecation. A complete diagnostic work-up (hematological analysis, radiology, ultrasound, and computed tomography), followed by surgery and histopathology, allowed us to diagnose the condition as unilateral urogenital disontogeny. The disorder was characterized by unilateral anomalies of the urinary tract (ectopic and dilated hydroureter, hydronephrosis, and renal dysplasia) associated with ipsilateral anomalies of the genital system (partial permanence of the duct of Wolff evolved into an epididymal-like structure and testicular agenesis). En bloc surgical excision of the complex of urogenital anomalies was performed with no complications during or after surgery. Surgery was considered to be effective in this dog since he no longer showed clinical signs of illness.

1,2,4-Oxadiazole is a heterocycle with wide reactivity and many useful applications. The reactive O-N bond is usually reduced using molecular hydrogen to obtain amidine derivatives. NH4CO2H-Pd/C is here demonstrated as a new system for the O-N reduction, allowing us to obtain differently substituted acylamidine, acylguanidine and diacylguanidine derivatives. The proposed system is also effective for the achievement of a reductive rearrangement of 5-(2′-aminophenyl)-1,2,4-oxadiazoles into 1-alkylquinazolin-4(1H)-ones. The alkaloid glycosine was also obtained with this method. The obtained compounds were preliminarily tested for their biological activity in terms of their cytotoxicity, induced oxidative stress, α-glucosidase and DPP4 inhibition, showing potential application as anti-diabetics.

Objective To determine the effect of the Klox fluorescence biomodulation system (Phovia) on the healing of surgical wounds. Study design Prospective, blinded, controlled clinical trial. Sample population Healthy dogs undergoing orthopedic surgery (n = 10). Methods Half of the length of each surgical wound was treated with Phovia, and the remaining 50% was treated with saline solution on the first day after surgery and every 3 days until day 13. Wound healing of treated and control areas within each wound was evaluated via macroscopic assessment and histological and immunohistochemical analysis of treated and control wounds. Results The areas treated with Phovia achieved lower histology scores (P = .001), consistent with complete re-epithelialization, less inflammation of the dermal layer, and greater and more regular deposition of collagen. According to immunohistochemistry, expression of factor VIII, epidural growth factor, decorin, collagen III, and Ki67 was increased in treated compared with untreated tissues. Conclusion Phovia therapy improved re-epithelialization, decreased dermal inflammation, and improved matrix formation in uncomplicated cutaneous incisional wounds by regulating the expression of key biological mediators. Clinical significance Phovia may be a beneficial adjunct to promote the healing of incisional wounds.

Neurodegenerative diseases (NDs) are one of major public health problems and their impact is continuously growing. Curcumin has been proposed for the treatment of several of these pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the ability of this molecule to reduce inflammation and aggregation of involved proteins. Nevertheless, the poor metabolic stability and bioavailability of curcumin reduce the possibilities of its practical use. For these reasons, many curcumin derivatives were synthetized in order to overcome some limitations. In this review will be highlighted recent results on modification of curcumin scaffold in the search of new effective therapeutic agents against NDs, with particular emphasis on AD.

The first determination of presence and biodistribution of PFOA in ninety specimens of sea urchin Paracentrotus lividus from two differently contaminated sites along Palermo’s coastline (Sicily) is reported. Analyses were performed on the sea urchins’ coelomic fluids, coelomocytes, gonads or mixed organs, as well as on seawater and Posidonia oceanica leaves samples from the collection sites. PFOA concentration ranged between 1 and 13 ng/L in seawater and between 0 and 794 ng/g in P. oceanica. The analyses carried out on individuals of P. lividus from the least polluted site (A) showed PFOA median values equal to 0 in all the matrices (coelomic fluid, coelomocytes and gonads). Conversely, individuals collected from the most polluted site (B) showed median PFOA concentrations of 21 ng/g in coelomic fluid, 153 ng/g in coelomocytes, and 195 ng/g in gonads. Calculated bioconcentration factors of log10BCF > 3.7 confirmed the very bioaccumulative nature of PFOA. Significant correlations were found between the PFOA concentration of the coelomic fluid versus the total PFOA concentration of the entire sea urchin. PERMANOVA (p = 0.001) end Welch's t-test (p P. lividus as sentinel species for PFOA biomonitoring.

The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.

