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Aims: This study evaluated the mechanisms involved in the chemopreventive effects of a mucoadhesive formulation (FITOPROT), containing curcuminoids from Curcuma longa L. (Zingiberaceae) and Bidens pilosa L. (Asteraceae) extract, against 5-FU-induced cellular toxicity using an in vitro oral mucositis model., Main Methods: Effects of FITOPROT on 5-FU-induced cytotoxicity in HaCaT and SSC-4 cells were evaluated by MTT assay. For mechanistic analyses, HaCaT cells were first pretreated with FITOPROT (0.005%) for 24h followed by treatment with FITOPROT and simultaneously exposed to 5-FU (10μg/mL) for additional 24h., Key Findings: FITOPROT was able to protect HaCaT cells from 5-FU-triggered cell damage. Moreover, the FITOPROT+5-FU association showed higher cytotoxic effects on SSC-4 cancer cells. Flow cytometry and/or fluorescence microscopy analysis showed FITOPROT was able to significantly reduce ROS generation and prevent mitochondrial changes in HaCaT cells. In addition, it avoided the release of cytochrome c from mitochondria to the cytoplasm in cells exposed to 5-FU, and restored their proliferative activity via Ki-67 expression. Furthermore, FITOPROT regulated 5-FU-induced oxidative stress via Nrf2 involvement. HaCaT cells pretreated/treated with FITOPROT also showed normal expression of TNF-R1 and NF-κB inflammatory proteins and decreased levels of pro-inflammatory cytokines (TNF, IL-1β, IL-6 and IL-8). Moreover, a high-resolution liquid chromatography-mass spectrometry analysis showed the presence of flavonoids rutin, glucoronylated quercetin and dimethylquercetin rutenoside in FITOPROT., Significance: It was showed that FITOPROT, an antioxidant phytochemicals-rich mucoadhesive formulation, exerts chemopreventive effects against 5-FU-triggered toxicity through antioxidant and anti-inflammatory mechanisms and restoration of proliferative capacity in HaCaT cells., (Copyright © 2017. Published by Elsevier Inc.)

Background: Topotecan (TPT) is a water-soluble derivate of camptothecin, which undergoes ring-opening hydrolysis in neutral solutions, leading to stability loss and poor cellular uptake. Lipid nanoencapsulation can improve TPT stability, and polymer-lipid hybrid nanoparticles (PLN) are interesting alternatives to improve TPT nanoencapsulation., Objective: This study seeks to prepare complexes between the cationic TPT and the negatively charged dextran sulfate (DS) with a view of improving drug loading, chemical stability and release control., Methods: The optimum ionic molar ratio in DS-TPT complexation was determined, and the selected complex was characterized by FTIR and solid-state 13C NMR. TPT solubility in the free and complexed forms was also assayed. TPT-PLN was then obtained via a microemulsion technique, and particle size, zeta potential, encapsulation efficiency, drug loading and drug recovery were determined. Additionally, the TPT stability and in vitro release were determined from PLN and compared with free TPT, TPT-DS complex and TPT encapsulated in nanostructured lipid carriers (NLC) of similar composition., Results: TPT-DS complexation was confirmed by FTIR and NMR. TPT solubility in the complex was drastically decreased when compared to free TPT. TPT-PLN had high encapsulation efficiency (97%) and drug loading capacity (5.5%). Additionally, TPT-PLN showed a mean diameter, polidispersivity index e zeta potential of 140 nm, 0.2 and -22 mV, respectively. The TPT chemical stability and release from PLN were observed to be superior when compared to NLC., Conclusion: PLN has shown to be a more effective nanosystem for TPT nanoencapsulation because TPT loading, stability and release were superior when compared to TPT-NLC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The topical application of Centella asiatica extract has been commonly used for many different purposes but especially for cosmetic use in the treatment of gynoid lipodystrophy. Asiaticoside, the most active component in this extract, is responsible for its therapeutic activities. However, little is known to date about asiaticoside skin penetration. Thus, an analytical method for asiaticoside quantification in different skin layers after the topical application of C. asiatica extract was developed and skin permeation studies were performed with the plant extract to apply the analytical method developed. An extraction procedure to recover asiaticoside from the biological matrix was also developed. Asiaticoside was assayed by HPLC/UV (high-performance liquid chromatography-ultraviolet detection) using a gradient of ACN (acetonitrile) and 0.2% phosphoric acid (flow rate of 1.0 mL/min). The analytical procedure was validated according to U. S. Food and Drug Administration guidelines. Selectivity was shown, as endogenous skin components did not interfere with the asiaticoside peak. Analytical curve was linear (3 to 60 µg/mL) and the lower limit of quantification was determined (3 µg/mL). Asiaticoside recoveries from skin samples were 95.1% and 66.7% for the stratum corneum and remaining skin, respectively. After 48 h of in vitro permeation studies, a substantial amount of asiaticoside was quantified in the skin layers. The presence of asiaticoside was also detected in the receptor solution of Franz diffusion cells after 48 h (5.81 ± 1.00 µg/mL). The method was reliable and reproducible for asiaticoside quantification in skin samples, thereby making it possible to determine the cutaneous penetration profile of this drug in permeation studies., Competing Interests: Conflict of Interest: There is no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Lipid nanoparticles have been extensively studied for drug delivery of antifungal drugs, especially for dermatophytosis treatments. They can accumulate in skin appendages and release drugs in a controlled manner and also increase skin moisture, due to the formation of an occlusive film. Since moisture heavily influences nail and skin permeability, these systems seem to pose great potential for antifungal drug delivery., Methods: We therefore compare skin and nail physiopathological structure and discuss the potential use of lipid nanoparticles in managing skin and nail mycoses, highlighting their unexplored use in onychomycosis., Results: Structural features become particularly relevant when treating local skin/nail disorders. Nail plate represents the most resistant barrier to the penetration of molecules. In recent years, at least 55 researches have been reported about lipid nanoparticles and, antifungal drugs. They have focused on production methods and nanoparticle ingredients influence on entrapment efficiency, fungal activity in vitro, stability, and drug release. Lipid nanoparticles such as SLN and NLC have shown great results in permeating the skin. Currently, however, there is just one study published using NLC applied directly to the nail plate. NLC containing voriconazole had a noteworthy impact on the penetration depth of a nanoencapsulated drug, which allowed its deeper penetration into porcine hooves than the unloaded drug., Conclusion: Evidence of the success of SLN and NLC in achieving high encapsulation efficiencies of antifungals and promoting cutaneous delivery indicates the potential of the systems in enhancing nail hydration and drug penetration into the nail plate., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Voriconazole-loaded nanostructured lipid carriers (VOR-NLC) were developed and drug penetration evaluated in porcine hooves in vitro. Synergistic effect of urea (Ur), selected among other known chemical enhancers according to hoof hydration potential, was also evaluated. VOR-NLC presented a high encapsulation efficiency (74.52±2.13%), approximate mean diameter of 230nm and were positively charged (+27.32±2.74mV). Stability studies indicated they were stable under refrigeration (4±2°C) for up to 150days. SEM images revealed hooves treated with VOR-NLC and VOR-NLC-Ur suffered a disturbance on the surface depicting high roughness and porosity. Permeation data showed a substantial VOR amount retained in superficial hooves sections independent of the formulation used (2.42±0.26; 2.52±0.36 and 2.41±0.60μg/cm 2 for unloaded VOR, VOR-NLC and VOR-NLC-Ur, respectively, p>0.05). Still, successive extractions, revealed the amount of VOR retained in deeper regions was significantly higher when VOR-NLC or VOR-NLC-Ur was used (0.17±0.04, 0.47±0.14 and 0.36±0.07μg/cm 2 for unloaded VOR, VOR-NLC and VOR-NLC-Ur, respectively, p<0.05). Such results indicate NLC are promising formulations for the management of onychomycosis. Further studies in diseased nail plates are necessary., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background  We evaluated a transrectus capitis posterior muscle triangle approach to the posterolateral foramen magnum, occipital condyles, jugular tubercle, and the fourth ventricle. We also assessed factors that affect the amount of bone removal required. Objective  To evaluate if the proposed approach is as effective as standard open approaches to expose the lateral portion of the foramen magnum. Methods  The proposed minimally invasive fully endoscopic approach was performed in 15 cadaveric specimens using 4-mm (0- and 45-degree) endoscopes. Results  Using a 5-cm straight paramedian incision, the rectus capitis posterior minor and major muscles were partially removed unilaterally, providing a corridor through the muscles to reach the foramen magnum region. After meticulous soft tissue dissection, key anatomical landmarks can be identified such as the greater occipital nerve, the vertebral artery that wraps around the atlanto-occipital joint, and the bony protuberance that heralds the occipital condyle. A suboccipital craniotomy associated with the transcondylar, supracondylar or paracondylar approach is performed depending on the amount of bone removal desired to maximize the surgical view. By doing so, the jugular foramen can be exposed laterally as well as the fourth ventricle medially. Conclusion  The proposed endoscopic approach can provide access through the transrectus capitis posterior muscle triangle leading directly to the occipital condyle. A stepwise approach is critical to gain a surgical corridor to the inferolateral petroclival region and the fourth ventricle.

