Τετάρτη, 10 Μαΐου 2017

ADHD drugs are associated with lower car crash risk

People with attention deficit hyperactivity disorder (ADHD) had a lower risk of motor vehicle crashes when they had received their medication, research published in JAMA Psychiatry shows.1The...
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Structural and functional characterization of a novel immunomodulatory glycoprotein isolated from ajowan ( Trachyspermum ammi L.)

Abstract

Ajowan (Trachyspermum ammi L.) spice has been used in food preparations and also as a traditional medicine in Ayurveda. Although a number of pharmacological activities have been attributed to ajowan, its role in immunomodulation is not known. The main objective of the present study is to examine the macromolecular immunomodulatory components. Macrophage activation was studied by nitric oxide (NO) release, phagocytosis and secretion of pro-inflammatory cytokines as the markers. Ethanol precipitate (fractional) of ajowan aqueous extract was subjected to conventional chromatography (Q Sepharose followed by Bio-Gel P-100). One of the proteins (30.7 kDa; ajowan glycoprotein or Agp) showed effective mitogenic activity towards splenocytes. Agp is a O-linked glycoprotein with the glycans contributing to one-third of the molecular mass. It has a high content of glutamic acid, serine, aspartic acid and proline whereas galactose (45.7%), arabinose (34.5%), glucose (7%), mannose (5%) and xylose (4%) are the constituent sugars. Secondary structure analysis indicated that Agp contains 79% α-helices and 21% random coil. Internal sequencing of the tryptic peptides did not show homology with the existing proteins in the database (BLAST). Agp at 1 μg/mL induced proliferation of B-cell enriched murine splenocytes and activated macrophages in releasing NO and promoted phagocytosis (p < 0.01). RAW 264.7 cells produced pro-inflammatory cytokines (IL-12, TNF-α and IFN-γ) at 1 μg/mL Agp (p < 0.01). Deproteinized Agp (dpAgp) failed to elicit activation of murine immune cells, whereas deglycosylated Agp (20 kDa; dgAgp) showed compromised efficiency. This is the first report of an immunomodulatory protein from ajowan.



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Predictors of thrombus formation after percutaneous left atrial appendage closure using the WATCHMAN device

Abstract

Percutaneous left atrial appendage (LAA) closure using the WATCHMAN device is a novel option for prevention of stroke associated with atrial fibrillation. However, device-related thrombus (DRT) formation is a concern after WATCHMAN implantation and the predictors of DRT still remain unclear. We aimed to clarify the predictors of DRT after WATCHMAN implantation by analyzing 78 patients (50 males, 72 ± 8 years, average CHA2DS2-VASc score of 4.3 + 1.8) who had undergone WATCHMAN implantation. WATCHMAN was successfully implanted in all patients and four (5%) developed DRT. Patients with DRT were more often female (75 vs. 34%, p = 0.094). CHA2DS2-VASc score was higher for patients with DRT (6.3 ± 2.5 vs. 4.2 ± 1.7, p = 0.022). Chronic kidney disease (100% vs. 43%, p = 0.024) and deep implantation of the device, which was defined as implant position below the LAA ostial plane (75 vs. 24%, p = 0.026), were more common in patients with DRT. HAS-BLED score (4.5 ± 1.0 vs. 3.5 ± 1.1, p = 0.074) was higher and oral anticoagulants (50 vs. 84%, p = 0.086) were less commonly prescribed for patients with DRT. Multivariable logistic regression analysis showed that higher CHA2DS2-VASc score (p = 0.022, OR 2.8) and deep implantation (p = 0.032, OR 24.7) were associated with DRT. These results suggest the possible role of CHA2S2-VASc scores and implantation depth in the development of DRT after percutaneous LAA closure using the WATCHMAN device.



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Peri-interventional neurological complication rates in patients undergoing carotid artery stenting depend on the side of the stenosis treated

Abstract

CAS has emerged as an alternative to carotid endarterectomy for the treatment of significant carotid artery stenosis. We investigated if the side of the stenosis treated has an influence on the neurological outcome of our patients. CAS was performed in 1124 patients at our center. The left carotid artery (group L) was intervened in 557 and the right carotid artery (group R) in 567 patients. Data of both patient groups were analyzed with respect to the total rate of peri-interventional ischemic cerebral events, defined as transient ischemic attacks, minor and major strokes, respectively. The total peri-interventional ischemic cerebral event rate was 10.1% in group L and 6.7% in group R (p = 0.042), respectively. The routine use of a filter wire resulted in a significant reduction of complication rates in group L (from 14.7 to 7.1%; p = 0.005) but not in group R (from 7.8 to 6.0%; p = 0.505). Ischemic cerebral events did not differ between group L and R, when only patients in whom a filter wire was used were analyzed (7.1% in group L and 6.0% in group R, p = 0.174). Peri-interventional ischemic cerebral complication rates in patients undergoing CAS differ with respect to the side treated. This may be due to a more frequent plaque mobilization caused by the guiding catheter.



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Clinical features and predictive value of serum inflammatory markers of perivascular involvement in immunoglobulin G4-related disease

Abstract

Vascular and/or perivascular involvements of sclerotic inflammation (perivasculitis) are a complication of immunoglobulin G4-related disease (IgG4-RD). We sought to examine clinical manifestations of perivasculitis by computed tomography (CT) in patients with elevated serum IgG4 levels, and then to evaluate some potential predictors of perivasculitis in definite IgG4-RD patients. From a database of patients with serum IgG4 measurements, we selected 81 patients with elevated serum IgG4 levels (≥135 mg/dl). Perivasculitis was defined radiologically as thickened contrast-enhanced rind surrounding the aorta and its major artery on CT imaging. We found 15 patients with perivasculitis; 10 patients in the definite (n = 37), four in the possible (n = 18), and one in the excluded (n = 26) IgG4-RD groups. Clinical predictors of perivasculitis were investigated in 34 untreated patients with definite IgG4-RD. Patients with perivasculitis (n = 10) had significantly higher age at diagnosis (74.2 ± 8.8 vs 63.5 ± 9.9 years, P = 0.006), higher levels of serum IgG4 (754 vs 292 mg/dl, P = 0.007) and C-reactive protein (CRP, 0.52 mg/dl vs 0.10 mg/dl, P = 0.001) than patients without perivasculitis (n = 24). The sensitivity and specificity of serum CRP ≥0.25 mg/dl for identifying perivasculitis in the definite IgG4-RD group were 100 and 71%, respectively (area under the receiver operating characteristic curve 0.863). Our results indicate that IgG4-related perivasculitis was associated with elevated levels of serum CRP and older age, and that CRP may be a useful marker for detecting perivascular involvement in IgG4-RD.



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Incidence and predictors of silent cerebral thromboembolic lesions after catheter ablation for atrial fibrillation in patients treated with direct oral anticoagulants

Abstract

There are few reports about the incidence and predictors of silent cerebral thromboembolic lesions (SCLs) after atrial fibrillation (AF) ablation in patients treated with direct oral anticoagulants (DOACs). The purpose of this study is to evaluate the incidence and predictors of SCLs after AF ablation with cerebral magnetic resonance imaging (C-MRI) in patients treated with DOACs. We enrolled 117 consecutive patients who underwent first AF ablation and received DOACs, including apixaban, dabigatran, edoxaban, and rivaroxaban. DOACs were discontinued after administration 24 h before the procedure, and restarted 6 h after the procedure. During the procedure, activated clotting time (ACT) was measured every 15 min, and intravenous heparin infusion was performed to maintain ACT at 300–350 s. All patients underwent C-MRI the day after the procedure. SCLs were detected in 28 patients (24%) after AF ablation. Age, female sex, the presence of persistent AF, left atrial volume, procedure time, radiofrequency energy, electrical cardioversion, and mean ACT showed no correlations with the incidence of SCLs. Multivariate analysis revealed independent predictors of SCLs were CHA2DS2VASc scores ≥3, left atrial appendage (LAA) emptying velocity ≤39 cm/s, and minimum ACT ≤260 s. Patients with both CHA2DS2VASc scores ≥3 and LAA flow velocity ≤39 cm/s had the highest incidence of SCLs 15 of 26 patients (58%). In patients treated with DOACs, CHA2DS2VASc score ≥3, minimum ACT ≤260 s, and LAA emptying velocity ≤39 cm/s were independent risk factors for the SCLs after AF ablation.



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Effects of pitavastatin on walking capacity and CD34 + /133 + cell number in patients with peripheral artery disease

Abstract

This multi-center prospective non-randomized comparative study investigated the effects of pitavastatin in patients with peripheral artery disease (PAD) in terms of exercise tolerance capacities and peripheral CD34+/133+ cell numbers. At baseline, a peripheral blood test was administered to 75 patients with PAD, along with a treadmill exercise test using the Skinner–Gardner protocol to measure asymptomatic walking distance (AWD) and maximum walking distance (MWD). Each patient was assigned to a 6-month pitavastatin treatment group (n = 53) or a control group (n = 22), according to the patient's preference. The tests were repeated in both groups at 3 and 6 months. Baseline AWD and MWD correlated positively with the ankle-brachial pressure index (r = 0.342, p = 0.0032 and r = 0.324, p = 0.0054, respectively). Both AWD and MWD values improved at 3 and 6 months compared with baseline, and the degrees of their improvement were higher in the pitavastatin treatment group. CD34+/133+ cell numbers did not change over time or between groups. Eighty-seven percent of patients in the treatment group attained low-density lipoprotein cholesterol levels below 100 mg/dL after 3 months. The study shows that pitavastatin may be effective in increasing exercise tolerance capacity in patients with PAD.



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The distribution of calcified nodule and plaque rupture in patients with peripheral artery disease: an intravascular ultrasound analysis

Abstract

In addition to plaque rupture (PR), calcified nodule (CN) may also have the potential to develop into arterial thrombus in the peripheral arteries. This study evaluated the distribution of plaque ruptures and calcified nodules in the peripheral arteries and their impact on the outcome of endovascular therapy (EVT). Consecutive 159 patients who underwent EVT with intravascular ultrasound guidance were enrolled. The position of CNs and PRs were assigned to any of common iliac artery, external iliac artery, common femoral artery, and superficial femoral artery. Forty-six (29%) patients had calcified nodule and twenty-eight (18%) patients had plaque rupture somewhere in the lower limb arteries. Although calcified nodules were evenly distributed throughout the length of the arteries plaque ruptures were predominantly located in the proximal segment of the iliofemoral arteries. Stent expansion ratio was significantly smaller in the target arteries with calcified nodules than in those with plaque rupture. Multivariate logistic regression analysis identified hemodialysis as an independent clinical predictor of calcified nodule (odds ratio 8.15, 95% confidence interval 1.73–38.3; P = 0.008). CN definitely affects incomplete stent deployment in the peripheral artery contributing to adverse events, on the other hand, PR has more acceptable outcomes after stent implantation. In the clinical setting, it is important that we realize the features of peripheral artery disease and its patient characteristics which having CNs and PRs to make a strategy for revascularization.



