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Background: The aim of this study was to investigate the efficacy of our modified cementing technique in reducing the rate of aseptic tibial loosening focusing on its relationship with keel length., Methods: Every participant who underwent primary total knee arthroplasty (TKA) between August 2014 and September 2022 with a minimum of 4-year follow-up using 1 of 3 implants were included: Persona + conventional cementing technique; Persona + modified cementing technique; and NexGen LPS-Flex. The modifications applied include better preparation of the bone surfaces and the cancellous bone cavities, pressurizing the cement and interstitial fluid suction at the same time, applying a layer of cement on the surfaces of the tibia and implant, and immobilizing the limb. Kaplan-Meier analyses were performed to estimate survivorship., Results: A total of 988 of 1039 primary TKAs (95.1%) were included with follow-up of 89.26 ± 7.32 months. Twenty eight (2.83%) TKA required revisions due to aseptic tibial loosening; 3 (1.1%) in the NexGen group, 21 (6.9%) in the conventionally cemented Persona group, and 4 (0.9%) within the modified cemented Persona group. Aseptic loosening occurred at a mean of 69.00 ± 2.65, 34.57 ± 22.90, and 68.50 ± 3.42, respectively. Survivorship for aseptic loosening was 98.9%, 93.1%, and 99.1% at 8 years, respectively. The revision rate for early (during the first 24 months) aseptic loosening was 4.6% in the conventionally cemented Persona group. No early aseptic loosening reported in other 2 groups., Conclusions: In conclusion, meticulous cementing techniques can reduce the rate of tibial loosening in shorter keel designs., (© 2024 The Authors.)

The COVID-19 pandemic has drawn significant attention to factors affecting disease severity, especially in older adults. This study explores the relationship between Klotho, an anti-aging protein, and COVID-19 severity. Conducted at Tehran's Firouzgar Hospital, this case-control study involved 279 participants, assessing serum levels of Klotho, inflammatory markers (C-reactive protein (CRP), Interleukin 6 (IL-6)), and Vitamin D. The findings indicate significantly lower Klotho levels in COVID-19 patients, especially those in the ICU, which correlate with elevated inflammatory markers and reduced Vitamin D levels. This inverse relationship between Klotho levels and disease severity underscores the protein's potential modulatory role in the inflammatory response to COVID-19. The study not only highlights the importance of Klotho as a biomarker for aging and disease severity but also suggests its potential therapeutic value in managing COVID-19, offering a novel perspective on targeting aging-related pathways to mitigate the impact of the disease. These insights open new avenues for research and intervention strategies to leverage anti-aging mechanisms to combat COVID-19 and potentially other age-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Knee osteoarthritis (KOA) is a prevalent musculoskeletal disease affecting joint mechanics. Considering the effect of step-width changes on the biomechanics of gait, especially the alteration of stability dynamics during narrow-base gait, this study investigated the kinematic parameters of the lower extremities during both normal and narrow-base walking in individuals with and without KOA., Methods: A cross-sectional study with 20 individuals with bilateral KOA and 20 controls was conducted. Participants walked on a treadmill at a preferred speed across normal and narrow paths. Joint angles and angular velocities in the sagittal and frontal planes were recorded, and mixed ANOVA was used to analyze group × condition effects., Results: Significant main effects of walking condition were observed for hip (p = 0.001) and ankle angles (p = 0.002) in the frontal plane, and knee (p = 0.004) and ankle angular velocities (p = 0.002) in the sagittal plane. Moreover, there were significant main effects of group on the hip (p = 0.01) and knee angles (p = 0.04) in the sagittal plane. KOA group showed higher peak hip adduction (p < 0.001) and ankle inversion (p = 0.02]) during narrow-base walking than on the normal path. People with KOA had also significantly higher peak angular velocity of knee flexion (p = 0.03), ankle dorsiflexion (p = 0.002), and ankle inversion (p = 0.03) during narrow-base walking., Conclusions: The findings suggest that KOA and narrow-base gait challenges may trigger distinct kinematic adaptation strategies, potentially contributing to cartilage degeneration and altering balance mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The objective of the present research was to develop chitosan-coated nanoliposomes using a modified heating method as a delivery system for simultaneous encapsulation of caffeine and roselle anthocyanin to fortify beverage. Response surface methodology was used to ascertain the optimized formulation, aiming to maximize the