Capsazepine antagonizes TRPV1 activation induced by thermal and osmotic stimuli in human odontoblast-like cells.

Objectives: Dental pain, which is the main reason for patients consulting dentists, is classified as a public health concern. The study of cellular and molecular mechanisms contributing to pain is a fundamental element for developing new analgesics. By using a selective antagonist in an in vitro model, this study aimed to establish the role of TRPV-1 in human odontoblast-like cells (OLCs) as a therapeutic target for dental pain mediated by noxious thermal and osmotic stimuli. Methods: OLCs were differentiated from dental pulp mesenchymal cells and TRPV1 expression was evaluated. Activation of TRPV-1 was determined by evaluating changes in calcium concentration after stimulation with mannitol and xylitol hyperosmotic solutions or DMEM heated at 45 °C, using the fluorescent calcium probe Fluo-4 AM. In addition, changes in fluorescence (F/F0) due to calcium flux were evaluated using fluorometry and flow cytometry. Simultaneously, the cells were co-stimulated with the selective antagonist capsazepine (CZP). Results: OLCs expressed DSPP and DMP-1, confirming their cellular phenotype. TRPV1 was expressed, and its activation by different stimuli produced an increase in cytosolic Ca2+ which was reduced by the antagonist. Both methods used to evaluate TRPV1 activation through the measurement of calcium probe fluorescence showed similar patterns. Conclusions: These results suggest that TRPV-1 modulation using an antagonist can be implemented as a pharmacological strategy for managing dental pain mediated by hyperosmotic and thermal stimuli.

Tratamiento con análogos de la hormona liberadora de gonadotrofinas (aGnRH) en niñas, niños y adolescentes / Treatment with gonadotropin-releasing hormone analogs (GnRHa) in childhood and adolescence

Desde hace varias décadas, los análogos de la hormona liberadora de gonadotrofinas (aGnRH) son el tratamiento de elección en la pubertad precoz central (PPC) en niñas y en niños. Causan una inhibición del eje hipotálamo-hipófiso-gonadal, disminuyen la secreción de gonadotrofinas, estradiol y testosterona; como consecuencia, producen una regresión de los caracteres sexuales secundarios durante el tratamiento. En los últimos años, estos análogos también se utilizan en adolescentes transgénero, en adolescentes y adultas jóvenes con enfermedades oncológicas, en algunas situaciones muy particulares en niños y niñas con talla baja, y en pacientes con trastornos del neurodesarrollo. En Argentina, los más utilizados son el acetato de triptorelina y el acetato de leuprolide en sus formas de depósito. Estos medicamentos han demostrado eficacia y seguridad. El objetivo de esta publicación es realizar una revisión y actualización del uso de los aGnRH en niños, niñas y adolescentes.

For several decades, gonadotropin releasing hormone analogs (GnRHa) are the medical treatment selected for central precocious puberty (CPP) in girls and boys. They generate an inhibition of the hypothalamus-pituitarygonadal axis decreasing LH, FSH, estradiol and testosterone secretion and, in this way, they produce a regression of secondary sexual characters under treatment. In the last years, these analogs are also used in trans adolescents, in adolescents and young adults with oncological diseases, in some very particular situations in children with short stature and in patients with neurodevelopmental disorders. In Argentina the most commonly used formulations are triptorelin and leuprolide acetate depot forms. These analogs have proven both their efficacy and their safety. The aim of this paper is to review and update about the use of GnRHa in children and adolescents.

[Treatment with gonadotropin-releasing hormone analogs (GnRHa) in childhood and adolescence]. / Tratamiento con análogos de la hormona liberadora de gonadotrofinas (aGnRH) en niñas, niños y adolescentes.

For several decades, gonadotropin releasing hormone analogs (GnRHa) are the medical treatment selected for central precocious puberty (CPP) in girls and boys. They generate an inhibition of the hypothalamus-pituitary-gonadal axis decreasing LH, FSH, estradiol and testosterone secretion and, in this way, they produce a regression of secondary sexual characters under treatment. In the last years, these analogs are also used in trans adolescents, in adolescents and young adults with oncological diseases, in some very particular situations in children with short stature and in patients with neurodevelopmental disorders. In Argentina the most commonly used formulations are triptorelin and leuprolide acetate depot forms. These analogs have proven both their efficacy and their safety. The aim of this paper is to review and update about the use of GnRHa in children and adolescents.