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Assessment of trough rivaroxaban concentrations on markers of coagulation activation in nonvalvular atrial fibrillation population

Abstract

Whether trough-phase rivaroxaban concentrations provide sufficient anticoagulation needs more study. We evaluated levels of coagulation activation markers in the trough concentration phase in nonvalvular atrial fibrillation (NVAF) patients, and the correlation between these markers and rivaroxaban concentration. Fifty-five Japanese NVAF patients received 24-week rivaroxaban treatment of either 15 or 10 mg once-daily in the morning. Of these, 26 patients had no history of anticoagulant therapy (naive group) and 29 had switched from warfarin (warfarin group). D-dimer and prothrombin fragment 1 + 2 (F1 + 2) levels, and protein C activities were measured at 0 (baseline), 12 and 24 weeks of rivaroxaban treatment just before the patient's regular dosing time (trough phase). For 49 patients, D-dimer, F1 + 2, and rivaroxaban concentrations were also measured twice between 28 and 32 weeks of rivaroxaban treatment at non-trough times to achieve a range of drug concentrations for correlation analysis. For the naive group, D-dimer and F1 + 2 levels were significantly reduced (p < 0.01) from baseline at 12 and 24 weeks. For the warfarin group, these values were unchanged for D-dimer but significantly increased (p < 0.01) for F1 + 2. Protein C activity was unchanged in the naive group and was increased (p < 0.01) in the warfarin group. Prothrombin time (r = 0.92, p < 0.0001) and activated partial thromboplastin time (r = 0.54, p < 0.0001) correlated with rivaroxaban concentration, but not D-dimer and F1 + 2 levels. In conclusion, rivaroxaban in the trough phase is comparable to warfarin in reducing D-dimer levels. Although trough level rivaroxaban suppresses F1 + 2 less than warfarin, the higher activities of protein C with rivaroxaban treatment compared to warfarin treatment may counterbalance this. Lack of correlation between rivaroxaban concentration and D-dimer and F1 + 2 levels suggests that trough concentrations of rivaroxaban reduce their concentrations as effectively as higher levels do.



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Impact of combined lipid lowering and blood pressure control on coronary plaque: myocardial ischemia treated by percutaneous coronary intervention and plaque regression by lipid lowering and blood pressure controlling assessed by intravascular ultrasonography (MILLION) study

Abstract

The aim of the study was to elucidate the aggressive reduction of both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) reduced coronary atherosclerotic plaque volume compared with a standard treatment of LDL-C and BP in Japanese patients with coronary artery disease (CAD). This study is a prospective, randomized, and open-labelled with a blind-endpoint evaluation study. A total of 97 patients (81 men, mean age 62.0 ± 9.6) with CAD undergoing intravascular ultrasonography (IVUS)-guided percutaneous coronary intervention (PCI) were randomized, and 68 patients had IVUS examinations at baseline and at 18–24 months follow-up. Patients were randomly assigned to standard or aggressive strategies targeting LDL-C and a BP of 100 mg/dL and 140/90 mmHg vs. 70 mg/dL and 120/70 mmHg, respectively. The primary endpoint was the percent change in coronary plaque volume. Both standard and aggressive strategies succeeded to achieve target levels of LDL-C and BP; 74.9 ± 14.7 vs. 63.7 ± 11.9 mg/dL (NS) and 124.1 ± 9.4/75.8 ± 7.7 vs. 113.6 ± 9.6/65.8 ± 9.4 mmHg (systolic BP; NS, diastolic BP; p < 0.05), respectively. Both groups showed a significant reduction in the coronary plaque volume of −9.4 ± 10.7% and −8.7 ± 8.6% (NS) in standard and aggressive therapies, respectively. Both standard and aggressive intervention significantly regressed coronary plaque volume by the same degree, suggesting the importance of simultaneous reductions of LDL-C and BP for prevention of CAD.



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Incorporation of lipolysis in monolayer permeability studies of lipid-based oral drug delivery systems

Abstract

Lipid-based drug delivery systems, a well-tolerated class of formulations, have been evaluated extensively to enhance the bioavailability of poorly soluble drugs. However, it has been difficult to predict the in vivo performance of lipid dosage forms based on conventional in vitro techniques such as cell monolayer permeability studies because of the complexity of the gastrointestinal processing of lipid formulations. In the current study, we explored the feasibility of coupling Caco-2 and Madin-Darby canine kidney monolayer permeability studies with lipolysis, a promising in vitro technique to evaluate lipid systems. A self-emulsifying lipid delivery system was formulated using a blend of oil (castor oil), surfactant (Labrasol® or PL497), and co-surfactant (lecithin). Formulations demonstrating high drug solubility and rapid self-emulsification were selected to study the effect of lipolysis on in vitro cell permeability. Lipolysis of the formulations was carried out using pancreatin as the digestive enzyme. All the digested formulations compromised monolayer integrity as indicated by lowered trans-epithelial electrical resistance (TEER) and enhanced Lucifer yellow (LY) permeability. Further, the changes in TEER value and LY permeability were attributable to the digestion products of the formulation rather than the individual lipid excipients, drug, digestion enzyme, or the digestion buffer. The digested formulations were fractionated into pellet, oily phase, and aqueous phase, and the effect of each of these on cell viability was examined. Interestingly, the aqueous phase, which is considered important for in vivo drug absorption, was responsible for cytotoxicity. Because lipid digestion products lead to disruption of cell monolayer, it may not be appropriate to combine lipolysis with cell monolayer permeability studies. Additional in vivo studies are needed to determine any potential side effects of the lipolysis products on the intestinal permeability barrier, which could determine the suitability of lipid-based systems for oral drug delivery.



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Erratum to: The role of particle size of glyburide crystals in improving its oral absorption



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Innovative pharmaceutical approaches for the management of inner ear disorders

Abstract

The sense of hearing is essential for permitting human beings to interact with the environment, and its dysfunctions can strongly impact on the quality of life. In this context, the cochlea plays a fundamental role in the transformation of the airborne sound waves into electrical signals, which can be processed by the brain. However, several diseases and external stimuli (e.g., noise, drugs) can damage the sensorineural structures of cochlea, inducing progressive hearing dysfunctions until deafness. In clinical practice, the current pharmacological approaches to treat cochlear diseases are based on the almost exclusive use of systemic steroids. In the last decades, the efficacy of novel therapeutic molecules has been proven, taking advantage from a better comprehension of the pathological mechanisms underlying many cochlear diseases. In addition, the feasibility of intratympanic administration of drugs also permitted to overcome the pharmacokinetic limitations of the systemic drug administration, opening new frontiers in drug delivery to cochlea. Several innovative drug delivery systems, such as in situ gelling systems or nanocarriers, were designed, and their efficacy has been proven in vitro and in vivo in cochlear models. The current review aims to describe the art of state in the cochlear drug delivery, highlighting lights and shadows and discussing the most critical aspects still pending in the field.



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Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative

Abstract

Doxorubicin is an effective anticancer drug; however, it is cardiotoxic and has poor oral bioavazilability. Quercetin is a plant-based flavonoid with inhibitory effects on P-glycoprotein (P-gp) and CYP3A4 and also antioxidant properties. To mitigate these therapeutic barriers, DoxQ, a novel derivative of doxorubicin, was synthesized by conjugating quercetin to doxorubicin. The purpose of this study is to mechanistically elucidate the in vitro safety and efficacy of DoxQ. Drug release in vitro and cellular uptake by multidrug-resistant canine kidney (MDCK-MDR) cells were quantified by HPLC. Antioxidant activity, CYP3A4 inhibition, and P-gp inhibitory effects were examined using commercial assay kits. Drug potency was assessed utilizing triple-negative murine breast cancer cells, and cardiotoxicity was assessed utilizing adult rat and human cardiomyocytes (RL-14). Levels of reactive oxygen species and gene expression of cardiotoxicity markers, oxidative stress markers, and CYP1B1 were determined in RL-14. DoxQ was less cytotoxic to both rat and human cardiomyocytes and retained anticancer activity. Levels of ROS and markers of oxidative stress demonstrate lower oxidative damage induced by DoxQ compared to doxorubicin. DoxQ also inhibited the expression and catalytic activity of CYP1B1. Additionally, DoxQ inhibited CYP3A4 and demonstrated higher cellular uptake by MDCK-MDR cells than doxorubicin. DoxQ provides a novel therapeutic approach to mitigate the cardiotoxicity and poor oral bioavailability of doxorubicin. The cardioprotective mechanism of DoxQ likely involves scavenging ROS and CYP1B1 inhibition, while the mechanism of improving the poor oral bioavailability of doxorubicin is likely related to inhibiting CYP3A4 and P-gp.



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Evaluating the effectiveness of a novel atomized liquid needle-free transdermal delivery system

Abstract

Needle-free jet injections constitute a crucial method for drug delivery. A novel liquid drug delivery system has been proposed recently, in which pressure atomizes liquid before delivering that atomized liquid to the patient's body; however, the mechanism and efficiency of the system are unclear. This study explored the shot delivery pressure, penetration depth, and cumulative amount of permeation of this system. This system was used to deliver 0.5% (w/v) methylene blue to agarose phantoms at various shot delivery pressures. Shots of methylene blue were also delivered to porcine skin samples at different shot delivery frequencies for light microscopy evaluation. A commercial microneedle array was used for comparing the effectiveness of the skin penetration depths. The array was gently stamped against porcine skin; methylene blue was subsequently applied to the area for different time points, followed by microscopic observations. In vitro skin penetration was tested using static Franz diffusion cells over 8 h. Finally, the feasibility of the system's clinical application was evaluated by analyzing the local analgesic effect in a heat nociceptive animal model. The penetration depths created using 100 shots at 100 psi were similar to those created using the commercial microneedle array for 2 h. Thermal stimulation responses showed that 15 min after diclofenac sodium was delivered by the system, heat nociception was significantly attenuated for 60 min. Our study presents a novel delivery system that may be useful for future clinical applications.