Combined therapy with corticosteroids and immunosuppressant-loaded nanostructured lipid carriers (NLC) could be useful in the treatment of skin diseases. To circumvent NLC loading capacity problems, loaded drugs should have different physicochemical characteristics, such as tacrolimus (TAC) and clobetasol (CLO). Therefore, in the present study, TAC and CLO were encapsulated in NLC (TAC-NLC, CLO-NLC and TAC+CLO-NLC), coated or otherwise with chitosan. Electron paramagnetic resonance (EPR) spectroscopy of different spin labels was used to investigate the impact of drug and oil incorporation on the lipid dynamic behavior of the lipid matrices. In addition, the impact of co-encapsulation on drug release and skin permeation was evaluated. Entrapment efficiency was greater than 90% for both drugs, even when the maximum drug loading achieved for TAC-NLC and CLO-NLC was kept at TAC+CLO-NLC, because TAC is more soluble in the solid lipid and CLO in the liquid lipid. EPR data indicated that both drugs reduced the lipid fluidity near the polar surface of the lipid matrix, which suggests their presence in this region. In addition, EPR data showed that liquid lipid is also present in more superficial regions of the nanoparticle matrix. CLO was released faster than TAC from TAC+CLO-NLC, probably because it is more soluble in the liquid lipid. TAC skin penetration was affected by CLO. A 5-fold increase in TAC penetration was observed from TAC+CLO-NLC when compared to TAC-NLC formulations. Coating also increased TAC and CLO permeation to deeper skin layers (1.8-fold and 1.6-fold, respectively). TAC+CLO-NLC seems to be an effective strategy for topical delivery of TAC and CLO, and thus constitutes promising formulations for the treatment of skin diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: This work aimed to evaluate semisolid formulations containing topotecan (TPT) loaded nanostructured lipid carriers (NLC) for topical treatment of skin cancers, as TPT is effective against a variety of tumours. A formulation which increases TPT skin permeation would be extremely desirable., Methods: TPT-NLC were prepared and incorporated in hydrogels with hydroxyethyl cellulose and chitosan (TPT-NLC-HEC and TPT-NLC-Ch, respectively). Control formulations were obtained by dispersing TPT in HEC and Ch hydrogels (TPT-HEC and TPT-Ch)., Key Findings: TPT-NLC-HEC and TPT-NLC-Ch showed to maintain the drug and nanoparticle dispersions stable for up to 30 days. When nanoparticles were incorporated into gels, TPT release was significantly decreased (P < 0.05). Still, TPT-NLC-HEC increased 2.37 times permeation compared with TPT-HEC (11.9 and 5.0 μg/cm 2 , respectively). Cell culture experiments with B16F10 melanoma demonstrated that nanoencapsulation significantly increased TPT cytotoxicity (P < 0.05). TPT-NLC was more toxic than free TPT, with IC50 value of 5.74 μg/ml, whereas free TPT had an IC50 > 20 μg/ml. As skin permeated values of TPT from developed formulation (TPT-NLC) were superior to melanoma IC50, it can be extrapolated that chemotherapeutic permeated amounts may be sufficient for a therapeutic effect., Conclusions: TPT-NLC-HEC may be a valuable tool for the topical treatment of skin cancers., (© 2017 Royal Pharmaceutical Society.)

The bone organ integrates the activity of bone tissue, bone marrow, and blood vessels and the factors ensuring this coordination remain ill defined. Bone sialoprotein (BSP) is with osteopontin (OPN) a member of the small integrin binding ligand N-linked glycoprotein (SIBLING) family, involved in bone formation, hematopoiesis and angiogenesis. In rodents, bone marrow ablation induces a rapid formation of medullary bone which peaks by ∼8 days (d8) and is blunted in BSP-/- mice. We investigated the coordinate hematopoietic and vascular recolonization of the bone shaft after marrow ablation of 2 month old BSP+/+ and BSP-/- mice. At d3, the ablated area in BSP-/- femurs showed higher vessel density (×4) and vascular volume (×7) than BSP+/+. Vessel numbers in the shaft of ablated BSP+/+ mice reached BSP-/- values only by d8, but with a vascular volume which was twice the value in BSP-/-, reflecting smaller vessel size in ablated mutants. At d6, a much higher number of Lin - (×3) as well as LSK (Lin - IL-7Rα - Sca-1 hi c-Kit hi , ×2) and hematopoietic stem cells (HSC: Flt3 - LSK, ×2) were counted in BSP-/- marrow, indicating a faster recolonization. However, the proportion of LSK and HSC within the Lin - was lower in BSP-/- and more differentiated stages were more abundant, as also observed in unablated bone, suggesting that hematopoietic differentiation is favored in the absence of BSP. Interestingly, unablated BSP-/- femur marrow also contains more blood vessels than BSP+/+, and in both intact and ablated shafts expression of VEGF and OPN are higher, and DMP1 lower in the mutants. In conclusion, bone marrow ablation in BSP-/- mice is followed by a faster vascular and hematopoietic recolonization, along with lower medullary bone formation. Thus, lack of BSP affects the interplay between hematopoiesis, angiogenesis, and osteogenesis, maybe in part through higher expression of VEGF and the angiogenic SIBLING, OPN. J. Cell. Physiol. 232: 2528-2537, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Marine life and its rich biodiversity provide a plentiful resource of potential new products for the society. Remarkably, marine organisms still remain a largely unexploited resource for biotechnology applications. Among them, marine sponges are sessile animals from the phylum Porifera dated at least from 580 million years ago. It is known that molecules from marine sponges present a huge therapeutic potential in a wide range of applications mainly due to its antitumor, antiviral, anti-inflammatory, and antibiotic effects. In this context, this article reviews all the information available in the literature about the potential of the use of marine sponges for bone tissue engineering applications. First, one of the properties that make sponges interesting as bone substitutes is their structural characteristics. Most species have an efficient interconnected porous architecture, which allows them to process a significant amount of water and facilitates the flow of fluids, mimicking an ideal bone scaffold. Second, sponges have an organic component, the spongin, which is analogous to vertebral collagen, the most widely used natural polymer for tissue regeneration. Last, osteogenic properties of marine sponges is also highlighted by their mineral content, such as biosilica and other compounds, that are able to support cell growth and to stimulate bone formation and mineralization. This review focuses on recent studies concerning these interesting properties, as well as on some challenges to be overcome in the bone tissue engineering field. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1717-1727, 2017., (© 2016 Wiley Periodicals, Inc.)

