Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial

Aims: Assess the efficacy and safety of saxagliptin added to a submaximal sulphonylurea dose vs. uptitration of sulphonylurea monotherapy in patients with type 2 diabetes and inadequate glycaemic control with sulphonylurea monotherapy. Methods and patients: A total of 768 patients (18–77 years; HbA_1c screening ≥ 7.5 to ≤ 10.0%) were randomised and treated with saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg vs. glyburide 10 mg for 24 weeks. Blinded uptitration glyburide was allowed in the glyburide‐only arm to a maximum total daily dose of 15 mg. Efficacy analyses were performed using ANCOVA and last‐observation‐carried‐forward methodology. Results: At week 24, 92% of glyburide‐only patients were uptitrated to a total glyburide dose of 15 mg/day. Saxagliptin 2.5 and 5 mg provided statistically significant adjusted mean decreases from baseline to week 24 vs. uptitrated glyburide, respectively, in HbA_1c (?0.54%, ?0.64% vs. +0.08%; both p < 0.0001) and fasting plasma glucose (?7, ?10 vs. +1 mg/dl; p = 0.0218 and p = 0.002). The proportion of patients achieving an HbA_1c < 7% was greater for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (22.4% and 22.8% vs. 9.1%; both p < 0.0001). Postprandial glucose area under the curve was reduced for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (?4296 and ?5000 vs. +1196 mg·min/dl; both p < 0.0001). Adverse event occurrence was similar across all groups. Reported hypoglycaemic events were not statistically significantly different for saxagliptin 2.5 (13.3%) and 5 mg (14.6%) vs. uptitrated glyburide (10.1%). Conclusion: Saxagliptin added to submaximal glyburide therapy led to statistically significant improvements vs. uptitration of glyburide alone across key glycaemic parameters and was generally well tolerated.     

Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma

Prostaglandins play a critical role in tumor development and growth by regulating numerous biologic processes, including tumor angiogenesis, with clear prognostic and therapeutic implications. The aim of this study was to investigate the prognostic relevance of cyclooxygenase-2 (COX-2) pathway activation in head and neck squamous cell carcinoma (HNSCC). COX-2 activity was analyzed in 52 consecutive patients by assessing protein expression and prostaglandin E(2) (PgE(2)) levels and was then correlated to vascular endothelial growth factor (VEGF) expression and tumor angiogenesis. We evaluated the prognostic impact of these parameters by Kaplan-Meier and Cox survival analysis. COX-2 expression by tumor cells was closely correlated to VEGF expression and to tumor vascularization. According to Kaplan-Meier analysis, patients with COX-2 tumor overexpression and with higher PgE(2) tumor levels had significantly shorter overall survival estimates (P = 0.022 and P = 0.033, respectively). Analogously, patients with more-vascularized tumors had worse survival than those with less-vascularized cancers (P = 0.032). Cox multivariate analysis demonstrated that the most significant prognostic factors were presence of lymph node metastasis, tumor vascularization, COX-2 protein expression, and PgE(2) tumor levels. This study demonstrates a close correlation between COX-2 pathway, VEGF expression, and tumor angiogenesis in HNSCC. In addition, COX-2 overexpression and higher tumor vascularization appear to predict a shorter survival in patients with head and neck cancer.     

Visual, motor and perceptual abilities at school age in children with isolated mild antenatal ventricular dilatation

Background

The detection of prenatal ventriculomegaly raises anxiety about possible neurological sequelae. A few studies have investigated possible neurodevelopmental sequelae in the first years after birth but no systematic assessment has been performed at school age.

Aims

The aim of this study was to assess minor neurological signs, perceptual and visual function in a cohort of children with isolated mild antenatal ventricular dilatation examined at school age.

Study design

Seventeen children with evidence of mild antenatal ventriculomegaly in the second and third trimester of pregnancy were included in the study.

Outcome measures

Children were assessed at school age (range 5 years 3 months-11 years, 11 months) using a structured neurological examination for minor neurological signs and age specific tests assessing perceptual motor abilities (Developmental Test of Visual-Motor Integration; Movement Assessment Battery for Children).