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Clinical Trial Designs in Juvenile Idiopathic Arthritis

Opinion statement

Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatic condition but still a disease of low prevalence. The paediatric rheumatology research community is often faced with significant challenges if only the common study designs such as the parallel group randomised control design are used. This systematic review evaluates the clinical designs used to date in experimental studies of JIA. Our review discusses the concept, advantages and disadvantages of each trial design type. Innovative trial designs are one of the ways we will move forward in developing an evidence base for paediatric rheumatology practice.



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Nutraceutical/Alternative Remedies in the Management of OA

Opinion statement

Treating patients with osteoarthritis requires careful individualization in order to achieve patient-specific goals, which may vary from obtaining short-term pain relief to achieving long-term maintenance of function or even preservation of cartilage. In response to specific patient goals, the provider makes use of a toolbox of physical, adjunctive, alternative, pharmacologic, and operative interventions. Among the alternative category are the nutraceuticals, which will be reviewed here with particular attention given to those agents with randomized control trial (RCT) data showing statistically significant benefits. Some of these can be used to minimize patient symptoms with very low risks. The safety of these agents is particularly important in treating patients with osteoarthritis as many of the patients are older with significant comorbidities. Further, it is very likely that it will be necessary for the patients to continue treatment for many years.



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Wnt Signaling in Osteoarthritis: a 2017 Update

Opinion statement

Osteoarthritis is a progressive degenerative disease of the joints in which the articular cartilage within the joints deteriorates with associated juxta-articular bone formation. While the etiology of OA is still under investigation, preclinical studies have determined that the Wnt/β-catenin signaling and bone morphogenic signaling pathways are important for the formation and repair of the joint tissues, and the effects are on both the phenotype and function of the joint tissue cells. In addition, individuals with polymorphisms in the gene, FRZB, that codes for the wnt signaling protein secreted frizzled related protein 3 (sFRP3) have higher risk of developing OA. A number of proof-of-concept preclinical studies have been performed on inhibitors of the Wnt signaling pathway, and have altered the disease progression. Proof of concept studies assessing the regenerative capacity of mesenchymal stem cells as treatments for painful knee OA have reported both encouraging and discouraging results. Therefore, the identification of the molecular pathways that are responsible for joint formation and repair has led to the development of new novel interventions for the treatment of OA that are now entering clinical trials. The ability to slow or reverse the progression of osteoarthritis may soon be within our reach.



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Clinical and imaging features of subependymal giant cell astrocytoma: report of 20 cases

Abstract

Background

Subependymal giant cell astrocytoma (SEGA) is a clinically benign brain tumor associated with tuberous sclerosis complex (TSC). There are still controversies on early diagnosis of the tumor.

Methods

CT and MR imaging of 20 patients with pathologically confirmed SEGA were retrospectively reviewed. Two radiologists evaluated the location, shape, size, number, edge, cerebral edema, homogeneous or heterogeneous appearance, attenuation and signal intensity, degree of enhancement and calcification of lesions. Their prognoses were based on clinical observations.

Results

SEGA showed similar features in imaging: an extra-axial, well-circumscribed, periventricular mass, isodense or slightly hyperdense on CT, hypointensity on T1-weighted imaging and isointensity to hyperintensity on T2-weighted imaging. The mass enhanced markedly and heterogeneously after the administration of contrast agent. Subependymal nodules were demonstrated in 5 cases. Remarkably, 17 patients (85%) showed ventricular dilatation and 14 patients (70%) showed calcification in CT and MR imaging. Moreover, perifocal edema was not significantly near the masses. Four cases are associated with tuberous sclerosis complex (TSC).

Conclusions

Although there are no pathognomonic imaging findings for SEGA, the following clinical and imaging features might be helpful for the diagnosis, such as the initial age of first or second decade, typical location in the periventricular regions adjacent to the foramen of Monro, hydrocephalus accompanied with raised intracranial pressure, TSC and marked heterogeneous enhancement.



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Diagnostic evaluation of patients with disorders of consciousness with diffusion tensor imaging

Abstract

Background

With the development of emergency and intensive medical technologies, the survival rate of traumatic brain injury has greatly increased. More and more patients have been converted from severe coma to alleviated state of consciousness, which can be subsequently classified within the framework of disorders of consciousness (DOC). We investigated the clinical application and characteristics of imaging indicators of diffusion tensor imaging (DTI) for the DOC patients.

Methods

DTI was performed on a total of 75 cases with a clinical diagnosis of DOC from January 2014 to December 2015 in Beijing Tiantan Hospital and PLA Army General Hospital (including 66 cases of unresponsive wakefulness state (UWS) patients and 9 cases of minimally conscious state (MCS) patients). The data for the imaging indicators, such as fractional anisotropy (FA) and mean diffusivity (MD), were separately collected from three relevant regions of interest (ROIs): brainstem, thalamus, and subcortex. The indicators of two groups with different conscious states were statistically analyzed, and correlation analyses were conducted for the mean values of FA and MD in the ROIs evaluated through clinical Coma Recovery Scale-Revised (CRS-R) scores.

Results

The FA value of the UWS group was evidentially lower than that of the MCS group (P < 0.05), while the MD value of the UWS group was higher than that of the MCS group (P < 0.05); the difference was statistically significant. The FA and MD values in the ROIs (locations: brainstem, thalamus, and subcortex) correlated with CRS-R scores, particularly in the thalamus.

Conclusion

DTI has a certain clinical reference value for DOC imaging grading. The more severe the DOC, the higher the MD value and the lower the FA value.



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Intracerebral malignant melanoma presenting as an Arteriovenous Malformation: case report and literature review

Abstract

Background

The authors introduced a rare case of intracranial malignant melanoma.

Case presentation

A 32 year-old male patient presented to the hospital with signs and symptoms commonly seen in the presentation of a hemorrhagic stroke. The patient was diagnosed as having an Arteriovenous Malformation (AVM) after a thorough history, physical examination and radiographic imaging were performed and assessed. However, intraoperative findings and postoperative histopathology findings revealed that the supposed AVM was in fact a malignant melanoma, appearing as an AVM of the brain, on radiographic imaging.

Conclusion

After reviewing related literature, our team realized that it was a rare finding for a melanoma pretending as a brain AVM.



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A case report of the unilateral approach to the ruptured right ICA aneurysm together with tuberculum sella meningioma and left ICA aneurysm

Abstract

Background

Tuberculum sellae meningioma associated with aneurysm is extremely rare with a limited number of individual cases previously reported. Because of the complicated anatomical structure of the skull base, comorbid disease in the sellae region is a challenging problem and is associated with high mortality in neurosurgery.

Case presentation

This case report describes a rare case of comorbid bilateral internal carotid artery aneurysms and tuberculum sellae meningioma. This 58-year-old female presented with headache and nausea. She had lost her light perception in the right eye, and the right optic disc was degenerated. She also had a 5-year history of hypertension. This patient underwent a right pterional craniotomy, and we accomplished to clip the bilateral intracranial aneurysms and concurrently remove the tumor. After the surgery, we confirmed that both of the aneurysms were completely isolated, and the tumor was adequately resected. This patient had not suffered other neurological deficits. Unfortunately, her visual acuity had not recovered.

Conclusions

As we know, this is the first report of a unilateral surgical approach to clip the bilateral intracranial aneurysms and concurrently remove the tumor. It may provide a reference for clinical treatment of the similar disease.



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Erratum to: Increasing Frequency of Seborrheic Keratosis Diagnoses as a Favorable Consequence of Teledermatology-Based Skin Cancer Screening: A Cross-sectional Study of 34,553 Patients



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Onychotillomania: Diagnosis and Management

Abstract

Onychotillomania, defined as self-induced trauma to the nail unit, either by picking or pulling at the nails, affects 0.9% of the population. It may lead to severe irreversible nail dystrophy, melanonychia, or infections. Although no large clinical trials have assessed the efficacy of treatments, cognitive-behavioral therapy, physical barrier methods, and pharmacological treatments have shown some benefits in case reports. The objective of this article is to review the prevalence, diagnostic criteria, etiology, historical and physical examination findings, pathological features, and current treatment methods. Onychotillomania remains a clinical challenge to dermatologists, pediatricians, internists, and psychiatrists in practice, as there are no evidence-based treatment methods.



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Oral Ulcers in Juvenile-Onset Systemic Lupus Erythematosus: A Review of the Literature

Abstract

Oral ulcers are the most common mucosal sign in juvenile-onset systemic lupus erythematosus (JSLE). The ulcers are one of the key clinical features; however, the terminology of oral ulcers, especially in JSLE patients, is often vague and ill-defined. In fact, there are several clinical manifestations of oral ulcers in JSLE, and some lesions occur when the disease is active, indicating that early management of the disease should be started. Oral ulcers are classified as lupus erythematosus (LE) specific, where the lesional biopsy shows a unique pattern of mucosal change in LE, and LE nonspecific, where the ulcers and their histopathological findings can be found in other oral diseases. Here, the clinical manifestations, diagnosis and management of oral ulcers in JSLE patients are reviewed.



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Discordance Between Physician- and Patient-Reported Disease Severity in Adults with Atopic Dermatitis: A US Cross-Sectional Survey

Abstract

Background

There is limited understanding of severity rating of atopic dermatitis in clinical practice.

Objectives

To evaluate the agreement between physician- and patient-rated severity of atopic dermatitis.

Methods

Data were collected from the 2014 Adelphi US Atopic Dermatitis Disease Specific Programme, a cross-sectional survey of physicians and their patients with a history of moderate-to-severe atopic dermatitis; patients voluntarily completed a questionnaire. Current disease severity (mild/moderate/severe), based on personal judgment, was rated independently by patients and their physicians. The weighted kappa statistic identified level of agreement between physicians and patients. Bivariate analyses characterized agreement; multi-nomial logistic regression identified factors associated with discordance.