Pellet-containing tablets for colon-specific drug delivery present higher targeting efficiency and lower costs when compared with monolithic tablets and pellet-filled capsules, respectively. In this study, pellets containing ketoprofen were coated with different acrylic polymers and submitted to compaction. The influence of formulation and process factors on film integrity was then evaluated. Pellets were prepared via extrusion-spheronization and coated using two acrylic polymers (Eudragit® FS 30 D and Opadry® 94 k28327, PMMA and PMA, respectively). The resulting pellets were mixed with placebo granules and compressed in a hydraulic press. Multiple regression showed that ketoprofen release from pellet-containing tablets is predominantly influenced by pellet content, hardness, friability, and disintegration time. PMA-containing tablets prepared under low compaction force or with low pellet content showed rapid disintegration (<1 min) and ketoprofen release similar to those of uncompressed coated pellets (∼30% at 360 min of experiment). On the other hand, PMMA-containing tablets showed a higher rupture level, and those prepared with higher pellet content gave rise to a non-disintegrating matrix. Coated pellets were shown to be able to target ketoprofen to the colonic region. Targeting capacity was dependent on the physicochemical characteristics of the tablets.

The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to develop mucoadhesive pellets on a thiolated pectin base using the extrusion-spheronization technique. Thiolation of pectin was performed by esterification with thioglycolic acid. The molecular weight and thiol group content of the pectins were determined. Pellets containing pectin, microcrystalline cellulose, and ketoprofen were prepared and their mucoadhesive properties were evaluated through a wash-off test using porcine intestinal mucosa. The in vitro ketoprofen release was also evaluated. Thiolated pectin presented a thiol group content of 0.69 mmol/g. Thiolation caused a 13% increase in polymer molecular weight. Pellets containing thiolated pectin were still adhering to the intestinal mucosa after 480 min and showed a more gradual release of ketoprofen. Conversely, pellets prepared with nonthiolated pectin showed rapid disintegration and detached after only 15 min. It can be concluded that thiolated pectin-based pellets can be considered a potential platform for the development of mucoadhesive drug delivery systems for the oral route., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Brachycephalus is a frog genus endemic to the Brazilian Atlantic Forest and characterized by the bright yellow-orange aposematic colors and the high degree of miniaturization. Herein, we describe a new species of Brachycephalus from Serra do Brigadeiro, Municipality of Ervália, Minas Gerais State, southeastern Brazil. Specimens were collected at high altitudes (i.e., 1266-1498 m above sea level) amidst the leaf litter. The new species is characterized by the presence of black connective tissue covering all dorsal muscles, body completely yellow-orange in life, presence of skull and post-cranial plates, large size (SVL of adults: 14.8-18.5 mm), bufoniform body, absence of metacarpal and metatarsal tubercles, and presence of harmonics in its advertisement call.

The increased prevalence of metronidazole-resistant infections has resulted in a search for alternative drugs for the treatment of trichomoniasis. In the present study, we report the preparation and in vitro activity of three 1,3-dioxolanes that contain tellurium (PTeDOX 01, PTeDOX 02, and PTeDOX 03) against Trichomonas vaginalis. Six concentrations of these compounds were analyzed for in vitro activity against ATCC 30236 isolate of T. vaginalis. PTeDOX 01 reported a cytotoxic effect against 100% of T. vaginalis trophozoites at a final concentration of 90μM with an IC 50 of 60μM. The kinetic growth curve of trophozoites indicated that PTeDOX 01 reduced the growth by 22% at a concentration of 90μM after an exposure of 12h, and induced complete parasite death at 24h. It induced cytotoxicity of 44% at 90μM concentration but and had no effect in lower concentrations in a culture of CHO-K1 cells. These results confirmed that PTeDOX 01 is an important drug for the treatment of T. vaginalis, and should be evaluated in other infectious agents as well., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

We assembled the mitogenome of Cypseloides fumigatus based on off-target sequences from ultraconserved elements sequencing. We found a total length of 16,850 bp, including 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and one control region, organized in the standard avian gene order. We have built a phylogenetic tree including 26 species of swifts that suggested C. fumigatus as sister species of C. cryptus, and indicated exciting opportunities for biogeographic inferences involving most continents, including Neartic vs Neotropical disjunctions and local radiations across the globe. Finally, we found cases of lack of reciprocal monophyly between named species and high intra-specific divergence, suggesting that population-level studies are warranted., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objectives: The aim of this study was to characterize the histomorphometric features of subgemmal neurogenous plaques (SNPs) to better understand their relationship to surrounding microanatomy included in the tissue biopsy samples of the tongue., Study Design: A 12-year retrospective study on the files of 3 oral pathology centers yielded 28 SNPs. Hematoxylin and eosin-stained sections were used for histologic analysis, and immunohistochemical staining for S100 protein was performed to better characterize the neural structures. Slides were scanned and histomorphometric analysis carried out using ImageScope software., Results: Twenty-one women (75%) and 6 men (21.4%) comprised the sample (mean age 46.4 and 49 years, respectively). Twenty cases (71.4%) were juxtaposed to the tongue epithelium and 16 cases (57.1%) were associated with lymphoid tissue. The mean area of the SNPs was 0.160 mm 2 , and the mean distance to the overlying epithelium was 0.312 mm., Conclusions: SNPs are normal neural structures located on the posterior border of the tongue that represent a non-neoplastic regional anatomic variation. In some cases, signs or symptoms may be present, and further investigation should be performed. Pathologists should be aware of this entity to avoid confusion with neural lesions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Various reports have described the transuncus (TU) approach as a selective route to the amygdala and hippocampus, but this approach has not yet been submitted to solid postoperative imaging analysis. The objective of this study was to evaluate the anatomy, surgical technique, postoperative imaging analysis, and outcome in a series of patients with temporal lobe epilepsy who underwent selective amigdalohippocampectomy via a TU approach., Methods: This was a prospective study of 25 consecutive patients who underwent selective amigdalohippocampectomy through a TU approach. The temporal stem and temporal pole were evaluated through different modalities of 3-Tesla magnetic resonance imaging, including tractography of optic radiation (OR), uncinate fascicle, and inferior fronto-occipital fascicle. Visual field analysis was performed with automated perimetry., Results: The mean age was 40 ± 8.21 years, and mean follow-up was 26.44 + 12.58 months. Postoperatively, 21 patients (84%) were classified as Engel I (good seizure control). Diffusion tensor imaging (DTI) data showed that 78.2% of patients had some structural damage to the temporal stem and fibers of the uncinate fascicle were identified postoperatively in only 3 patients (13.04%). The inferior fronto-occipital fascicle was identified in 18 patients (78.3%); however, subsequent DTI analysis of the remaining fibers showed them to be damaged. Integrity of the OR did not differ between these 2 groups., Conclusions: A TU approach is a feasible and efficient approach to selective amigdalohippocampectomy for surgical treatment of temporal lobe epilepsy. Postoperative DTI analysis suggests that a TU approach results in more injury to the temporal stem and its associated white matter fiber tracts than expected by previous anatomic studies; however, it was efficient in preserving OR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To present the outcomes of posterior cruciate ligament (PCL) double-bundle reconstruction using autologous hamstring tendons, with a minimum follow-up of two years., Methods: Evaluation of 16 cases of PCL injury that underwent double-bundle reconstruction with autogenous hamstring tendons, between 2011 and 2013. The final sample consisted of 16 patients, 15 men and one woman, with a mean age of 31 years (21-49). The predominant mechanism was motorcycle accident in half of the cases. There was a mean interval of 15 months between the time of lesion and the surgery (three to 52 months). Five lesions were isolated and 11, associated. Clinical evaluation, application of validated scores, and measurements with use of the KT-1000 were performed., Results: The analysis showed a mean preoperative Lysholm score of 50 points (28-87), progressing to 94 points (85-100) postoperatively. The IKDC score also demonstrated improvement. In the preoperative evaluation, four and 12 patients were respectively classified as C (abnormal) and D (very unusual), and in the postoperative evaluation six as A (normal) and ten as B (close to normal). In the post-operative evaluation by KT1000 arthrometer, 13 patients showed difference between 0-2 mm and 3 between 3 and 5 mm, when compared with the contralateral side., Conclusion: Autologous hamstring tendons are a viable option in double-bundle reconstruction of the PCL, with good clinical results in a minimum follow-up of two years.

