Effect of vildagliptin as add-on therapy to a low-dose metformin

AIM: To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus (T2DM) patients who have inadequate control with metformin monotherapy.METHODS: Eligible patients were randomized to receive vildagliptin 100 mg qd or metformin (500 mg qd for 2 wk and then 500 mg bid) added to open label metformin 500 mg bid for the 24 wk. The primary endpoint was baseline to endpoint hemoglobin A_1c (HbA_1c) change.RESULTS: The adjusted mean change from baseline in HbA_1c at the 24th wk was -0.51% in the vildagliptin/metformin group (mean baseline HbA_1c: 7.4%) and -0.37% in the metformin monotherapy group (mean baseline HbA_1c: 7.3%). The mean difference was -0.14% with 95% Confidence Interval (-0.24%, -0.05%). As non-inferiority (margin of 0.4%) was achieved, a test for superiority was performed. This test showed statistically significant superiority of the combination over monotherapy group (P = 0.002). Gastrointestinal (GI) adverse events were significantly more frequent in the metformin group than the combination group (21.0% vs 15.4%, P = 0.032).CONCLUSION: In patients with T2DM inadequately controlled with metformin up to 1000 mg daily, the addition of vildagliptin 100 mg daily achieved larger HbA_1c reduction with fewer GI events than with increasing the metformin dose.     

Tamsulosin alters levofloxacin pharmacokinetics in prostates derived from rats with acute bacterial prostatitis

The combination of levofloxacin and α₁ adrenergic antagonist treatment is the current preferred choice for both bacterial and non-bacterial prostatitis. The aim of this study is to explore the influence of α₁ adrenergic antagonists on the pharmacokinetics of levofloxacin using rat models with acute bacterial prostatitis (ABP) induced by direct injection with Escherichia coli (ATCC25922). A total of 96 model rats were randomly assigned into two groups: the experimental group (treated with both tamsulosin and levofloxacin, n=48) and the control group (treated with levofloxacin and solvents, n=48). Six rats from each group were euthanized to collect blood, liver, kidney and prostate samples at the time points of 0.125, 0.25, 0.5, 1, 2, 4, 8 and 12 h after drug administration. The levofloxacin concentrations were detected by high performance liquid chromatography (HPLC), and the pharmacokinetic parameters were calculated using the 3p97 software program. There were no obvious differences (P>0.05) between the experimental and control groups in the major pharmacokinetic parameters of levofloxacin, including the halftime (t_1/2), time to peak (t_peak), clearance rate (CL), maximum concentration (C_max) and area under the curve (AUC_0∼12), in the plasma or in the hepatic and kidney tissues of the model rats. However, in the prostatic tissues, tamsulosin increased the C_max, prolonged the t_1/2 and decreased the CL of levofloxacin (P<0.05). These results indicate that tamsulosin may enhance the effect of levofloxacin in the treatment of bacterial prostatitis without changing the drug concentration in the liver and kidney.     

儿童和青少年误吞磁性异物致消化道损伤的文献分析

目的研究儿童误吞磁性异物致消化道损伤的诊断及处理措施。方法通过Google、Medline、ISIWebofKnowledge、0vid、万方、维普、CNKI、学位论文、会议论文数据库及申请文献传递等方式收集1987年6月至2010年4月国内外所有以英文、中文、日文和韩文发表的关于误吞磁性异物而导致相应消化道并发症的文献。研究内容包括发病年龄、性别、国家和地区分布、磁性异物的数量、磁性异物来源、临床表现、诊断及取除异物的方法等。结果共收集了来自17个国家和地区的98例吞咽磁性异物病例。其中18岁以下未成年人94例．5岁以下儿童占62．2％（61／98）．高发年龄为3岁（16．3％,16／98）。所吞咽的磁性异物来源玩具73例（74．5％）,医疗仪器8例（8．2％）,饰品4例（4．1％）,其他13例（6．2％）：异物数量2-100枚．其中11例（11．2％）伴有异食癖或孤癖症等精神症状。所有病例均存在不同程度延误诊治的情况．其中1例因严重感染而死亡。开腹探查发现．消化道损伤包括从食管至结肠不同部位的穿孔和肠瘘,其中小肠损伤占51．0％,其次是小肠．结肠瘘占15．3％。除2例患儿急诊经内镜取除异物外．其余患儿行肠切除吻合术和肠瘘修补术。结论2枚以上的磁性异物会导致严重消化道损伤．需要早期明确诊断并手术治疗。对5岁以下儿童需要更多的预防措施。     

Fibronectin fragments active in chondrocytic chondrolysis can be chemically cross-linked to the alpha5 integrin receptor subunit