Results

Overall, 678 patients were included (369 [54.4%] were women, 525 [77.4%] were White, mean age was 39.3 years). Agreement was moderate (weighted kappa = 0.52): compared with physician ratings, patient-rated severity was higher in 76 patients (11.2%), lower in 137 patients (20.2%), and matched in 465 patients (68.6%). There were no differences in the rates of agreement between physician and patient ratings based on physician specialty (p = 0.6781), objective severity measures [Eczema Area and Severity Index score (p = 0.5308), percent body surface area affected (p = 0.9872), and current systemic immunosuppressant use (p = 0.9197)]. Multivariate analysis showed patients with a worse quality of life (Dermatology Life Quality Index) were more likely to rate a higher severity (relative risk ratio 1.04, 95% confidence interval 1.00–1.08; p = 0.0460). Physicians were more likely to rate a higher severity with a greater physician-reported sleep disturbance (relative risk ratio 1.71, 95% confidence interval 1.01–2.89; p = 0.0440).

Conclusions

Almost one-third of patients rated atopic dermatitis severity differently from their physicians, supporting the importance of the patient perspective in the severity assessment of atopic dermatitis and the need for greater communication between patients and physicians.



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Contents Vol. 81, 2016


Hum Hered 2016;81:I-IV

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A Not So Benign Papular Eruption.

No abstract available

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Primary Cutaneous Leiomyosarcoma Arising in a Patient With Li-Fraumeni Syndrome. A Neoplasm With Unusual Histopathologic Features and Loss of Heterozygosity at TP53 Gene.

No abstract available

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Psoriasiform, Hyperpigmented Plaques of the Palms and Soles.

No abstract available

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Generalized Dyschromia and Erythematous Papules in a 66-Year-Old Man.

No abstract available

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Cutaneous Plasmacytosis: A Clinicopathologic Study of a Series of Cases and Their Treatment Outcomes.

Introduction: Cutaneous plasmacytosis (CP) is a rare skin disorder characterized by multiple reddish brown nodules with polyclonal plasma cell proliferation. It has most often been reported to affect the trunk but is also known to affect the face and extremities in adults and is predominantly seen in Asians. The etiology is poorly understood, and there is no consensus on treatment methods. Methods: Five cases diagnosed to have CP were collated from our institution. Their clinicopathologic features and treatment outcomes were reviewed. Results: Four of the 5 patients presented with lesions that affected multiple sites of the body including the trunk, axillae, face, and limbs. The remaining patient had lesions localized to his axillae. The lesions were generally asymptomatic. All patients had hypergammaglobulinaemia but only one had a faint monoclonal band detected on immunofixation. Common findings in the biopsy results for all patients were perivascular plasma cell infiltrates without light chain restriction on kappa/lambda staining, as well as mast cell infiltrates. Partial remission of cutaneous lesions was observed in 3 of the patients, with 2 of them responding well to psoralen and ultraviolet A radiation therapy. Conclusion: CP presents with distinctive clinical features and characteristic histological features including polyclonal perivascular plasma cell infiltrates. The axilla seems to be a frequent and characteristic site of involvement and may be a useful clinical clue to the condition. In the management of patients with CP, it is important to exclude secondary causes of plasmacytic infiltrates. While there are no clearly established treatment modalities for CP, psoralen and ultraviolet A radiation therapy may be a viable option in view of the clinical improvement observed in our patients who received it. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A New, Firm, Solitary Nodule in a Patient With HIV/AIDS-Question.

No abstract available

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Nodular Sclerodermatous Chronic Cutaneous Graft-Versus-Host Disease (GvHD): A New Clinicopathological Variant of Cutaneous Sclerodermatous GvHD Resembling Nodular/Keloidal Scleroderma.

Cutaneous chronic graft-versus-host disease (GvHD) has a broad spectrum of clinicopathological presentations, the most common ones being poikiloderma, lichen planus-like eruptions, lichen sclerosus-like lesions, morphea-like plaques, and deep sclerosis. New forms of chronic cutaneous GvHD with different clinicopathological characteristics have been described, most of them mimicking cutaneous manifestations of autoimmune diseases. We report the case of a 35-year-old man who underwent allogenic stem cell transplantation for a therapy-associated acute myeloid leukemia and developed an acute GvHD with involvement of skin and gastrointestinal tract. He subsequently presented with chronic sclerodermatous cutaneous GvHD, followed by the appearance of indurated erythematous papules and plaques located on his back, resembling the nodular/keloidal form of cutaneous scleroderma on both clinical and histopathological grounds. This peculiar clinicopathologic presentation of chronic cutaneous GvHD was never described previously. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Recurrent Cutaneous Angiosarcoma of the Scalp With Aberrant Expression of S100: A Case Report.

Angiosarcoma (AS) is a malignant mesenchymal neoplasm of endothelial origin with a predominantly lymphatic immunophenotype, which accounts for less than 1% of all sarcomas. Cutaneous AS of the scalp is associated with high rates of local recurrence and a poor prognosis. Histologically, poorly differentiated AS often comprises solid epithelioid cells, although rare variants involving spindle cells have been reported; diagnosis requires immunohistochemical analysis using vascular cell markers. We report on a cutaneous spindle-cell AS of the scalp in a female patient; key features included spontaneous regression after biopsy, local recurrence 2 years later, and aberrant nuclear staining for S100 protein in an area of the tumor not expressing CD34 or D2-40. Tumor cells exhibited positivity for vascular markers CD31, CD34, D2-40, ERG and FLI-1 and were negative for myoid markers ([alpha]SMA and desmin), epithelial (EMA and cytokeratin AE1/AE3) and melanocyte markers (HMB45 and melan-A). Cutaneous spindle-cell AS of the scalp is a rare variant with a poor prognosis. Diagnosis of spindle-cell AS was confirmed by immunohistochemical analysis using CD31, CD34, ERG, FLI-1, podoplanin (D2-40), and claudin-5. Although a number of authors have noted aberrant expression of cytokeratins, CD30, CD117 and neuroendocrine markers (synaptophysin and chromogranin A) in AS, intense positive nuclear staining for S100 protein in neoplastic cells has not hitherto been observed. This article reports on a spindle-cell AS of the scalp notable for aberrant expression of S100, spontaneous regression and recurrence 2 years later at the same site and displaying identical histological and immunohistochemical features. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Annular Lichenoid Dermatitis (of Youth): Report of a Case With Lichen Planus-Like Features.

Annular lichenoid dermatitis of youth (ALDY), a dermatosis with peculiar clinical and pathological features, represents still a debated entity, given its similarity, among others, with mycosis fungoides. A case of ALDY in a 50-year-old male patient is reported. Clinically, the patient presented an oval scleroderma-like plaque on the right flank. Histology and immunohistochemistry showed the classic appearance described in ALDY. T-cell receptor rearrangement was absent. Interestingly, a focus consistent with lichen planus was observed. The lesion resolved with topical steroids and at a follow-up of 24 months no recurrence has been registered. The case described herein supports the hypothesis that ALDY is a reactive lichenoid dermatosis, closely related to lichen planus. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Unusual Case of Dactylitis With Nail Unit Involvement.

No abstract available

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Hailey-Hailey Disease With Coexistent Herpes Virus Infection: Insights Into the Diagnostic Conundrum of Herpetic/Pseudoherpetic Features in Cutaneous Acantholytic Disorders.

The specific histopathologic diagnosis of a primary acantholytic disorder takes into account the distribution and extent of acantholysis, presence or absence of dyskeratosis, nature of the dermal inflammatory cell infiltrate, and immunofluorescence findings. Herpes virus infection is a common cause of secondary acantholysis where distinctive viral cytopathic changes aid in making it a clear-cut diagnosis in majority of cases. We present a case of coexistence of Hailey-Hailey disease and herpes simplex virus infection to compare and contrast their histopathologic features. This is imperative because acantholytic cells from primary acantholytic disorders may occasionally show cytological features traditionally associated with herpes virus infection (pseudoherpetic changes). The objective of this article is to create a greater awareness of pseudoherpetic changes and also to explore the clinical significance of coexistence of a primary acantholytic disorder and herpes virus infection, as in this case. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Palisaded Neutrophilic and Granulomatous Dermatitis/Interstitial Granulomatous Dermatitis Overlap: A Striking Clinical and Histologic Presentation With "Burning Rope Sign" and Subsequent Mirror-Image Contralateral Recurrence.

Palisaded neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis are uncommon granulomatous dermatoses that often arise in association with rheumatoid arthritis. These 2 entities have overlapping features and may exist on a spectrum. We report an intriguing case of a 53-year-old man with advanced rheumatoid arthritis who presented with a large indurated painful truncal plaque with a palpable cord in addition to a papulonodular eruption on his dorsal hands. Furthermore, our patient had a recurrence in a near-identical mirror-image pattern on the contralateral trunk. The constellation of clinical and histopathological findings in our patient further suggests that palisaded neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis exist as overlapping disease entities on a continuum. In addition, we propose that recurrence of skin findings may be indicative of the severity of the underlying systemic disease process. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Genomic Assessment of Blitz Nevi Suggests Classification as a Subset of Blue Nevus Rather Than Spitz Nevus: Clinical, Histopathologic, and Molecular Analysis of 18 Cases.

Blitz nevi/tumors are a distinct subset of melanocytic neoplasia which show mixed morphologic features of Spitz and blue nevus. Genomically, most blue nevi have GNAQ or GNA11 mutations while most Spitzoid neoplasms have either an HRAS mutation or translocations involving MET, ROS, BRAF, ALK1, NTRK1, and RET. The criteria used for the assessment of malignancy in blue and Spitzoid lesions are different, and these lesions have different prognostic markers. In this study, we assess the clinical, morphological, and genomic changes in 18 cases of Blitz nevi/tumors to better characterize this subset of neoplasms and determine their optimal genomic classification. Most lesions occurred on the extremities followed by the head and neck region typical of blue nevi. Histology showed most cases having a prominent plexiform growth pattern with cells aggregating around the adnexal structures and neurovascular bundles also typical of blue nevi. Using next generation sequencing, we detected the presence of somatic mutations in GNAQ or GNA11 in 4 of 7 cases (57%) of Blitz nevi with sufficient DNA available for sequencing. Normal skin samples in these 4 cases were sequenced to confirm that the GNAQ or GNA11 mutations were somatic mutations. All 4 cases were negative for immunohistochemical assessment for wild-type BRAF, RET, ALK, and NTRK1 and mutational analysis of HRAS was also negative in all cases. Hence, our study suggests that Blitz nevi/tumors are a distinct subset which genomically are best classified as a subset of blue nevi. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Mucocutaneous Hyperpigmentation in a Patient With a History of Both Minocycline and Silver Ingestion.