Desde hace varias décadas, los análogos de la hormona liberadora de gonadotrofinas (aGnRH) son el tratamiento de elección en la pubertad precoz central (PPC) en niñas y en niños. Causan una inhibición del eje hipotálamo-hipófiso-gonadal, disminuyen la secreción de gonadotrofinas, estradiol y testosterona; como consecuencia, producen una regresión de los caracteres sexuales secundarios durante el tratamiento. En los últimos años, estos análogos también se utilizan en adolescentes transgénero, en adolescentes y adultas jóvenes con enfermedades oncológicas, en algunas situaciones muy particulares en niños y niñas con talla baja, y en pacientes con trastornos del neurodesarrollo. En Argentina, los más utilizados son el acetato de triptorelina y el acetato de leuprolide en sus formas de depósito. Estos medicamentos han demostrado eficacia y seguridad. El objetivo de esta publicación es realizar una revisión y actualización del uso de los aGnRH en niños, niñas y adolescentes.

Pseudomonas fluorescens Showing Antifungal Activity against Macrophomina phaseolina, a Severe Pathogenic Fungus of Soybean, Produces Phenazine as the Main Active Metabolite.

Pseudomonas fluorescens 9 and Bacillus subtilis 54, proposed as biofungicides to control Macrophomina phaseolina, a dangerous pathogen of soybean and other crops, were grown in vitro to evaluate their ability to produce metabolites with antifungal activity. The aim of the manuscript was to identify the natural compounds responsible for their antifungal activity. Only the culture filtrates of P. fluorescens 9 showed strong antifungal activity against M. phaseolina. Its organic extract contained phenazine and mesaconic acid (1 and 2), whose antifungal activity was tested against M. phaseolina, as well as Cercospora nicotianae and Colletotrichum truncatum, other pathogens of soybean; however, only compound 1 exhibited activity. The antifungal activity of compound 1 was compared to phenazine-1-carboxylic acid (PCA, 3), 2-hydroxyphenazine (2-OH P, 4), and various semisynthetic phenazine nitro derivatives in order to perform a structure-activity relationship (SAR) study. PCA and phenazine exhibited the same percentage of growth inhibition in M. phaseolina and C. truncatum, whereas PCA (3) showed lower activity against C. nicotianae than phenazine. 2-Hydroxyphenazine (4) showed no antifungal activity against M. phaseolina. The results of the SAR study showed that electron attractor (COOH and NO2) or repulsor (OH) groups significantly affect the antifungal growth, as well as their α- or ß-location on the phenazine ring. Both PCA and phenazine could be proposed as biopesticides to control the soybean pathogens M. phaseolina, C. nicotianae, and C. truncatum, and these results should prompt an investigation of their large-scale production and their suitable formulation for greenhouse and field applications.

Pathophysiology of COVID-19: Everywhere You Look You Will See ACE2!

Angiotensin converting enzyme 2 (ACE2) seems to be a central actor in the pathophysiology of SARS-Cov-2 infection. First, it acts as the receptor for the virus and permits its attachment to cells expressing ACE2. Second, the relative deficiency of ACE2 during infection could be linked to several clinical features encountered during the disease, like ARDS and coagulation abnormalities. This study explores the strong link between ACE2 and the majority of risk factors for the severe evolution of COVID-19. It seems that all these risks factors are linked to an increased level of ACE2 and/or imbalance in ACE/ACE2.

Neoadjuvant Therapy for Neuroendocrine Neoplasms: Recent Progresses and Future Approaches.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors, their treatment being challenging and requiring a multidisciplinary approach. Though the only curative treatment is surgery, up to 50% of patients are diagnosed with metastatic disease. In the last years, neoadjuvant chemo(radio)therapy has become part of the standard of care in the treatment of different cancer types. However, evidence of its efficacy and safety in NEN patients has not yet been confirmed in the literature. The aim of the present review is to perform an extensive review of the scientific evidence for neoadjuvant therapy in patients with gastroenteropancreatic and thoracic NENs.

