Publication date: Available online 7 June 2016
Source:Archives of Oral Biology
Author(s): Marisa Sukapattee, Sitthichai Wanachantararak, Varisara Sirimaharaj, Noppakun Vongsavan, Bruce Matthews
ObjectiveTo determine if full crown preparation causes an increase in pulpal blood flow (PBF), indicating inflammation, in human subjects.DesignThe experiments were carried out on 35 intact, mandibular posterior teeth in 13 subjects: 32 were abutments for 16 fixed bridges that replaced first molars; the other 3 were first premolars adjacent to abutment teeth that served as un-operated controls. Crown preparations were made using an air-rotor with water-spray under regional block anaesthesia (4% articaine with epinephrine 1:100,000). PBF was recorded with a laser Doppler flow meter (LDF) before and after administering the anaesthetic, with the LDF probe on the buccal enamel. PBF was then recorded from the abutment teeth with the probe on buccal dentine after preparing the buccal surfaces of both teeth, after completing the crown preparations, and after 1 and 7 days. PBF was also recorded from the buccal enamel of the control teeth on each occasion.ResultsThe mean±S.D. PBF values before and after anaesthesia were 2.63±2.13 and 2.42±2.38P.U. respectively, which were not significantly different (Paired t-test). The mean values for the abutment teeth after buccal preparation, after complete crown preparation, and after 1 and 7days were 5.20±2.49, 4.53±2.52, 4.92±2.98 and 5.48±2.65P.U. respectively. The 4 values for each tooth were not significantly different (two-way RM ANOVA). In the control group, the values under all six conditions were not significantly different.ConclusionsRegional block anaesthesia produced no change in PBF, nor did full-crown preparation, neither immediately after the procedure nor 1 and 7days later.
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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 7 Ιουνίου 2016
Effect of full crown preparation on pulpal blood flow in man
Identification and Characterization of Mitochondrial Subtypes in Caenorhabditis elegans via Analysis of Individual Mitochondria by Flow Cytometry
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Improvement of core-fucosylated glycoproteome coverage via alternating HCD and ETD fragmentation
Publication date: Available online 6 June 2016
Source:Journal of Proteomics
Author(s): Cheng Ma, Jingyao Qu, Xu Li, Xinyuan Zhao, Lei Li, Cong Xiao, Garrett Edmunds, Ebtesam Gashash, Jing Song, Peng George Wang
Core-fucosylation (CF) plays important roles in regulating biological processes in eukaryotes. Alterations of CF-glycosites or CF-glycans in bodily fluids correlate with cancer development. Therefore, global research of protein core-fucosylation with an emphasis on proteomics can explain pathogenic and metastasis mechanisms and aid in the discovery of new potential biomarkers for early clinical diagnosis. In this study, a precise and high throughput method was established to identify CF-glycosites from human plasma. We found that alternating HCD and ETD fragmentation (AHEF) can provide a complementary method to discover CF-glycosites. A total of 407 CF-glycosites among 267 CF-glycoproteins were identified in a mixed sample made from six normal human plasma samples. Among the 407 CF-glycosites, 10 are without the N-X-S/T/C consensus motif, representing 2.5% of the total number identified. All identified CF-glycopeptide results from HCD and ETD fragmentation were filtered with neutral loss peaks and characteristic ions of GlcNAc from HCD spectra, which assured the credibility of the results. This study provides an effective method for CF-glycosites identification and a valuable biomarker reference for clinical research.Biological significanceCF-glycosytion plays an important role in regulating biological processes in eukaryotes. Alterations of the glycosites and attached CF-glycans are frequently observed in various types of cancers. Thus, it is crucial to develop a strategy for mapping human CF-glycosylation. Here, we developed a complementary method via alternating HCD and ETD fragmentation (AHEF) to analyze CF-glycoproteins. This strategy reveals an excellent complementarity of HCD and ETD in the analysis of CF-glycoproteins, and provides a valuable biomarker reference for clinical research.
Graphical abstract
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Comparative leaf proteomics of drought-tolerant and -susceptible peanut in response to water stress
Publication date: Available online 6 June 2016
Source:Journal of Proteomics
Author(s): Ramesh Katam, Katsumi Sakata, Prashanth Suravajhala, Tibor Pechan, Devaiah M. Kambiranda, Karamthot Sivasankar Naik, Baozhu Guo, Sheikh M. Basha
Water stress (WS) predisposes peanut plants to fungal infection resulting in pre-harvest aflatoxin contamination. Major changes during water stress including oxidative stress, lead to destruction of photosynthetic apparatus and other macromolecules within cells. Two peanut cultivars with diverse drought tolerance characteristics were subjected to WS, and their leaf proteome was compared using two-dimensional electrophoresis complemented with MALDI-TOF/TOF mass spectrometry. Ninety-six protein spots were differentially abundant to water stress in both cultivars that corresponded to 60 non-redundant proteins. Protein interaction prediction analysis suggests that 42 unique proteins showed interactions in tolerant cultivar while 20 showed interactions in the susceptible cultivar, activating other proteins in directed system response networks. Four proteins: glutamine ammonia ligase, chitin class II, actin isoform B, and beta tubulin, involved in metabolism, defense and cellular biogenesis, are unique in tolerant cultivar and showed positive interactions with other proteins. In addition, four proteins: serine/threonine protein phosphate PP1, choline monooxygenase, peroxidase 43, and SNF1-related protein kinase regulatory subunit beta-2, that play a role as cryoprotectants through signal transduction, were induced in drought tolerant cultivar following WS. Eleven interologs of these proteins were found in Arabidopsis interacting with several proteins and it is believed that similar mechanisms/pathways exist in peanut.SignificancePeanuts (Arachis hypogaea L.) are a major source of plant protein grown in subtropical and tropical regions of the world. Pre-harvest aflatoxin contamination is a major problem that affects peanut crop yield and food safety. Poor understanding of molecular and cellular mechanisms associated with aflatoxin resistance is largely responsible for the lack of progress in elucidating a process/methodology for reducing aflatoxin contamination in peanuts. Drought perturbs the invasion of the aflatoxin producing fungus and thus affects the quality and yield of peanut. Therefore, more studies involving the effects of drought stress to determine the molecular changes will enhance our understanding of the key metabolic pathways involved in the combined stresses. The changes associated with the biotic and abiotic interactions within the peanut will be used to determine the metabolic pathways involved in the stress tolerance. This research would be beneficial in identifying the tolerant molecular signatures and promoting food safety and consumer health through breeding superior quality peanut cultivars.