Minocycline is a derivative of tetracycline. It has been widely used in dermatology for the treatment of acne and rosacea. One of its adverse effects is pigmentation of various body tissues. Clinically, 3 main distinct types of hyperpigmentation by minocycline have been distinguished: type I, with blue-gray to black pigment on the face in areas of scarring or inflammation; type II, with blue-gray pigment on normal skin of the legs, forearms and on the shins; and type III, with a diffuse muddy-brown discoloration in areas of sun exposure. In the current report, we present the case of a 50-year old man with a history of severe acne treated with minocycline in the past, who currently complained about discoloration of his face. He had also taken colloidal silver supplements for "good health" about 16 years ago. Physical examination revealed gray-blue discoloration on the face, sclera, hard palate and back. Histologic examination showed intracellular pigment deposits in macrophages of the superficial dermis in a perivascular and an interstitial distribution. The pigment stained with Fontana-Masson and von Kossa, whereas it was Perls' iron negative. This case does not fit well into any of the previously described patterns of minocycline-related hyperpigmentation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Pruritic Annular Eruption.

No abstract available

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IJMS, Vol. 18, Pages 1028: NGF and Its Receptors in the Regulation of Inflammatory Response

There is growing interest in the complex relationship between the nervous and immune systems and how its alteration can affect homeostasis and result in the development of inflammatory diseases. A key mediator in cross-talk between the two systems is nerve growth factor (NGF), which can influence both neuronal cell function and immune cell activity. The up-regulation of NGF described in inflamed tissues of many diseases can regulate innervation and neuronal activity of peripheral neurons, inducing the release of immune-active neuropeptides and neurotransmitters, but can also directly influence innate and adaptive immune responses. Expression of the NGF receptors tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) is dynamically regulated in immune cells, suggesting a varying requirement for NGF depending on their state of differentiation and functional activity. NGF has a variety of effects that can be either pro-inflammatory or anti-inflammatory. This apparent contradiction can be explained by considering NGF as part of an endogenous mechanism that, while activating immune responses, also activates pathways necessary to dampen the inflammatory response and limit tissue damage. Decreases in TrkA expression, such as that recently demonstrated in immune cells of arthritis patients, might prevent the activation by NGF of regulatory feed-back mechanisms, thus contributing to the development and maintenance of chronic inflammation.

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The FOXO transcription factor controls insect growth and development by regulating juvenile hormone degradation in the silkworm, Bombyx mori [Gene Regulation]

Forkhead box O (FOXO) functions as the terminal transcription factor of the insulin signaling pathway and regulates multiple physiological processes in many organisms, including lifespan in insects. However, how FOXO interacts with hormone signaling to modulate insect growth and development is largely unknown. Here, using the transgene-based CRISPR/Cas9 system, we generated and characterized mutants of the silkworm Bombyx mori FOXO (BmFOXO) to elucidate its physiological functions during development of this lepidopteran insect. The BmFOXO mutant (FOXO-M) exhibited growth delays from the first larval stage and showed precocious metamorphosis which pupating at the end of the fourth instar (trimolter) rather than at the end of the fifth instar as in the wild-type (WT) animals. However, different from previous reports on precocious metamorphosis caused by juvenile hormone (JH) deficiency in silkworm mutants, the total developmental time of the larval period in the FOXO-M was comparable to that of the WT. Exogenous application of 20-hydroxyecdysone (20E) or of the JH analog rescued the trimolter phenotype. RNA-seq and gene expression analyses indicated that genes involved in JH degradation but not in JH biosynthesis were up-regulated in the FOXO-M compared with the WT animals. Moreover, we identified several FOXO-binding sites in the promoter of genes coding for JH-degradation enzymes. These results suggest that FOXO regulates JH degradation rather than its biosynthesis, which further modulates hormone homeostasis to control growth and development in B. mori. In conclusion, we have uncovered a pivotal role for FOXO in regulating JH signaling to control insect development.

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The Cox1 Carboxyl-terminal Domain is a Central Regulator of Cytochrome c Oxidase Biogenesis in Yeast Mitochondria [Gene Regulation]

Cytochrome c oxidase (CcO) is the last electron acceptor in the respiratory chain. The CcO core is formed by mitochondrial DNA-encoded Cox1, Cox2, and Cox3 subunits. Cox1 synthesis is highly regulated; for example, if CcO assembly is blocked, Cox1 synthesis decreases. Mss51 activates translation of COX1 mRNA and interacts with Cox1 protein in high-molecular-weight complexes (COA complexes) to form the Cox1 intermediary assembly module. Thus, Mss51 coordinates both Cox1 synthesis and assembly. We previously reported that the last 15 residues of the Cox1 C-terminus regulate Cox1 synthesis by modulating an interaction of Mss51 with Cox14, another component of the COA complexes. Here, using site-directed mutagenesis of the mitochondrial COX1 gene from Saccharomyces cerevisiae, we demonstrate that mutations P521A/P522A and V524E disrupt the regulatory role of the Cox1 C-terminus. These mutations, as well as C-terminus deletion (Cox1ΔC15), reduced binding of Mss51 and Cox14 to COA complexes. Mss51 was enriched in a translationally active form that maintains full Cox1 synthesis even if CcO assembly is blocked in these mutants. Moreover, Cox1ΔC15, but not Cox1-P521A/P522A and Cox1-V524E, promoted formation of aberrant supercomplexes in CcO assembly mutants lacking Cox2 or Cox4 subunits. The aberrant supercomplex formation depended on the presence of cytochrome b and Cox3, supporting the idea that supercomplex assembly factors associate with Cox3 and demonstrating that supercomplexes can be formed even if CcO is inactive and not fully assembled. Our results indicate that the Cox1 C-terminal end is a key regulator of CcO biogenesis, and that it is important for supercomplex formation/stability.

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Inflammatory cytokines down-regulate the barrier protective prostasin-matriptase proteolytic cascade early in experimental colitis [Enzymology]

Compromised gastrointestinal barrier function is strongly associated with the progressive and destructive pathologies of the two main forms of IBD, Ulcerative Colitis (UC) and Crohns disease (CD). Matriptase is a membrane-anchored serine protease encoded by Suppression of Tumorigenicity-14 (ST14) gene, which is critical for epithelial barrier development and homeostasis. Matriptase barrier protective activity is linked with the glycosyl-phosphatidyl-inositol (GPI)-anchored serine protease prostasin, which is a co-factor for matriptase zymogen activation. Here we show that mRNA and protein expression of both matriptase and prostasin are rapidly down-regulated in the initiating inflammatory phases of dextran sulphate sodium (DSS)-induced experimental colitis in mice, and significantly, the loss of these proteases precedes the appearance of clinical symptoms, suggesting their loss may contribute to disease susceptibility. We used heterozygous St14 hypomorphic mice expressing a promoter-linked beta-gal reporter to show that inflammatory colitis suppresses the activity of the St14 gene promoter. Studies in colonic T84 cell monolayers revealed that barrier disruption by the colitis associated Th2-type cytokines, IL-4 and IL-13, down-regulates matriptase as well as prostasin through phosphorylation of the transcriptional regulator STAT6 and that inhibition of STAT6 with uberoylanilide hydroxamic acid (SAHA) restores protease expression and reverses cytokine induced barrier dysfunction. Both matripase and prostasin are significantly down-regulated in colonic tissues from human subjects with active UC or CD, implicating the loss of this barrier protective protease pathway in the pathogenesis of IBD.

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Cell death-inducing DNA fragmentation factor A-like effector A and fat-specific protein 27{beta} coordinately control lipid droplet size in brown adipocytes [Cell Biology]

Adipose tissue stores neutral lipids and is a major metabolic organ involved in regulating whole-body energy homeostasis. Triacylglycerol is stored as unilocular large lipid droplets (LDs) in white adipocytes and as multilocular small LDs in brown adipocytes. Proteins of the cell death-inducing DNA fragmentation factor A (DFFA)-like effector (Cide) family include CideA, CideB, and fat-specific protein of 27 (FSP27). Of these, FSP27 has been shown to play a crucial role in the formation of unilocular large LDs in white adipocytes. However, the mechanisms by which brown adipocytes store small and multilocular LDs remain unclear. An FSP27 isoform, FSP27β, was recently identified. We herein report that CideA and FSP27β are mainly expressed in brown adipose tissue and that FSP27β overexpression inhibits CideA-induced LD enlargements in a dose-dependent manner in COS cells. Furthermore, RNAi-mediated FSP27β depletion resulted in enlarged LDs in HB2 adipocytes, which possess the characteristics of brown adipocytes. Brown adipocytes in FSP27-knockout mice that express CideA, but not FSP27β, had larger and fewer LDs. Moreover, we confirmed that FSP27β and CideA form a complex in brown adipose tissue. Our results suggest that FSP27β negatively regulates CideA-promoted enlargement of LD size in brown adipocytes. FSP27β appears to be responsible for the formation of small and multilocular LDs in brown adipose tissue, a morphology facilitating free fatty acid transport to mitochondria adjacent to LDs for oxidation in brown adipocytes.

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Single-particle electron microscopy structure of UDP-glucose:glycoprotein glucosyltransferase suggests a selectivity mechanism for misfolded proteins [Molecular Biophysics]

The enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) mediates quality control of glycoproteins in the endoplasmic reticulum by attaching glucose to N-linked glycan of misfolded proteins. As a sensor, UGGT ensures that misfolded proteins are recognized by the lectin chaperones and do not leave the secretory pathway. The structure of UGGT and the mechanism of its selectivity for misfolded proteins have been unknown for 25 years. Here, we used negative-stain electron microscopy and small-angle X-ray scattering to determine the structure of UGGT from Drosophila melanogaster at 18 Å resolution. Three-dimensional reconstructions revealed a cage-like structure with a large central cavity. Particle classification revealed flexibility that precluded determination of a high-resolution structure. Introduction of biotinylation sites into a fungal UGGT expressed in E. coli allowed identification of the catalytic and first thioredoxin-like domain. We also used hydrogen-deuterium exchange mass spectrometry to map the binding site of an accessory protein, Sep15, to the first thioredoxin-like domain. The UGGT structural features identified suggest that the central cavity contains the catalytic site and is lined with hydrophobic surfaces. This enhances the binding of misfolded substrates with exposed hydrophobic residues and excludes folded proteins with hydrophilic surfaces. In conclusion, we have determined the UGGT structure, which enabled us to develop a plausible functional model of the mechanism for UGGT's selectivity for misfolded glycoproteins.