In patients with controlled acromegaly, indices of glucose homeostasis correlate with IGF-1 levels rather than with type of treatment.

OBJECTIVE: Acromegaly is accompanied by abnormalities in glucose and lipid metabolism which improve upon treatment. Few studies have investigated whether these improvements differ between treatment modalities. This study aimed to compare glucose homeostasis, lipid profiles and postprandial gut hormone response in patients with controlled acromegaly according to actual treatment. DESIGN: Cross-sectional study at a tertiary care centre. PATIENTS: Twenty-one patients with acromegaly under stable control (ie insulin growth factor 1 [IGF1] levels below sex- and age-specific thresholds and a random growth hormone level <1.0 µg/L) after surgery (n = 5), during treatment with long-acting somatostatin analogues (n = 10) or long-acting somatostatin analogues + pegvisomant (n = 6) were included. MEASUREMENTS: Glucose, insulin, total cholesterol and high-density lipoprotein-cholesterol were measured in fasting serum samples. Glucose, insulin, triglycerides, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 were measured during a mixed meal test. Insulin sensitivity was evaluated by a hyperinsulinaemic-euglycaemic clamp. RESULTS: There were no significant differences in glucose tolerance, insulin sensitivity or postprandial gut hormone responses between the three groups. Positive correlations between IGF1 levels and HbA1c, fasting glucose and insulin levels and postprandial area under the curve (AUC) of glucose and insulin and also an inverse association between IGF1 and glucose disposal rate were found in the whole cohort (all p < .05, lowest p = .001 for postprandial AUC glucose with rs  = 0.660). CONCLUSION: In this cross-sectional study in patients with controlled acromegaly, there were no differences in glucose homeostasis or postprandial substrate metabolism according to treatment modality. However, a lower IGF1 level seems associated with a better metabolic profile.

Preparation, Characterization and In Vitro Biological Evaluation of Novel Curcumin Derivatives as Cytotoxic and Apoptosis-Inducing Agents.

BACKGROUND: Curcumin is a natural polyphenol and lead compound of the rhizomes of curcuma longa and it has been widely used for pharmacological activities. OBJECTIVE: In this study, a series of novel derivatives of curcumin, with this group linked to a 2-amino-4- phenylpyran-3-carbonitrile system, have been synthesized and tested for their antitumor activities in vitro against a panel of three human cancer cell lines (MCF-7, A2780, and U-87MG). METHODS: The in vitro cytotoxic activity of the synthesized compounds was tested on three cancer cell lines (MCF-7, A2780, and U-87MG) using MTT colorimetric assay. Meanwhile, the ability of the active compounds to induce apoptosis in cancer cells was investigated by examination of caspase-3 and caspase-9 and mitochondrial membrane potential assay. RESULTS: Under relatively mild conditions in ethanol, the reaction of a series of substrates afforded the corresponding derivatives of curcumin mostly in good yields (13 analogues, 48-94% yields). Bioassay results indicated that compounds L6 (para-Bromo), L9 (para-Nitro) and L12 (meta-Methoxy) were the most active members in this study demonstrating potent activities against A2780 cancer cells and experimental results of fluorescent staining and flow cytometry analysis revealed that L6 and L9 could induce apoptosis in A2780 cells with apoptosis ratios of about 40% and 46%, respectively at 24h of treatment at 15.35µM and 23µM in A2780 cells. On the other hand, they could increase the caspase-3 activity slightly (10%), while having no significant impact on the activities of caspase-9. CONCLUSION: Those two derivatives could be considered as useful templates for future development to obtain more potent antitumor agents.

Novel Cross-Linked Ocular Bandage Gel Improves Reepithelialization After Photorefractive Keratectomy: A Randomized, Masked Prospective Study.