Results

Only one of the 17 children had abnormal results. The remaining 16 had normal results on all the tests, irrespective of the magnitude and the symmetry of the dilatation or of its evolution on neonatal scan.

Conclusions

Our results suggest that children who had mild isolated prenatal ventricular dilatation are unlikely to develop even minor motor or perceptual difficulties at school age.     

Ferret odor as a processive stress model in rats: neurochemical, behavioral, and endocrine evidence

Predator odors have been shown to elicit stress responses in rats. The present studies assessed the use of domestic ferret odor as a processive stress model. Plasma corticosterone and adrenocorticotropin hormone levels were higher after 30 min of exposure to ferret odor (fur/skin) but not control odors, ferret feces, urine, or anal gland secretions. Behavioral differences were also found between ferret and the control odors as tested in a defensive withdrawal paradigm. In addition, c-fos messenger RNA expression in several brain areas previously associated with processive stress was significantly higher in ferret odor-exposed rat brains than in control odor-exposed brains. These results suggest that ferret odor produces a reliable unconditioned stress response and may be useful as a processive stress model.     

Lack of contextual modulation of habituated neuroendocrine responses to repeated audiogenic stress

Exposure to stress reliably activates the hypothalamo-pituitary-adrenocortical (HPA) axis response in rodents, which is significantly reduced (habituated) following repeated exposures. In the current study, it was first established that HPA axis response habituation to repeated loud noise lasted for at least 4 weeks in rats. In the next experiment, a contextual extinction procedure following repeated loud noise exposures failed to restore the habituated HPA axis response. Although an additional study indicated some recovery of responses when the context was modified on a test day following habituation, this effect could be mostly attributed to the familiarity with the contextual cues. A final study confirmed that rats could distinguish between the contexts used and further indicated that context preexposures reduce acute HPA axis responses to loud noise. These studies therefore provide no support for the hypothesis that contextual cues regulate HPA axis response habituation.     

Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear

Fear conditioning and fear extinction play key roles in the development and treatment of anxiety-related disorders, yet there is little information concerning experiential variables that modulate these processes. Here we examined the impact of exposure to a stressor in a different environment on subsequent fear conditioning and extinction, and whether the degree of behavioral control that the subject has over the stressor is of importance. Rats received a session of either escapable (controllable) tail shock (ES), yoked inescapable (uncontrollable) tail shock (IS), or control treatment (home cage, HC) 7 days before fear conditioning in which a tone and foot shock were paired. Conditioning was measured 24 h later. In a second experiment rats received ES, IS or HC 24 h after contextual fear conditioning. Extinction then occurred every day beginning 7 days later until a criterion was reached. Spontaneous recovery of fear was assessed 14 days after extinction. IS potentiated fear conditioning when given before fear conditioning, and potentiated fear responding during extinction when given after conditioning. Importantly, ES potently interfered with later fear conditioning, decreased fear responding during fear extinction, and prevented spontaneous recovery of fear. Additionally, we examined if the activation of the ventral medial prefrontal cortex (mPFCv) by ES is critical for the protective effects of ES on later fear conditioning. Inactivation of the mPFCv with muscimol at the time of the initial experience with control prevented ES-induced reductions in later contextual and auditory fear conditioning. Finally, we explored if the protective effects of ES extended to an unconditioned fear stimulus, ferret odor. Unlike conditioned fear, prior ES increased the fear response to ferret odor to the same degree as did IS.     

Human herpesvirus 8 seroprevalence and evaluation of nonsexual transmission routes by detection of DNA in clinical specimens from human immunodeficiency virus-seronegative patients from central and southern Italy, with and without Kaposi's sarcoma