Graphical abstract
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Ameloblastoma: 25 Year Experience at a Single Institution
Abstract
Ameloblastoma is a rare, locally aggressive odontogenic neoplasm, accounting for fewer than 1 % of head and neck tumors. Recent literature suggests that the initial surgical approach and histologic growth patterns are the most important prognostic determinants in ameloblastoma. The aim of this study was to compare the clinical presentation, management, and outcomes of patients with ameloblastoma with data reported in the literature; the study spanned 2 decades at a single institution. The institution's database was searched for all patients with pathologically confirmed ameloblastoma, diagnosed between 1990 and 2015. The data collected included sex, age, clinical and imaging findings, management, histologic pattern, clearance of surgical margins, length of follow-up, time to recurrence, and disease-related mortality. The potential risk factors of recurrence were evaluated using log-rank test, proportional hazard model, and Fisher exact test. Review of the database yielded 54 patients with pathologically confirmed ameloblastoma and follow-up. Recurrence was noted in 13 (24 %) patients. Surgical approach was associated with the risk of recurrence (6.1 % following radical resection vs. 52 % following limited surgery, p = 0.002). There were trends toward higher recurrence rate in the group with pathologically documented positive margins (p = 0.054) and in follicular ameloblastoma (p = 0.35). Transformation into ameloblastic carcinoma was identified in two patients. There was no disease-related mortality. Our study confirms the recent data regarding the importance of radical surgical resection in management of ameloblastoma. Surgical approach appears to be the strongest predictor of tumor clearance.
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Development of Innovative Feedback Device for Swallowing Therapy
Abstract
Dysphagia, which results from various disorders, may increase the risk of aspiration pneumonia, dehydration, and malnutrition. The aim of this study was to develop an innovative evaluation and treatment system for swallowing therapy using virtual reality (VR) feedback and electrical stimulation (ES), and to make an initial evaluation of its potential. In this system, the activation of the submental muscle and acceleration of laryngeal movement are used as the evaluation and feedback information. Twenty-one patients with chronic dysphagia for an average of 26.3 months were recruited for the VR feedback study. Each participant underwent 16 treatment sessions. After therapy, the Functional Oral Intake Scale results changed from 3.3 ± 1.5 to 5.0 ± 1.6 with statistical significance (p = 0.000). Thirteen healthy subjects were enrolled in the ES study. ES was applied for more than 2 s while the subjects were swallowing. With and without ES, swallowing triggering times were 456.17 ± 106.92 and 552.13 ± 105.97 ms, respectively. These differences were statistically significant (p = 0.04). Accelerations of laryngeal movement were 0.23 ± 0.1 g (g = 9.8 m/s2) and 0.20 ± 0.08 g, respectively, with a significant statistical difference (p = 0.033). The feasibility of a prototype that combines swallowing evaluation, VR feedback therapy, and synchronized ES is demonstrated for further clinical trials. Further comprehensive clinical studies are needed to verify the clinical efficacy of the device.
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Whole-brain changes in white matter microstructure after radiotherapy for nasopharyngeal carcinoma: a diffusion tensor imaging study
Abstract
Radiation-induced local white matter (WM) damage has been observed by diffusion tensor imaging (DTI) within a priori-defined regions of interest following radiotherapy (RT) for nasopharyngeal carcinoma (NPC). In this study, we aimed to detect WM changes throughout the brain of NPC patients by DTI. Tract-based spatial statistics (TBSS) was used to analyze DTI data from 81 NPC patients. Fractional anisotropy (FA) and mean diffusivity (MD) were quantified across the whole brain in separate groups: pre-RT, and <6, 6–12, and >12 months post-RT. We found that fractional anisotropy values were significantly lower in the right frontal, parietal, and occipital WM <6 months post-RT compared with pre-RT and remained significantly lower in the right frontal and parietal WM at >12 months. MD values were significantly higher in the right occipital, bilateral temporal, right occipital–temporal junction, left parietal, left centrum semiovale, and left frontal–parietal junction WM <6 months post-RT and remained higher in the right occipital WM at >12 months. This study suggests that changes in white matter microstructure following RT for NPC were widespread, complex, and dynamic. Diffusion tensor imaging with TBSS analysis allows for early non-invasive detection of RT-induced WM damage.
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Acute invasive fungal rhinosinusitis: our experience with 18 cases
Abstract
Acute invasive fungal rhinosinusitis (AIFRS) is a rapidly progressive life threatening infection that is seen most commonly among immunocompromised patients. We present a case series of 18 patients clinically and histopathologically diagnosed with AIFRS with a mean follow-up of 9.11 ± 2.51 months (range 6–17). Demographic data, apparent symptoms and signs, underlying disorders, and outcomes are discussed. The mean age was 39.56 ± 20.66 years (range 2–75). The most common underlying diseases were diabetes mellitus (50 %) and leukemia (44.44 %). Mucosal biopsy confirmed fungal invasion of the nasal mucosa in all cases. The main fungi were Rhizopus oryzae (55.56 %), Absidia mucor (16.67 %), and Aspergillus fumigatus (27.78 %). Headache and facial pain (77.8 %), facial paresthesia (55.6 %), and ophthalmoplegia (33.3 %) were the most common symptoms and signs. Computed tomography and endoscopic findings showed various stages of sinonasal (100 %), pterygopalatine fossa (55.56 %), orbital (44.45 %), and cerebral (5.56 %) involvement. All patients underwent serial surgical debridement (3.78 ± 1.80 times; range 2–8) simultaneously with systemic antifungal therapy and proper management of the underlying disease. The most extreme case with brain involvement survived and recovered with no evidence of recurrent disease following treatment. All patients were considered cured after two endoscopic negative histopathologic evaluations. Three patients (16.67 %) died, one from uncontrolled leukemia and two due to renal failure. AIFRS is a potentially fatal condition, however, early diagnosis and management of the underlying disease accompanied with systemic antifungal and aggressive serial surgical intervention appears to be effective in reducing mortality in most patients.
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For staining of ALK protein, the novel D5F3 antibody demonstrates superior overall performance in terms of intensity and extent of staining in comparison to the currently used ALK1 antibody
Abstract
Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm. Approximately 50 % of IMTs show an anaplastic lymphoma kinase (ALK) gene fusion resulting in ALK overexpression on immunohistochemistry (IHC). A novel anti-ALK monoclonal antibody (D5F3) has been suggested to be of superior sensitivity to the ALK1 antibody which is currently used. We compared the performance of D5F3 in detecting ALK protein expression in IMTs from various anatomic sites compared to the currently utilized ALK1. We selected 25 IMTs from our surgical pathology files (2005–2015). The novel rabbit monoclonal anti-human CD246 (clone D5F3) and the currently used mouse monoclonal anti-human CD246 (clone ALK1) were used for immunohistochemical staining (IHC) in an automated slide stainer. The percentage of immunoreactive tumor cells (0, <5 %, 5–50 %, >50 %) and cytoplasmic staining intensity (graded 0–3) were assessed and compared between the two antibodies. Fluorescence in situ hybridization (FISH) studies for ALK gene rearrangement were performed on 11 tumors. D5F3 antibody stained 76 % and ALK1 antibody stained 72 % of IMTs (p = 0.747). Compared to staining with ALK1, D5F3 stained a higher proportion of cases extensively (>50 % cells) (76 vs. 28 %, p < 0.001) and with high intensity (grade 3 76 % vs 0; p < 0.001). FISH and IHC findings (for both antibodies) were concordant in 9/10 (90 %) IMTs, in which results were informative. The novel anti-ALK rabbit monoclonal antibody (D5F3 clone) demonstrates superior overall performance in term of intensity and extent of staining of ALK protein in IMT. We found IHC staining with both antibody clones to correlate equally well with FISH results for detection of ALK rearrangement.