Simple Summary Small rodents and, in particular, rabbits require special attention during anaesthesia since they develop a high level of stress following painful procedures or manipulations. The transversus abdominis plane (TAP) block is a locoregional technique that has been shown to provide good perioperative analgesia for abdominal surgery, reducing the stress during recovery from anaesthesia and the need for systemic analgesic drugs. The aim of this cadaveric study was to describe a US-guided lateral TAP block technique in rabbits and evaluate the spread of the dye administered by a single injection. Our results showed that this US-guided block is applicable and easy to perform in rabbits. However, a single injection of local anaesthetic may fail to cover the sensory component of the entire abdomen. It would be interesting to evaluate the same technique in vivo but using a double injection point, as recently described in other species. Abstract The aims of the study were to describe the ultrasonographic-guided lateral TAP block in rabbit cadavers and evaluate the spread of a lidocaine/methylene blue solution through a single fascial infiltration. The US-guided block and anatomical dissections were performed in 17 New Zealand rabbit cadavers. The probe was placed perpendicular to the column, one centimetre ventrally to the transverse processes, halfway between the iliac crest and the costal margin. External oblique (EO), internal oblique (IO), and transversus abdominis (TA) muscles were visualised, and 1 mL/kg of lidocaine 2% plus methylene blue 1% was injected. After dissection, the branches of spinal nerves stained were measured. Moreover, the percentage of length and height of the area marked were calculated. A good visualisation of the TAP was obtained in all 34 hemiabdomens. T11 nerve eminence was successfully stained in 52% of cases. T12, L1, and L2 were stained in 75%, 95%, and 100% of cases, respectively. L3 and L4 were stained in 60% and 40% of cases, respectively. The lateral TAP block with a single point of injection can be easily performed in rabbits, but it is not sufficient to cover the nerve eminences of the cranial abdomen. The two-point TAP block (lateral and subcostal) could represent a better option, particularly when large surgical incisions are required.

The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit small angle x-ray scattering (SAXS) to investigate the structural features of the SARS-CoV-2 Mpro monomer-dimer equilibrium, by revealing the corresponding equilibrium dissociation constant and the associated thermodynamic parameters. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected through combinatorial design. Our results show that a clear picture connecting the ability of inhibitors to disrupt the Mpro dimerization with the loss of catalytic activity cannot be provided, thus highlighting the possible role of allosteric effects for the regulation of Mpro functionality.

In Europe, approximatively 100 000 to 500 000 tendon repairs are performed every year. These procedures are associated with a considerable rate of postoperative complications (from 6% to 11%). Autologous micro‐grafts (AAMG) and stromal vascular fraction (SVF) have been shown to improve tendon healing in 60% to 70% of treated rodents. The purpose of this study was to evaluate the effects of AAMG in a sheep model with tendinopathy. We used sheep models because, as a large animal, they are more comparable to humans. The hypothesis was that SVF injection would improve tendon healing compared with the control group, reducing inflammatory and matrix degrading, while increasing anti‐inflammatory expression and collagen synthesis in the early stage of tendon injury. Sixteen Apennine sheep aged 2 to 5 years underwent 500 UI type I collagenase injection into both common calcaneal tendons (CCT) to induce tendinopathy. After 15 days (T0), one CCT in every ovine underwent randomly to 2.5 mL of AAMG obtained by mechanical disruption and the contralateral CCTs received no treatment. Clinical, ecographic, and sonographic evaluations were performed after 4 weeks (T1) and 8 weeks (T2). Histological, immunohistochemical, real‐time polymerase chain reaction (RT‐PCR), and biomechanical evaluations were performed at T2. At T2, the treated group showed a final tendon diameter (9.1 ± 1.4 mm) and a hardness expression (62%) that were similar to the original healthy tendon (8.1 ± 1.1 mm; 100%), with a significant recovery compared with the control group (9.5 ± 1.7 mm; 39%). Moreover, histological analysis of the treated group revealed an improvement in the fiber orientation score, fiber edema score, infiltrative‐inflammatory process, and necrosis score (4.3 ± 3.3) compared with control group (8.8 ± 2.9). Immunohistochemically, the treated group showed high expression of collagen 1, Factor VIII and significantly low expression of collagen 3. These data were confirmed by RT‐PCR analysis. The study findings suggested that AAMGs obtained through mechanical disruption present a safe, efficient, and reliable technique, enhancing tendon healing., The group treated with stromal vascular fraction showed a final tendon diameter and a percentage hardness expression that were similar to the original healthy tendon.

Background: Pantarsal arthrodesis is a salvage procedure carried out for the treatment of tarsal joint disease, including severe osteoarthritis with intractable pain in the tarsocrural joint, tarsal fractures, shearing injuries, tarsocrural joint instability, and failure of the common calcaneal tendon. Although medial plating is preferable, the high incidence of post-surgery complications is possible. Using thin, pre-contouring or easy contouring, locking plates might reduce the incidence of such complications. However, to date, there are no pre-contouring and dedicated locking plates forpantarsal arthrodesis with medial placement.Case Description: The case of an 18-month-old female stray European cat has been referred because of a severe tibiotarsal injury improperly treated with an intramedullary pin. The patient was submitted for medial pantarsal arthrodesis, performed with the Compact UniLock 2.0™ locking plate systema (DePuy Synthes, Oberdorf, Switzerland). The authors hypothesized that this particularly innovative osteosynthesis system could present advantages compared to the systems already in use for medial pantarsal arthrodesis and therefore reduce the risk of complications.Conclusion: This innovative titanium locking system, because of its versatile contour function and thinness, allowed the good functional recovery of the limb and showed numerous advantages over traditional systems.

The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial−mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin.