Background: During glioma surgery "maximal safe resection" must be the main goal. Intraoperative magnetic resonance imaging (iMRI) associated with awake craniotomy (AC) is a valuable tool to achieve this objective. In this article, AC with a "next-door" iMRI concept is described in a stepwise protocol., Methods: This is a retrospective analysis of 18 patients submitted to AC using iMRI; a stepwise protocol is also discussed., Results: The mean age was 41.7 years. Hemiparesis, aphasia, and seizures were the main initial symptoms of the patients. Sixty-six percent of the tumors were located in the left hemisphere. All tumors were near or within eloquent areas. Fifty-three percent of the cases were glioblastomas multiforme and 47% of the patients had low grade gliomas. The mean surgical time and iMRI time were 4 h 4 min and 30 min, respectively. New resection was performed in 33% after iMRI. Extent of resection (EOR) higher than 95% was possible in 66.7% of the patients. The main reason of EOR lower than 95% was positive mapping of eloquent areas (6 patients). Eighty percent of the patients experienced improvement of their deficits immediately after the surgery or had a stable clinical status whereas 20% had neurological deterioration, however, all of them improved after 30 days., Conclusion: AC associated with "next-door" iMRI is a complex procedure, but if performed using a meticulous technique, it may improve the overall tumor resection and safety of the patients., Competing Interests: There are no conflicts of interest.

Objectives: In 2012, Kamboh and colleagues published a genome-wide association study that identified the DCHS2 gene (rs1466662 T/A) influencing the age at onset of Alzheimer's disease (AD). We aimed to investigate if there is association between the DCHS2 gene and amnestic mild cognitive impairment (aMCI) and AD in a sample of the Brazilian population., Methods: 143 controls, 79 aMCI and 299 AD patients were selected and submitted to the same protocol of tests. Genotyping was performed using the Real Time PCR RESULTS: Amnestic MCI patients showed a higher prevalence of AA than controls and a lower frequency of TT when compared with controls. We also stratified the sample according to the APOE ε4 status. No difference in DCHS2 genotype or allelic frequency occurred in the APOE ε4 allele carrier subgroup. Amnestic MCI patients showed a higher frequency of AA genotype and a lower frequency of TA and TT when compared with controls in APOE ε4 allele non-carrier subgroup. The allelic distribution followed the same pattern. In AD group, we observed a significant difference with a higher A allelic frequency in AD in this subgroup. A multiple logistic regression demonstrated that in APOE ε4 non-carriers, allele rs1466662 was associated to aMCI group. Different variables were associated with aMCI and AD according to APOE ε4 status in our sample. Low level of education was associated with AD, while diabetes mellitus type 2 was associated with aMCI. Copyright © 2016 John Wiley & Sons, Ltd., Conclusions: Our findings suggest a possible role for DCHS2 gene in aMCI and AD., (Copyright © 2016 John Wiley & Sons, Ltd.)

Preconditioning can induce a cascade of cellular events leading to neuroprotection against subsequent brain insults. In this study, we investigated the chronic effects of hypoxic preconditioning on spontaneous recurrent seizures (SRS), neuronal death, and spatial memory performance in rats subjected to pilocarpine (Pilo)-induced status epilepticus (SE). Rats underwent a short hypoxic episode (7% O2+93% N2; 30min on two consecutive days) preceding a 4-h SE (HSE group). Control groups were rats submitted to SE only (SE), rats subjected to hypoxia only (H) or normoxia-saline (C). Animals were monitored for the occurrence of SRS, and spatial memory performance was evaluated in the radial-arm maze. Hippocampal sections were analyzed for cell death and mossy fiber sprouting at 1 or 60days after SE. Compared to SE group, HSE had increased SE latency, reduced number of rats with SRS, reduced mossy fiber sprouting at 60days, and reduced cell death in the hilus and the CA3 region 1 and 60days after SE. Additionally, HSE rats had better spatial memory performance than SE rats. Our findings indicated that short hypoxic preconditioning preceding SE promotes long-lasting protective effects on neuron survival and spatial memory., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to assess the characteristics of the CaP/Col composites, in powder and fiber form, via scanning electron microscopy (SEM), pH and calcium release evaluation after immersion in SBF and to evaluate the performance of these materials on the bone repair process in a tibial bone defect model. For this, four different formulations (CaP powder - CaPp, CaP powder with collagen - CaPp/Col, CaP fibers - CaPf and CaP fibers with collagen - CaPf/Col) were developed. SEM images indicated that both material forms were successfully coated with collagen and that CaPp and CaPf presented HCA precursor crystals on their surface. Although presenting different forms, FTIR analysis indicated that CaPp and CaPf maintained the characteristic peaks for this class of material. Additionally, the calcium assay study demonstrated a higher Ca uptake for CaPp compared to CaPf for up to 5 days. Furthermore, pH measurements revealed that the collagen coating prevented the acidification of the medium, leading to higher pH values for CaPp/Col and CaPf/Col. The histological analysis showed that CaPf/Col demonstrated a higher amount of newly formed bone in the region of the defect and a reduced presence of material. In summary, the results indicated that the fibrous CaP enriched with the organic part (collagen) glassy scaffold presented good degradability and bone-forming properties and also supported Runx2 and RANKL expression. These results show that the present CaP/Col fibrous composite may be used as a bone graft for inducing bone repair.

