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Depth of focus (DOF) is defined as the axial range in which the specimen stage moves without losing focus while the imaging apparatus remains stable. It may not be possible to capture an image that includes the entire specimen in focus due to the narrow DOF in microscopic systems. Extended depth of focus (EDOF) is used to overcome this limitation in microscopic systems. Although the researchers have developed so many EDOF microscope approaches, this research field still has some crucial shortcomings such as high computational costs, complexity and execution time, requiring additional equipment, low precise characterization of curves, and edges in images, varying performance depending on the specimen and microscope, using only gray levels of input images to acquire the pixel's focus values. In order to minimize these shortcomings and comprehensively analyze the performance of EDOF approaches, a novel multi-focus image data set is generated, and a deep learning-based EDOF microscope approach is proposed in this study. When compared with the state-of-art EDOF approaches, our study provides various crucial contributions such as the first EDOF approach based on unsupervised deep learning, providing more accurate and specimen-free EDOF, generating a novel multi-focus image data, not requiring any pre- or post-processing technique and acquiring the pixel's focus degrees using deep features. In order to evaluate the effectiveness of the suggested approach, 20 different EDOF approaches are applied to a multi-focus image data set containing 9 image collections (4 synthetic and 5 microscope image collections) in total. Performance analysis metrics with and without requiring a reference image are preferred to identify which EDOF microscope approach can extract more essential details from the multi-focus images for the synthetic and microscope image collections, which are Root Mean Square Error (RMSE), Peak Signal Noise Ratio (PSNR), Universal Quality Index (UQI), Correlation Coefficient (CC), Perception-based Image Quality Evaluator (PIQE), Blind/Referenceless Image Spatial Quality Evaluator (BRISQUE), Extension of Universal Quality Index for N Images (UQIN), and Naturalness Image Quality Evaluator (NIQE). Objective and subjective analysis of this study demonstrates that unsupervised deep learning model is more efficient to transmit crucial details from multi-focus images. Moreover, the suggested EDOF microscope approach with highest PSNR, UQI, CC, UQIN and lowest RMSE, PIQE, BRISQUE, NIQE produces higher performance than the state-of-art approaches. [ABSTRACT FROM AUTHOR]

The wingless/integrase‐1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic‐acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA‐Al(OH)3 administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK‐974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5‐HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5‐HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5‐HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK‐3β and WNT5A levels, which had been induced by airway inflammation, in a dose‐dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad‐2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin‐17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK‐3β phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model. [ABSTRACT FROM AUTHOR]

