Small molecule-mediated tribbles homolog 3 promotes bone formation induced by bone morphogenetic protein-2.

Although bone morphogenetic protein-2 (BMP2) has demonstrated extraordinary potential in bone formation, its clinical applications require supraphysiological milligram-level doses that increase postoperative inflammation and inappropriate adipogenesis, resulting in well-documented life-threatening cervical swelling and cyst-like bone formation. Recent promising alternative biomolecular strategies are toward promoting pro-osteogenic activity of BMP2 while simultaneously suppressing its adverse effects. Here, we demonstrated that small molecular phenamil synergized osteogenesis and bone formation with BMP2 in a rat critical size mandibular defect model. Moreover, we successfully elicited the BMP2 adverse outcomes (i.e. adipogenesis and inflammation) in the mandibular defect by applying high dose BMP2. Phenamil treatment significantly improves the quality of newly formed bone by inhibiting BMP2 induced fatty cyst-like structure and inflammatory soft-tissue swelling. The observed positive phenamil effects were associated with upregulation of tribbles homolog 3 (Trib3) that suppressed adipogenic differentiation and inflammatory responses by negatively regulating PPARγ and NF-κB transcriptional activities. Thus, use of BMP2 along with phenamil stimulation or Trib3 augmentation may be a promising strategy to improve clinical efficacy and safety of current BMP therapeutics

Topical Hpmc/s-nitrosoglutathione Solution Decreases Inflammation And Bone Resorption In Experimental Periodontal Disease In Rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor, which exerts antioxidant, anti-inflammatory, and microbicidal actions. Intragingival application of GSNO was already shown to decrease alveolar bone loss, inflammation and oxidative stress in an experimental periodontal disease (EPD) model. In the present study, we evaluated the potential therapeutic effect of topical applications of hydroxypropylmethylcellulose (HPMC)/GSNO solutions on EPD in Wistar rats. EPD was induced by placing a sterilized nylon (3.0) thread ligature around the cervix of the second left upper molar of the animals, which received topical applications of a HPMC solutions containing GSNO 2 or 10 mM or vehicle (HPMC solution), 1 h prior to the placement of the ligature and then twice daily until sacrifice on day 11. Treatment with HPMC/ GSNO 10 mM solution significantly reduced alveolar bone loss, oxidative stress and TNF-alpha e IL-1 beta levels in the surrounding gingival tissue, and led to a decreased transcription of RANK and TNF-alpha genes and elevated bone alkaline phosphatase, compared to the HPMC group. In conclusion, topical application of HPMC/GSNO solution is a potential treatment to reduce inflammation and bone loss in periodontal disease.11National Council for Scientific and Technological Development - CNPq [478380/2011-9, 309390/2011-7]Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Potentiation of sensory responses in ventrobasal thalamus in vivo via selective modulation of mGlu1 receptors with a positive allosteric modulator.

Metabotropic glutamate subtype 1 (mGlu1) receptor is thought to play a role in synaptic responses in thalamic relay nuclei. The aim of this study was to evaluate the positive allosteric modulator (PAM) Ro67-4853 as a tool to modulate thalamic mGlu1 receptors on single thalamic neurones in vivo. Ro67-4853, applied by iontophoresis onto ventrobasal thalamus neurones of urethane-anaesthetised rats, selectively enhanced responses to the agonist (S)-3,5-dihydroxy-phenylglycine (DHPG), an effect consistent with mGlu1 potentiation. The PAM was also able to enhance maintained responses to 10 Hz trains of sensory stimulation of the vibrissae, but had little effect on responses to single sensory stimuli. Thus Ro67-4853 appears to be a highly selective tool that can be useful in investigating how mGlu1 receptor potentiation can alter neural processing in vivo. Our results show the importance of mGlu1 in sensory processing and attention mechanisms at the thalamic level and suggest that positive modulation of mGlu1 receptors might be a useful mechanism for enhancing cognitive and attentional processes

Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation

The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol-based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV-1BaL and HIV-1 JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV-1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms. © 2014 Dezzutti et al

Bacteriological and cytological findings during the late puerperal period after two different treatments of retained placenta followed by acute puerperal metritis

The aim of the study was to compare the effect of two acute puerperal metritis (APM) treatment protocols on uterine condition during the late puerperal period (5th to 7th week). Late gestation healthy cows (n = 21) were divided randomly in three equal groups. Parturitions were induced. Treatments of APM were started on the third day postpartum (PP). Group A was treated with an oxytocin analogue carbetocin for three days and intrauterine administration of cephapirin between days 15 and 17. Group B was given intramuscular injection of ceftiofur for five days followed by two injections of prostaglandin F2α, at an interval of 12 h, on the eighth day PP. Group C served as the control group with no treatment. Body temperature was recorded daily for 14 days PP. Uterine biopsies for bacteriology, and uterobrush samples for cytology, were taken once a week from the 5th to 7th week postpartum. No differences were found in body temperature on day 14 PP, presence of bacteriological infections and disappearance of uterine inflammatory signs diagnosed by cytological examination between experimental groups