Purpose: To compare, in a masked manner, a novel cross-linked hyaluronic acid ocular bandage gel (OBG) versus standard-of-care bandage contact lens (BCL) plus artificial tears with respect to safety and effectiveness in healing epithelial defects created for photorefractive keratectomy (PRK). Methods: This was a randomized, reading center-masked, exploratory study. Forty-five patients (myopic without significant anisometropia) scheduled for bilateral PRK (9-mm epithelial defect) were randomized post-PRK to treatment with OBG 8 times daily for 3 days, followed by 4 times daily for 11 days (Group 1); OBG 4 times daily for 14 days (Group 2); or BCL and artificial tears (Control). A masked reading center used image analysis of digital slit lamp photos of the fluorescein-stained cornea to evaluate defect size during the 14-day postoperative follow-up period. Effectiveness endpoints were (1) time to complete closure of the corneal defect and (2) proportion of patients with complete healing on day 3 postoperatively, whose defect remained closed. Safety assessments included findings for adverse events and vision, Standard Patient Evaluation of Eye Dryness (SPEED™) Questionnaire, slit lamp, intraocular pressure, and fundus examinations. Results: The proportion of patients with complete healing at 3 days was 73.3%, 86.7%, and 66.7% of patients in Groups 1, 2, and Control, respectively. On day 2, the mean wound size was 6%-26% smaller in Groups 1 and 2 compared with Control. No safety concern arose. SPEED scores were not significantly different across groups. Conclusion: OBG offers a well-tolerated and effective therapy for quickly reepithelializing the cornea following trauma, disease, or surgery.

The Impact of Agent Orange Exposure on Prostate Cancer Outcomes.

PURPOSE: In this study we explored the effect of Agent Orange exposure on prostate cancer survival in VA (Veterans Affairs) patients receiving androgen deprivation therapy for advanced prostate cancer. MATERIALS AND METHODS: We retrospectively examined the association between Agent Orange exposure in men with prostate cancer in national VA databases who were being treated with androgen deprivation therapy. Patients were diagnosed with prostate cancer from 2000 to 2008 with followup through May 2016. Clinical, pathological and demographic variables were compared by Agent Orange exposure. Associations of Agent Orange with overall survival, skeletal related events and cancer specific survival were performed using adjusted Cox proportional hazard models after IPSW (inverse propensity score weighted) adjustment. RESULTS: Overall 87,344 patients were identified. The 3,475 Agent Orange exposed patients were younger (p <0.001), had lower prostate specific antigen (p = 0.002) and were more likely to receive local therapy and chemotherapy (p <0.001) than the 83,869 nonexposed patients. The Charlson comorbidity index was similar in the groups (p = 0.40). After IPSW adjustment Agent Orange exposure was associated with improved overall survival (HR 0.84, 95% CI 0.73-0.97, p = 0.02). However, no difference was observed in the risk of skeletal related events (HR 1.04, 95% CI 0.80-1.35, p = 0.77) or cancer specific survival (HR 0.79, 95% CI 0.60-1.03, p = 0.08). CONCLUSIONS: Agent Orange exposure was associated with a decreased risk of death in men receiving androgen deprivation therapy for advanced prostate cancer. It does not appear to be associated with worse oncologic outcomes.

The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study.

BACKGROUND: Statins are thought to possess antineoplastic properties related to their effect on cell proliferation and steroidogenesis. Progression to castrate resistant prostate cancer (CaP) includes de-regulation of androgen synthesis suggesting a role for statins in this setting. Our goal was to assess the role of statin use on oncologic outcomes in patients with advanced CaP being treated with androgen deprivation therapy (ADT). METHODS: The national VA database was used to identify all men diagnosed with CaP who were treated with ADT for at least 6 months between 2000 and 2008 with follow-up through May 2016. Our cohort was stratified based on statin use of at least 6 months duration during the same time. Multivariable Cox proportional hazards analyses with inverse propensity score weighted (IPSW) adjustment were calculated to assess for primary outcomes of CaP-specific survival (CSS), overall survival (OS) and skeletal related events (SREs). RESULTS: A total of 87,346 patients on ADT were included in the study cohort, 53,360 patients used statins and 33,986 did not. Statin users were younger in age (median 73 vs. 76, P < 0.001), more likely to have a higher Charlson comorbidity index (CCI) >3 (3.1% vs. 2.5%, P < 0.001) and more likely to have a high grade (Gleason score 8-10) cancer (12.3% vs. 10.9%, P < 0.001). Statin users had longer OS (median 6.5 vs. 4.0 years P < 0.001) and decreased death from CaP (5-year CSS 94.0% vs. 87.3%, P < 0.001). Statin use was also associated with longer time to a SRE (median 5.9 vs. 3.7 years, P < 0.001). On multivariable Cox proportional hazards analysis with inverse propensity score weighted, statin use was an independent predictor of improved OS (hazard ratio [HR] 0.66, confidence interval [CI] 0.63-0.68; P < 0.001), CSS (HR 0.56, 95% CI 0.53-0.60; P < 0.001), and SREs (HR 0.64, 95%CI 0.59-0.71; P < 0.001) when controlling for age, race, Charlson comorbidity index, prostate-specific antigen, and Gleason score. CONCLUSION: The use of statins in men on ADT for CaP is associated with improved CSS and OS. Statins are inexpensive, well-tolerated medications that offer a promising adjunct to ADT, but require further prospective studies.