OBJECTIVE: To determine whether fibronectin fragments (Fn-f) known to enhance cartilage matrix degradation and to alter chondrocyte metabolism, bind on the chondrocyte cell surface close enough to the alpha(5)beta(1) fibronectin (Fn) receptor to be chemically cross-linked to it. DESIGN: Biotinylated Fn-fs were added to chondrocytes, followed by cross-linking with dithiobissulfosuccinimidyl propionate, and the resultant alpha(5) complexes trapped on to antialpha(5)-agarose. Adherent material was analysed by probing with avidin-HRP. In a more specific approach in which only proximal targets could be cross-linked, photoaffinity labeled Fn-fs or Fn were added to cells, the derivatives activated and the cross-linked material analysed. Interaction of biotinylated Fn-fs and Fn with insolubilized alpha(5)beta(1) receptor was also visualized and quantified. RESULTS: Biotinylated Fn-fs and Fn, but not a control of BSA, were cross-linked to alpha(5) protein in the presence of the propionate. Photoaffinity label Fn-f and Fn, but not BSA, were cross-linked to alpha(5) protein as well. Interaction was decreased by addition of an excess of unlabeled Fn-f or Fn. Fn-fs bound to alpha(5)beta(1)-agarose, although the affinity was 30-fold weaker and the stoichiometry 20-fold greater when the smallest Fn-f was compared to native Fn. CONCLUSIONS: These data are consistent with a role for the alpha(5) subunit in Fn-f activities and suggest that the Fn-fs bind proximal or directly to alpha(5) receptors. The weaker, higher stoichiometry interaction of Fn-fs with receptor suggests that fragmentation has allowed de novo interactions not possible in native Fn.     

Differential expression of adenosine A1 and A2A receptors after upper cervical (C2) spinal cord hemisection in adult rats

BACKGROUND: In an animal model of spinal cord injury, a latent respiratory motor pathway can be pharmacologically activated via adenosine receptors to restore respiratory function after cervical (C2) spinal cord hemisection that paralyzes the hemidiaphragm ipsilateral to injury. Although spinal phrenic motoneurons immunopositive for adenosine receptors have been demonstrated (C3-C5), it is unclear if adenosine receptor protein levels are altered after C2 hemisection and theophylline administration. OBJECTIVE: To assess the effects of C2 spinal cord hemisection and theophylline administration on the expression of adenosine receptor proteins. METHODS: Adenosine A1 and A2A receptor protein levels were assessed in adult rats classified as (a) noninjured and theophylline treated, (b) C2 hemisected, (c) C2 hemisected and administered theophylline orally (3x daily) for 3 days only, and (d) C2 hemisected and administered theophylline (3x daily for 3 days) and assessed 12 days after drug administration. Assessment of A1 protein levels was carried out via immunohistochemistry and A2A protein levels by densitometry. RESULTS: Adenosine A1 protein levels decreased significantly (both ipsilateral and contralateral to injury) after C2 hemisection; however, the decrease was attenuated in hemisected and theophylline-treated animals. Attenuation in adenosine A1 receptor protein levels persisted when theophylline administration was stopped for 12 days prior to assessment. Adenosine A2A protein levels were unchanged by C2 hemisection; however, theophylline reduced the levels within the phrenic motoneurons. Furthermore, the decrease in A2A levels persisted 12 days after theophylline was withdrawn. CONCLUSION: Our findings suggest that theophylline mitigates the effects of C2 hemisection by attenuating the C2 hemisection-induced decrease in A1 protein levels. Furthermore, A2A protein levels are unaltered by C2 hemisection but decrease after continuous or interrupted theophylline administration. The effects on protein levels may underlie the stimulant actions of theophylline.     

A Comparison of Intravenous Sedation With Two Doses of Dexmedetomidine: 0.2?μg/kg/hr Versus 0.4?μg/kg/hr

The present study investigated the physiologic and sedative effects between two different continuous infusion doses of dexmedetomidine (DEX). Thirteen subjects were separately sedated with DEX at a continuous infusion dose of 0.2 µg/kg/hr for 25 minutes after a loading dose of 6 µg/kg/hr for 5 minutes (0.2 group) and a continuous infusion dose of 0.4 µg/kg/hr for 25 minutes after a loading dose of 6 µg/kg/hr for 5 minutes (0.4 group). The recovery process was then observed for 60 minutes post infusion. The tidal volume, mean arterial pressure, and heart rate in both groups decreased significantly during infusion, but they were within a clinically acceptable level. A Trieger dot test plot error ratio in the 0.4 group was significantly higher than that in the 0.2 group until 15 minutes post infusion. Sedation appears to be safe at the infusion doses of DEX studied. However, increasing maintenance infusion doses of DEX from 0.2 µg/kg/hr to 0.4 µg/kg/hr delays some recovery parameters.     