Introduction Preservation of the temporal branches of the facial nerve during anterolateral craniotomies is important. Damaging it can inflict undesirable cosmetic defects to the patient. The supraorbital trans-eyebrow approach (SOTE) is a versatile keyhole craniotomy but still has a high rate of frontalis muscle (FM) palsy. Objective Anatomical study to implement the interfascial dissection during the SOTE to preserve the nerves to the FM. Methods Slight modification of the standard technique of the SOTE was performed in 6 cadaveric specimens (12 sides). Results Distal rami to the FM were exposed. The standard "u-shape" incision of the FM can cross over the nerves. Alternatively, an "l-shape" incision was performed until the superior temporal line (STL). An interfascial dissection was performed near to the STL and the interfascial fat pad was used as a protective layer for the nerves. Conclusion Various pathologies can be addressed with the SOTE. In the majority of the cases the cosmetic results are good, but FM palsy remains a drawback of this approach. The interfascial dissection may be used in an attempt to prevent frontalis rami palsy.

Objectives: The aim of this study was to investigate in vitro the epidermal targeting potential of clobetasol propionate-loaded nanostructured lipid carriers (CP-NLC) when compared to that of chitosan-coated (CP-NLC-C)., Methods: CP-NLC were prepared by microemulsion method and characterized by dynamic light scattering, transmission electron microscopy, in vitro release and permeation studies. To verify epidermal targeting, permeation studies were performed in two sets of experiments. For the first set, the skin was removed from the diffusion cell and stratum corneum (SC) was separated from the remaining skin (RS). For the second set, the whole epidermis (EP) was separated from the dermis (DER). CP quantification was performed in each skin layer., Key Findings: A novel clobetasol propionate-loaded NLC was produced with 1/5th of the drug dose used in commercial formulations and, even so, presented greater skin permeation. Both chitosan-coated and uncoated NLC enhanced the amount of CP in the epidermis more than 80-fold when compared to the commercial formulation (20.26 ± 2.77; 17.85 ± 0.49 and 0.22 ± 0.02 μg/cm(2) , respectively). Differently from chitosan-coated NLC, the uncoated NLC did not show dermal retention., Conclusions: NLC proved to be a system with potential for targeting drug delivery to the epidermal layer., (© 2016 Royal Pharmaceutical Society.)

The pathologically synchronized neuronal activity in temporal lobe epilepsy (TLE) can be triggered by network events that were once normal. Under normal conditions, hippocampus and medial prefrontal cortex (mPFC) work in synchrony during a variety of cognitive states. Abnormal changes in this circuit may aid to seizure onset and also help to explain the high association of TLE with mood disorders. We used a TLE rat model generated by perforant path (PP) stimulation to understand whether synchrony between dorsal hippocampal and mPFC networks is altered shortly before a seizure episode. We recorded hippocampal and mPFC local field potentials (LFPs) of animals with spontaneous recurrent seizures (SRSs) to verify the connectivity between these regions. We showed that SRSs decrease hippocampal theta oscillations whereas coherence in theta increases over time prior to seizure onset. This increase in synchrony is accompanied by a stronger coupling between hippocampal theta and mPFC gamma oscillation. Finally, using Granger causality we showed that hippocampus/mPFC synchrony increases in the pre-ictal phase and this increase is likely to be caused by hippocampal networks. The dorsal hippocampus is not directly connected to the mPFC; however, the functional coupling in theta between these two structures rises pre-ictally. Our data indicates that the increase in synchrony between dorsal hippocampus and mPFC may be predictive of seizures and may help to elucidate the network mechanisms that lead to seizure generation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We proposed a 3D model to evaluate the role of platybasia and clivus length in the development of Chiari I (CI). Using a computer aided design software, two DICOM files of a normal CT scan and MR were used to simulate different clivus lengths (CL) and also different basal angles (BA). The final posterior fossa volume (PFV) was obtained for each variation and the percentage of the volumetric change was acquired with the same method. The initial normal values of CL and BA were 35.65 mm and 112.66º respectively, with a total PFV of 209 ml. Ranging the CL from 34.65 to 29.65 - 24.65 - 19.65, there was a PFV decrease of 0.47% - 1.12% - 1.69%, respectively. Ranging the BA from 122.66º to 127.66º - 142.66º, the PFV decreased 0.69% - 3.23%, respectively. Our model highlights the importance of the basal angle and clivus length to the development of CI.

Bone Sialoprotein (BSP) is a member of the "Small Integrin-Binding Ligand N-linked Glycoproteins" (SIBLING) extracellular matrix protein family of mineralized tissues. BSP has been less studied than other SIBLING proteins such as Osteopontin (OPN), which is coexpressed with it in several skeletal cell types. Here we review the contribution of genetically engineered mice (BSP gene knockout and overexpression) to the understanding of the role of BSP in the bone organ. The studies made so far highlight the role of BSP in skeletal mineralization, as well as its importance for proper osteoblast and osteoclast differentiation and activity, most prominently in primary/repair bone. The absence of BSP also affects the local environment of the bone tissue, in particular hematopoiesis and vascularization. Interestingly, lack of BSP induces an overexpression of OPN, and the cognate protein could be responsible for some aspects of the BSP gene knockout skeletal phenotype, while replacing BSP for some of its functions. Such interplay between the partly overlapping functions of SIBLING proteins, as well as the network of cross-regulations in which they are involved should now be the focus of further work., (Copyright © 2016 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.)

Based on morphological, bioacoustics, and morphological traits, the genus Scinax has been subdivided into two major clades: S. catharinae and S. ruber. The first clade includes S. catharinae and S. perpusillus groups, whereas the second clade includes S. rostratus and S. uruguayus groups. Chromosome morphology, NOR and C-banding patterns of variation support these clades. This study aims the cytogenetic characterization of five species currently included in the S. perpusillus group: Scinax sp. (gr. perpusillus), S. arduous, S. belloni, S. cosenzai, and S. v-signatus, including standard cytogenetic techniques and repetitive DNA FISH probes. All species had 2n = 24 chromosomes. Nucleolar organizing regions occurred in chromosome pair 6 in all species, but differed in their locations among some species, suggesting a putative synaponomastic character for the clade. In S. belloni, the first chromosome pair was a metacentric, contrasting with the submetacentric first pair reported in all other species of the genus. Scinax sp. (gr. perpusillus) and S. v-signatus had similar karyotypic formulae, suggesting they are related species. Scinax cosenzai had a divergent C-banding pattern. Repetitive DNA probes hybridized more frequently in chromosomal subtelomeric regions in all species indicating recent cladogenesis in these species. Karyotypic evidence indicates unreported high levels of stabilization within S. perpusillus and in S. catharinae clade, resulting in a wealth of characters potentially informative for higher phylogenetic analyses.

Objective: Comparing Health-Related Quality of Life (HRQoL) scores in patients with chronic hepatitis C undergoing double and triple antiviral therapy and analyzing possible factors related to HRQoL., Method: HRQoL was assessed using the Short Form 36 and Chronic Liver Disease Questionnaire, which were applied at baseline and at weeks 4, 12 and 16 of treatment to 32 patients divided into two groups: double therapy with pegylated interferon (IFN-PEG) and ribavirin, and triple therapy with PEG-IFN, ribavirin and telaprevir., Results: The reduction of HRQoL was greater in patients receiving triple therapy compared to those treated with two drugs, the most critical time is at 12 weeks in both groups. After removal of telaprevir, the triple therapy group significantly improved their HRQoL scores. Anxiety and depression before treatment, employment status and race are significantly related to diminished HRQoL., Conclusion: Patients undergoing double and triple therapy have diminished HRQoL indexes, but the addition of telaprevir chooses a more significant decrease.