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Ameloblastoma: 25 Year Experience at a Single Institution
Abstract
Ameloblastoma is a rare, locally aggressive odontogenic neoplasm, accounting for fewer than 1 % of head and neck tumors. Recent literature suggests that the initial surgical approach and histologic growth patterns are the most important prognostic determinants in ameloblastoma. The aim of this study was to compare the clinical presentation, management, and outcomes of patients with ameloblastoma with data reported in the literature; the study spanned 2 decades at a single institution. The institution's database was searched for all patients with pathologically confirmed ameloblastoma, diagnosed between 1990 and 2015. The data collected included sex, age, clinical and imaging findings, management, histologic pattern, clearance of surgical margins, length of follow-up, time to recurrence, and disease-related mortality. The potential risk factors of recurrence were evaluated using log-rank test, proportional hazard model, and Fisher exact test. Review of the database yielded 54 patients with pathologically confirmed ameloblastoma and follow-up. Recurrence was noted in 13 (24 %) patients. Surgical approach was associated with the risk of recurrence (6.1 % following radical resection vs. 52 % following limited surgery, p = 0.002). There were trends toward higher recurrence rate in the group with pathologically documented positive margins (p = 0.054) and in follicular ameloblastoma (p = 0.35). Transformation into ameloblastic carcinoma was identified in two patients. There was no disease-related mortality. Our study confirms the recent data regarding the importance of radical surgical resection in management of ameloblastoma. Surgical approach appears to be the strongest predictor of tumor clearance.
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Role of a brain-gut axis in energy balance [Physiology]
The starvation-inducible coactivator cAMP response element binding protein (CREB)–cAMP-regulated transcription coactivator (Crtc) has been shown to promote starvation resistance in Drosophila by up-regulating CREB target gene expression in neurons, although the underlying mechanism is unclear. We found that Crtc and its binding partner CREB enhance energy homeostasis by stimulating the...
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Odor combinations influence mouse behavior [Neuroscience]
The mechanisms by which odors induce instinctive behaviors are largely unknown. Odor detection in the mouse nose is mediated by >1, 000 different odorant receptors (ORs) and trace amine-associated receptors (TAARs). Odor perceptions are encoded combinatorially by ORs and can be altered by slight changes in the combination of activated...
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SMIT1/myo-inositol regulate ion channels via PIP2 [Neuroscience]
Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. However, whether myo-inositol accumulation during osmoregulation affects signaling and excitability...
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Folding of the serpin antithrombin III [Biochemistry]
Although proteins generally fold to their thermodynamically most stable state, some metastable proteins populate higher free energy states. Conformational changes from metastable higher free energy states to lower free energy states with greater stability can then generate the work required to perform physiologically important functions. However, how metastable proteins fold...
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Dopaminergic reinnervation by 24-y-old transplants [Neuroscience]
Clinical trials using cells derived from embryonic ventral mesencephalon have shown that transplanted dopaminergic neurons can survive and function in the long term, as demonstrated by in vivo brain imaging using 18F-fluorodopa and 11C-raclopride positron emission tomography. Here we report the postmortem analysis of a patient with Parkinson's disease who...
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Relevance of in vitro biophysical studies [Biological Sciences]
In his letter, Alberti (1) does not challenge any of the central results in our paper (2), including the main proof that upward curvature in the logarithm of the unfolding rate of a protein as a function of an applied mechanical force implies that underlying energy landscape is multidimensional. However,...
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Computational power of network exploration [Physical Sciences]
We very much appreciate Einarsson's interest in our work (1) and his well-articulated observations regarding the computational complexity of dynamic programming algorithms for the Subset Sum Problem (SSP) (2). We would like to distinguish clearly between the concept we propose and the physical device we used to demonstrate that concept....
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Genes and sociality [Anthropology]
Unraveling the complex sequence of molecular, biochemical, and neuronal cascades that transpire between gene action and behavioral phenotypes has been an exceptionally tough scientific nut to crack. The difficulties in connecting the links between genes and behavior have been especially problematic for social phenotypes, including species-typical social structure, in which...
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Population projections with migration uncertainty [Statistics]
We produce probabilistic projections of population for all countries based on probabilistic projections of fertility, mortality, and migration. We compare our projections to those from the United Nations' Probabilistic Population Projections, which uses similar methods for fertility and mortality but deterministic migration projections. We find that uncertainty in migration projection...
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Variation in patterns of aging [Evolution]
Do all species experience the declines of old age? No. Do we currently have theories that accurately predict which species escape these declines? In PNAS, Warner et al. (1) demonstrate that the answer to this question is also "no." Understanding the breadth and diversity of the patterns of aging across...
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Anchored protein folding [Biological Sciences]
In a recent article in PNAS, Zhuravlev et al. (1) determine unfolding trajectories of the Src tyrosine kinase SH3 (Src homology 3) domain [Protein Data Base (PDB) ID code 1SRL]. Using laser optical tweezing, constant force was applied to the SH3 N and C termini (residues 9 and 59), and...
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Thyroid computed tomography imaging: pictorial review of variable pathologies
Abstract
Focal and diffuse thyroid abnormalities are commonly encountered during the interpretation of computed tomography (CT) exams performed for various clinical purposes. These findings can often lead to a diagnostic dilemma, as the CT reflects the nonspecific appearances. Ultrasound (US) examination has a superior spatial resolution and is considered the modality of choice for thyroid evaluation. Nevertheless, CT detects incidental thyroid nodules (ITNs) and plays an important role in the evaluation of thyroid cancer.
In this pictorial review, we cover a wide spectrum of common and uncommon, incidental and non-incidental thyroid findings from CT scans. We also discuss the most common incidental thyroid findings, best practices for their evaluation, and recommendations for their management. In addition, we explore the role of imaging in the assessment of thyroid carcinoma (before and after treatment) and preoperative thyroid goiter, as well as localization of ectopic and congenital thyroid tissue.
Teaching Points
• Thyroid disorders tend to have non-specific CT appearances.
• ITNs are common on neck CT.
• ITN management depends on nodule size, age, health status, lymphadenopathy, and invasion.
• CT is used in assessment of cancer extension, mass effect, invasion, and recurrence.