• Use of Asparagopsis taxiformis oil macerate (Bromoil) to supply bromoform to lambs. • Ruminal methane production is reduced by up to 75% by Bromoil. • No bromoform residues were found in lambs' meat. • Growth performance was reduced with Bromoil. • Bromoil feeding led to an inflammation of the lamb's rumen wall. The red seaweed Asparagopsis taxiformis has a potent antimethanogenic effect, which has been proven both in vitro and in vivo. Vegetable oil immersions of this seaweed (hereafter Bromoil) help stabilise the bromoform (CHBr 3) responsible for its antimethanogenic effect. We evaluate the effects of increasing the levels of CHBr 3 in lamb diets on growth performance, methane (CH 4) production, animal health and meat quality. Twenty-four Merino Branco ram lambs were fed a ground complete compound feed, supplemented with 50 mL/kg DM of sunflower oil with different CHBr 3 content. The treatments were defined by the CHBr 3 doses in the oil: 0 mg (control – B0), 15 mg (B15), 30 mg (B30) and 45 mg (B45) of CHBr 3 per kg of feed DM. The feed was prepared daily by mixing Bromoil with the compound feed. At the end of the experiment, the lambs were sacrificed, the ruminal content was collected for in vitro fermentation to evaluate CH 4 production and organic matter (OM) degradability, and the rumen mucosa was sampled for histological examination. Meat samples were collected for chemical composition and CHBr 3 analysis. The half-life of CHBr 3 in the air-exposed feed was 3.98 h making it very difficult to establish the practiced level of CHBr 3 supplementation. Lambs−fed treatments B30 and B45 decreased DM intake by up to 28%. Average daily gain was also reduced due to CHBr 3 supplementation, with B45 showing results 40% lower than B0. DM feed conversion ratio was similar for all treatments. The degradability of OM, the volume of total gas and of gas without CH 4 were unaffected by the experimental treatments, evaluated by the in vitro method. However, the volume of CH 4 decreased by up to 75% for treatments above 30 mg/kg DM, while the yield of CH 4 /g OM degraded was reduced by up to 78% with treatments above 30 mg/kg DM. Meat chemical composition was not affected by Bromoil supplementation and no traces of CHBr 3 were found in meat samples. During this experiment, the animals presented normal health and behaviour. However, postslaughter examination of the rumen showed distinct lesions on the ventral region of the rumen mucosa of animals supplemented with Bromoil. These lesions were more severe in the animals receiving treatments B30 and B45. This research determined that although concentrations of CHBr 3 in the diet above 30 mg/kg DM helped to reduce CH 4 emissions, it negatively affected the performance and rumen wall. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to identify the effect of trimetazidine (TMZ), an antianginal drug, on detrusor smooth muscle (DSM) contractility and its possible mechanisms of action. Methods: We performed in-vitro contractility studies on isolated mouse DSM strips and investigated the effect of TMZ on Ca2+ levels in fura-2-loaded A7r5 cells. Key findings: TMZ (300 or 1000 µM) inhibited carbachol (CCh)- and KCl-induced contractions and produced a concentration-dependent (10–1000 µM) relaxation in KCl-precontracted DSM strips. TMZ-induced relaxation was markedly decreased by BaCl2, an inward-rectifying K+ channel blocker, but was not altered by preincubation with tetraethylammonium, glibenclamide, 4-aminopyridine, propranolol, L-NAME or methylene blue. TMZ (300 or 1000 µM) reduced both the CaCl2-induced contraction of depolarized DSM strips under Ca2+-free conditions and the CCh-induced contraction of DSM strips preincubated with nifedipine in Ca2+-containing Krebs solution. Furthermore, TMZ (1000 µM) significantly decreased the Ca2+ levels in fura-2-loaded A7r5 cells. Conclusions: TMZ decreased DSM contractility and caused a concentration-dependent relaxation of the tissue possibly through its actions on Ca2+ transients and K+ channels. Our results provide preclinical evidence that TMZ would be a potential candidate to treat disorders related to the overactivity of the bladder. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used in a wide variety of diseases due to their analgesic and anti‐inflammatory effects, but their usage have been limited due to significant ulcerogenic side effects. In the present study, we aimed to evaluate the effect of α‐lipoic acid (ALA) treatment on the anti‐inflammatory activity of indomethacin (Indo) as well as the possible therapeutic effect of ALA on high dose Indo‐induced gastropathy in female mice. Mice were treated with Indo (5 or 30 mg/kg, p.o) alone or in combination with ALA (50, 100 or 200 mg/kg, i.p). in vivo anti‐inflammatory effect was evaluated by formalin‐induced paw edema measured as paw thickness and edema. Gastric damage was evaluated macroscopically and histologically by scoring mucosal hemorrhage, erosion, edema and inflammation. To our results, Indo was ineffective at 5 mg/kg, but co‐treatment with Indo and ALA significantly reduced paw edema, implying that ALA augmented the anti‐inflammatory effect of subtherapeutic dose of Indo. However, ALA was not able to induce a further increase in the anti‐inflammatory effect of Indo at 30 mg/kg. Unlike the treatment with Indo at 5 mg/kg, Indo at 30 mg/kg caused severe gastric damage that prevented by co‐treatment with ALA. These results suggest that combination of ALA with NSAIDs can both increase anti‐inflammatory effect and prevent NSAIDs‐induced gastric damage. ALA would be promising adjuvant that can reduce dose for effective NSAID therapy, which improves safety profile of NSAIDs especially in cases long‐term administration of high dose needed. [ABSTRACT FROM AUTHOR]