Enalapril maleate is a widely used drug, which is chemically unstable when mixed with excipients resulting in enalaprilat and diketopiperazine as the main degradation products. The preparation of enalapril sodium salt has been used to improve drug stability in solid dosage forms; however, product rejection is observed when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. In this study, granules were prepared by melting granulation using stearic acid or glyceryl monostearate, with a view to developing more stable enalapril maleate solid dosage forms. The granules were prepared in a laboratory-scale high shear mixer and compressed in a rotary machine. Size distribution, flow properties, in vitro drug release and enalapril maleate chemical stability were evaluated and compared with data obtained from tablets prepared without hydrophobic binders. All formulations showed good physical properties and immediate drug release. The greatest improvement in the enalapril maleate stability was observed in formulations containing stearic acid. This study showed that hot melting granulation could be successfully used to prepare enalapril maleate granules which could substitute the in situ formation of enalapril sodium salt, since they provided better enalapril stability in solid dosage forms.

Introduction: Several studies towards the development of an effective treatment for intestinal mucositis have been reported, since this condition represents a major problem in clinical oncology practice due to cytotoxic effects of chemotherapy. However standardized protocols and universally accepted treatment options are yet to be established., Objectives: Given above, this study evaluated the protective effects of a mucoadhesive formulation containing both Bidens pilosa L. (Asteraceae) (BP) and curcuminoids from Curcuma longa L. (Zingiberaceae) (CL) on intestinal mucositis induced by 5-fluoruoacil (5-FU) in mice., Results: As expected, animals only treated with 5-FU (200 mg/kg) showed a significant reduction of 60.3 and 42.4% in villi and crypts size, respectively, when compared to control. On the other hand, the proposed therapeutic/prophylactic treatment with mucoadhesive formulations managed to reduce histopathologic changes in mice bearing mucositis, especially at 125 mg/kg BP + 15 mg/kg CL dose. The formulation promoted an increase of 275.5% and 148.7% for villi and crypts size, respectively. Moreover, chemotherapy-related weight loss was reduced by 7.4% following the treatment. In addition, an increase of 10 and 30.5% in red and white blood cells was observed when compared to 5-FU group. Furthermore, treatments with the mucoadhesive formulation containing BP/CL up modulated Ki-67 and Bcl-2 expression while reduced pro-apoptotic regulator Bax. The formulation also modulated inflammatory response triggered by 5-FU through reduction of 68% of myeloperoxidase activity and a 4-fold increase in anti-inflammatory IL-10 levels. In parallel, the oxidative stress via lipid peroxidation was reduced as indicated by decrease of 63% of malondialdehyde concentrations. Additionally, the new formulation presented low acute oral systemic toxicity, being classified in the category 5 (2000 mg/kg < LD 50  < 5000 mg/kg) of the Globally Harmonized Classification System., Conclusions: This study showed an interesting potential of the mucoadhesive formulation of BP/CL for the treatment of 5-FU-induced intestinal mucositis. Given the perspectives for the development of a new medicine, clinical studies are in progress to better understand the protective effects of this innovative formulation in treating mucositis.

Introduction: Intestinal mucositis is a frequent limiting factor in anticancer therapy and there is currently no broadly effective treatment targeted to cure this side effect., Objective: This study aimed to evaluate the effects of a mucoadhesive formulation containing curcuminoids (MFC) from Curcuma longa L. on the pathogenesis of 5-fluorouracil (5-FU)-induced intestinal mucositis., Methods: Three intraperitoneal 5-FU injections (200 mg/kg) were used to induce intestinal mucositis in adult Swiss male mice. Treatment was provided orally (MFC 3.75, 7.5 and 15 mg/kg), thirty minutes before 5-FU injections, daily until euthanasia. Duodenal samples were collected to perform morphometric and histopathological analysis, to investigate the expression of Ki-67, p53, Bax and Bcl-2 by immunohistochemistry, to evaluate neutrophil activity myeloperoxidase (MPO)-mediated and oxidative stress by malondialdehyde (MDA) determination. Mice body weight was assessed as well., Results: As expected, 5-FU induced a significant weight loss (∼17%, P  < 0.001), shortening in villi height (∼55.4%) and crypts depth (∼47%), and increased (∼64%) the histological severity score when compared to other groups ( P  < 0.05). These pathological changes were markedly alleviated by the three MFC treatment doses ( P  < 0.05), in special with the dose MFC 15 mg/kg. This dose also stimulated cell proliferation by ∼90% in the epithelial cells lining from villi and crypts ( P  < 0.05), reduced MPO levels and MDA formation by 60% and 44%, respectively ( P  < 0.05)., Conclusions: Our data suggest the therapeutic potential of the formulation for treating intestinal mucositis in mice. Supplementary studies are underway searching for the elucidation of mechanisms involved in the protective effects of MFC in order to make this formulation a clinical tool for mucositis treatment.

Background: Evidences suggest that GAB2 and BDNF genes may be associated with Alzheimer's disease (AD). We aimed to investigate the GAB2 rs2373115 and BDNF rs6265 polymorphisms and the risk of AD in a Brazilian sample., Methods: 269 AD patients and 114 controls were genotyped with Real-time PCR. Multifactor dimensionality reduction (MDR) was employed to explore the effects of gene-gene interactions., Results: GAB2 and BDNF were not associated with AD in our sample. Nevertheless BDNF Val allele (rs6265) presented a synergic association with the APOE ε4 allele. A multiple logistic regression demonstrated that the APOE ε4 allele and years of education were the best predictors for AD. In ε4 non-carriers sex, education and hypertension were independently correlated with AD, while in ε4 carriers we did not observe any association. The findings were further confirmed by bootstrapping method., Conclusions: Our data suggest that the interaction of BDNF and APOE has significant effect on AD. Moreover in absence of ε4, female sex, low level of education and hypertension are independently associated with AD. Interventions aimed to prevent AD should focus on these factors and also taking into account the APOE alleles.

Matrix proteins of the SIBLING family interact with bone cells, extracellular matrix and mineral and are thus in a key position to regulate the microenvironment of the bone tissue, including its hematopoietic component. In this respect, osteopontin (OPN) has been implicated in the hematopoietic stem cell (HSC) niche as negative regulator of the HSC function. We investigated the impact on hematopoietic regulation of the absence of the cognate bone sialoprotein (BSP). BSP knockout (-/-) mice display increased bone marrow cellularity, and an altered commitment of hematopoietic precursors to myeloid lineages, leading in particular to an increased frequency of monocyte/macrophage cells. The B cell pool is increased in -/- bone marrow, and its composition is shifted toward more mature lymphocyte stages. BSP-null mice display a decreased HSC fraction among LSK cells and a higher percentage of more committed progenitors as compared to +/+. The fraction of proliferating LSK progenitors is higher in -/- mice, and after PTH treatment the mutant HSC pool is lower than in +/+. Strikingly, circulating levels of OPN as well as its expression in the bone tissue are much higher in the -/-. Thus, a BSP-null bone microenvironment affects the hematopoietic system both quantitatively and qualitatively, in a manner in part opposite to the OPN knockout, suggesting that the effects might in part reflect the higher OPN expression in the absence of BSP., (© 2014 Wiley Periodicals, Inc.)