• CT plays a role in preoperative planning in patients with symptomatic goiter.
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Cl − channels in apoptosis
Abstract
A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K+, Cl−, and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl− channels LRRC8, TMEM16/anoctamin, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines. Its presence also determines sensitivity towards cytostatic drugs such as cisplatin. Recent data point to a molecular and functional relationship of LRRC8A and anoctamins (ANOs). ANO6, 9, and 10 (TMEM16F, J, and K) augment apoptotic Cl− currents and AVD, but it remains unclear whether these anoctamins operate as Cl− channels or as regulators of other apoptotic Cl− channels, such as LRRC8. CFTR has been known for its proapoptotic effects for some time, and this effect may be based on glutathione release from the cell and increase in cytosolic reactive oxygen species (ROS). Although we find that CFTR is activated by cell swelling, it is possible that CFTR serves RVD/AVD through accumulation of ROS and activation of independent membrane channels such as ANO6. Thus activation of ANO6 will support cell shrinkage and induce additional apoptotic events, such as membrane phospholipid scrambling.
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Time to Detection with BacT/Alert FA Plus Compared to BacT/Alert FA Blood Culture Media
Abstract
Rapid identification of the causative pathogen in patients with bacteremia allows adjustment of antibiotic therapy and improves patient outcomes. We compared in vitro and real-life time to detection (TTD) of two blood culture media, BacT/Alert FA (FA) and BacT/Alert FA Plus (FA Plus), for the nine most common species of bacterial pathogens recovered from blood samples. Experimental data from simulated cultures was compared with microbiology records of TTD for both culture media with growth of the species of interest in clinical blood cultures. In the experimental conditions, median TTD was 3.8 hours (23.9 %) shorter using FA Plus media. The magnitude of reduction differed between species. Similarly, in real life data, FA Plus had shorter TTD than FA media; however, the difference between culture media was smaller, and median TTD was only 1 hour (8.5 %) less. We found shorter TTD with BacT/Alert FA Plus culture media, both experimentally and in real-life conditions and unrelated to antibiotic neutralization, highlighting the importance of appropriate blood culture media selection.
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Hepatitis B and Schistosoma co-infection in a non-endemic area
Abstract
Schistosomiasis is related to the development of liver fibrosis and portal hypertension. Chronic co-infection with HBV and Schistosoma has been associated in endemic areas with a higher risk for a more severe liver disease. However, no studies have assessed the real importance of this co-infection in non-endemic regions. This is a retrospective observational study of Sub-Saharan immigrants attending between October 2004 and February 2014. Patients with chronic HBV infection with and without evidence of schistosomal infection were compared. Epidemiological, analytical, and microbiological data were analysed. Likelihood of liver fibrosis based on APRI and FIB-4 indexes was established. A total of 507 patients were included in the study, 170 (33.5 %) of them harbouring evidence of schistosome infection. No differences were found in transaminase, GGT, and ALP levels. In fibrosis tests, a higher proportion of patients with HVB and S. mansoni detection reached possible fibrosis scores (F > 2) when compared to patients without schistosomiasis: 17.4 vs 14.2 % and 4.3 % vs 4.2 % (using high sensitivity and high specificity cut-offs respectively), although differences were not statistically significant (p = 0.69, p = 0.96). For possible cirrhosis (F4) score, similar results were observed: 4.3 % of co-infected patients vs 2.1 % of mono-infected ones, p = 0.46. According to these datas, in non-endemic regions the degree of hepatic fibrosis in patients with chronic hepatitis B is not substantially modified by schistosome co-infection.
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Larva migrans syndrome caused by Toxocara and Ascaris roundworm infections in Japanese patients
Abstract
Larva migrans syndrome (LMS) caused by Toxocara and Ascaris roundworms is generally believed to be more common in children, while a report from Japan suggests that it is more common in adults. We conducted a large-scale retrospective study to confirm these findings and to clarify what caused the difference between Japan and other countries, to reveal overlooked aspects of this disease. The clinical information of 911 cases which we diagnosed as Toxocara or Ascaris LMS during 2001 and 2015 was analysed. Information used included age, sex, address (city or county), chief complaint, present history, dietary history, overseas travelling history, medical imaging findings and laboratory data (white blood cell count, peripheral blood eosinophil number and total IgE). The sex ratio of the disease was 2.37 (male/female = 641/270). The number of patients not younger than 20 years old were 97.8 and 95.1 % among males and females, respectively. Major disease types were visceral, ocular, neural and asymptomatic. The visceral type was more prevalent in older patients, while younger patients were more vulnerable to ocular symptoms. More than two-thirds of the patients whose dietary habits were recorded had a history of ingesting raw or undercooked animal meat. LMS caused by Toxocara or Ascaris is primarily a disease of adult males in Japan, who probably acquired infections by eating raw or undercooked animal meat/liver. Healthcare specialists should draw public attention to the risk of raw or undercooked animal meat in Europe as well.
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Incidence and predictors of cardiovascular disease, chronic kidney disease, and diabetes in HIV/HCV-coinfected patients who achieved sustained virological response
Abstract
Data on the effects of sustained virologic response (SVR) to hepatitis C virus (HCV) therapy on the outcome of extrahepatic complications are scarce. We conducted this study to assess the impact of SVR on the occurrence of chronic kidney disease (CKD), diabetes mellitus (DM), and cardiovascular disease (CVD) in a cohort of human immunodeficiency virus (HIV)-infected patients. We analyzed coinfected HIV/HCV patients in the Management of Standardized Evaluation of Retroviral HIV Infection (MASTER) cohort. Only event-free patients with a serum HCV-RNA determination at baseline were included. Patients were divided into four groups: INF-exposed with SVR; INF-exposed without SVR; spontaneous HCV clearance; untreated viremic patients. We estimated the incidence of extrahepatic complications and employed Kaplan–Meier curves and Cox regression to assess the association of SVR/INF strata adjusted for a series of confounders. Data from 1676 patients were analyzed (20.29 % started an INF-based regimen). Overall, the incidence of CKD, DM, CVD, and death was 5.32 [95 % confidence interval (CI) 3.99–6.98], 10.13 (95 % CI 8.20–12.37), 6.79 (95 % CI 5.26–8.65), and 13.49 (95 % CI 11.29–16.0) per 1000 person-years of follow-up, respectively. In the Cox model for treated patients, SVR was not associated with a lower risk of CKD, DM, CVD, and death compared to non-SVR. Cirrhosis was significantly associated with a higher risk of CKD [hazard ratio (HR) 2.13; 95 % CI 1.06–4.31], DM (HR 3.48; 95 % CI 2.18–5.57), and death (HR 6.18; 95 % CI 4.1–9.31), but not of CVD (HR 1.14; 95 % CI 0.57–2.3). There are still many unknowns regarding the impact of SVR on the occurrence of extrahepatic complications in coinfected HIV/HCV patients. Further investigations are needed in order to elucidate the role of SVR as an independent prognostic factor for extrahepatic events.
