Trend in dental research output in Iran over a period of 20 years (1990–2009)

Introduction: The number of scientific papers is a conventional metric for the measurement of a country’s research performance in a particular area. Objective: To evaluate the trend in Iranian publications of dental research results in peer-reviewed international scientific journals over the period 1999–2009, using national and international databases, and to compare the results with other countries. Methods: The search process was performed by two independent persons in PubMed and Iranian Medline (IranMedex). Data extraction included the year of publication, total number of dental papers in each year, total number of Iranian dental papers in each year and number of papers with a high level of evidence; these were compared with those in other Asian countries. Results: The total number of dental articles indexed in PubMed during the studied period was 207,689, with 671 being written by researchers who stated their affiliation as Iran. Although the proportion of Iranian dental articles to all published dental articles was 0.01% in 1990, this increased to 1.4% in 2009. Of all clinical trials indexed in PubMed from 1990 to 2009, only 0.62% had an author from Iran. The collaboration rate of authors ranged between 1 and 10. Turkey and Iran had a larger number of dental research publications compared with other Asian countries assessed in this study. Conclusion: During the last two decades, there has been a considerable increase in the number of dental papers by Iranian researchers indexed in the PubMed database.Key words: Dental, research, Iran     

Phase 3 evaluation of HP802‐247 in the treatment of chronic venous leg ulcers

In 2012 we reported promising results from a phase 2 clinical trial of HP802‐247, a novel spray‐applied investigational treatment for chronic venous leg ulcers consisting of human, allogeneic fibroblasts and keratinocytes. We now describe phase 3 clinical testing of HP802‐247, its failure to detect efficacy, and subsequent investigation into the root causes of the failure. Two randomized, controlled trials enrolled a total of 673 adult outpatients at 96 centers in North America and Europe. The primary endpoint was the proportion of ulcers with confirmed closure at the end of 12 weeks of treatment. An investigation into the root cause for the failure of HP802‐247 to show efficacy in these two phase 3 trials was initiated immediately following the initial review of the North American trial results. Four hundred twenty‐one patients were enrolled in the North American (HP802‐247, 211; Vehicle 210) and 252 in the European (HP802‐247, 131; Vehicle 121) trials. No difference in proportion of closed ulcers at week 12 was observed between treatment groups for either the North American (HP802‐247, 61.1%; Vehicle 60.0%; p = 0.5896) or the European (HP802‐247, 47.0%; Vehicle 50.0%; p = 0.5348) trials. Thorough investigation found no likelihood that design or execution of the trials contributed to the failure. Variability over time during the trials in the clinical response implicated the quality of the cells comprising HP802‐247. Concordance between the two separate, randomized, controlled trials with distinct, nonoverlapping investigative sites and independent monitoring teams renders the possibility of a Type II error vanishingly small and provides strong credibility for the unexpected lack of efficacy observed. The most likely causative factors for the efficacy failure in phase 3 was phenotypic change in the cells (primarily keratinocytes) leading to batch to batch variability due to the age of the cell banks.     

Glutamatergic systems in the bed nucleus of the stria terminalis,effects on cardiovascular system

The bed nucleus of the stria terminalis (BST) is a part of the limbic system. Two studies have shown that microinjection of l-glutamate in the BST elicited cardiovascular depressive and bradycardic responses, but in one study, both pressor and depressor responses were observed in the chemical stimulation of BST by glutamate in the urethane-anesthetized rats. Also, the roles of glutamate receptor subtypes have not been investigated yet. The aim of this study was to find the effects of glutamate and its receptors on the blood pressure and heart rate in the BST of urethane-anesthetized rats. The drugs (50 nl) were microinjected into the BST of anaesthetized rats. The blood pressure and heart rate were recorded throughout each experiment. The average changes in the mean arterial pressure and heart rate at different intervals were compared both within each case group and between the case and the control groups, using repeated measures ANOVA. Microinjection of l-glutamate (0.25 M) into the BST resulted in the decrease of the mean arterial pressure (−18.85 ± 3.84 mmHg) and heart rate (−18 ± 4 beats/min). Injection of AP5, antagonist of glutamate NMDA receptor (2.5 , 5 mM) and CNQX, antagonist of glutamate AMPA receptor (0.5, 1 mM) had no significant effect on the mean arterial pressure and heart rate. Either Ap5 or CNQX, when co-injected with glutamate, abolished the depressor and bradycardic effects of glutamate, suggesting that simultaneous activation of both glutamate receptors is necessary for the effect of glutamate system to emerge.     

Agreement between DSM-IV and ICD-10 criteria for opioid use disorders in two Iranian samples

The aim of this study was to determine the agreement between the two systems in opioid users in the general population and a clinical sample. Two series of data were used in this study. The first was the data of 236 home-residing opioid abusers aged 15–64, who had previously participated in the Iran Mental Health Survey (IranMHS) in 2011, and the second was the data of 104 general psychiatry patients from inpatient or outpatient wards of two psychiatry hospitals in Tehran. Opioid use disorders were evaluated with CIDI-version 2.1. The disorders were assessed in all participants who used opioid substances for at least 5 times during the past 12 months. In the sample from the general population, the agreement between the two systems on the diagnosis of dependence was excellent (0.81). The agreement between the two systems on the diagnosis of abuse and harmful use was 0.41. In the clinical sample, the agreement between the two systems on the diagnosis of dependence or any opioid use disorder was 0.96 and 0.93, respectively. The agreement between abuse and harmful use was 0.9 and − 0.02 with and without regarding hierarchy, respectively. The inter-rater reliability of both DSM-IV and ICD-10 systems for all diagnosis was more than 0.95. The results of the diagnosis of dependence in the two systems had a weak concordance with treatment. The diagnostic criteria of DSM-IV and ICD-10 regarding dependence are very similar and the diagnosis produced by each system is concordant with the other system. However, the two systems have noticeable discrepancies in the diagnosis of abuse and harmful use. The discrepancies result from their conceptual differences and necessitate further revision in the definition of these disorders in the two systems.     