Objective: This study aims to estimate the prevalence of thyroid diseases and anti-TPO status. We searched for an association among presence of immune reconstitution and use of stavudine, didanosine and protease inhibitors with thyroid diseases., Materials and Methods: A cross-sectional study was performed to analyze the records of 117 HIV-infected patients who had their CD4+ cell count, viral load, anti-TPO, TSH and free T4 levels collected on the same day. Immune reconstitution was considered in those whose T CD4+ count was below 200 cells/mm3, but these values increased above 200 cells/mm3 after the use of antiretrovirals. The odds ratio obtained by a 2x2 contingency table and a chi-square test were used to measure the association between categorical variables., Results: The prevalence of thyroid disease was 34.18%; of these, 4.34% were positive for anti-TPO. There was an association of risk between stavudine use and subclinical hypothyroidism (OR = 4.19, 95% CI: 1.29 to 13.59, X2 = 6.37, p = 0.01). Immune reconstitution achieved protection associated with thyroid disease that was near statistical significance OR = 0.45, 95% CI: 0.19 to 1.04, X2 = 3.55, p = 0.059., Conclusion: The prevalence of thyroid disease in the sample studied was higher than what had been found in the literature, with a low positive anti-TPO frequency. The historical use of stavudine has an association of risk for the presence of subclinical hypothyroidism, and immune reconstitution has trends towards protection for the presence of thyroid diseases.

Bovine mastitis is a major threat to animal health and the dairy industry. Staphylococcus aureus is a contagious pathogen that is usually associated with persistent intramammary infections, and biofilm formation is a relevant aspect of the outcome of these infections. Several biological activities have been described for snake venoms, which led us to screen secretions of Bothrops jararacussu for antibiofilm activity against S. aureus NRS155. Crude venom was fractionated by size-exclusion chromatography, and the fractions were tested against S. aureus. Biofilm growth, but not bacterial growth, was affected by several fractions. Two fractions (15 and 16) showed the best activities and were also assayed against S. epidermidis NRS101. Fraction 15 was identified by TripleTOF mass spectrometry as a galactose-binding C-type lectin with a molecular weight of 15 kDa. The lectin was purified from the crude venom by D-galactose affinity chromatography, and only one peak was observed. This pure lectin was able to inhibit 75% and 80% of S. aureus and S. epidermidis biofilms, respectively, without affecting bacterial cell viability. The lectin also exhibited a dose-dependent inhibitory effect on both bacterial biofilms. The antibiofilm activity was confirmed using scanning electron microscopy. A pre-formed S. epidermidis biofilm was significantly disrupted by the C-type lectin in a time-dependent manner. Additionally, the lectin demonstrated the ability to inhibit biofilm formation by several mastitis pathogens, including different field strains of S. aureus, S. hyicus, S. chromogenes, Streptococcus agalactiae, and Escherichia coli. These findings reveal a new activity for C-type lectins. Studies are underway to evaluate the biological activity of these lectins in a mouse mastitis model.

Gastrointestinal mucositis induced during cancer treatment is considered a serious dose-limiting side effect of chemotherapy and/or radiotherapy. Frequently, interruption of the cancer treatment due to this pathology leads to a reduction in cure rates, increase of treatment costs and decrease life quality of the patient. Natural products such as Bidens pilosa L. (Asteraceae), represent a potential alternative for the treatment of mucositis given its anti-inflammatory properties. In this study, B. pilosa glycolic extract was formulated (BPF) with poloxamer, a mucoadhesive copolymer, was used for treatment of 5-fluorouracil (5-FU)-induced mucositis in mice. As expected, animals only treated with 5-FU (200 mg/kg) presented marked weight loss, reduction of intestinal villi, crypts and muscular layer, which was associated with severe disruption of crypts, edema, inflammatory infiltrate and vacuolization in the intestinal tissue, as compared to the control group and healthy animals only treated with BPF. On the other hand, the treatment of intestinal mucositis-bearing mice with BPF (75, 100 or 125 mg/kg) managed to mitigate clinical and pathologic changes, noticeably at 100 mg/kg. This dose led to the restoration of intestinal proliferative activity through increasing Ki-67 levels; modulated the expression of Bax, Bcl2 and p53 apoptotic markers protecting intestinal cells from cell death. Moreover, this treatment regulated lipid peroxidation and inflammatory infiltration. No acute toxic effects were observed with this formulation. This work demonstrated that BPF was safe and effective against 5-FU-induced intestinal mucositis in mice. Additional studies are already in progress to further characterize the mechanisms involved in the protective effects of this technological formulation toward the development of a new medicine for the prevention and treatment of intestinal injury in patients undergoing chemotherapy/radiotherapy.

Osteopontin (OPN) and bone sialoprotein (BSP) are coexpressed in osteoblasts and osteoclasts, and display overlapping properties. We used daily injection of parathyroid hormone 1-84 (iPTH) over the calvaria of BSP knockout (-/-) mice to investigate further their functional specificity and redundancy. iPTH stimulated bone formation in both +/+ and -/- mice, increasing to the same degree periosteum, osteoid and total bone thickness. Expression of OPN, osterix, osteocalcin (OCN) and DMP1 was also increased by iPTH in both genotypes. In contrast to +/+, calvaria cell cultures from -/- mice revealed few osteoblast colonies, no mineralization and little expression of OCN, MEPE or DMP1. In contrast, OPN levels were 5× higher in -/- versus +/+ cultures. iPTH increased alkaline phosphatase (ALP) activity in cell cultures of both genotypes, with higher OCN and the induction of mineralization in -/- cultures. siRNA blocking of OPN expression did not alter the anabolic action of the hormone in BSP +/+ calvaria, while it blunted iPTH effects in -/- mice, reduced to a modest increase in periosteum thickness. In -/- (not +/+) cell cultures, siOPN blocked the stimulation by iPTH of ALP activity and OCN expression, as well as the induction of mineralization. Thus, full expression of either OPN or BSP is necessary for the anabolic effect of PTH at least in the ectopic calvaria injection model. This suggests that OPN may compensate for the lack of BSP in the response to this hormonal challenge, and provides evidence of functional overlap between these cognate proteins., (© 2014 Wiley Periodicals, Inc., A Wiley Company.)

Unlabelled: Bacteria are extremely versatile organisms that rapidly adapt to changing environments. When bacterial cells switch from planktonic growth to biofilm, flagellum formation is turned off and the production of fimbriae and extracellular polysaccharides is switched on. BolA is present in most Gram-negative bacteria, and homologues can be found from proteobacteria to eukaryotes. Here, we show that BolA is a new bacterial transcription factor that modulates the switch from a planktonic to a sessile lifestyle. It negatively modulates flagellar biosynthesis and swimming capacity in Escherichia coli. Furthermore, BolA overexpression favors biofilm formation, involving the production of fimbria-like adhesins and curli. Our results also demonstrate that BolA is a protein with high affinity to DNA and is able to regulate many genes on a genome-wide scale. Moreover, we show that the most significant targets of this protein involve a complex network of genes encoding proteins related to biofilm development. Herein, we propose that BolA is a motile/adhesive transcriptional switch, specifically involved in the transition between the planktonic and the attachment stage of biofilm formation., Importance: Escherichia coli cells possess several mechanisms to cope with stresses. BolA has been described as a protein important for survival in late stages of bacterial growth and under harsh environmental conditions. BolA-like proteins are widely conserved from prokaryotes to eukaryotes. Although their exact function is not fully established at the molecular level, they seem to be involved in cell proliferation or cell cycle regulation. Here, we unraveled the role of BolA in biofilm development and bacterial motility. Our work suggests that BolA actively contributes to the decision of bacteria to arrest flagellar production and initiate the attachment to form structured communities, such as biofilms. The molecular studies of different lifestyles coupled with the comprehension of the BolA functions may be an important step for future perspectives, with health care and biotechnology applications., (Copyright © 2015 Dressaire et al.)