Dose-response assessment of chemically modified curcumin in experimental periodontitis.

BACKGROUND: CMC2.24, a novel tri-ketonic chemically modified compound based on natural di-ketonic curcumin, has been shown to reduce bone loss and inflammatory mediators in experimental periodontitis, however, a potential dose-response relationship was not determined. The purpose of this study was to assess the effects of different doses of CMC2.24 on inflammation and bone resorption in vivo and also to describe on the effects of CMC2.24 on macrophage response. METHODS: CMC2.24 was administered daily to animals for 28 days by oral gavage, at the following doses: 0 (control), 1, 3, 10, and 30 mg/kg of body weight. Experimental periodontitis was induced by injections of lipopolysaccharide (LPS) into the gingival tissues. Outcomes assessed were bone resorption, detection of tartrate-resistant acid phosphatase, and determination of gene expression. In vitro, macrophages (RAW264.7) were treated with different concentrations of CMC2.24: 1, 3, 10, and 30 µM and then subjected to different activation stimuli. Gene expression, phagocytic activity, production of reactive oxygen species (ROS) and cytokine production were evaluated. RESULTS: CMC2.24 inhibited bone resorption, osteoclastogenesis, and tumor necrosis factor (TNF)-α expression in vivo. These beneficial responses reached maximum levels at a dose of 1 mg/kg, i.e. no dose-dependent effect. In vitro, CMC2.24 reduced the production of TNF-α and interleukin-10, inhibited phagocytic activity and stimulated production of ROS. A dose-dependent effect was observed only for ROS production. CONCLUSION: Low doses of CMC2.24 (1 mg/kg/day) administered orally were sufficient to significantly inhibit alveolar bone resorption associated with the experimental periodontal disease; whereas in vitro macrophage inflammatory gene expression and phagocytosis were reduced, whereas production of ROS was stimulated.

The Use of 68Ga-DOTATATE PET/CT in the Non-invasive Diagnosis of Optic Nerve Sheath Meningioma: A Case Report.

We hereby report the case of a patient with optic nerve sheath meningioma (ONSM), whose diagnosis and multidisciplinary management was guided by the use of Gallium-68 (68Ga)-labeled dodecanetetraacetic acid-tyrosine-3-octreotate (DOTATATE) positron emission tomography (PET)/computed tomography (CT) scan. We briefly review the diagnosis and management of ONSM, and review the literature on the role and current status of nuclear imaging with somatostatin receptor ligands in the non-invasive diagnosis and management of meningiomas.

Discovery of traditional Chinese medicine monomers and their synthetic intermediates, analogs or derivatives for battling P-gp-mediated multi-drug resistance.

P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) is a well-documented and predominant phenotype hampering patients' response to cancer chemotherapy. Although the past several decades have witnessed the development of three generations of P-gp inhibitors, they have not lived up to the high expectations owing to their drawbacks, as exemplified by limited efficacy, drug-drug interactions (DDIs) and severe untoward reactions. The discovery of artemisinin is a testimony of the importance of traditional Chinese medicine (TCM) in innovative drug discovery. In search for a new generation of chemo-sensitizers, P-gp modulators originated from TCM have attracted increasing concern in the research community. In addition to identify TCM monomers or their synthetic intermediates as P-gp modulators, massive medicinal chemistry efforts have been made in discovering promising structural analogs and derivatives of them. Among these, compounds with dual role both as P-gp inhibitor and cytotoxic agent have continuously emerged. Hence, in this article, we will mainly enumerate the representative work conducted in the discovery of TCM monomers and their synthetic intermediates, analogs or derivatives as reversers of P-gp-mediated MDR.