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The effect of tooth brushing, irrigation, and topical tetracycline administration on the reduction of oral bacteria in mechanically ventilated patients: a preliminary study
Abstract
Background
One of the main causes of ventilator-associated pneumonia (VAP) is thought to be aspiration of oropharyngeal fluid containing pathogenic microorganisms. The aim of this study was to examine the effects of various oral care methods on the reduction of oral bacteria during intubation.
Methods
First, the effect of mechanical oral cleaning was investigated. The bacterial count on the tongue and in the oropharyngeal fluid was measured after tooth brushing, irrigation, and three hours after irrigation in mechanically ventilated patients at the intensive care unit (ICU).
Next, the efficacy of topical administration of tetracycline and povidone iodine on the inhibition of bacterial growth on the tongue and in the oropharyngeal fluid was examined in oral cancer patients during neck dissection.
Results
The number of bacteria in the oropharyngeal fluid was approximately 105–106 cfu/mL before surgery, but increased to 108 cfu/mL after intubation. Oral care with tooth brushing and mucosal cleaning did not reduce oral bacteria, while irrigation of the oral cavity and oropharynx significantly decreased it to a level of 105 cfu/mL (p < 0.001). However, oral bacteria increased again to almost 108 cfu/mL within three hours of irrigation.
Oral bacteria did not decrease by topical povidone iodine application. In contrast, 30 min after topical administration of tetracycline, the number of oral bacteria decreased to 105 cfu/mL, and remained under 106 cfu/mL throughout the entire experimental period of 150 min.
Conclusions
While the present studies are only preliminary, these results indicate that irrigation of the oral cavity and oropharynx followed by topical antibiotic administration may reduce oral bacteria in mechanically ventilated patients.
Trial registration
UMIN000018318, 1 August 2015.
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The mediating role of general self-efficacy in the association between perceived social support and oral health-related quality of life after initial periodontal therapy
Abstract
Background
Although initial periodontal therapy can ease some physical and psychological discomforts from periodontitis and improve patients' oral health-related quality of life (OHRQoL), it is also vital to find positive resources from psychological and social aspects to promote the overall OHRQoL. This study aims to explore the associations of perceived social support (PSS) and general self-efficacy with OHRQoL and the mediating role of general self-efficacy in PSS-OHRQoL association after initial periodontal therapy.
Methods
A prospective case series study was conducted among consecutive outpatients with chronic periodontitis during the period of July 2014–April 2015. A total of 145 eligible patients responded to OHRQoL questionnaire and periodontal examination at baseline. About 4 to 5 weeks after initial periodontal therapy, 120 patients completed the second OHRQoL measurement and periodontal examination, along with PSS and general self-efficacy measurement. The Wilcoxon matched-pairs signed-rank test was used to determine the difference between baseline and post-treatment OHRQoL scores and periodontal parameters. Hierarchical linear regression analysis was used to explore the associations of PSS and general self-efficacy with post-treatment OHRQoL after adjusting for some demographic and periodontal variables. Asymptotic and resampling strategies were performed to explore the mediating role of general self-efficacy.
Results
Initial periodontal therapy resulted in a significant improvement in the mean total score and all domains of OHRQoL and all periodontal parameters measured. In hierarchical linear regression analysis, clinical attachment loss (CAL) was significantly and positively associated with post-treatment OHRQoL score (β = 0.265, p < 0.01), while PSS (β = −0.303, p < 0.01) and general self-efficacy (β = −0.221, p < 0.01) were significantly and negatively associated with post-treatment OHRQL score, respectively. A significant mediating role of general self-efficacy (a*b = −0.139, BCa 95 % CI: −0.298, −0.011) in the association between PSS and post-treatment OHRQoL was revealed, and the proportion of the mediating role of general self-efficacy was 31.4 %.
Conclusions
Initial periodontal therapy could significantly improve all aspects of OHRQoL. PSS and general self-efficacy could be the positive resources for improving OHRQoL after initial periodontal therapy among patients with periodontitis. General self-efficacy partly mediated the association between PSS and post-treatment OHRQoL.
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Early gastric cancer metastasizing to the rectum, possibly via a hematogenous route: a case report and review of literature
Abstract
Background
The most common pattern of recurrence of gastric cancer (GC) is peritoneal dissemination. However, rectal metastasis via hematogenous or lymphatic spread is exceedingly rare. We present a case of a 65-year-old man with an intramucosal GC who developed a rectal recurrence, possibly via a hematogenous route.
Case presentation
A 65-year-old man underwent curative endoscopic submucosal dissections for the intramucosal GCs at the anterior wall of the fornix twice. The third GC at the similar location was treated by radical laparoscopic proximal gastrectomy; microscopic examination revealed well-differentiated tubular adenocarcinoma confined to the lamina propria mucosae (T1aN0M0, stage IA). Follow-up colonoscopy revealed a 30-mm submucosal mass in the rectal wall 2 years later, and a metastasis of gastric origin was suspected histopathologically. After a staging laparoscopy confirmed the absence of findings suggestive of serosal involvement or peritoneal dissemination, including negative peritoneal washing cytology, a laparoscopic low anterior resection with lymph node dissection was performed. Microscopically, the tumor was found to mainly be located in the submucosal layer and showed features of moderately differentiated tubular adenocarcinoma. The serosal surface was free of disseminated tumor. Lymph node metastases were identified. Immunohistochemically, there were foci of carcinoma cells that were positive for cytokeratin 20; however, they were negative for cytokeratin 7. Negative staining for caudal-type homeobox 2, a transcription factor indicating goblet cell differentiation, combined with absence of intramucosal carcinoma in the rectal mucosa, suggested a diagnosis of metastatic adenocarcinoma of gastric origin. The absence of evidence of peritoneal dissemination suggested hematogenous or lymphatic spread.
Conclusion
Although rectal metastasis from GC, particularly when attributable to hematologic or lymphatic metastasis, is very rare, metastatic gastric adenocarcinoma should be considered as a differential diagnosis for patients who present with a rectal tumor and a past history of GC, even if it is an early GC.
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National surveillance of Staphylococcus epidermidis recovered from bloodstream infections in Belgian hospitals
Objectives
The objectives of this study were: (i) to determine the species diversity of CoNS isolated from bloodstream infections collected during a national surveillance study; and (ii) to examine the antimicrobial resistance and genomic diversity among Staphylococcus epidermidis isolates.
MethodsEighty CoNS were identified by MALDI-TOF. Antimicrobial resistance determination, molecular characterization of resistance and virulence genes, and molecular typing were performed for S. epidermidis isolates.