This chapter presents the most recent results in the development of fluorinatedantibioticsby taking into consideration modern challenges of multidrug-resistant pathogens. After a brief introduction on the direct and indirect effects offluorineand fluorinated moieties in regulating biological activity, the chapter is developed in three main subsections discussing the two major classes of fluorinatedantibiotics, fluoroquinolonesandoxazolidinones, plus an overview of recent research on the antibiotic activity of fluorinated analogs oftetracyclines,peptidomimetics,triazoles, andnucleosides. Discussed aspects include: (1) Synthesis and challenges posed by the introduction of fluorinated moieties in specific positions of the main scaffold; (2) mechanism of action andstructure–activity relationshipsin which the introduction or modification of fluorinated substituent is crucial to control efficacy; and (3) resistance mechanisms and solutions to treat resistant pathogens.

Background Canine otitis externa is a painful condition which can be challenging to treat due to difficulties in the administration of otic medication. This can be due to lack of owner compliance in the application of ear drops or due to the resentment that some dogs demonstrate when attempts are made to administer topical medication into a sensitive ear canal. The aim of the study was to assess the efficacy of a topical LED-illuminated gel (LIG) in canine otitis externa in comparison to standard of care therapy. Dogs with spontaneous otitis externa were randomly allocated in three groups: groups QW received LIG once weekly; BW received LIG twice weekly; group C received enrofloxacin and silver sulfadiazine twice daily. LIG consists of a topical application of a gel containing chromophores that, when illuminated by a LED lamp, re-emit fluorescent light which can stimulate physiological responses, promoting healing and controlling bacteria. The evaluation protocol (T0 to T5) considered clinical assessment (OTIS-3-index-scoring-system; pruritus-severity-scale; pain-severity-score; aural temperature), cytological scoring system, quali-quantitative bacteriologic assessment. Results All groups (QW, n = 21; BW, n = 23; C, n = 20) showed improvement during the study (QW: P P P − 4 for pruritus, total OTIS-3 and temperature assessments; BW: P − 4 for all clinical, cytological and bacteriologic assessments; C: P P − 4 for bacteriologic assessment). The highest clinical score reduction occurred in Group BW (P 3; P 4 and P − 4 in T5). BW reached the clinically relevant effect level at T3 (− 3.26 ± 1.21 levels), QW reached it at T4 (− 3.24 ± 0.99), C did not reach it. No differences between groups were seen in the reduction of CFU/mL (T0-T5). Conclusions All treatment groups showed a positive clinical effect. LIG administered twice-a-week was the most favourable protocol of the study. LIG may be considered beneficial in the management of canine otitis externa; it seems to be effective in controlling the clinical condition, including the signs of inflammation and local pain, the bacterial growth, and it may help increasing treatment compliance.

Objective The aim of this study was to evaluate the inter- and intra-observer reliability of plain digital radiographs for assessing normal feline femoral and tibial joint reference angles in the sagittal and frontal planes. Study Design This was a cadaveric radiographic anatomical study. that involved 20 short-haired domestic adult cats. Materials and Methods Sagittal and frontal plane tibial and femoral joint angles of 40 limbs were measured twice by three observers with different levels of experience. Inter- and intraobserver reliability was determined by the intra-class correlation coefficient (ICC). An ICC > 0.75 was considered high correlation, 0.74 > ICC > 0.60 good correlation, 0.59 > ICC > 0.4 fair correlation and an ICC Results Mean ± standard deviation angles were anatomic lateral proximal femoral angle (aLPFA) 110.6 ± 3.6; anatomic lateral distal femoral angle (aLDFA) 91.9 ± 2.1; mechanical lateral proximal femoral angle; mLPFA (mLPFA) 107.3 ± 3.6; mechanical lateral distal femoral angle (mLDFA) 95.5 ± 1.7; femoral neck anteversion (FNA) 121.9 ± 4.1; anatomical caudal proximal femoral angle (aCPFA) 156.1 ± 3.9; anatomical caudal distal femoral angle (aCDFA) 101.4 ± 1.4; mechanical medial proximal tibial angle (mMPTA) 93.5 ± 1.2; mechanical medial distal tibial angle (mMDTA) 100.5 ± 2.3; mechanical cranial proximal tibial angle (mCrPTA) 113.1 ± 3.2; tibial plateau angle (TPA) 23.1 ± 3.2; mechanical cranial proximal tibial angle (mCrDTA) 86.7 ± 3.1.The intra-observer ICC indicated high correlation for 70% or more of the measurements. The inter-observer agreement among observers was high. These results show that the radiographic method for measuring femoral and tibial joint angles was good or high, except for FNA and mCrDTA. Conclusions This study provides some radiographic anatomical and mechanical joint angles of the femurs and tibias of normal domestic short-haired cats. We found good reliability for both intra- and interobserver measurements.