Diabetes‐induced endothelial dysfunction is critical for the development of diabetic cardiovascular complications. The aim of this study was to investigate the effect of niclosamide (Nic) on vascular endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. Male Sprague–Dawley rats were injected with a single intraperitoneal injection of STZ (75 mg/kg) to induce type 1 diabetes, and Nic (10 mg/kg) was intraperitoneally administered per day for 4 weeks. Endothelial function was evaluated as carbachol (CCh, an endothelium-dependent vasodilator)-evoked relaxation in the experiments performed on isolated thoracic aortas. The changes in the protein expressions of phosphorylated eNOS at serine 1177 (p-eNOSSer1177) and phosphorylated VASP at serine 239 (p-VASPSer239) of the rat aortas were analyzed by western blotting to determine whether NO/cGMP signaling is involved in the mechanism of Nic. STZ-injected rats had higher fasting blood glucose and less body weight compared to control rats (p < 0.05). Nic treatment did not affect blood glucose levels or body weights of the rats. CCh-induced endothelium-dependent relaxation of the aortic rings was significantly decreased in diabetic rats compared to control (Emax = 66.79 ± 7.41% and 90.28 ± 5.55%, respectively; p < 0.05). CCh-induced relaxation response was greater in Nic-treated diabetic rats compared to diabetic rats (Emax = 91.56 ± 1.20% and 66.79 ± 7.41%, respectively; p < 0.05). Phosphorylation of eNOS and VASP in aortic tissues was significantly reduced in diabetic rats, which were markedly increased by Nic treatment (p < 0.05). We demonstrated that Nic improved endothelial dysfunction possibly through the activation of NO/cGMP signaling without affecting hyperglycemia in diabetic rats. Our results suggesting that Nic has potential of repurposing for diabetic cardiovascular complications. [ABSTRACT FROM AUTHOR]

Purpose: To assess visual acuity in 5-year-old children with LEA chart and to estimate the frequency of reduced visual acuity in this age. Method: Study aimed at children attending the last year of preschool education in Public Kindergartens and Private Social Solidarity Institutions (IPSS) under the influence Regional Health Administration of the Médio Tejo, in Portugal. The 15-line LEA charts at 3 m were used and the presentation visual acuity was measured monocularly starting with the right eye. The ETDRS-fast methodology was used. Results: A total of 3072 children participated, being 51% male and 54% from rural area. A rate of 13.7% children with a reduced level of visual acuity was found, that is, visual acuity worse or equal to 0.2 logMAR in at least one eye, or an interocular difference greater than two lines. Conclusion: This research shows that reduced VA frequency rate in children between 5 and 6 years old is high. The literature presents amblyopia (refractive and/or strabismic) and uncorrected refractive errors without amblyopia as the main cause of reduced VA in childhood, and these anomalies negatively affect child development, especially at the educational level. Reduced VA interferes with performance on a number of key tasks in the learning process. Thus, it is important to preserve the running program to identify these deficits and lead to their correction before the beginning of the school stage. [ABSTRACT FROM AUTHOR]