encapsulation efficiency, minimize the particle size, and maximize the zeta potential. The liposomes fabricated under the optimized conditions (lecithin to cholesterol ratio of 13 and wall to core ratio of 2.16) showed encapsulation efficiency values of 66.73 % for caffeine and 97.03 % for anthocyanin, with a size of 268.1 nm and a zeta potential of -39.11 mV. Fourier transform infrared spectroscopy confirmed the formation of hydrogen bonds between the polar sites of lecithin and the loaded core compounds. Thermal analysis suggested the successful encapsulation of the caffeine and anthocyanin. Transmission and scanning electron microscopy images confirmed a uniform spherical shape with a smooth surface. Fortifying the model beverage with the liposome and the chitosan-coated nanoliposome revealed higher values of encapsulation efficiency of anthocyanin (70.33 ± 3.11 %), caffeine (86.37 ± 2.17 %) and smaller size (280.5 ± 0.74 nm) of the chitosan-coated nanoliposomes at the end of 60th e days. A hedonic sensory test of the fortified beverage with chitosan-coated nanoliposomes confirmed an improvement in the organoleptic properties of the beverage by masking its bitterness (receiving three more sensory scores in perceiving the bitterness intensity). Overall, our study indicates that the high potential of the chitosan-coated nanoliposomes for the simultaneous loading of the caffeine and anthocyanin, as well as their possible application in food and beverage formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pentavalent antimonials are the mainstay treatment against different clinical forms of leishmaniasis. The emergence of resistant isolates in endemic areas has led to treatment failure. Unraveling the underlying resistance mechanism would assist in improving the treatment strategies against resistant isolates. This study aimed to investigate the RNA expression level of glutathione synthetase (GS), Spermidine synthetase (SpS), trypanothione synthetase (TryS) genes involved in trypanothione synthesis, and thiol-dependent reductase (TDR) implicated in drug reduction, in antimony-sensitive and -resistant Leishmania tropica isolates. We investigated 11 antimony-resistant and 11 antimony-sensitive L. tropica clinical isolates from ACL patients. Drug sensitivity of amastigotes was determined in mouse macrophage cell line J774A.1. The RNA expression level in the promastigote forms was analyzed by quantitative real-time PCR. The results revealed a significant increase in the average expression of GS, SpS, and TrpS genes by 2.19, 1.56, and 2.33-fold in resistant isolates compared to sensitive ones. The average expression of TDR was 1.24-fold higher in resistant isolates, which was insignificant. The highest correlation coefficient between inhibitory concentration (IC 50 ) values and gene expression belonged to the TryS, GS, SpS, and TDR genes. Moreover, the intracellular thiol content was increased 2.17-fold in resistant isolates compared to sensitive ones and positively correlated with IC 50 values. Our findings suggest that overexpression of trypanothione biosynthesis genes and increased thiol content might play a key role in the antimony resistance of L. tropica clinical isolates. In addition, the diversity of gene expression in the trypanothione system and thiol content among L. tropica clinical isolates highlighted the phenotypic heterogeneity of antimony resistance among the parasite population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Aseptic loosening due to mechanical failure of bone cement is considered to be a leading cause of revision of joint replacement systems. Detailed quantified information on the number, size and distribution pattern of pores can help to obtain a deeper understanding of the bone cement's fatigue behavior. The objective of this study was to provide statistical descriptions for the pore distribution characteristics of laboratory bone cement specimens with different amounts of antibiotic contents. For four groups of bone cement (Palacos) specimens, containing 0.3, 0.6, 1.2 and 2.4 wt/wt% of telavancin antibiotic, seven samples per group were micro computed tomography scanned (38.97 μm voxel size). The images were first preprocessed in Mimics and then analyzed in Dragonfly, with the level of threshold being set such that single-pixel pores become visible. The normalized pore volume data of the specimens were then used to extract the logarithmic histograms of the pore densities for antibiotic groups, as well as their three-parameter Weibull probability density functions. Statistical comparison of the pore distribution data of the antibiotic groups using the Mann-Whitney non-parametric test revealed a significantly larger porosity (p < 0.05) in groups with larger added antibiotic contents (2.4 and 0.6 wt/wt% vs 0.3 wt/wt%). Further analysis revealed that this effect was associated with the significantly larger frequency of micropores of 0.1-0.5 mm diameter (p < 0.05) in groups with