GLP-1 RA Treatment Patterns Among Type 2 Diabetes Patients in Five European Countries.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a relatively new class of injectable drugs used in the treatment of type 2 diabetes (T2D). This retrospective database study evaluated real-world treatment patterns of T2D patients initiating GLP-1 RAs in Belgium (BE), France (FR), Germany (DE), The Netherlands (NL) and Sweden (SE). METHODS: Adult T2D patients initiating exenatide twice daily (exBID), exenatide once weekly (exQW), liraglutide (LIRA) or lixisenatide (LIXI) during 2013 were identified using the QuintilesIMS (QuintilesIMS, Durham, NC, and Danbury, CT, USA) longitudinal retail pharmacy databases (LRx; BE/FR/DE/NL) and national health register data (SE). Therapy initiation date was termed 'index date.' Eligible patients had ≥180-day pre- and variable follow-up (minimum ≥360 days post-index). Baseline patient and treatment characteristics were assessed. Treatment modification and persistence were evaluated over the 1-year follow-up. Kaplan-Meier (KM) survival curves evaluated stopping of the index therapy (first of discontinuation or switch) over the available follow-up. RESULTS: A total of 4339 exBID, 1499 exQW, 20,955 LIRA and 1751 LIXI patients were included in the analysis (45.1-61.9% female; mean age range 57.1-62.9 years). Mean follow-up ranged from 17.7 to 30.7 months. Across countries/databases, the proportion experiencing a treatment modification at 1-year ranged from 84.1 to 93.8% for exBID, 53.3-73.4% for exQW and 59.5-80.5% for LIRA patients. The proportion of LIXI patients with treatment modification was 55.0% in Belgium (N = 20) and 96.9% in Germany (LIXI taken off the German market in April 2014). In KM analyses, LIRA patients had the lowest proportion stopping therapy, while exBID patients had the highest proportion stopping therapy, across databases, with the exception of LIXI patents. CONCLUSION: Treatment patterns varied among GLP-1 RA patients, and persistence was generally highest among LIRA and lowest among exBID across countries. Longer term data would be useful, given the recent approval of several GLP-1 RA therapies. FUNDING: Eli Lilly and Co., Indianapolis, IN, USA.

Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes.

INTRODUCTION: Myelodysplastic syndromes (MDSs) are associated with significant morbidity due to ineffective hematopoiesis. Given the limited number of drugs approved by the FDA, there is a need for new therapeutic options. Ezatiostat is a novel agent targeting oxidative stress via inhibition of glutathione S-transferase 1. AREAS COVERED: Herein, the authors summarize the standard of care in order to build the framework for therapeutic advancements. The purpose of this paper is to review the body of preclinical and clinical research literature on the investigational agent ezatiostat hydrochloride (TLK199) for the treatment of MDSs. The article includes details of the pathophysiology, pharmacology, toxicity and efficacy of ezatiostat hydrochloride from controlled studies in patients with myelodysplasia. EXPERT OPINION: MDS clonal heterogeneity and clonal architecture complexity has presented a significant technical challenge in developing effective therapies. Ezatiostat offers a unique and specific mechanism to improve the transfusion burden associated with myelodysplasia. Since it is tolerable as a monotherapy, combining ezatiostat with agents such as lenalidomide may have the most potential benefit.

Progress of 99Tcm-labeled glucose and its analogs in tumor imaging / 中华核医学与分子影像杂志

The clinical value of 18F-FDG PET/CT in tumor imaging has been widely recognized.However,the related cost is high.SPECT is used more widely.So 99Tcm-labeled radiopharmaceuticals can be easily accessed.The recent progress of glucose and its analogs labeled by 99Tcm in tumor imaging is focused.