Simple Summary Mesenchymal stem cells are located in bone marrow, adipose tissue, synovial membrane, and muscular tissue. They have an immunosuppressive, anti-inflammatory, and antifibrotic effect. Tissue engineering considers the usage of mesenchymal stem cells as a possible option for regenerating tissues, with respect to bone and cartilage, due to their ability to differentiate into multiple cytotypes (including chondrocytes and osteoblasts). Herein, we characterize a non-invasive solution based on Rigenera® technology, a mechanical disaggregation method able to produce autologous adipose tissue-derived micrografts which are analogous to adipose-derived stem cells. Abstract Within the adult canine population, disabilities and symptoms including joint pain and functional impairment are commonly observed in articular cartilage lesions and present a challenging feat in the operating room. Clinical settings require less invasive and more minimally manipulated measures facilitated by innovative and advanced technology. Mesenchymal stem cells have recently been proposed and, furthermore, autologous adipose tissue administration via injection has emerged as a new albeit somewhat controversial therapeutic tool. The purpose of this study is to characterize canine autologous micro-fragmented adipose tissue (micrografts) by mechanical approach without substantial manipulations. Adipose tissue samples collected from six dogs were processed by a Rigenera device and by enzymatic digestion from two different body regions (lumbar and thigh region). Interestingly, the immunophenotypic analysis attested that cells from Rigenera® were highly positive for the mesenchymal stem cells markers CD73 and CD90, less positive for hematopoietic CD45 and CD34, and negative for MHC class II antibodies (which play a role in immune responses). Finally, the Rigenera® technology obtained micrografts with a 35% higher expression of the IL10 gene with relevant anti-inflammatory activities compared to the enzymatic digestion protocol. This evidence suggests a potential improved clinical outcome capable of modulating inflammation and immune responses.

This Review aims to provide early stage researchers with an updated guide to applications of photochemically produced singlet oxygen and, at the same time, widen the experienced researcher's perspectives in a holistic approach to singlet oxygen chemistry. Without being exhaustive, literature between 2010 and early 2018 has been surveyed by focusing on a critical evaluation of new knowledge and applications. After an introductory section concerning singlet oxygen production, detection, and interactions with biological systems, subsequent sections describe current applications of singlet-oxygen-enabled technology. Besides strictly chemical synthesis applications, attention has been given to the usage of singlet oxygen in photochemically assisted therapies as well as in environmental remediation. Additionally, the potential of expanding singlet oxygen chemistry to unexplored fields has been discussed.

The aim of this experimental study was to evaluate the sedative and cardiorespiratory effects of alfaxalone and midazolam after intramuscular administration in pigs. Fourteen pigs, weighing 18 to 22 kg, aged between 55 and 70 days, American Society of Anaesthesiologists classification 2, affected by congenital reducible umbilical hernia, were included in the study. Alfaxalone (5 mg/kg) and midazolam (0.5 mg/kg) mixed in the same syringe were administered into the neck muscle. Pain on injection, quality of sedation and time to achieve lateral recumbency were recorded. Heart rate (HR), respiratory frequency (fR), and rectal temperature (RT) were recorded at 0 (baseline: before drug administration), 10, 15, and 20 min after the injection. Oxygen saturation of haemoglobin (SpO2), arterial blood pH, arterial oxygen (PaO2) and carbon dioxide (PaCO2) tensions and bicarbonate concentration (HCO3-) were recorded at 10, 15, and 20 min after injection. Continuous data were analysed using a repeated-measure analysis of variance (ANOVA) and aP-value < 0.05 was considered significant. Ten animals out of fourteen showed no pain on injection, whereas the remaining four exhibited mild pain. The time from the end of injection to lateral recumbency was 266 ± 40 s. The quality of sedation ranged between good to very good. No significant changes in the variables monitored were observed between the time points. In conclusion, the intramuscular administration of alfaxalone and midazolam in pigs at the doses used induced reliable and fast sedation, without pain on injection and moderate respiratory effects.

A convenient approach to the synthesis of alkyl esters of aspirin (ASA-OR) has been developed. The synthesis of ASA-OR has been realized in two steps: (1) direct esterification of salicylic acid with alcohols in the presence of dicyclohexylcarbodiimide to give alkyl salicylates (SAL-OR); (2) acetylation of SAL-OR with acetyl chloride to yield ASA-OR. Molecular mechanics simulations, performed to calculate the kinetic radii of several ASA-OR, indicated that the pentyl and hexyl acetylsalicylates possess the best properties to cross cell membranes. The in vitro biological tests demonstrate their anti-inflammatory activity, superimposable to that of aspirin. The results of our study suggest that ASA-OR may be used as anti-inflammatory drugs for topical application.