larger antibiotic content (2.4 wt/wt% vs and 0.6 and 0.3 wt/wt%), implying that the elution of the added antibiotic produces micropores in this diameter range mainly. Based on this observation and the fatigue test results in the literature, it was suggested that micropore clusters have a detrimental effect on the mechanical properties of bone cement and play a major role in initiating fatigue cracks in highly antibiotic added specimens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Determination of the ventricle size in idiopathic normal pressure hydrocephalus (iNPH) is essential for diagnosis and follow-up of shunt results. Fully automated segmentation methods are anticipated to optimize the accuracy and time efficiency of ventricular volume measurements. We evaluated the accuracy of preoperative and postoperative ventricular volume measurements in iNPH by a magnetic resonance imaging (MRI)-based licensed software for fully automated quantitative assessment., Methods: Forty-eight patients diagnosed with iNPH were retrospectively analyzed. All patients received a ventriculoperitoneal shunt and had symptom grading and routine MRI preoperatively and 3-6 months postoperatively. Ventricular volumes, generated by fully automated T1-weighted imaging volume sequence segmentation, were compared with semiautomatic measurements and routine radiologic reports. The relation of postoperative ventricular size change to clinical response was evaluated., Results: Fully automated segmentation was achieved in 95% of the MRIs, but showed various rates of 8 minor segmentation errors. The correlation between both segmentation methods was very strong (r >0.9) and the agreement very good using Bland-Altman analyses. The ventricular volumes differed significantly between semiautomated and fully automated segmentations and between preoperative and postoperative MRI. The fully automated method systematically overestimated the ventricles by a median 15 mL preoperatively and 14 mL postoperatively; hence, the magnitudes of volume changes were equivalent. Routine radiologic reports of ventricular size changes were inaccurate in 51% and lacked association with treatment response. Objectively measured ventricular volume changes correlated moderately with postoperative clinical improvement., Conclusions: A fully automated volumetric method permits reliable evaluation of preoperative ventriculomegaly and postoperative ventricular volume change in idiopathic normal pressure hydrocephalus., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Combination therapy has been considered one of the most promising approaches for improving the therapeutic effects of anticancer drugs. This is the first study that uses two different antioxidants in full-characterized niosomal formulation and thoroughly evaluates their synergistic effects on breast cancer cells. In this study, in-silico studies of hydrophilic and hydrophobic drugs (ascorbic acid: Asc and curcumin: Cur) interactions and release were investigated and validated by a set of in vitro experiments to reveal the significant improvement in breast cancer therapy using a co-delivery approach by niosomal nanocarrier. The niosomal nanoparticles containing surfactants (Span 60 and Tween 60) and cholesterol at 2:1 M ratio were prepared through the film hydration method. A systematic evaluation of nanoniosomes was carried out. The release profile demonstrated two phases (initial burst followed by sustained release) and a pH-dependent release schedule over 72 h. The optimized niosomal preparation displayed superior storage stability for up to 2 months at 4 °C, exhibiting extremely minor changes in pharmaceutical encapsulation efficiency and size. Free dual drugs (Asc + Cur) and dual-drug loaded niosomes (Niosomal (Asc + Cur)) enhanced the apoptotic activity and cytotoxicity and inhibited cell migration which confirmed the synergistic effect of co-encapsulated drugs. Also, significant up-regulation of p53 and Bax genes was observed in cells treated with Asc + Cur and Niosomal (Asc + Cur), while the anti-apoptotic Bcl-2 gene was down-regulated. These results were in correlation with the increase in the enzyme activity of SOD, CAT, and caspase, and the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) upon treatment with the mentioned drugs. Furthermore, these anti-cancer effects were higher when using Niosomal (Asc + Cur) than Asc + Cur. Histopathological examination also revealed that Niosomal (Asc + Cur) had a lower mitosis index, invasion, and pleomorphism than Asc + Cur. These findings indicated that niosomal formulation for co-delivery of Asc and Cur would offer a promising delivery system for an effective breast cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Consumer exposure to cosmetic ingredients is estimated in a tiered manner. Simple Tier1 deterministic aggregate exposure modelling generates a worst case estimate of exposure. Tier1 assumes that a consumer uses all cosmetic products