Effect of 10-hydroxycamptothecin on functional bleb following antiglaucomatous filtering surgery / 中华实验眼科杂志

Background The filtration surgery is the main method of treating glaucoma,which usually fails due to postoperative scarring.The study about application of anti-scarring agents in filtration surgery is a hotspot.Objective This study was to investigate whether topical administration of hydroxycamptothecin (HCPT) could be used to prevent postoperative scarring in after experimental glaucoma filtration surgery,and explore its optimal dose.Metbods Trabeculectomy was performed on the right eyes of 40 New Zealand white rabbits to establish the trabeculectomy animal models.The rabbits were then randomized into normal saline solution group,0.3 g/L mitomycin C(MMC) group,0.3 g/L HCPT group and 1.0 g/L HCPT group based on the intraoperative topical drugs using randomized number table method.The different drugs above-mentioned were put beneath the conjunctival flap and scleral flap for 5 minutes during the surgery.The intraocular pressure (IOP) was measured before and day 1,4,7,14,21 and 28 after the surgery with Icare tonometer,and the filtering area and height were measured under the slit lamp microscope to assess the efficacy of various drugs.The adverse effects were evaluated by examining the responses of the ocular anterior segment and retinal change.The specimens at operative zone were obtained in 7,14 and 28 days after surgery with the size 5 mm×5 mm for the hematoxylin-eosin staining and Masson trichrome staining to estimate the anti-fibrosis effect of various drugs,and to evaluate the survival time of functional bleb.Kaplan-Meier analysis was used to compare the survival time of functional bleb of different groups.The use and care of the animals complied with the Regulation for the Administration of Affair Concerning Experimental Animals by State Science and Technology Committee.Results The IOP was significantly different in the rabbits from different groups among various time points (Fgroup =20.79,P =0.00 ; Ftime =85.34,P =0.00 ; Fiion =2.13,P =0.01).From 1 day through 28 days after operation,the IOPs in MMC group and 1.0 g/L HCPT group were significantly lower than those before operation (all at P＜0.05).The survival time of functional bleb of different groups was (11.3 ±2.8),(19.5 ±2.4),(13.3 ±2.2) and (20.2 ± 4.5) days,respectively,showing a significant difference (log rank =11.92,P ＜ 0.01),with a considerable prolong in the 1.0 g/L HCPT group.No significant change was found in the bleb area and height among the four groups within 7 days after operation,but postoperative 7,14,28 days,the area and height values of bleb were significantly smaller in the normal saline solution group and 0.3 g/L HCPT group compared with the MMC group and 1.0 g/L HCPT group (all at P ＜ 0.05).Histopathological examination showed loosen subconjunctival tissue,less inflammatory cells and weaker collagenous fibrillary staining in the MMC group and 1.0 g/L HCPT group in comparison with the normal saline solution group and 0.3 g/L HCPT group.Conclusions The topical administration of 1.0 g/L HCPT inhibit the inflammatory response and collagen fibrosis and therefore prolong the survival time of functional bleb after glaucomatous filtering surgery.

Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial.

INTRODUCTION: Insulin degludec is an ultra-long-acting insulin with a flat time-action profile and duration of action >42 h. Data from several studies have shown insulin degludec to have a favorable therapeutic profile in type 1 and type 2 diabetes. MATERIALS AND METHODS: This was a 6-week, parallel-group, randomized controlled trial carried out in 65 Japanese patients with type 1 diabetes, previously treated with mealtime insulin aspart and either insulin glargine or neutral protamine Hagedorn insulin. Patients were randomized to receive either insulin degludec or insulin detemir, each once daily and at the same unit dose as pretrial basal insulin. During the trial, basal insulin was titrated according to a prespecified algorithm in order to achieve a fasting plasma glucose target of 80-109 mg/dL. RESULTS: No severe hypoglycemia occurred; there was no significant difference in confirmed hypoglycemia rates with insulin degludec and insulin detemir (rate ratio degludec/detemir 0.78; 95% confidence interval 0.45-1.34). The rate of nocturnal confirmed hypoglycemia was 69% lower with insulin degludec than with insulin detemir (rate ratio 0.31; 95% confidence interval 0.13-0.78). Final fasting plasma glucose levels were similar (insulin degludec 147 mg/dL, insulin detemir 136 mg/dL), despite differing baseline fasting plasma glucose levels. CONCLUSIONS: In conclusion, no concerns relating to hypoglycemia or general safety were observed when initiating insulin degludec in Japanese patients with type 1 diabetes at the same unit dose as previous basal insulin. This trial was registered with ClinicalTrials.gov (no. NCT00841087).