Cell survival and proliferation are central to carcinogenesis, involving various mechanisms among which those that impede apoptosis are important. In this, the role of the molecular chaperone Hsp60 is unclear since it has been reported that it can be both, pro- or anti-apoptotic. A solution to this riddle is crucial to the development of anti-cancer therapies targeting Hsp60. We addressed this question using a tumor cell line, NCI-H292, and [Cu(3,5-bis(2′-pyridyl)-1,2,4-oxadiazole) 2 (H 2 O) 2 ](ClO 4 ) 2 , CubipyOXA , a copper-containing compound with cytotoxic properties. We treated cells with various doses of the compound and measured cell viability; apoptosis indicators; and levels of Hsp60, pro-Caspase-3 (pC3), Caspase-3 (C3), and complex Hsp60/pC3, with complementary methods. The quantitative dose-response curves of the levels of Hsp60, activated C3, inactivated pC3, Hsp60/pC3 complex and indicators of cell apoptosis, and cell death, all coincided to show that CubipyOXA has pro-apoptotic activity and promotes cell death. The curves also indicate that the pro-apoptotic effects of CubipyOXA could likely be due to a lowering of Hsp60 levels and to its blocking the formation of the Hsp60/pC3 complex and/or its dissociating the complex when already formed, thus, interfering with the anti-apoptotic action of Hsp60. These findings shed some light on how a tumor cell may avert apoptosis using Hsp60 and point to the anti-cancer potential of drugs, such as CubipyOXA , which interfere with Hsp60/pC3 complex formation, and thus allow the apoptotic cascade to proceed. In view of these findings it becomes clear that the novel compound CubipyOXA should be considered a potential, high-efficiency antitumor agent deserving further testing.

Objective This article describes the sonoelastographic features of the patellar ligament of sound dogs and tests feasibility, reproducibility and repeatability. Methods Clinically healthy medium-to-large breed dogs were enrolled. Sonoelastographic images of the patellar ligaments were obtained in lateral recumbency with the stifle flexed by an experienced operator and by a senior veterinary student. The elasticity colour map included red (soft), green (intermediate) and blue (hard). Tissue elasticity was measured by calculating the percentage of softness with dedicated software. Categorical, qualitative data analysis was performed using a weighted kappa statistic for repeatability and reproducibility. A categorical qualitative assessment was performed based on a grading scale of 1 to 5 (soft, mostly soft, intermediate, mostly hard and hard). Results Fourteen clinically normal dogs were considered. A total of 28 patellar ligaments were examined. Overall, 25 of the patellar ligaments were graded as soft or mostly soft and the remaining 3 as intermediate. Repeatability was 86.2%, with a weighted kappa of 0.64 (good), for the well-trained sonographer and 83.3%, with a weighted kappa of 0.53 (moderate), for the senior student. Reproducibility was 86.2%, with a weighed kappa of 0.65 (good). Clinical Significance Sonoelastography of the canine patellar ligament is a feasible and reproducible technique. Patellar ligaments in clinically normal dogs showed highly elastic biomechanical properties.

Background: The treatment and diagnosis of Alzheimer’s Disease (AD) are two of the most urgent goals for research around the world. The cognitive decline is generally associated with the elevated levels of extracellular senile plaques, intracellular neurofibril- lary tangles (NFTs), and with a progressive shutdown of the cholinergic basal forebrain neurons transmission. Even if several key targets are under fervent investigation in the cure of AD, till now, the only approved therapeutic strategy is the treatment of symptoms by using cholinesterases inhibitors. It has been demonstrated that both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes are not only responsible of acetylcho- line levels, but also play an pivotal role in A -aggregation during the early stages of senile plaque formation. On the other hand the difficult management of AD is also related to ef- fective diagnostic methods and efficient assays for the study of pathological features. In such complex a wide framework, heterocyclic molecules are essential backbone to build new and selective drugs as well as diagnostic probes. Methods: The goal of this review is to examine a selected sample of relevant applications of five- and six-membered heterocycles in AD's therapeutic approaches. Results: Concerning the research on AD, the contribution of heterocyclic compounds is huge and here we report some representative examples. The review is organized in two main sections focused on five and six-membered het- erocycles. The analyzed cases have been classified on the base of the structural features of molecules, taking into account the progressive increase in heteroatoms number. Conclusion: The discovery of an effective therapy or a diagnostic protocol for AD is still far, but consistent improvements are underway and contribution of heterocyc- lic compounds will be consistent and hopefully determinant.

Background Chronic intestinal pseudo-obstruction (CIPO) is a rare clinical syndrome in veterinary medicine characterized by severe intestinal dysmotility without evidence of mechanical occlusion of the intestinal lumen. The exact pathogenesis of CIPO is unknown. Case presentation A 1-year-old male Miniature Bull Terrier dog was presented with a history of chronic weight loss, regurgitation, lethargy, vomiting and diarrhea. The dog was submitted for exploratory laparotomy. A full thickness intestinal biopsy was taken and a CIPO was suspected. The clinical condition deteriorated and the dog was euthanized. At gross examination the small intestine was severely dilated. Histologically severe fibrosis of the submucosa and severe atrophy of the tunica muscularis were present in small intestine and colon. Immunohistochemical examination with a panel of antibodies for gastro-intestinal neuromuscular disease-associated antigens revealed a severely reduced expression of alpha-smooth muscle actin in the tunica muscularis. Conclusions This case report describes the gross, histological and immunohistochemical findings of CIPO affecting a 1-year-old Miniature Bull Terrier; on the basis of these findings a myopathic form of CIPO is hypothesized in this case.