concomitantly daily, at maximum frequency, and products always contain the ingredient at the maximum allowed % w/w concentration. Refining exposure assessment from worst case to more realistic estimates uses evidence from surveys of actual use levels of ingredients and Tier2 probabilistic models, where distributions of consumer use data can be applied. In Tier2+ modelling, occurrence data provides evidence of products on the market actually containing the ingredient. Three case studies are presented using this tiered approach to illustrate progressive refinement. The scale of refinements from Tier1 to Tier2+ modelling for the ingredients, propyl paraben, benzoic acid and DMDM hydantoin were: 0.492 to 0.026; 1.93 to 0.042 and 1.61 to 0.027 mg/kg/day exposure dose. For propyl paraben, moving from Tier1 to Tier2+ represents a refinement from 49-fold to 3-fold overestimate of exposure when compared to a maximum estimate of 0.01 mg/kg/day exposure seen in human studies. Such refinements from worst case to realistic levels of exposure estimation can be critical in the demonstration of consumer safety., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employed by the Cosmetics Industry. C Alexander-White is an independent consultant in chemicals safety assessment who was commissioned by Cosmetics Europe specifically for this project as a specialist in cosmetics safety evaluation and scientific writer., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulse contour cardiac output monitoring systems allow real-time and continuous estimation of hemodynamic variables such as cardiac output (CO) and stroke volume variation (SVV) by analysis of arterial blood pressure waveforms. However, evaluating the performance of CO monitoring systems to measure the small variations in these variables sometimes used to guide fluid therapy is a challenge due to limitations in clinical reference methods. We developed a non-clinical database as a tool for assessing the dynamic attributes of pressure-based CO monitoring systems, including CO response time and CO and SVV resolutions. We developed a mock circulation loop (MCL) that can simulate rapid changes in different parameters, such as CO and SVV. The MCL was configured to simulate three different states (normovolemic, cardiogenic shock, and hyperdynamic) representing a range of flow and pressure conditions. For each state, we simulated stepwise changes in the MCL flow and collected datasets for characterizing pressure-based CO systems. Nine datasets were generated that contain hours of peripheral pressure, central flow and pressure waveforms. The MCL-generated database is provided open access as a tool for evaluating dynamic characteristics of pressure-based CO algorithms and systems in detecting variations in CO and SVV indices. In an example application of the database, a CO response time of 10 s, CO and SVV resolutions with lower and upper limits of (-9.1%, 8.4%) and (-5.0%, 3.8%), respectively, were determined for a pressure-based CO benchtop system. This tool will support a more comprehensive assessment of pressure-based CO monitoring systems and algorithms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Recent advances in the artificial pancreas system provide an emerging treatment option for type 1 diabetes. The performance of the blood glucose regulation directly relies on the accuracy of the glucose-insulin modeling. Sorenson model involves the behavior of different organs and offers precise representation. However, the high complexity of such a model makes the controller design procedure a hard task. Therefore, the high-order nonlinear Sorensen model as a popular high-fidelity physiological model is opted in this paper to analyze the glucose-insulin interactions in great detail, and a new robust nonlinear approach to regulate the blood glucose concentration (BGC) in Type-I diabetic patients is proposed. Inspiring the backstepping technique, for designing an acceptable controller, the model is divided into three main subsystems such that in each subsystem, the virtual control input laws are obtained using both Lyapunov stability and input-to-state theorems. Since the measurement of the parameters in the glucose-insulin system is not accurate, parametric uncertainties are defined in the investigated model. Furthermore, owing to the fact that the only measurable state variable is blood glucose, the estimation of inaccessible state variables is an important issue that is properly considered by the unscented Kalman filter (UKF) estimator. The suggested approach is compared to H ∞ , robust H ∞ , and linear parameter-varying control approaches. The comparison results on 500 simulated patients imply a remarkable superiority of the proposed controller approach to the compared methods in terms of the BGC tracking and the algorithm robustness in the presence of food intake disturbance patterns., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 ISA. All rights reserved.)