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A split-luciferase complementation, real-time reporting assay enables monitoring of the disease-associated transmembrane protein TREM2 in live cells [Cell Biology]

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single transmembrane molecule uniquely expressed in microglia. TREM2 mutations are genetically linked to Nasu-Hakola disease and associated with multiple neurodegenerative disorders, including Alzheimer's disease (AD). TREM2 may regulate microglial inflammation and phagocytosis through coupling to the adaptor protein, TYRO protein tyrosine kinase binding protein (TYROBP). However, there is no functional system for monitoring this protein-protein interaction. We developed a luciferase-based modality for real-time monitoring of TREM2/TYROBP coupling in live cells that utilizes split-luciferase complementation technology based on TREM2 and TYROBP fusion to the C- or N-terminal portion of the Renilla luciferase gene. Transient transfection of human embryonic kidney 293 cells with this reporter vector increased luciferase activity upon stimulation with an antiTREM2 antibody, which induces their homodimerization. This was confirmed by ELISAbased analysis of the TREM2-TYROBP interaction. Antibody-mediated TREM2 stimulation enhanced Syk tyrosine kinase activity and uptake of S. aureus in microglial cell line BV-2 in a Syk kinasedependent manner. Interestingly, the TREM2 T66M mutation significantly enhanced luciferase activity without stimulation, indicating constitutive coupling to TYROBP. Finally, flow cytometry analyses indicated significantly lower surface expression of T66M TREM2 variant than wild type or other TREM2 variants. These results demonstrate that our TREM2 reporter vector is a novel tool for monitoring the TREM2-TYROBP interaction in real-time.

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Understanding phospholipid function: why are there so many lipids? [Membrane Biology]

In the 1970′s phospholipids were still considered mere building blocks of the membrane lipid bilayer, but the subsequent realization that phospholipids could also serve as second messengers brought new interest to the field. My own passion for the unique amphipathic properties of lipids led me to seek other, non-signaling functions for phospholipids, particularly in their interactions with membrane proteins. This seemed the last frontier in protein chemistry and enzymology to be conquered. I was fortunate to find my way to Eugene Kennedy′s laboratory where both membrane proteins and phospholipids were foci of study thus providing a jumping-off point for advancing our fundamental understanding of lipid synthesis, membrane protein biosynthesis, phospholipid and membrane protein trafficking and the cellular roles of phospholipids. After purifying and characterizing enzymes of phospholipid biosynthesis in Escherichia coli and cloning of several of the genes encoding these enzymes in E. coli and Saccharomyces cerevisiae, I was in a position to alter phospholipid composition in a systematic manner during the cell cycle in these microorganisms. My group was able to establish contrary to common assumption − derived from the fact that membrane proteins retain activity in detergent extracts − that phospholipid environment is a strong determining factor in the function of membrane proteins. We showed that molecular genetic alterations in membrane lipid composition results in many phenotypes, and uncovered direct lipid-protein interactions that govern dynamic structural and functional properties of membrane proteins. Here I present my personal ″reflections″ on how our understanding of phospholipid functions has evolved.

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Pharmacological targeting of Rad6 enzyme-mediated translesion synthesis overcomes resistance to platinum-based drugs [Cell Biology]

Platinum drug-induced crosslink repair requires the concerted activities of translesion synthesis (TLS), Fanconi anemia (FA) and homologous recombination repair pathways. The E2 ubiquitin-conjugating enzyme Rad6 is essential for TLS. Here, we show that Rad6 plays a universal role in platinum-based drug tolerance. Using a novel Rad6-selective small molecule inhibitor (SMI#9) targeting the Rad6 catalytic site, we demonstrate that SMI#9 potentiates the sensitivities of cancer cells with innate or acquired cisplatin or oxaliplatin resistance. IdU/CldU pulse-labeling experiments showed that Rad6 is necessary for overcoming cisplatin-induced replication fork stalling, as replication-restart was impaired in both SMI#9-pretreated and Rad6B-silenced cells. Consistent with the role of Rad6/TLS in late S phase, SMI#9-induced DNA replication inhibition occurred preferentially in mid/late-S phase. The compromised DNA repair and chemosensitization induced by SMI#9 or Rad6B depletion were associated with decreased platinum drug-induced PCNA and FANCD2 monoubiquitinations (surrogate markers of TLS and FA pathway activation, respectively) and with attenuated FANCD2, Rad6, γH2AX and Pol η foci formation and cisplatin-adduct removal. SMI#9-pretreatment synergistically increased cisplatin inhibition of MDA-MB-231 triple-negative breast cancer cell proliferation and tumor growth. Using an isogenic HCT116 colon cancer model of oxaliplatin resistance, we further show that γH2AX, and monoubiquitinated PCNA and FANCD2 are constitutively upregulated in oxaliplatin-resistant HCT116 (HCT116-OxR) cells and that γH2AX, and PCNA and FANCD2 monoubiquitinations are induced by oxaliplatin in parental HCT116 cells. SMI#9 pretreatment sensitized HCT116-OxR cells to oxaliplatin. These data deepen insights into the vital role of Rad6/TLS in platinum-drug tolerance and reveal clinical benefits of targeting Rad6 with SMI#9 for managing chemoresistant cancers.

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Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains [Membrane Biology]

Epigallocatechin gallate (EGCG) is the principal bioactive ingredient in green tea and has been reported to have many health benefits. EGCG influences multiple signal transduction pathways related to human diseases, including redox, inflammation, cell cycle, and cell adhesion pathways. However, the molecular mechanisms of these varying effects are unclear, limiting further development and utilization of EGCG as a pharmaceutical compound. Here, we examined the effect of EGCG on two representative transmembrane signaling receptors, integrin αIIbβ3 and epidermal growth factor receptor (EGFR). We report that EGCG inhibits talin-induced integrin αIIbβ3 activation, but it activates αIIbβ3 in the absence of talin both in a purified system and in cells. This apparent paradox was explained by the fact that the activation state of αIIbβ3 is tightly regulated by the topology of β3 transmembrane domain (TMD); increases or decreases in TMD embedding can activate integrins. Talin increases the embedding of integrin β3 TMD resulting in integrin activation, whereas we observed here that EGCG decreases it, thus opposing talin-induced integrin activation. In the absence of talin, EGCG decreases the TMD embedding which can also disrupt the integrin α-β TMD interaction, leading to integrin activation. EGCG exhibited similar paradoxical behavior in EGFR signaling. EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF, but inhibits EGF-induced EGFR activation. Thus, this widely ingested polyphenol exhibits pleiotropic effects on transmembrane signaling by modifying the topology of TMDs.

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An assessment of quality of life for early phase after adjuvant radiotherapy in breast cancer survivors: a Korean multicenter survey (KROG 14–09)

Quality of life (QoL) has become a major concern as the survival time of breast cancer increases. We investigated the changes in QoL through comprehensive categorical analysis, for the first three years after ...

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The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy

Publication date: Available online 10 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Daniel Martin, Franz Rödel, Panagiotis Balermpas, Claus Rödel, Emmanouil Fokas
Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world, and 70–90% of all cases originate from infection with human papilloma viruses (HPV). Primary chemoradiotherapy (CRT) is the standard treatment for ASCC, but local and/or distant failure still occur in up to 30% of patients. HPV-associated ASCC and tumors with a higher density of tumor infiltrating lymphocytes (TIL) carry a better prognosis. Furthermore, HPV can render tumors more immunogenic, whereas it correlates with elevated TIL densities. This comprehensive review highlights the progress made in understanding the immune microenvironment of anal intraepithelial neoplasias and ASCC in the context of HPV. Here, we discuss the immunomodulatory potential of CRT, the prognostic impact of immune checkpoint markers, and the rationale for including immunotherapies to further improve the clinical outcome in patients with ASCC.



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The sleeping ugly: tumour microenvironment's act to make or break the spell of dormancy

Publication date: Available online 10 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Laurie Gay, Ilaria Malanchi
Metastasis is the main cause of death for most cancer patients. It appears clear from clinical observations that the majority of cancers, particularly carcinoma do not follow a linear model of metastatic progression, where cancer cells shed from the primary tumour, disseminate to a distant organ and immediately outgrow to form clinical metastasis. Certainly, while cancer spreading is an early event, metastasis occurs much later during tumour progression and frequently arises several years after primary tumour resection. The time spent by disseminated cancer cells (DTCs) in a distant organ before their outgrowth is term metastatic latency. We will examine here the current knowledge of the mechanisms allowing metastatic latency and discuss the crucial role of the DTCs' tissue microenvironment in this process.



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Effective dose rate coefficients for exposure to contaminated soil

Abstract

The Oak Ridge National Laboratory Center for Radiation Protection Knowledge has undertaken calculations related to various environmental exposure scenarios. A previous paper reported the results for submersion in radioactive air and immersion in water using age-specific mathematical phantoms. This paper presents age-specific effective dose rate coefficients derived using stylized mathematical phantoms for exposure to contaminated soils. Dose rate coefficients for photon, electron, and positrons of discrete energies were calculated and folded with emissions of 1252 radionuclides addressed in ICRP Publication 107 to determine equivalent and effective dose rate coefficients. The MCNP6 radiation transport code was used for organ dose rate calculations for photons and the contribution of electrons to skin dose rate was derived using point-kernels. Bremsstrahlung and annihilation photons of positron emission were evaluated as discrete photons. The coefficients calculated in this work compare favorably to those reported in the US Federal Guidance Report 12 as well as by other authors who employed voxel phantoms for similar exposure scenarios.



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Biochemical analysis of cerebrospinal fluid in the laboratories of deployed medical treatment facilities: are Multistix 10 SG strip and iSTAT useful?

Introduction

During military deployment, the diagnosis and the management of acute bacterial meningitis can be problematic, as deployed Medical Treatment Facilities (MTFs) often have a limited laboratory diagnostic capability. However, French Role 2 and 3 MTFs have point-of-care (POC) testing to perform urinary (Multistix 10 SG strip) and blood (iSTAT handheld analyser) biochemical testing mentioned in AMedP8.5. The purpose of this study was to compare the accuracy of this urine test strip and of the iSTAT CHEM8 and CG4 cartridges with a standard hospital bench top analyser in order to determine if these POC devices have a potential role in the biochemical analysis of cerebrospinal fluid (CSF protein, CSF glucose and CSF lactate, respectively).