Heat shock protein 60 kDa (Hsp60) is a chaperone classically believed to be involved in assisting the correct folding of other mitochondrial proteins. Hsp60 also plays a role in cytoprotection against cell stressors, displaying for example, antiapoptotic potential. Despite the plethora of studies devoted to the mechanism of Hsp60's function, especially in prokaryotes, fundamental issues still remain unexplored, including the definition of its role in cancer. Key questions still unanswered pertain to the differences in structure-function features that might exist between the well-studied prokaryotic GroEL and the largely unexplored eukaryotic Hsp60 proteins. In this article we discuss these differences in sequence, structure, and roles of Hsp60, focusing on the human ortholog with the view of devising compounds to block its ability to favour tumor-cell growth and survival. Compounds currently known to directly or indirectly affect Hsp60 functions, such as protein folding, HIF-1α accumulation, or Hsp60-induced cell proliferation, are discussed along with strategies that might prove effective for developing Hsp60-targeting drugs for anticancer therapy.

The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5- yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4- oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.

OBJECTIVE To determine effects of the size and location of regions of interest (ROIs) in the renal cortex of unsedated dogs on renal perfusion variables determined by use of contrast-enhanced ultrasonography (CEUS). ANIMALS 12 client-owned adult (1.5 to 2 years old) Labrador Retrievers (8 males and 4 females; mean ± SD body weight, 27 ± 1.6 kg). PROCEDURES Each dog received 2 bolus injections of sulfur hexafluoride during CEUS. Three small oval ROIs (area of each ROI, 0.11 cm2) located in a row with a distance of 1 mm between adjacent ROIs and 1 large oval ROI (area, 1 cm2) that encompassed the 3 smaller ROIs were manually drawn in the renal cortex. The ROIs were located at a depth of 1.5 to 2.0 cm in the near field of the renal cortex. Software analysis of time-intensity curves within each ROI was used to identify peak enhancement, time to peak enhancement, regional blood flow, and mean transit time. RESULTS The location and size of the ROIs of unsedated dogs did not cause significant differences in the mean values of the renal perfusion variables. CONCLUSIONS AND CLINICAL RELEVANCE The development of CEUS has provided a unique means for visually examining and quantifying tissue perfusion. Results of this study indicated that it was possible to use small or large ROIs during renal CEUS to evaluate renal perfusion in dogs.

The presence in the mRNA of premature stop codons (PTCs) results in protein truncation responsible for several inherited (genetic) diseases. A well-known example of these diseases is cystic fibrosis (CF), where approximately 10% (worldwide) of patients have nonsense mutations in the CF transmembrane regulator (CFTR) gene. PTC124 (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)-benzoic acid), also known as Ataluren, is a small molecule that has been suggested to allow PTC readthrough even though its target has yet to be identified. In the lack of a general consensus about its mechanism of action, we experimentally tested the ability of PTC124 to promote the readthrough of premature termination codons by using a new reporter. The reporter vector was based on a plasmid harboring the H2B histone coding sequence fused in frame with the green fluorescent protein (GFP) cDNA, and a TGA stop codon was introduced in the H2B-GFP gene by site-directed mutagenesis. Additionally, an unprecedented computational study on the putative supramolecular interaction between PTC124 and an 11-codon (33-nucleotides) sequence corresponding to a CFTR mRNA fragment containing a central UGA nonsense mutation showed a specific interaction between PTC124 and the UGA codon. Altogether, the H2B-GFP-opal based assay and the molecular dynamics (MD) simulation support the hypothesis that PTC124 is able to promote the specific readthrough of internal TGA premature stop codons.

OBJECTIVE To evaluate the effects of a medetomidine-ketamine combination on tear production of clinically normal cats by use of the Schirmer tear test (STT) 1 before and during anesthesia and after reversal of medetomidine with atipamezole. ANIMALS 40 client-owned crossbred domestic shorthair cats (23 males and 17 females; age range, 6 to 24 months). PROCEDURES A complete physical examination, CBC, and ophthalmic examination were performed on each cat. Cats with no abnormalities on physical and ophthalmic examinations were included in the study. Cats were allocated into 2 groups: a control group (n = 10 cats) anesthetized by administration of a combination of medetomidine hydrochloride (80 μg/kg) and ketamine hydrochloride (5 mg/kg), and an experimental group (30) anesthetized with the medetomidine-ketamine combination and reversal by administration of atipamezole. Tear production of both eyes of each cat was measured by use of the STT I before anesthesia, 15 minutes after the beginning of anesthesia, and 15 minutes after administration of atipamezole. RESULTS Anesthesia with a medetomidine-ketamine combination of cats with no ophthalmic disease caused a significant decrease in tear production. The STT I values returned nearly to preanesthetic values within 15 minutes after reversal with atipamezole, whereas the STT I values for the control group were still low at that point. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that a tear substitute should be administered to eyes of cats anesthetized with a medetomidine-ketamine combination from the time of anesthetic administration until at least 15 minutes after administration of atipamezole.