ResultsThe majority (76%) of CoNS were identified as S. epidermidis. Among these S. epidermidis, 77% were resistant to methicillin [methicillin-resistant S. epidermidis (MRSE)] and showed multiresistance to other antimicrobials. Genes implicated in resistance were erm(C), erm(A) and msr(A) for erythromycin, aacA-aphD and aadC for aminoglycosides, tet(K) for tetracycline and mupA for high-level resistance to mupirocin. Molecular typing showed that 34/40 MRSE isolates (85%) belonged to clonal complex (CC) 2 that could be subdivided into CC2-I (ST2) and CC2-II (ST5, ST59 and ST88). In contrast, methicillin-susceptible S. epidermidis displayed high genomic diversity. The majority (70%) of S. epidermidis isolates contained an icaA or arcA gene. The icaA gene was found in the CC2-I subgroup, whereas arcA was more common in methicillin-susceptible S. epidermidis.
ConclusionsS. epidermidis was frequently recovered among CoNS isolated from bloodstream infections with a high proportion of MRSE being multiresistant. A large number of S. epidermidis belonged to CC2, a clone that is disseminated worldwide. More studies are needed to understand its clonal evolutionary success.
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Emergence of azole-resistant Candida parapsilosis causing bloodstream infection: results from laboratory-based sentinel surveillance in South Africa
Objectives
To compare Candida species distribution and antifungal susceptibility at South African public- and private-sector hospitals.
MethodsFrom February 2009 through to August 2010, laboratory-based surveillance for candidaemia was undertaken at 11 public-sector hospitals and >85 private-sector hospitals across South Africa. A case was defined as a patient of any age admitted to a sentinel hospital with isolation of Candida species from blood culture. Viable isolates were identified and tested for antifungal susceptibility at a reference laboratory. Demographic and limited clinical data were abstracted from laboratory records.
ResultsIn total, 2172 cases of candidaemia were detected. Among patients with available data, almost two-thirds were critically ill (719/1138, 63%). On multivariable analysis, neonates [adjusted OR (aOR), 2.2; 95% CI, 1.5–3.1; P < 0.001] and patients diagnosed in Gauteng province (aOR, 1.9; 95% CI, 1.3–2.7; P < 0.001) or in the private sector (aOR, 1.9; 95% CI, 1.2–3.2; P = 0.008) were significantly more likely to be infected with Candida parapsilosis than any other Candida species. Of 531 C. parapsilosis isolates, only 199 (37%) were susceptible to fluconazole and voriconazole; 44% (123/282) of fluconazole-resistant isolates were voriconazole cross-resistant. Factors associated with fluconazole non-susceptible C. parapsilosis infection on multivariable analysis included diagnosis in Gauteng province (aOR, 4.2; 95% CI, 2.7–6.7; P < 0.001), an ICU (aOR, 2.3; 95% CI, 1.5–3.6; P < 0.001) or the private sector (aOR, 2.2; 95% CI, 1.4–3.5; P < 0.001).
ConclusionsThe dominance of triazole non-susceptible C. parapsilosis limits the choice of antifungal agents for management of candidaemia among critically ill neonates, children and adults in resource-limited South African hospitals.
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Comparative effects of overproducing the AraC-type transcriptional regulators MarA, SoxS, RarA and RamA on antimicrobial drug susceptibility in Klebsiella pneumoniae
Objectives
In Klebsiella pneumoniae, overproduction of RamA and RarA leads to increased MICs of various antibiotics; MarA and SoxS are predicted to perform a similar function. We have compared the relative effects of overproducing these four AraC-type regulators on envelope permeability (a combination of outer membrane permeability and efflux), efflux pump and porin production, and antibiotic susceptibility in K. pneumoniae.
MethodsRegulators were overproduced using a pBAD expression vector. Antibiotic susceptibility was measured using disc testing. Envelope permeability was estimated using a fluorescent dye accumulation assay. Porin and efflux pump production was quantified using proteomics and validated using real-time quantitative RT–PCR.
ResultsEnvelope permeability and antibiotic disc inhibition zone diameters both reduced during overproduction of RamA and to a lesser extent RarA or SoxS, but did not change following overproduction of MarA. These effects were associated with overproduction of the efflux pumps AcrAB (for RamA and SoxS) and OqxAB (for RamA and RarA) and the outer membrane protein TolC (for all regulators). Effects on porin production were strain specific.
ConclusionsRamA is the most potent regulator of antibiotic permeability in K. pneumoniae, followed by RarA then SoxS, with MarA having very little effect. This observed relative potency correlates well with the frequency at which these regulators are reportedly overproduced in clinical isolates.
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A randomized clinical trial comparing ritonavir-boosted lopinavir versus maraviroc each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection
Objectives
The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus maraviroc, both with tenofovir disoproxil/emtricitabine as the backbone.
MethodsWe conducted a prospective, open, randomized clinical trial. Individuals attending the emergency room because of potential sexual exposure to HIV and who met criteria for receiving PEP were randomized to one of two groups: tenofovir disoproxil/emtricitabine (245/200 mg) once daily plus either ritonavir-boosted lopinavir (400/100 mg) or maraviroc (300 mg) twice daily. Five follow-up visits were scheduled for days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov: NCT01533272.
ResultsOne-hundred-and-seventeen individuals were randomized to receive ritonavir-boosted lopinavir and 120 to maraviroc (n = 237). PEP non-completion at day 28 was 38% (n = 89), with significant differences between arms [ritonavir-boosted lopinavir 44% (n = 51) versus maraviroc 32% (n = 38), P = 0.05]. We performed a modified ITT analysis including only those patients who attended on day 1 (n = 182). PEP non-completion in this subgroup was also significantly higher in the ritonavir-boosted lopinavir arm (27% versus 13%, P = 0.004). The proportion of patients with low adherence was similar between arms (52% versus 47%, P = 0.56). Adverse events were reported by 111 patients and were significantly more common in the ritonavir-boosted lopinavir arm (72% versus 51%, P = 0.003). No seroconversions were observed during the study.
ConclusionsPEP non-completion and adverse events were both significantly higher in patients allocated to ritonavir-boosted lopinavir. These data suggest that maraviroc is a well-tolerated antiretroviral that can be used in this setting.
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HIV virological failure and drug resistance in a cohort of Tanzanian HIV-infected adults
Objectives
There are few data on ART failure rates and drug resistance from Tanzania, where there is a wide diversity of non-B HIV subtypes. We assessed rates and predictors of virological failure in HIV-infected Tanzanians and describe drug resistance patterns in a subgroup of these patients.
MethodsART-naive, HIV-1-infected adults enrolled in a randomized controlled trial between November 2006 and 2008 and on ≥24 weeks of first-line NNRTI-containing ART were included. Population-based genotyping of HIV-1 protease and reverse transcriptase was performed on stored plasma from patients with virological failure (viral load >1000 copies/mL at ≥24 weeks of ART) and at baseline, where available.