Methods

Agreement between the index methods and the reference methods (suitable kits on the Cobas 6 000 System) was evaluated by parallel testing of 30 CSF samples by both techniques. For CSF protein, agreement between the strip and the reference method was evaluated determining the coefficient. For CSF glucose and CSF lactate subgroups, least squares linear regressions were calculated and Bland-Altman analyses were performed.

Results

The Multistix 10 SG strip can be used to make a semiquantitative determination of CSF protein. A good agreement between the strip and the reference method was observed ( coefficient: 0.93 (IC95 0.82 to 1)). This strip is thus well adapted to demonstrate an elevation of CSF protein level as observed in acute bacterial meningitis. The iSTAT CHEM8 and CG4+ cartridges correlated well with the reference methods for the determination of CSF glucose and CSF lactate, respectively (r2>0.98) but exhibited a negative bias (~ –7% and ~ –15%, respectively).

Conclusions

The combined use of the Multistix 10 SG strip and of the iSTAT system appears to be an attractive solution for the biochemical investigation of CSF in medical treatment facilities with limited laboratory diagnostic capability.



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Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Abstract

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, i.e., 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio (VCDR), a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P-values (P = 3.07 × 10−61), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.

This article is protected by copyright. All rights reserved



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Conditional ablation of Raptor in the male germ line causes infertility due to meiotic arrest and impaired inactivation of sex chromosomes [Research]

Rapamycin is a clinically important drug that is used in transplantation and cancer therapy but which causes a number of side effects, including male infertility. Its canonical target, mammalian target of rapamycin complex 1 (mTORC1), plays a key role in metabolism and binds chromatin; however, its precise role in the male germ line has not been elucidated. Here, we inactivate the core component, Raptor, to show that mTORC1 function is critical for male meiosis and the inactivation of sex chromosomes. Disruption of the Raptor gene impairs chromosomal synapsis and prevents the efficient spreading of silencing factors into the XY chromatin. Accordingly, mRNA for XY-linked genes remains inappropriately expressed in Raptor-deficient mice. Molecularly, the failure to suppress gene expression corresponded with deficiencies in 2 repressive chromatin markers, H3K9 dimethylation and H3K9 trimethylation, in the XY body. Together, these results demonstrate that mTORC1 has an essential role in the meiotic progression and silencing of sex chromosomes in the male germ line, which may explain the infertility that has been associated with such inhibitors as rapamycin.—Xiong, M., Zhu, Z., Tian, S., Zhu, R., Bai, S., Fu, K., Davis, J. G., Sun, Z., Baur, J. A., Zheng, K., Ye, L. Conditional ablation of Raptor in the male germline causes infertility due to meiotic arrest and impaired inactivation of sex chromosomes.



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The ratio of dihomo-{gamma}-linolenic acid to deoxycholic acid species is a potential biomarker for the metabolic abnormalities in obesity [Research]

Bile acid (BA) signaling regulates fatty acid metabolism. BA dysregulation plays an important role in the development of metabolic disease. However, BAs in relation to fatty acids have not been fully investigated in obesity (OB)-related metabolic disorders. A targeted metabolomic measurement of serum BA and free fatty acid profiles was applied to sera of 381 individuals in 2 independent studies. The results showed that the ratio of dihomo--linolenic acid (DGLA) to DCA species (DCAs) was significantly increased in OB individuals with type 2 diabetes (T2DM) from a case–control study and decreased in the remission group of OB subjects with T2DM after metabolic surgery. The changes were closely associated with their metabolic status. These results were consistently confirmed in both serum and liver of mice with diet-induced OB, implying that such a metabolic alteration in circulation reflects changes occurring in the liver. In vitro studies of human liver L-02 cell lines under BA treatment revealed that DCA and its conjugated form, TDCA, significantly inhibited mRNA expression of fatty acid transport protein 5 in the presence of DGLA, which was involved in hepatocyte DGLA uptake. Thus, the DGLA: DCAs ratio may be a promising biomarker for metabolic abnormalities in OB.—Lei, S., Huang, F., Zhao, A., Chen, T., Chen, W., Xie, G., Zheng, X., Zhang, Y., Yu, H., Zhang, P., Rajani, C., Bao, Y., Jia, W., Jia, W. The ratio of dihomo--linolenic acid to deoxycholic acid species is a potential biomarker for the metabolic abnormalities in obesity.



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Risk assessment of manual handling operations at work with the key indicator method (KIM-MHO) — determination of criterion validity regarding the prevalence of musculoskeletal symptoms and clinical conditions within a cross-sectional study

Abstract

Background

Manual handling operations (MHO) are known to be risk factors for work-related upper limb disorders (WRULDs), e.g. symptoms and conditions such as carpal tunnel syndrome. To estimate the risk of WRULDs, a Key Indicator Method (KIM) for the risk assessment of MHO was developed. The method was validated in regard to different criteria, including face validity, criterion validity, reliability and further aspects concerning utility. This paper describes the KIM-MHO and criterion validity of this method with reference to prevalence of musculoskeletal disorders (MSDs).

Methods

A cross-sectional sample of 643 employees exposed to MHO was compared to a reference group of 804 unexposed subjects predominantly working at visual display terminals. The Nordic Questionnaire and a standardized clinical examination were used to obtain the 7-day and 12-months prevalence of symptoms and clinical conditions of the musculoskeletal system. Job specific exposure levels to MHO were assessed by ergonomists using the KIM-MHO. The resulting risk scores were categorized into risk categories 1 - low risk (reference group), 2 - increased risk, 3 - highly increased risk, and 4 - high risk. Log-linear Poisson regression models were applied to obtain adjusted prevalence ratios (PR) with 95%-confidence intervals.

Results

The 7-day prevalence of symptoms for subjects in risk category 3 compared to risk category 1 was significant for the regions shoulder [women (w): PR 1.8 (1.2–2.7), men (m): PR 2.3 (1.2–4.4)], elbow [w: PR 3.3 (1.5–7.2), m: PR 2.4 (0.8–7.3)], and hand/wrist [w: PR 3.0 (1.7–5.3), m: PR 5.5 (2.7–11.3)]. The 7-day prevalence of symptoms for risk category 4 was also significant for the regions shoulder [w: PR 1.9 (1.3–2.8), m: PR 1.9 (1.3–2.7)], elbow [w: PR 4.5 (2.3–8.7), m: PR 3.3 (2.1–5.4)], and hand/wrist [w: PR 4.2 (2.6–6.9), m: PR 5.5 (3.5–8.5)]. The 12-months prevalence in these joint regions show comparable increases in the risk categories 3 and 4.

Conclusions

The KIM-MHO is valid in regard to criterion validity. The hypothesis could be confirmed, that high risk scores were associated with an increased prevalence of symptoms and clinical conditions especially in the shoulder, elbow and hand/wrist regions among employees exposed to MHO.



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Cost-effectiveness of surgical interventions for the management of osteoarthritis: a systematic review of the literature

Abstract

Background

The primary purpose of this study is to assess the existing evidence on the cost-effectiveness of surgical interventions for the management of knee and hip osteoarthritis by systematically reviewing published economic evaluation studies.

Methods

A systematic review was conducted for the period 2004 to 2016. Electronic databases were searched to identify both trial and model based economic evaluation studies that evaluated surgical interventions for knee and hip osteoarthritis.

Results

A total of 23 studies met the inclusion criteria and an assessment of these studies showed that total knee arthroplasty (TKA), and total hip arthroplasty (THA) showed evidence of cost-effectiveness and improvement in quality of life of the patients when compared to non-operative and non-surgical procedures. On the other hand, even though delaying TKA and THA may lead to some cost savings in the short-run, the results from the study showed that this was not a cost-effective option.

Conclusions

TKA and THA are cost-effective and should be recommended for the management of patients with end stage/severe knee and hip OA. However, there needs to be additional studies to assess the cost-effectiveness of other surgical interventions in order for definite conclusions to be reached.



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Experimental Investigation of Isothermal Section of the B-Cr-Fe Phase Diagram at 1353 K

The isothermal section of the B-Cr-Fe ternary system was studied experimentally at 1353 K. X-ray diffraction and scanning electron microscopy equipped with EDX analyzer were used for determination of phase equilibria and composition of the coexisting phases in the B-Cr-Fe model alloys after long-term annealing (1500–2205 h). Two iron borides FeB and Fe2B, six chromium borides Cr2B, Cr5B3, CrB, Cr3B4, CrB2, and CrB4 and also iron and chromium solid solutions (α(Fe,Cr), α(Cr,Fe), γ(Fe,Cr)) and β-rhombohedral B were observed in the alloys. High solubilities of the third element in binary borides and no ternary phase were found. Based on the experimental results, isothermal section of the B-Cr-Fe system at 1353 K was determined.

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A Comparative Study of Partial Replacement of Wheat Flour with Whey and Soy Protein on Rheological Properties of Dough and Cookie Quality

The development of wheat-based foods that are enriched with proteins is increasingly popular. The purpose of this study was to compare the effects of partial replacement of wheat flour with whey and soy proteins (0–30%) on the rheological properties of dough and cookie-making quality. The incorporation of whey protein (WP) diluted the concentration of gluten, leading to an increase in dough development time (MDT) and breakdown torque and a decrease in stability time (MST) and minimum torque (MMT). The gelation of WP during the heat treatment increased dough peak torque (MPT), , and . As a contrast, the addition of soy protein (SP) increased dough MST, MDT, and MMT. The aggregation of SP helped increase and decrease tan δ of the dough in oscillatory shear tests. The weak gelling effects and higher water absorption of SP decreased MPT, , and of the dough during heat treatment. With SP, the spread ratio of cookies first decreased from 6.39 to 5.66 and then increased to 6.86, and the overall acceptability scores ranged from 6.62 to 7.02, indicating that the formed soy protein network helped maintain the dough structure for obtaining an improvement in the quality of bakery products.

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Applied Gaussian Process in Optimizing Unburned Carbon Content in Fly Ash for Boiler Combustion

Recently, Gaussian Process (GP) has attracted generous attention from industry. This article focuses on the application of coal fired boiler combustion and uses GP to design a strategy for reducing Unburned Carbon Content in Fly Ash (UCC-FA) which is the most important indicator of boiler combustion efficiency. With getting rid of the complicated physical mechanisms, building a data-driven model as GP is an effective way for the proposed issue. Firstly, GP is used to model the relationship between the UCC-FA and boiler combustion operation parameters. The hyperparameters of GP model are optimized via Genetic Algorithm (GA). Then, served as the objective of another GA framework, the predicted UCC-FA from GP model is utilized in searching the optimal operation plan for the boiler combustion. Based on 670 sets of real data from a high capacity tangentially fired boiler, two GP models with 21 and 13 inputs, respectively, are developed. In the experimental results, the model with 21 inputs provides better prediction performance than that of the other. Choosing the results from 21-input model, the UCC-FA decreases from 2.7% to 1.7% via optimizing some of the operational parameters, which is a reasonable achievement for the boiler combustion.