Novel aryl/alkyl azole derivative compounds C1 and C2 were screened for in vivo anti-nociceptive and anti-inflammatory activities by using the hot plate test and formalin-induced hind paw edema test, respectively. The ability of these compounds to inhibit cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenase (5/15-LOX) were evaluated in vitro by using a colorimetric method. C1 (30 and 50 mg/kg, i.p.) and C2 (3 and 30 mg/kg, i.p.) increased the latency to withdrawal in the hot plate test, indicating an anti-nociceptive activity. C1(30 and 50 mg/kg) and C2 (3,30 and 50 mg) were able to decrease formalin-induced edema, indicating their anti-inflammatory properties. C1and C2 exhibited inhibitory effects on the activity of COX(1-2) and 15-LOX. However, neither C1 nor C2 showed an inhibitory effect on 5-LOX. This study demonstrates that C1 and C2 have anti-nociceptive and anti-inflammatory activities, that are partially mediated by inhibition of COX and LOX enzymes. Our results suggest that C1and C2, novel aryl/alkyl azole compounds, could serve as lead compounds to develop novel therapeutic options for the treatment of pain and inflammation. [ABSTRACT FROM AUTHOR]

We evaluated the therapeutic potential of a sustained nitric oxide (NO)-releasing compound to correct the molecular hallmarks and pathophysiology of priapism, an important but poorly characterize erectile disorder. 1,5-Bis-(dihexyl-N-nitrosoamino)-2,4-dinitrobenzene (C6) and an inactive form of the compound [1,5-bis-(dihexylamino)-2,4-dinitrobenzene (C6)] were tested in neuronal cell cultures and penile lysates for NO release (Griess assay) and biological activity (cGMP production). The effect of local depot C6' or C6 was evaluated in mice with a priapic phenotype due to double neuronal and endothelial NO synthase deletion (dNOS-/-) or human sickle hemoglobin transgenic expression (Sickle). Changes in NO signaling molecules and reactive oxygen species (ROS) surrogates were assessed by Western blot. The physiological response after C6' treatment was assessed using an established model of electrically stimulated penile erection. C6' generated NO, increased cGMP, and dose dependently increased NO metabolites. C6' treatment reversed abnormalities in key penile erection signaling molecules, including phosphodiesterase type 5, phosphorylated endothelial nitric oxide synthase, and phosphorylated vasodilator-stimulated phosphoprotein. I Sickle mice, C6' also attenuated the increased ROS markers gp91phox, 4-hydroxynonenal, and 3-nitrotyrosine. Finally, C6' corrected the excessive priapic-/- erection response of dNOS-/- mice. Exogenous sustained NO release from C6' corrects pathological erectile signaling in mouse models of priapism and suggests novel approaches to human therapy. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) generated by neuronal NO synthase (nNOS) initiates penile erection, but has not been thought to participate in the sustained erection required for normal sexual performance. We now show that cAMP-dependent phosphorylation of nNOS mediates erectile physiology, including sustained erection. nNOS is phosphor-ylated by cAMP-dependent protein kinase (PKA) at serine(S)1412. Electrical stimulation of the penile innervation increases S1412 phosphorylation that is blocked by PKA inhibitors but not by PI3-kinase/Akt inhibitors. Stimulation of cAMP formation by forskolin also activates nNOS phosphorylation. Sustained penile erection elicited by either intracavernous forskolin injection, or augmented by forskolin during cavernous nerve electrical stimulation, is prevented by the NOS inhibitor L-NAME or in nNOS-deleted mice. Thus, nNOS mediates both initiation and maintenance of penile erection, implying unique approaches for treating erectile dysfunction [ABSTRACT FROM AUTHOR]