ResultsA total of 2403 patients [median (IQR) age 37 (32–43) years; 70% female] were studied. The median (IQR) baseline CD4+ T cell count was 128 (62–190) cells/μL. Predominant HIV subtypes were A, C and D (92.2%). The overall rate of virological failure was 14.9% (95% CI 13.2%–16.1%). In adjusted analyses, significant predictors of virological failure were lower CD4+ T cell count (P = 0.01) and non-adherence to ART (P < 0.01). Drug resistance mutations were present in 87/115 samples (75.7%); the most common were M184V/I (52.2%) and K103N (35%). Thymidine analogue mutations were uncommon (5.2%). The prevalence of mutations in 45 samples pre-ART was 22%.
ConclusionsHigh levels of early ART failure and drug resistance were observed among Tanzanian HIV-1-infected adults enrolled in a well-monitored study. Initiating treatment early and ensuring optimal adherence are vital for the success and durability of first-line ART in these settings.
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Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals
Objectives
Co-formulated elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine is among the preferred regimens for first-line ART. A population approach was used to characterize the pharmacokinetics of elvitegravir and cobicistat and identify individual factors and co-medications influencing their disposition, taking into consideration the interaction between the two compounds.
MethodsThe study population included 144 HIV-infected individuals who provided 186 and 167 elvitegravir and cobicistat plasma concentrations, respectively. First, distinct NONMEM® analyses were conducted for elvitegravir and cobicistat, including individual demographic, clinical and genetic factors as potential covariates. Elvitegravir and cobicistat interaction was then assessed through different inhibitory models. Simulations based on the final model served to compare expected drug concentrations under standard and alternative dosage regimens.
ResultsClearance with between-subject variability was 7.6 L/h [coefficient of variation (CV) 16.6%] and volume of distribution 61 L for elvitegravir and 16.0 L/h (CV 41.9%) and 88.3 L, respectively, for cobicistat. Concomitant administration of non-ritonavir-boosted atazanavir decreased elvitegravir clearance by 35%, likely due to UDP-glucuronosyl transferase (UGT) 1A1 inhibition. Concomitant administration of non-ritonavir-boosted atazanavir and ritonavir-boosted darunavir decreased cobicistat clearance by 47% and 27%, respectively. The final interaction model included cobicistat exposure (AUC0–24) on elvitegravir clearance. Simulations confirmed that a reduced elvitegravir dose of 85 mg co-administered with cobicistat and atazanavir produces a concentration–time course comparable to the standard regimen without atazanavir.
ConclusionsElvitegravir and cobicistat pharmacokinetic variability appears to be mainly explained by drug–drug interactions that may be encountered in routine clinical practice. In these cases, therapeutic drug monitoring and surveillance for potential toxicities would be justified.
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Intravenous amoxicillin/clavulanate for the prevention of bacteraemia following dental procedures: a randomized clinical trial
Objectives
Although controversy exists regarding the efficacy of antibiotic prophylaxis for patients at risk of infective endocarditis, expert committees continue to publish recommendations for antibiotic prophylaxis regimens. This study aimed to evaluate the efficacy of four antimicrobial regimens for the prevention of bacteraemia following dental extractions.
MethodsThe study population included 266 adults requiring dental extractions who were randomly assigned to the following five groups: control (no prophylaxis); 1000/200 mg of amoxicillin/clavulanate intravenously; 2 g of amoxicillin by mouth; 600 mg of clindamycin by mouth; and 600 mg of azithromycin by mouth. Venous blood samples were collected from each patient at baseline and at 30 s, 15 min and 1 h after dental extractions. Samples were inoculated into BACTEC Plus culture bottles and processed in the BACTEC 9240. Conventional microbiological techniques were used for subcultures and further identification of the isolated bacteria. The trial was registered at ClinicalTrials.gov with ID number NCT02115776.
ResultsThe incidence of bacteraemia in the control, amoxicillin/clavulanate, amoxicillin, clindamycin and azithromycin groups was: 96%, 0%, 50%, 87% and 81%, respectively, at 30 s; 65%, 0%, 10%, 65% and 49% at 15 min; and 18%, 0%, 4%, 19% and 18% at 1 h. Streptococci were the most frequently identified bacteria. The percentage of positive blood cultures at 30 s post-extraction was lower in the amoxicillin/clavulanate group than in the amoxicillin group (P < 0.001). The incidence of bacteraemia in the clindamycin group was similar to that in the control group.
ConclusionsBacteraemia following dental extractions was undetectable with amoxicillin/clavulanate prophylaxis. Alternative antimicrobial regimens should be sought for patients allergic to the β-lactams.
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Ciprofloxacin and ceftriaxone alter cytokine responses, but not Toll-like receptors, to Salmonella infection in vitro
Objectives
Antibiotics that enhance host natural defences to infection offer an alternative approach to treating infections. However, mechanisms underlying such processes are poorly understood. The aim of this study was to investigate the effects of clinically relevant concentrations of two antibiotics on bacterial interactions with murine macrophages.
MethodsAdhesion of Salmonella Typhimurium SL1344 to and invasion by Salmonella Typhimurium SL1344 of antibiotic-treated or untreated J774 murine macrophages were measured using a tissue culture infection model. Expression of genes central to the Toll-like receptor (TLR) signalling pathway of macrophages infected with Salmonella was analysed using the RT2 Profiler PCR Array. Cytokine production was measured by ELISA.
ResultsAdhesion of Salmonella Typhimurium SL1344 to J774 macrophage monolayers was increased when macrophages were exposed to ciprofloxacin and ceftriaxone, while invasion was decreased by ciprofloxacin. Expression of IL-1β and TNF-α mRNA was greater in SL1344-infected macrophages that had been treated with ciprofloxacin or ceftriaxone than in macrophages exposed to antibiotics alone or SL1344 alone. TLR mRNA was down-regulated by SL1344 infection, a response that was not altered by antibiotic pretreatment.
ConclusionsClinically relevant concentrations of two antibiotics differentially enhanced the response of immune cells and their interaction with bacteria, increasing bacterial adhesion to macrophages and increasing cytokine production. As increased expression of IL-1β fosters apoptosis of Salmonella-infected macrophages and clearance by neutrophils, the immunomodulatory potential of these antibiotics may explain, in part, why these two drugs continue to be used to treat salmonellosis successfully.
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Prospective evaluation of the OXA-48 K-SeT assay, an immunochromatographic test for the rapid detection of OXA-48-type carbapenemases
Objectives
There is an urgent need for accurate and fast diagnostic tests to identify MDR bacteria. Here, we evaluated an immunochromatographic assay (the OXA-48 K-SeT assay) to detect OXA-48-like carbapenemase-producing Enterobacteriaceae from culture colonies.