Background: Endoscopic endonasal surgery is the main transsphenoidal approach for pituitary surgery in many centers; however, few studies compare the endoscopic and microscopic surgical approaches with regard to long-term follow-up. This single-center study aimed to compare the 2 techniques over 15 years., Methods: Medical records and magnetic resonance images from 40 patients with primary transsphenoidal surgery for Cushing's disease at Sahlgrenska University Hospital between 2003 and 2018 were reviewed. 14 patients who underwent microscopic surgery and 26 patients who underwent endoscopic surgery were included in this study., Results: In the microscopic group, 12 of 14 patients achieved endocrine remission, compared to 19 of 26 patients in the endoscopic group (n. s.). Three patients in each group developed a late recurrence. Complications were seen in 5 patients in the microscopic group and in 8 patients in the endoscopic group (n. s.). No serious complications, such as carotid artery damage, cerebrovascular fluid leakage, epistaxis, or meningitis, occurred in any group. The postoperative hospital stay was shorter in the endoscopic than in the microscopic group., Conclusions: Endoscopic endonasal surgery for Cushing's disease showed no difference in remission, recurrence, and complication rates compared to the microscopic approach. The endoscopic group had a shorter postoperative hospital stay than the microscopic group, which in part may be due to the minimal invasiveness of the endoscopic approach., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To develop an effective Management Information System (MIS) that is empowered by predictive models that can forecast the demand of end-stage cancer home hospitalized patients in individual and population levels, and help palliative care service systems operate smoothly where the demand is highly fluctuating, resources are limited, expensive, and hardly adjustable in a short time, and the backlog and shortage costs are high., Method: Inspired by real problems faced by a palliative care center providing various medical, nursing, psychological, and social services in a home-based setting, two Long Short-Term Memory (LSTM) based deep learning models are proposed for demand forecasting at both individual and population levels. The individual-level model can predict the type and time of the next service required for a specific patient with a given demographic and health profile, and the population-level model helps with the prediction of next week's demand for various services in a center supporting a specific patient population. Predicted demand informs on optimal resource and operations plan through a well designed MIS., Results: Experiments were conducted on a dataset consisting of more than 4000 cancer patients with a Palliative Performance Scale (PPS) of 40 and below discharged from hospital to home under a national palliative care center's home hospitalization service in Iran from September 2012 to July 2019. The models outperformed conventional time-series forecasting methods where applicable. Results indicate that the proposed models were capable of forecasting patients' demand with astonishing performances both individually and on larger scales., Conclusion: Intelligent demand forecasting can help palliative care home hospitalization systems to overcome the challenge of progressive demand growth when a considerable portion of patients are approaching death, followed by a sudden drop in demand when those patients pass away. It helps to improve resource utilization and quality of care concurrently., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In this trial, additive effects of acupuncture to selective serotonin reuptake inhibitors (SSRIs) treatment for reducing anxiety, were investigated., Methods: 112 patients with anxiety disorder were randomly divided into three groups including SSRIs alone (drug group), SSRIs with sham acupuncture (control group) and SSRI with acupuncture (acupuncture group), and treated for 4 weeks. At the beginning of the study and on day 28, Spielberger State-Trait Anxiety Inventory (STAI) questionnaire was completed and serum levels of cortisol were measured., Results: 105 patients completed the treatment period. STAI score showed significant differences among the three groups at the end of the study; importantly, changes in STAI score in the acupuncture group were significantly larger than the other groups. A decrease in cortisol levels was observed in all groups; though statistically non-significant, this decrease in the acupuncture group was larger., Conclusion: Acupuncture combined with SSRIs can significantly improve anxiety state compared to anti-anxiety therapy using SSRIs alone., (Copyright © 2021. Published by Elsevier Ltd.)