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OBJECTIVE To determine if FK506-binding proteins (FKBPs) are localized to the autonomic nerve supply of the human penis because FK506 (an immunosuppressant drug) has been linked to enhanced nerve regeneration after nerve injury and neurodegenerative diseases by binding to FKBPs, a select group of immunophilins. MATERIALS AND METHODS Human lower genitourinary tract specimens were obtained and embedded in paraffin wax. The tissue was sectioned (10 µm) and processed for immunohistochemistry using antibodies for FKBPs 12, 38, 52, 65, 135 and neuronal nitric oxide synthase (nNOS). To confirm specificity of the antibody, we processed some tissue in the absence of primary antibody, with mouse or rabbit IgG, and with a blocking peptide for FKBP12. RESULTS In the pelvis, immunoreactivity for all the FKBPs and nNOS was localized to the periprostatic ganglia although FKBP12 was the only FKBP localized to nerve bundles in this location. In penile tissue, immunoreactivity for all five FKBPs and nNOS was localized to nerves, although immunoreactivity for FKBP38 was minimal. The FKBPs were also evident in epithelial, endothelial and smooth muscle cells of the prostate and penis. Negative controls did not produce staining. CONCLUSIONS Identification and localization of immunophilins to nerves coursing in prostate and penile tissue suggest a likely molecular basis to apply immunophilin ligand therapy to protect or regenerate cavernosal nerves. Our findings support the hypothesis that immunosuppressant drugs such as FK506, working via specific receptor mechanisms, are potentially useful to sustain erectile function in men after radical prostatectomy. [ABSTRACT FROM AUTHOR]

A key role for nitric oxide (NO) in penile erection is well established, but the relative roles of the neuronal NO synthase (nNOS) versus endothelial forms of NOS are not clear. nNOS- and endothelial NOS-deficient mice maintain erectile function and reproductive capacity, questioning the importance of NO. Alternatively, residual NO produced by shorter transcripts in the nNOS-/- animals might suffice for normal physiologic function. We show that the β splice variant of nNOS elicits normal erection despite a decrease in stimulus-response characteristics and a 5-fold increased sensitivity to the NOS inhibitor, L-NAME. Residual nNOSβ generates only 10% of the normal NO level in vitro but produces citrulline and diaphorase staining reflecting in vivo NOS activity in pelvic ganglion nerves that is comparable to WT animals. Thus, alternatively spliced forms of nNOS are major mediators of penile erection and so may be targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Considerable evidence has demonstrated the importance of PGE synthesis in the pathogenesis of periodontal disease. Although various cyclooxygenase inhibitors have been known to block periodontal PGE synthesis and prevent disease progression in animal models, there are few reports comparing relative efficacies of various inhibitors of arachidonic acid (ARA) metabolism. We have developed a sensitive in vitro assay to measure PGE synthesis in periodontal tissues. The apparent IC values (i.e. the concentration of drug which causes 50% inhibition of maximum PGE synthesis) have been determined for a series of arachidonic acid analogues as well as competitive and non-competitive cyclooxygenase inhibitors. Periodontal tissue homogenates were incubated in the presence ofH-arachidonic acid for 45 min at 37°C. Inhibitors were tested at 10-10 M and at zero concentration to measure conversion ofH-arachidonate toH-PGE. Log or half log dilutions of inhibitors were tested in triplicate for each assay. Radiolabeled PGE was extracted from homogenates, purified by reverse phase chromatography and quantitated by double antibody capture. RIA was performed on each homogenate to determine the amount of endogenous unlabeled PGE present in the sample to correct for antibody capture recovery. The apparent IC values were determined for each drug by averaging two or more replicate assays. Specific total enzymatic activity of periodontal tissue homogenates was typically 5-11 pg PGE/min/mg tissue. The following series of compounds were tested and are listed in order of increasing IC values: α-tocopherol (3.3×10 M), ketoprofen (5.4×10 M), indomethacin (1.0×10 M), flurbiprofen (1.5×10 M), meclofenamate (1.5×10 M), naproxen (2.5×10 M), docosahexaenoic acid (1.0×10 M), eicosapentaenoic acid (1.5×10 M), and ibuprofen (1.5×10 M). These data will enable the rational design of pharmacological formulations to inhibit periodontal tissue PGE synthesis and resultant inflammation, attachment loss and bone resorption. [ABSTRACT FROM AUTHOR]

Focuses on the benefits of the immunosuppresant drugs FK506 in protecting penile innervation from degeneration following nerve-crush injury. Effects of FK506 treatment on intracavernosal pressure response and nerve morphology after cavernous nerve injury; Neurotropic and neuroprotective effect of immunophilin.