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From Human Mesenchymal Stem Cells to Insulin-Producing Cells: Comparison between Bone Marrow- and Adipose Tissue-Derived Cells

The aim of this study is to compare human bone marrow-derived mesenchymal stem cells (BM-MSCs) and adipose tissue-derived mesenchymal stem cells (AT-MSCs), for their differentiation potentials to form insulin-producing cells. BM-MSCs were obtained during elective orthotopic surgery and AT-MSCs from fatty aspirates during elective cosmetics procedures. Following their expansion, cells were characterized by phenotyping, trilineage differentiation ability, and basal gene expression of pluripotency genes and for their metabolic characteristics. Cells were differentiated according to a Trichostatin-A based protocol. The differentiated cells were evaluated by immunocytochemistry staining for insulin and c-peptide. In addition the expression of relevant pancreatic endocrine genes was determined. The release of insulin and c-peptide in response to a glucose challenge was also quantitated. There were some differences in basal gene expression and metabolic characteristics. After differentiation the proportion of the resulting insulin-producing cells (IPCs), was comparable among both cell sources. Again, there were no differences neither in the levels of gene expression nor in the amounts of insulin and c-peptide release as a function of glucose challenge. The properties, availability, and abundance of AT-MSCs render them well-suited for applications in regenerative medicine. Conclusion. BM-MSCs and AT-MSCs are comparable regarding their differential potential to form IPCs. The availability and properties of AT-MSCs render them well-suited for applications in regenerative medicine.

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Do Successive Preterm Births Increase the Risk of Postpartum Depressive Symptoms?

Background. Postpartum depression and preterm birth (PTB) are major problems affecting women’s health. PTB has been associated with increased risk of postpartum depressive symptoms (PDS). However, it is unclear if PTB in women with a prior history of PTB is associated with an incremental risk of PDS. This study aims to determine if PTB in women with a prior history of PTB is associated with an incremental risk of PDS. Methods. Data come from the 2009–2011 national Pregnancy Risk Assessment Monitoring System. Study sample included 55,681 multiparous women with singleton live births in the index delivery. Multiple logistic regression was used to examine the association between PTB and PDS. Results. The risk of PDS was 55% higher in women with PTB in both deliveries (aRR = 1.55; 95% CI = 1.28–1.88) and 74% higher in women with PTB in the index delivery only (aRR = 1.74; 95% CI = 1.49–2.05), compared to women with term deliveries. Conclusions. Preterm birth is a risk factor for PDS. PTB in women with a prior history of PTB is not associated with an incremental risk of PDS. Routine screening for PDS should be conducted for all women and closer monitoring should be done for high risk women with PTB.

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Analyses of Mineral Content and Heavy Metal of Honey Samples from South and East Region of Turkey by Using ICP-MS

The substantial of mineral ingredients in honey may symbolize the existence of elements in the plants and soil of the vicinity wherein the honey was taken. The aim of this study was to detect the levels of 13 elements (Potassium (K), Sodium (Na), Calcium (Ca), Iron (Fe), Zinc (Zn), Cadmium (Cd), Copper (Cu), Manganese (Mn), Lead (Pb), Nickel (Ni), Chromium (Cr), Aluminum (Al), and Selenium (Se)) in unifloral and multifloral honey samples from south and east regions of Turkey. Survey of 71 honey samples from seven different herbal origins, picked up from the south and east region of Turkey, was carried out to determine their mineral contents during 2015-2016. The mineral contents were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The most abundant minerals were K, Na, and Ca ranging within 1.18–268 ppm, 0.57–13.1 ppm, and 0.77–4.5 ppm, respectively. Zn and Cu were the most abundant trace element while Pb, Cd, Ni, and Cr were the lowest heavy metals in the honey samples surveyed, with regard to the concentrations of heavy metals such as Zn, Cu, Pb, Cd, Ni, and Cr suggested and influence of the botanical origin of element composition. Geochemical and geographical differences are probably related to the variations of the chemical components of honey samples.

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Active Ingredients of Epimedii Folium and Ligustri Lucidi Fructus Balanced GR/HSP90 to Improve the Sensitivity of Asthmatic Rats to Budesonide

This study aimed to investigate the possible molecular mechanisms of active ingredients of Epimedii Folium (EF) and Ligustri Lucidi Fructus (LLF) combined with Budesonide (Bun) in asthmatic rats. Rats were divided into 5 groups, including normal group, asthma model group, Bun group, group of active ingredients of EL and LLF (EL), and group of coadministration of Bun with EL (Bun&EL). The asthmatic model was prepared by ovalbumin sensitizing and challenging. Lymphocyte apoptosis, GR protein and binding, and the protein and mRNA of GRα, GRβ, and HSP90 were tested. The results showed that Bun&EL ① markedly increased lymphocyte apoptosis, GR and HSP90 protein, and GR binding in BALF and ② enhanced the expressions of GRα and HSP90 and the ratio of GRα to GRβ or to HSP90 both in protein and in mRNA levels in lung, ③ while decrease occurred in GRβ mRNA and the mRNA ratio of GRβ to HSP90 compared with asthma or Bun group. Moreover, there was a significant correlation between GRα and GRβ in protein level, or between GRα and HSP90 both in protein and in mRNA levels. EL may effectively enhance the sensitivity of asthmatic rats to Bun via balancing GR/HSP90. And these findings will be beneficial for the treatment of asthma in the future.

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A Fisher’s Criterion-Based Linear Discriminant Analysis for Predicting the Critical Values of Coal and Gas Outbursts Using the Initial Gas Flow in a Borehole

The risk of coal and gas outbursts can be predicted using a method that is linear and continuous and based on the initial gas flow in the borehole (IGFB); this method is significantly superior to the traditional point prediction method. Acquiring accurate critical values is the key to ensuring accurate predictions. Based on ideal rock cross-cut coal uncovering model, the IGFB measurement device was developed. The present study measured the data of the initial gas flow over 3 min in a 1 m long borehole with a diameter of 42 mm in the laboratory. A total of 48 sets of data were obtained. These data were fuzzy and chaotic. Fisher’s discrimination method was able to transform these spatial data, which were multidimensional due to the factors influencing the IGFB, into a one-dimensional function and determine its critical value. Then, by processing the data into a normal distribution, the critical values of the outbursts were analyzed using linear discriminant analysis with Fisher’s criterion. The weak and strong outbursts had critical values of 36.63 L and 80.85 L, respectively, and the accuracy of the back-discriminant analysis for the weak and strong outbursts was 94.74% and 92.86%, respectively. Eight outburst tests were simulated in the laboratory, the reverse verification accuracy was 100%, and the accuracy of the critical value was verified.

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Population Aspects of Fishes in Geba and Sor Rivers, White Nile System in Ethiopia, East Africa

This study was carried out to assess the diversity, condition factor, length-weight relationship, and sex ratio of fishes in Geba and Sor Rivers located in Baro-Akobo Basin, White Nile system within Ethiopia. Fish samples were collected in one wet and one dry season. The length-weight relationships were fitted using power equation for the most abundant species. A total of 348 fish specimens were collected using gillnets and hooks. These were identified into eight species and one Garra sp. representing seven genera and four families. Family Cyprinidae was the most dominant with six species (66.7%). Labeobarbus intermedius, Labeobarbus nedgia, and Labeo cylindricus were the most abundant fish species, respectively, with 60.72%, 16.83%, and 14.66% index of relative importance (IRI). The diversity index was higher for Geba River ( = 1.50) than for Sor River ( = 1.10). All the three most abundant species had negative allometric growth. Seasonal variations in the mean Fulton condition factor (FCF) were statistically significant for L. cylindricus (). There was variation in the sex ratio with the females dominating in all the three most abundant species. Further investigation into the fish diversity, food, feeding, and reproductive behaviors of fish species especially in the tributaries of these rivers and their socioeconomic aspects is recommended.

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Effect of Color Light Stimulation Using LED on Sleep Induction Time

The effects of color are already being used widely. For this reason, in this study, an attempt was made to use such effects of color to examine the changes in sleep onset through the use of the preferred and nonpreferred color light stimulation. Color light stimulations were randomly presented to the subjects, and based on these colors, the changes in sleep onset were examined through the EEG. Also, to quantify the physiological changes that were caused by each color light stimulation, the changes in the HRV were examined through ECG to determine the level of activation of the autonomous nervous system. The results showed that sleep onset time was changed based on the light stimulation. The result of the EEG analysis showed that sleep onset time was most significantly shortened in preferred color light stimulation. Also, the result of HRV was the fastest change about both the time domain and the frequency domain in the preferred color light stimulation. Therefore, because the preferred color light stimulation activated the parasympathetic nervous system, sleep was induced quickly. Also, by simply using the HRV, the differences in the index of HRV showed changes of sleep onset according to the color light stimulation.

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Skilled Birth Attendance among Women in Tharaka-Nithi County, Kenya

Background. The burden of maternal mortality is concentrated in sub-Saharan Africa with an estimation of 500 000 deaths annually. In 2012, about forty million births occurred without a skilled attendant in developing countries. Skilled birth attendance improves maternal and newborn survival. The aim of this study therefore was to establish the level of skilled birth attendance and the associated factors. Methods. A cross-sectional survey was carried out using structured questionnaires as tools of data collection. Systematic sampling was used to select the respondents from the facilities that were stratified. The dependent variable was skilled birth attendance. Descriptive statistics were used to generate proportions and percentages while chi-square and Fisher’s exact tests were used to draw inferences. Association was significant if . Results. The level of utilisation of skilled birth attendance was 77%. Skilled birth attendance was noted to be associated with age, level of education, average family income, parity, distance to the health facility, timing of initiation of antenatal care, level of facility attended during pregnancy, and birth preparedness status. Conclusion. The level of skilled birth attendance among women in Tharaka-Nithi County, Kenya, despite being higher than in some counties, requires improvement.

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