Functional analysis of swallowing outcomes after supracricoid partial laryngectomy

BACKGROUND: In this study, we analyzed swallowing recovery after supracricoid partial laryngectomy (SCPL). METHODS: We retrospectively reviewed 27 patients treated with SCPL (September 1997 to March 2005). We evaluated recovery course, nutritional outcomes, and swallowing using objective analysis. Modified barium swallow (MBS) study results identified swallowing physiology and therapeutic effectiveness. RESULTS: Average length of hospitalization was 7.7+/-9.2 days; time to decannulation was 5.3+/-8.2 weeks. The most common complications included pneumonia and subcutaneous emphysema (26%). Twenty-two patients had MBS studies, in which initially, all patients aspirated due to neoglottic incompetency, and impaired base of tongue and laryngeal movements. Although aspiration rates did not change significantly over time, use of appropriately selected swallowing strategies effectively protected the airway (p= .0365). Ultimately, 81% of patients returned to complete oral intake with median tube removal at 9.4 weeks. CONCLUSION: SCPL produces severe dysphagia initially. Our findings suggest that objective swallowing assessment is important for return to oral nutrition after SCPL.     

Intravenous sedation with low-dose dexmedetomidine: its potential for use in dentistry

This study investigated the physiologic and sedative parameters associated with a low-dose infusion of dexmedetomidine (Dex). Thirteen healthy volunteers were sedated with Dex at a loading dose of 6 mcg/kg/h for 5 minutes and a continuous infusion dose of 0.2 mcg/kg/h for 25 minutes. The recovery process was observed for 60 minutes post infusion. The tidal volume decreased significantly despite nonsignificant changes in respiratory rate, minute ventilation, oxygen saturation, and end-tidal carbon dioxide. The mean arterial pressure and heart rate also decreased significantly but within clinically acceptable levels. Amnesia to pin prick was present in 69% of subjects. A Trieger dot test plot error ratio did not show a significant change at 30 minutes post infusion despite a continued significant decrease in bispectral index. We conclude that sedation with a low dose of Dex appears to be safe and potentially efficacious for young healthy patients undergoing dental procedures.     

Role of P2X_7 receptors in the development of diabetic retinopathy

The P2X7 receptor is one of the members of the family of purinoceptors which are ligand-gated membrane ion channels activated by extracellular adenosine 5'-triphosphate. A unique feature of the P2X7 receptor is that its activation can result in the formation of large plasma membrane pores that allow not only the flux of ions but also of hydrophilic molecules of up to 900 Da. Recent studies indicate that P2X7-mediated signaling can trigger apoptotic cell death after ischemia and during the course of certain neurodegenerative disorders. Expression of the P2X7 receptor has been demonstrated in most types of cells in the retina. This purinoceptor mediates the contraction of pericytes and regulates the spatial and temporal dynamics of the vasomotor response through cell-to-cell electrotonic transmission within the microvascular networks. Of potential clinical significance, investigators have found that diabetes markedly boosts the vulnerability of retinal microvessels to the lethal effect of P2X7 receptor activation. This purinergic vasotoxicity may result in reduced retinal blood flow and disrupted vascular function in the diabetic retina. With recent reports indicating an association between P2X7 receptor activation and inflammatory cytokine expression in the retina, this receptor may also exacerbate the development of diabetic retinopathy by a mechanism involving inflammation.     

Mechanism of sperm capacitation and the acrosome reaction: role of protein kinases

Mammalian sperm must undergo a series of biochemical and physiological modifications, collectively called capacitation, in the female reproductive tract prior to the acrosome reaction (AR). The mechanisms of these modifications are not well characterized though protein kinases were shown to be involved in the regulation of intracellular Ca²⁺ during both capacitation and the AR. In the present review, we summarize some of the signaling events that are involved in capacitation. During the capacitation process, phosphatidyl-inositol-3-kinase (PI3K) is phosphorylated/activated via a protein kinase A (PKA)-dependent cascade, and downregulated by protein kinase C α (PKCα). PKCα is active at the beginning of capacitation, resulting in PI3K inactivation. During capacitation, PKCα as well as PP1γ2 is degraded by a PKA-dependent mechanism, allowing the activation of PI3K. The activation of PKA during capacitation depends mainly on cyclic adenosine monophosphate (cAMP) produced by the bicarbonate-dependent soluble adenylyl cyclase. This activation of PKA leads to an increase in actin polymerization, an essential process for the development of hyperactivated motility, which is necessary for successful fertilization. Actin polymerization is mediated by PIP₂ in two ways: first, PIP₂ acts as a cofactor for phospholipase D (PLD) activation, and second, as a molecule that binds and inhibits actin-severing proteins such as gelsolin. Tyrosine phosphorylation of gelsolin during capacitation by Src family kinase (SFK) is also important for its inactivation. Prior to the AR, gelsolin is released from PIP₂ and undergoes dephosphorylation/activation, resulting in fast F-actin depolymerization, leading to the AR.     