The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained.

The renal resistive index (RI) is the ratio of the difference between maximum and minimum (end diastolic) flow velocity derived from the Doppler spectrum of intrarenal (segmental/interlobar) arteries. It is a good indicator for acute renal disease, acute tubular necrosis, and renal obstruction. To our knowledge, no reports are available about the values of renal RI in unsedated horses. The aim of this study was to establish a normal reference range (mean ± standard error) and to assess the reliability of the renal RI obtained using transabdominal ultrasonography in unsedated healthy horses. Thirteen conscious Thoroughbred horses judged healthy based on physical examination, complete blood count, biochemical profile, urinalysis, and ultrasonography were included. The peak-systolic and end-diastolic velocities of interlobar and arcuate arteries were measured. Intrarenal arteries were scanned by pulsed Doppler ultrasonography to calculate RI. The comparison of left versus right kidneys was analyzed with analysis of covariance (ANCOVA) procedure. Significant differences (P

Objective To determine the efficacy of topical application of the autologous platelet gel (PG) in canine chronic protracted decubital ulcers. Study Design Prospective, randomized, blind controlled clinical trial. Animals Dogs (n = 18) with bilateral chronic wounds caused by protracted decubitus ulcers. Methods For each dog, wound side was randomized to receive either platelet gel (group PG) every 5 days for 5 dressing changes, or paraffin gauzes dressings (group C), as negative control. Wound healing and wound surfaces were compared at admission and then evaluated every 5th day, until day 25. Outcome variables were: open wound area, reduction of open wound surface compared to admission and to each preceding dressing change, time to complete epithelialization. Results Significant differences in healing process were observed at day 5 and continued throughout the entire study period (P

BACKGROUND: Idiopathic inflammatory bowel disease (IBD) is a common chronic enteropathy in dogs. There are no published studies regarding the use of probiotics in the treatment of canine IBD. The objectives were to compare responses to treatment with either combination therapy (prednisone and metronidazole) or probiotic strains (VSL#3) in dogs with IBD. METHODOLOGY AND PRINCIPAL FINDINGS: Twenty pet dogs with a diagnosis of IBD, ten healthy pet dogs, and archived control intestinal tissues from three euthanized dogs were used in this open label study. Dogs with IBD were randomized to receive either probiotic (D-VSL#3, n = 10) or combination drug therapy (D-CT, n = 10). Dogs were monitored for 60 days (during treatment) and re-evaluated 30 days after completing treatment. The CIBDAI (P

Objectives: To assess the value of the intra-articular Wallace distractor in stifle arthroscopy in the dog. Methods-Ex-vivo study: ten cadaver limbs of dogs were used to explore the stifle joints by arthroscopy each once without and once with the aid of a Wallace distractor. Radiographs and observational data were used to assess the degree of joint distraction and to evaluate any collateral intra-articular damages. In vivo study: distractor-assisted arthroscopy was thereafter performed in 12 consecutive clinical cases of dogs with cranial cruciate ligament rupture. The use of the Wallace distractor, clinical setting, time to complete joint evaluation were recorded. Results: In the cadaver study, radiographic findings showed a significant increase of the joint space after the insertion of the distractor. Visual range during arthroscopy employing the Wallace distractor increased substantially and facilitated the assessment of all visible intra-articular structures. Mean time to evaluate the femoropatellar space was 4,1 minutes, to observe cruciate ligaments 6,5 minutes and to complete joint inspection 10,1 minutes. In the clinical study, the use of Wallace distractor allowed improved arthroscopic observation of all relevant structures, without sub-patellar fat pad removal. Mean time to complete joint inspection was 28,5 minutes. Clinical significance: The use of the Wallace joint distractor may be helpful in the arthroscopic assessment of the canine stifle. It is easy to insert, it allows a considerable distraction of the joint making it easier visibility and reducing the possible need to remove the sub patellar fat pad. With its blunt pins Wallace joint distractor limits the risk of iatrogenic damage and can be easy to use even for surgeons who do not have much experience in knee arthroscopy.

5-Pentafluorophenyl-1,2,4-oxadiazoles, differently substituted at C(3), have been synthesized and used to functionalize the aliphatic primary hydroxyl functionalities of triethanolamine, under mild conditions. UV–visible absorption and emission spectra are reported, for both tri- and difunctionalised molecules, showing their potential applications as light-emitters in optoelectronic devices.

An adult discus (Symphisodon aequifasciatus) with a history of buphthalmia and anorexia was referred, from an aquarium, for clinical examination. Surgery was performed to enucleate the eye and obtain a definitive diagnosis. Macroscopic examination revealed a yellowish mass that affected the eye. Histologic examination of the mass revealed a poorly demarcated, high cellular infiltrative mesenchymal neoplasm composed of ovoidal-spindloid cells with elongated nuclei and with scant cytoplasm arranged in a solid pattern. Throughout the tumor, there were scattered foci of cartilaginous differentiation that stained deeply with alcian blue and stained metachromatically with toluidine blue. The neoplastic cells were immunolabeled to varying degrees by antibodies against vimentin and SOX-9. Based on morphologic, histochemical, and immunohistochemical characteristics, the tumor was diagnosed as a chondrosarcoma.