High responsivity and 1/f noise of an ultraviolet photodetector based on Ni doped ZnO nanoparticles

This study involves the novel fabrication of a high responsivity, fast response, and low-cost (UV) photodetector (PD) based on ZnO/Ni nanoparticles deposited on a glass substrate. The ZnO/Ni nanoparticles were synthesized using a polyol process. The structure and the morphology of the samples were characterized by X-ray diffraction (XRD) and Transmission Electron Microscopy (TEM). Optical properties were measured using UV-visible, diffuse reflectance and photoluminescence (PL) spectroscopy. The photodetector exhibited high photoresponse characteristics under 375 nm laser excitation. Our device shows a high responsivity (121 A W⁻¹) with rise time (about 5.52 s) and fall time (about 12 s) at a bias voltage of 1 V. The device exhibits excellent reproducibility and stability characteristics with time. The noise spectra obtained from the UV photodetector were caused by the 1/f noise. The noise-equivalent power (NEP) is 1.08 × 10⁻⁹ W. Thus, the polyol process can be a useful and effective method for improving the performance of ZnO/Ni UV photodetectors.

This study involves the novel fabrication of a high responsivity, fast response, and low-cost (UV) photodetector (PD) based on ZnO/Ni nanoparticles deposited on a glass substrate.     

Engineered nanomedicine for myeloma and bone microenvironment targeting

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d,l-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA-b-PEG and alendronate-conjugated polymer PLGA-b-PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.The incidence of bone metastasis is common in 60–80% of cancer patients (1). During bone metastasis, cancer cells induce a sequence of changes in the microenvironment such as secreting cytokines to increase the activity of osteoclasts via the parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-κB ligand (RANKL), and interleukin-6 (IL-6), resulting in increased bone resorption and secretion of growth factors from the bone matrix (2). This creates a “vicious cycle” of bone metastasis, where bone marrow becomes packed with cancer cells that develop resistance to conventional chemotherapy, and leads to devastating consequences of bone fractures, pain, hypercalcaemia, and spinal cord and nerve compression syndromes (2, 3). Multiple myeloma (MM) is a plasma cell cancer that proliferates primarily in bone marrow and causes osteolytic lesions (1). Antiresorption agents, such as bisphosphonates, may alleviate bone pain, but they are ineffective at inducing bone healing or osteogenesis in MM patients (4).Bortezomib is a proteasome inhibitor that has shown marked antitumor effects in patients with MM. Proteasome inhibitors, such as bortezomib, are also effective at increasing bone formation, both preclinically and clinically (5–9). However, the major drawback of bortezomib use in early stages of MM development is its toxicity, specifically, peripheral neuropathy (5). Therefore, we aimed to develop a method to deliver bortezomib with decreased off-target side effects by using bone-specific, bortezomib-loaded nanoparticles (NPs). The NP system was based on biodegradable, biocompatible, and Food and Drug Administration (FDA)-approved components, which are both clinically and translationally relevant. NPs derived from poly(d,l-lactic-co-glycolic acid) (PLGA), a controlled release polymer system, are an excellent choice because their safety in the clinic is well established (10, 11). Polyethylene glycol (PEG)-functionalized PLGA NPs are especially desirable as PEGylated polymeric NPs have significantly reduced systemic clearance compared with similar particles without PEG (12, 13). A number of FDA-approved drugs in clinical practice use PEG for improved pharmaceutical properties such as enhanced circulation in vivo (12, 13). To target NPs to bone [rich in the mineral hydroxyapatite (HA)], the calcium ion-chelating molecules of bisphosphonates represent a promising class of ligands (14). Bisphosphonates, upon systemic administration, are found to deposit in bone tissue, preferentially at the high bone turnover sites, such as the metastatic bone lesions, with minimal nonspecific accumulation (14) and were used herein to deliver NPs to the bone.A few systems explored for MM treatment have been tested in vitro including the following: (i) snake venom and silica NPs (15); (ii) thymoquinone and PLGA-based particles (16); (iii) curcumin and poly(oxyethylene) cholesteryl ether (PEG-Chol) NPs (17), polyethylenimine-based NPs for RNAi in MM (18), paclitaxel-Fe₃O₄ NPs (19), and liposomes (20). However, none of the above-mentioned systems have aimed to manipulate the bone marrow microenvironment rather than the myeloma cells directly (21). To date, there are no reports of using bone-targeted, controlled release, polymeric NPs with stealth properties for MM therapy. In this study, we designed NPs bearing three main components: (i) a targeting element that can selectively bind to bone mineral; (ii) a layer of stealth (PEG) to minimize immune recognition and enhance circulation; and (iii) a biodegradable polymeric material, forming an inner core, that can deliver therapeutics and/or diagnostics in a controlled manner. In this study, the physicochemical properties of a range of NPs was investigated (including NP size, charge, targeting ligand density, drug loading, and drug release kinetics) and an optimal formulation with ideal properties and maximal drug encapsulation was used for in vivo efficacy studies. We fine-tuned the NP targeting ligand density to optimize its bone-binding ability and further investigated its application for targeting myeloma in the bone microenvironment. We believe our NP system has the potential to increase drug availability by improving pharmacokinetics and biodistribution that can provide bone microenvironment specificity, which may increase the therapeutic window and most certainly decrease the off-target effects (12, 13).     

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.