Pyoderma gangrenosum received this name due to the notion that this disease was related to infections caused by bacteria in the genus Streptococcus. In contrast to this initial assumption, today the disease is thought to have an autoimmune origin. Necrotizing fasciitis was first mentioned around the fifth century AD, being referred to as a complication of erysipelas. It is a disease characterized by severe, rapidly progressing soft tissue infection, which causes necrosis of the subcutaneous tissue and the fascia. On the third day of hospitalization after antecubital venipuncture, a 59-year-old woman presented an erythematous and painful pustular lesion that quickly evolved into extensive ulceration circumvented by an erythematous halo and accompanied by toxemia. One of the proposed etiologies was necrotizing fasciitis. The microbiological results were all negative, while the histopathological analysis showed epidermal necrosis and inflammatory infiltrate composed predominantly of dermal neutrophils. Pyoderma gangrenosum was considered as a diagnosis. After 30 days, the patient was discharged with oral prednisone (60 mg/day), and the patient had complete healing of the initial injury in less than two months. This case was an unexpected event in the course of the hospitalization which was diagnosed as pyoderma gangrenosum associated with myelodysplastic syndrome.

The morphogene bolA plays a significant role in the adaptation of Escherichia coli to general stresses. In general, bacteria can thrive and persist under harsh conditions, counteracting external stresses by using varied mechanisms, including biofilm formation, changes in cell shape, size and protein content, together with alterations in the cell wall structure, thickness and permeability. In E. coli, an increased expression of bolA occurs mainly under stress challenges and when bacterial morphology changes from rod-like to spherical. Moreover, BolA is able to induce biofilm formation and changes in the outer membrane, making it less permeable to harmful agents. Although there has been substantial progress in the description of BolA activity, its role on global cell physiology is still incomplete. Proteins with strong homology to BolA have been found in most living organisms, in many cases also exerting a regulatory role. In this review we summarize current knowledge on the role of BolA, mainly in E. coli, and discuss its implication in global regulation in relation to stress.

Objective: The aim of this study was to investigate a possible relationship between obesity and decreased mobility of the talocrural joint and in turn chronic venous disease., Subjects and Methods: One hundred obese patients recruited at Hospital Santa Casa de Maringa, Parana were enrolled by order of arrival at the hospital in a randomized quantitative cross-sectional study. Inclusion criteria were patients with a body mass index above 30 kg/m(2) and the exclusion criteria were infectious conditions that would interfere with the assessment. Patients were graded according to the clinical, etiological, anatomical and pathophysiological classification. Talocrural goniometry was performed to assess the degree of mobility of the legs. The Kolmogorov-Smirnov normality test, Kruskal-Wallis test, Dunn's Multiple comparison test and analysis of variance were used for statistical analysis tests with an alpha error of 5% being considered acceptable., Results: The increase in body mass index is correlated to the reduction in joint mobility (Kruskal-Wallis test: p-value <0.0001) and increase in clinical, etiological, anatomical and pathophysiological classification is correlated to a decrease in joint mobility and the increase in age is associated with an increase in clinical, etiological, anatomical and pathophysiological classification (Kruskal-Wallis test: p-value <0.0001)., Conclusion: Obesity is associated with deterioration in joint mobility and worsening of chronic venous disease., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

The aim of this study was to develop lipid nanoparticles to deliver genistein (GEN) to deeper skin layers. To do so, the impact of lipid dynamic behavior (nanoparticle flexibility) on stability, release and skin permeation studies was verified. GEN-loaded solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were obtained and characterization was undertaken. Freshly prepared nanoparticles were produced with similar features (i.e., drug loading). However, a higher level of crystallization in GEN-SLN formulation was observed in differential scanning calorimetry experiments. Electron paramagnetic resonance measurements showed a lower mobility of the spin labels in the SLN, which would indicate that NLC could be more flexible than SLN. Despite the fact that NLC demonstrated more fluidity, GEN was released more slowly from NLC than from SLN. Skin permeation studies demonstrated that lipid nanoparticles increased GEN skin retention. More flexible particles (NLC) also favored drug penetration into deeper skin layers. GEN-NLC would seem to be a promising formulation for GEN topical delivery., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A 32-year-old female, was diagnosed in 2004 with a C1 HIV1 infection, using zidovudine/lamivudine 300/150 mg BID and lopinavir/ritonavir 400/100 mg BID, in addition to prophylaxis with trimethoprim-sulfamethoxazole 800/160 mg QD, but no prophylaxis with macrolide antibiotics. The patient presented with a severe headache and was prescribed two capsules of the anti-migraine drug Ormigrein™, which contained ergotamine tartrate 1 mg, caffeine 100 mg, paracetamol 220 mg, hyoscyamine sulfate 87.5 mcg, and atropine sulfate 12.5 mcg. Afterwards she was prescribed one capsule of Ormigrein every 30 minutes for a total of six capsules a day. The patient took the medication as prescribed but developed a pain in her left ankle three days later, which evolved to the need for amputation.

Facial cosmetic procedures are increasingly requested, and dermal filler materials have been widely used as a nonsurgical option since the 1980s. However, injectable fillers have been implicated in local adverse reactions. Therefore, the aim of this article was to describe the use of fine needle aspiration cytology (FNAC) in the diagnosis of foreign-body reactions to the perioral injection of dermal fillers. A 69-year-old woman presented with a painful nodule on her right nasolabial fold. Intraoral FNAC was performed, and cytologic smears were examined under optical and polarized light microscopy, showing birefringent microspheres, confirming the diagnosis of an adverse reaction caused by polymethyl methacrylate filler. FNAC is a less invasive method to confirm the diagnosis of adverse reactions caused by perioral cosmetic dermal fillers., (Copyright © 2014. Published by Mosby, Inc.)

Objective: The aim of this study was to analyze the effects of aging on the degree of thoracic kyphosis and peak torque of the trunk flexor and extensor muscles among women without a densitometric diagnosis of osteoporosis., Methods: Thirty women were selected to make up three groups: young women (n = 10; 24.60 ± 2.27 years of age); adults (n = 10; 43.50 ± 2.88); and elderly women (n = 10; 62.40 ± 2.67). Bone mineral density (BMD), degree of thoracic kyphosis and peak torque of the trunk flexors and extensors were evaluated. Differences between the groups were evaluated using the Kruskal-Wallis ANOVA and Mann-Whitney U tests. Pearson's correlation coefficient was used to assess correlations between the variables. The significance level was taken to be 5% (p ≤ 0.05)., Results: The elderly group presented a greater degree of thoracic kyphosis (p = 0.009) and lower peak torque of the trunk flexors and extensors than the young group. The adult group presented lower peak torque of the trunk than the young group. A negative correlation was observed between age and peak torque of the trunk flexors and extensors (p ≤ 0.001), and a positive correlation between age and the degree of thoracic kyphosis (r = 0.58; p ≤ 0.001). The elderly group presented higher values for the eccentric/concentric ratio of the peak torque for flexors (p = 0.03) and extensors (p = 0.02)., Conclusion: This study suggests that physiological aging may be associated with a greater degree of thoracic kyphosis and lower muscle strength of the trunk flexors and extensors. Moreover, the elderly women showed a relative capacity for preservation of eccentric strength.