On the gauge boson's properties in a candidate technicolor theory

The technicolor scenario replaces the Higgs sector of the standard model with a strongly interacting sector. One candidate for a realization of such a sector is two-technicolor Yang-Mills theory coupled to two degenerate flavors of adjoint, massless techniquarks. Using lattice gauge theory the properties of the technigluons in this scenario are investigated as a function of the techniquark mass towards the massless limit. For that purpose the minimal Landau gauge two-point and three-point correlation functions are determined, including a detailed systematic error analysis. The results are, within the relatively large systematic uncertainties, compatible with a behavior very similar to QCD at finite techniquark mass. However, the limit of massless techniquarks exhibits features which could be compatible with a (quasi-)conformal behavior.Comment: 27 pages, 17 figures, 1 table; v2: persistent notational error corrected, some minor modification

Renormalization of the Yang-Mills theory in the ambiguity-free gauge

The renormalization procedure for the Yang-Mills theory in the gauge free of the Gribov ambiguity is constructed. It is shown that all the ultraviolet infinities may be removed by renormalization of the parameters entering the classical Lagrangian and the local redefinition of the fields.Comment: 20 pages. Some explanations extended, one reference added. Final version published in the journa

A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED

RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes. METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement. RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity

Exercise interventions significantly reduce fasting insulin, but not fasting glucose, in women with polycystic ovary syndrome when compared with no intervention: A systematic review and meta-analysis

Aims: Polycystic ovary syndrome (PCOS) is a common condition that affects approximately 20% of reproductive‐aged women. PCOS is also associated with insulin resistance; women with PCOS are more insulin resistant than body mass index–matched controls. Methods: A systematic review was completed; randomised controlled trials that compared physical activity with control groups were evaluated in a meta‐analysis. Outcomes related to glucose homeostasis were analysed. Change from baseline to end of intervention values were reported as mean difference (MD) and 95% confidence intervals (CI). Results: There was evidence of a favourable effect of exercise on fasting insulin levels (MD −2.62 μIU/ml, CI −4.46 to −0.77; I2 = 92%; 236 participants, eight trials), but not for fasting blood glucose. Reductions in fasting insulin were found for all exercise modalities (aerobic, resistance or combined exercise), but were strongest in resistance training groups (MD −3.99 μIU/ml, CI −5.97 to −2.00; I2 = 54%; 50 participants, three trials). Change from baseline HOMA index also favoured exercise (MD −0.59, CI −1.02 to −0.17; I2 = 89%; 146 participants, seven trials) but evidence of effect was only present in aerobic exercise groups (MD −0.77, CI −1.28 to −0.26; I2 = 65%; 75 participants, four trials). Summary: Exercise, regardless of modality, reduces fasting insulin, but not fasting blood glucose, in women with PCOS compared with those receiving no intervention. However, a cautious approach should be adopted in interpreting these findings due to the wide CIs and evidence of considerable heterogeneity. Despite the statistically significant results, it is unclear if these improvements are clinically relevant

A simulation study of the reaction of human heart to biphasic electrical shocks

BACKGROUND: This article presents a study, which examines the effects of biphasic electrical shocks on human ventricular tissue. The effects of this type of shock are not yet fully understood. Animal experiments showed the superiority of biphasic shocks over monophasic ones in defibrillation. A mathematical computer simulation can increase the knowledge of human heart behavior. METHODS: The research presented in this article was done with different models representing a three-dimensional wedge of ventricular myocardium. The electrophysiology was described with Priebe-Beuckelmann model. The realistic fiber twist, which is specific to human myocardium was included. Planar electrodes were placed at the ends of the longest side of the virtual cardiac wedge, in a bath medium. They were sources of electrical shocks, which varied in magnitude from 0.1 to 5 V. In a second arrangement ring electrodes were placed directly on myocardium for getting a better view on secondary electrical sources. The electrical reaction of the tissue was generated with a bidomain model. RESULTS: The reaction of the tissue to the electrical shock was specific to the initial imposed characteristics. Depolarization appeared in the first 5 ms in different locations. A further study of the cardiac tissue behavior revealed, which features influence the response of the considered muscle. It was shown that the time needed by the tissue to be totally depolarized is much shorter when a biphasic shock is applied. Each simulation ended only after complete repolarization was achieved. This created the possibility of gathering information from all states corresponding to one cycle of the cardiac rhythm. CONCLUSIONS: The differences between the reaction of the homogeneous tissue and a tissue, which contains cleavage planes, reveals important aspects of superiority of biphasic pulses. ..