Background: The present study aims to analyse the in vivo behaviour of nanohydroxyapatite and to assess its regenerative capacity in dogs affected by periodontal disease. Methods and findings: The dogs employed in the study were randomly subdivided into a control group and an experimental group. After clinical, instrumental and radiological examinations, all the subjects underwent dental prophylaxis and a bioptic sample was taken. A histopathological examination of the periodontal tissues, in correspondence to teeth with periodontopathy ranging between stages 2 and 3, followed. Regenerative therapy with applications of nanohydroxyapatite was administered only to the dogs of the experimental group. After a period of between 35 and 40 days, a further clinical, instrumental and radiological examination was carried out and a bioptic sample taken solely on the dogs whose histological examinations showed changes ascribable to periodontal disease. The results of the histopathological examination demonstrated that only the dogs in the experimental group, who underwent dental prophylaxis together with the administration of nanohydroxyapatite, showed clear signs of improvement with respect to their initial condition. Conclusions: In conclusion the study demonstrated that the nanohydroxyapatite represents a valid osteoconductive and osteoinductive graft product and confirmed its regenerative potential in periodontal therapy in dogs.

SummaryA 20-month-old male Rottweiler dog was presented with the complaint of chronic right forelimb lameness that was unresponsive to conservative treatment. Physical examination allowed for the topographical identification of the source of the problem as a firm enlargement of the soft tissues that was partially movable from humeral bone and compatible with an alteration of the triceps brachii muscle. Radiographic images showed signs that were highly suggestive of myositis ossificans. Computed tomography allowed for a more accurate characterization of the lesion, to exclude involvement of the elbow joint and humeral bone, and to localize anatomically the lesion in the caput accessorium and longum of the triceps brachii muscle. Surgical excision of the ossified portion of the triceps muscle was performed. Histological examination of the excised tissue substantiated the diagnosis of myositis ossificans. A one year clinical and radiographic follow-up examination showed a complete recovery, with no evidence of complications or recurrence. Despite myositis ossificans in dogs having previously been identified in the hindlimbs, this case of myositis ossificans circumscripta of the triceps muscle suggests that it may also occur in the muscles of the forelimb.

SummaryObjectives: To evaluate how the inclination and torsional deformity of the hemipelvis using extra-rotation as a model affect acetabular angle (AA) and dorsal acetabular rim angle (DARA) assessment with computed tomography (CT).Methods: A normal canine hemipelvis positioned in dorsal recumbency was scanned with a 16-slice multidetector CT scanner, with different degrees of torsional deformity, using extra-rotation around the long axis (0–5–10–15°) of the hemipelvis. Each degree of extra-rotation was acquired at 0°, +20° and –20° of gantry tilt, to mimic different pelvic inclinations on its transverse axis. Cranial and central individual acetabular angles (IAA) and central DARA were calculated and correlated with inclination and torsional deformity.Results: A very strong negative correlation was found between cranial and central IAA, pelvic inclination, and torsional deformity. A very strong positive correlation was found between DARA, pelvic inclination, and torsional deformity.Clinical significance: Pelvic inclination and torsional deformity affect acetabular angles assessment with CT. The greater the inclination (ilia far from the tabletop in dorsal recumbency) and torsional deformity of the pelvis, the worse the acetabulum appeared. A standardized scanning protocol for acetabular morphology assessment is needed and it should consider pelvic inclination. The actual relevance of pelvic torsional deformity is not well known and it should be investigated more thoroughly.

A five-year-old dog was referred with a five-month history of lethargy, decreased appetite, cough and intermittent forelimb lameness. Radiographs revealed an intra-thoracic lesion and a marked periosteal bone apposition of the second digit on the left forelimb. As it was palisading and circumferential, the latter appeared typical of hypertrophic osteopathy (HO). A grass awn in a sub-lobar ramification of the right caudal bronchus was identified and removed by bronchoscopy. At three months follow-up, the digit appeared clinically normal. On radiographs the periosteal bone reaction had decreased, indicative of resolving hypertrophic osteopathy. Thoracic radiographs showed no abnormalities five months after foreign body removal and the bone lesion on the digit had disappeared. Successful treatment of the pulmonary foreign body abscess led to spontaneous regression of HO and eventually to complete resolution of clinical signs. To the authors' knowledge, this is the first reported case of HO secondary to a bronchial-pulmonary grass an abscess.

Evaluation of the muscular relaxant effect of dexmedetomidine or medetomidine in cats P. Scrollavezza & A. M. Tambella & C. Vullo & A. Palumbo Piccionello Published online: 8 July 2009 # Springer Science + Business Media B.V. 2009