Site of disease and treatment protocol as correlates of swallowing function in patients with head and neck cancer treated with chemoradiation

BACKGROUND: The relationship between type of chemoradiation treatment, site of disease, and swallowing function has not been sufficiently examined in patients with head and neck cancer treated primarily with chemoradiation. METHODS: Fifty-three patients with advanced-stage head and neck cancer were evaluated before and 3 months after chemoradiation treatment to define their swallowing disorders and characterize their swallowing physiology by site of lesion and chemoradiation protocol. One hundred forty normal subjects were also studied. RESULTS: The most common disorders at baseline and 3 months after treatment were reduced tongue base retraction, reduced tongue strength, and slowed or delayed laryngeal vestibule closure. Frequency of functional swallow did not differ significantly across disease sites after treatment, although frequency of disorders was different at various sites of lesion. The effects of the chemotherapy protocols were small. CONCLUSIONS: The site of the lesion affects the frequency of occurrence of specific swallow disorders, whereas chemoradiation protocols have minimal effect on oropharyngeal swallow function.     

Effect of prostaglandin E1 on preservation injury of canine liver grafts preserved in UW solution

This study investigated whether prostaglandin E₁ (PGE₁) could reduce hepatic injury to the liver graft caused by harvesting and 24-h preservation in University of Wisconsin (UW) solution in a canine model. The PGE₁-treated group was intravenously administered 0.5 g/kg per minute of PGE₁ for 30 min before harvesting, as well as a concentration of 1 mg/l PGE₁ in the washout and UW solutions. In both the PGE₁-treated and the control group, all recipients survived for 1 week or more after transplantation. Arterial ketone body ratio (AKBR) remained over 1.0 in the early postoperative period. The PGE₁ group showed significant reductions in guanase, GOT, and LDH during the early postoperative period compared to the untreated control group. Histological examination disclosed partial mitochondrial swelling, hepatocyte vacuolation, and necrosis in the control group, while such abnormalities were rarely seen in the PGE₁ group. These results suggest that PGE₁ can effectively reduce hepatic injury to liver grafts preserved in UW solution prior to transplantation.     

Protection of Icariin Against Hydrogen Peroxide‐Induced MC3T3‐E1 Cell Oxidative Damage

ObjectiveThe aim of the present study was to evaluate the potential protective mechanism of icariin against oxidative damage caused by hydrogen peroxide in MC3T3‐E1 cells.MethodsMC3T3‐E1 cells were treated with different concentrations of icariin to explore the optimal dose of icariin. MC3T3‐E1 cells were divided into groups treated with various concentrations of hydrogen peroxide (H₂O₂; 0, 0.1, 0.2, 0.5, 1, and 2 mM) for 24 h to induce oxidative damage and cell viability was assessed by Cell Counting Kit‐8 (CCK‐8) assay. Then, cells were divided into five groups: control, H₂O₂ (0.2 mM), icariin (0.1 μM) and H₂O₂ (0.2 mM), + icariin (0.1 μM). Cell viability was detected by CCK‐8 assay. In addition, the content of glutathione and superoxide dismutase and the activity level of malondialdehyde in these treatment groups were determined. Alkaline phosphatase (ALP) and alizarin red S (ARS) staining were also performed to measure the early and late osteogenesis, respectively. Protein expression of β‐catenin and cyclin D1 was measured by western blot assay. Then, we used an antagonist of Wnt/β‐catenin signaling pathway (DKK‐1) and western blot analysis to further explore potential mechanism.ResultsAfter 24 h of exposure to 0.2 mM H₂O₂, the viability of MC3T3‐E1 cells was significantly decreased compared to that of the control cells. We first found that icariin can promote cell proliferation of MC3T3‐E1 cells in a dose‐dependent manner, with the dosage 0.1 μM showing the best pro‐proliferative effect. Furthermore, icariin could promote the protein expression of OSX and RUNX2. The results showed that icariin can reverse the inhibitory osteogenic effects of MC3T3‐E1 caused by H₂O₂. In addition, icariin could increase the Wnt‐signaling related proteins. The results showed that MC3T3‐E1 cells in the H₂O₂ (0.2 mM) + icariin (0.1 μM) + Wnt‐signaling antagonist (DKK‐1) group had weaker ALP and ARS staining compared with that observed in the control and H₂O₂ (0.2 mM) + icariin (0.1 μM) groups. The ALP activity and calcium content were decreased in the 0.2 mM H₂O₂ + 0.1 μM icariin + DKK‐1 group compared to that observed in the 0.2 mM H₂O₂ + 0.1 μM icariin group.ConclusionThe results showed that icariin can increase the viability of MC3T3‐E1 cells, reverse the oxidative stress induced by H₂O₂ and protect MC3T3‐E1 cells against H₂O₂‐induced inhibition of osteogenic differentiation, which may occur through the Wnt/β‐catenin signaling pathway.