In order to investigate the seroprevalence of human herpesvirus 8 (HHV-8) infection in central and southern Italy, sera from human immunodeficiency virus (HIV)-seronegative subjects, with and without Kaposi's sarcoma (KS), were analyzed by immunofluorescence assay, using BC-3, a cell line latently infected with HHV-8. High titers of antibody against HHV-8 lytic and latent antigens were detected in all 50 KS patients studied, while in 50 HIV-seronegative subjects without KS, 32 (64%) were found positive for HHV-8 antibodies. Titers in the sera of these patients were lower than those for KS patients. This data suggests that HHV-8 infection is not restricted to KS patients and that the prevalence of HHV-8 infection in the general population may be correlated with differing rates of prevalence of KS in different parts of the world. In view of these findings, possible nonsexual transmission routes were evaluated. Nested PCR was used to test for the presence of HHV-8 DNA in saliva, urine, and tonsillar swabs from KS and non-KS patients. In KS patients, 14 out of 32 tonsillar swabs (43.7%), 11 out of 24 saliva samples (45.8%), and just 2 out of 24 urine samples (8.3%) tested positive for HHV-8 DNA. In the control group, on the contrary, none of the 20 saliva and 20 urine specimens was positive for HHV-8 DNA; only 1 out of 22 tonsillar swabs gave a positive result. This data supports the hypothesis that HHV-8 infects the general population in a latent form. The reactivation of viral infection may result in salivary shedding of HHV-8, contributing to viral spread by nonsexual transmission routes.     

Down-regulation of nitric oxide synthase-2 and cyclooxygenase-2 pathways by p53 in squamous cell carcinoma

The goal of this study was to analyze the correlation between inducible nitric oxide synthase (iNOS) and COX-2 activities and p53 gene status in head and neck squamous cell carcinomas (HNSCCs) in vivo and in vitro. In a series of 43 HNSCCs we observed an up-regulation of both iNOS and COX-2 pathways in tumor tissues and both activities were correlated each other (rs = 0.612 and P = 0.0002). We also found that p53-mutated HNSCCs (25 cases, 58.1%) showed higher levels of iNOS activity and cGMP in comparison with wild-type p53 tumors (18 cases, 41.9%) (P = 0.0005 and P = 0.01), as well as higher iNOS immunohistochemical expression (P = 0.03). Analogously, higher PgE2 levels were documented in p53-mutated HNSCCs when compared with wild-type p53 tumors (P = 0.015) and COX-2 protein expression was higher in p53-mutated HNSCCs (P = 0.007). A431 cancer cells expressing a p53 temperature-sensitive mutant showed an approximately 1.9- and 2.6-fold decrease in spontaneous NO(2-)/NO(3-) and PgE2 synthesis at permissive temperature, respectively, when compared with the same cells at nonpermissive temperature (P 相似文献   

Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis

To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis.     

Relaxin induces mast cell inhibition and reduces ventricular arrhythmias in a swine model of acute myocardial infarction.

Resident cardiac mast cells, located mainly around coronary vessels and in the right atrium close to the sinoatrial node, are the main repository of cardiac histamine. Inflammatory activation of cardiac mast cells, as occurs upon acute myocardial infarction, causes the release of histamine and prostanoids. These substances lead to severe tachyarrhythmias, cardiodepressive effects and coronary spasm, thus contributing to myocardial damage and early, lethal outcome. Relaxin, known to inhibit mast cell activation, has been recently validated as a cardiotropic hormone, being produced by the heart and acting on specific heart receptors. In this study, we report on a swine model of heart ischemia/reperfusion, currently used to test cardiotropic drugs, in which human recombinant relaxin (2.5 and 5 microg/kg b.w.), given at reperfusion upon a 30-min ischemia, markedly reduced cardiac injury as compared with the vehicle-treated animals. Evidence is provided that relaxin, at both the assayed doses, causes a clear-cut, significant reduction of plasma histamine, increase in cardiac histamine content and decrease in cardiac mast cell degranulation. This is accompanied by a reduction of oxidative cardiac tissue injury (assessed as tissue malondialdehyde) and of the occurrence of severe ventricular arrhythmias. In conclusion, this study provides further insight into the cardioprotective effects of relaxin, which also involve mast cell inhibition, and confirms the relevance of histamine in the pathophysiology of ischemia-reperfusion-induced cardiac injury and dysfunction. It also offers additional evidence for the potential therapeutic effects of relaxin in animal models of disease involving mast cell activation.