MethodsOne hundred and sixty-one collection isolates with characterized β-lactamase content and 185 non-duplicate consecutive clinical isolates referred to the Associated French National Reference Center between 15 February and 15 March 2015 were used to evaluate the OXA-48 K-SeT assay. Among these 346 isolates, 100 were OXA-48-like carbapenemase producers, 3 were OXA-48-like producers lacking carbapenemase activity and 243 were ESBL, AmpC, oxacillinase and/or non-OXA-48 carbapenemase producers.
ResultsAll 100 OXA-48-like carbapenemase producers were correctly detected by the OXA-48 K-SeT assay, including OXA-48 (n = 73), OXA-181 (n = 18), OXA-162 (n = 1), OXA-204 (n = 4), OXA-232 (n = 2) and OXA-244 (n = 2) variants. The three OXA-48 variants lacking carbapenemase activity, OXA-163 (n = 2) and OXA-405 (n = 1), were not detected. All non-OXA-48 producers gave a negative result with the OXA-48 K-SeT assay. No cross-reaction was evidenced with the carbapenemases (VIM, IMP, NDM and KPC), ESBLs (TEM, SHV and CTX-M), AmpCs (CMY-2, DHA-2 and ACC-1) and oxacillinases (OXA-1, -2, -9 and -10). Overall, the sensitivity and specificity of the assay were 100% for OXA-48-like carbapenemase detection.
ConclusionsThe OXA-48 K-SeT assay was efficient, rapid and easy to implement in the routine workflow of a clinical microbiology laboratory for the confirmation of OXA-48-like carbapenemase-producing Enterobacteriaceae. It could complete the existing panel of tests available for the confirmation of OXA-48-like carbapenemases, especially in countries with high OXA-48 prevalence.
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Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors
Objectives
Dolutegravir shows a high barrier to resistance with no previously reported cases of acquired integrase mutations during first-line therapy. In this study, rapid development of the G118R mutation arose following a switch from first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy. The G118R mutation also arose in a treatment-experienced patient switched to dolutegravir monotherapy. The genetic basis for G118R selection and potential phenotypic outcome was ascertained.
Patient and methodsGenotypic analysis was performed on patients with virological failure (<1000 copies/mL) on dolutegravir-containing regimens. The Los Alamos database was queried for glycine codon 118 polymorphisms. Cell culture selections and phenotypic drug susceptibility assays assessed resistance via the G118R pathway.
ResultsWe report on two patients who developed viral failure while on dolutegravir monotherapy. Both patients had been on a current or previous regimen containing integrase inhibitors. Virological failure (<1000 copies/mL) emerged early within 2 months following the dolutegravir switch. The appearance of G118R in these two cases and subtype C and CRF02_AG in vitro selections were related to a rare GGA natural polymorphism at codon 118 (1.5% prevalence), facilitating a GGA to AGA transition. Cell culture selections were used to assess the in vitro progression of the G118R pathway leading to cross-resistance to all integrase inhibitors.
ConclusionsAlthough resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy can facilitate the acquisition of G118R.
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Tert-butyl benzoquinone: mechanism of biofilm eradication and potential for use as a topical antibiofilm agent
Objectives
Tert-butyl benzoquinone (TBBQ) is the oxidation product of tert-butyl hydroquinone (TBHQ), an antimicrobial food additive with >40 years of safe use. TBBQ displays potent activity against Staphylococcus aureus biofilms in vitro. Here, we report on studies to further explore the action of TBBQ on staphylococcal biofilms, and provide a preliminary preclinical assessment of its potential for use as a topical treatment for staphylococcal infections involving a biofilm component.
MethodsThe antibacterial properties of TBBQ were assessed against staphylococci growing in planktonic culture and as biofilms in the Calgary Biofilm Device. Established assays were employed to measure the effects of TBBQ on biofilm structure and bacterial membranes, and to assess resistance potential. A living-skin equivalent was used to evaluate the effects of TBBQ on human skin.
ResultsTBBQ eradicated biofilms of S. aureus and other staphylococcal species at concentrations ≤64 mg/L. In contrast to other redox-active agents exhibiting activity against biofilms, TBBQ did not cause substantial destructuring of the biofilm matrix; instead, the antibiofilm activity of the compound was attributed to its ability to kill slow- and non-growing cells via membrane perturbation. TBBQ acted synergistically with gentamicin, did not damage a living-skin equivalent following topical application and exhibited low resistance potential.
ConclusionsThe ability of TBBQ to eradicate biofilms appears to result from its ability to kill bacteria regardless of growth state. Preliminary evaluation suggests that TBBQ represents a promising candidate for development as a topical antibiofilm agent.
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T-2307, a novel arylamidine, is transported into Candida albicans by a high-affinity spermine and spermidine carrier regulated by Agp2
Objectives
T-2307, a novel arylamidine, exhibits potent broad-spectrum activities against pathogenic fungi, particularly Candida albicans. We previously reported that T-2307 uptake was mainly mediated by a saturable high-affinity carrier at the MIC for C. albicans. Since we hypothesized that the potent anticandidal activity arose from accumulation via the high-affinity carrier, we characterized the specificity and kinetic features of the carrier.
MethodsThe MICs of T-2307 for C. albicans strains were evaluated in the presence and absence of potential competitive substrates. The cells were exposed to [14C]T-2307, [14C]spermine or [14C]spermidine in the presence of unlabelled T-2307, pentamidine, propamidine, or competitive substrates if necessary, and the radioactivity in the cells was measured. C. albicans gene deletion was performed using a one-step PCR-based technique.
ResultsCoapplication with exogenous spermine or spermidine decreased the antifungal activity and uptake of T-2307 in C. albicans strains. T-2307 competitively inhibited spermine and spermidine uptake with inhibition constants similar to its Km for the high-affinity carrier. The comparison of MICs and kinetic values between T-2307 and other diamidine compounds suggested that the different antifungal properties could be partially attributable to the variations in their affinity with the carrier. Studies of gene deletion mutants revealed that T-2307 was transported into C. albicans by a high-affinity spermine and spermidine carrier regulated by Agp2.
ConclusionsUptake of T-2307 via the high-affinity spermine and spermidine carrier regulated by Agp2 could contribute to its potent antifungal activity. Further investigation is required to identify the high-affinity carrier for potential targeting with novel therapies.
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High incidence of neutropenia in patients with prolonged ceftaroline exposure
Objectives
We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline.
MethodsWe retrospectively identified adult patients who received ceftaroline for ≥7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia.
ResultsThe overall rate of incident neutropenia was 10%–14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22–44; range 13–68) in patients who developed neutropenia and 15 days (IQR 9–29; range 7–64) in patients without neutropenia] was associated with incident neutropenia (P = 0.048). The median total number of ceftaroline doses received [63 (IQR 44–126; range 36–198) by neutropenic patients and 32 (IQR 22–63; range 14–180) by non-neutropenic patients] was also associated with incident neutropenia (P = 0.023).
ConclusionsThe overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use.
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