Ultrasound plays a considerable role in human and animal reproduction in terms of early detection of pregnancy, prediction of parturition time, and diagnosis of fetal abnormalities. The present study aimed to evaluate the ultrasound implementation for monitoring of gestation in mini-lop rabbits. Fifteen heads of pubertal does were selected and kept in normal conditions of feeding and temperature. Animals were mated with three bucks from the same breed. The pregnancy monitoring was begun from five days post-mating (dpm) to kindling using a 12.5 MHz ultrasonic transducer. The examinations were performed at fixed dpm for all does (5, 7, 12, 16, 20, and 26). Furthermore, randomly selected does (2-3 does per day; one doe was fixed) were subjected to daily ultrasound examination to estimate the relationship between the ultrasound biometrics with the gestational age (GA) and days to parturition. The pregnancy rate was 80%, and the mean number of live kits at birth was 4.2 in the present study. Based on the ultrasound records, the gestation length can be divided into three tertiles of pregnancy (TOP) in rabbits. The first TOP (0-10 dpm) was monitored by detecting and measuring the gestational sac diameter from 6 to 10 dpm. The 2nd TOP (11-12 dpm) was characterized by detection and measurement of Crown Rump Length and Fetal Heart Rate. From 15 to 20 dpm, bi-parietal diameter and head circumference were positively correlated with the GA (p-value < 0.05). Abdominal circumference and femur length were detectable and measurable during the 3rd TOP (21 dpm-kindling). Pregnancy was detected as early as six dpm with acceptable markers in mini-lop rabbits. Highly significant negative correlations were detected between days to parturition and the sonographic biometrics. Three abnormal fetuses were successfully detected and described, too., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SARS-CoV-2 as a new global threat has affected global population for one year. Despite the great effort to eradicate this infection, there are still some challenges including different viral presentation, temporal immunity in infected individuals and variable data of viral shedding. We studied 255 COVID-19 suspected individuals to assess the viral shedding duration and also the antibody development against SARS-CoV-2 among the cases. Real Time RT-PCR assay was applied to determine the virus presence and SARS-CoV-2 antibodies were evaluated using SARS-CoV-2 IgM and IgG kits. 113 patients were confirmed for COVID-19 infection. The patients were followed until negative PCR achieved. The median viral shedding among studied population was obtained 34.16 (±17.65) days which was not significantly associated with age, sex and underlying diseases. Shiver and body pain were found in prolonged form of the infection and also patients who had gastrointestinal problems experienced longer viral shedding. Moreover, IgG was present in 84% of patients after 150 days. According to this data, the median viral shedding prolongation was 34.16 days which indicates that 14 days isolation might not be enough for population. In addition, IgG profiling indicated that it is persistent in a majority of patients for nearly 6 months which has brought some hopes in vaccine efficacy and application., Competing Interests: Declaration of competing interest Authors declare no potential conflict of interest that could negatively influence the study., (Copyright © 2021 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Background: SARS-CoV-2 induced coagulopathy can lead to thrombotic complications such as stroke. Cerebral venous sinus thrombosis (CVST) is a less common type of stroke which might be triggered by COVID-19. We present a series of CVST cases with SARS-CoV-2 infection., Methods: In a multinational retrospective study, we collected all cases of CVST in SARS-CoV-2 infected patients admitted to nine tertiary stroke centers from the beginning of the pandemic to June 30th, 2020. We compared the demographics, clinical and radiological characteristics, risk factors, and outcome of these patients with a control group of non-SARS-CoV-2 infected CVST patients in the same seasonal period of the years 2012-2016 from the country where the majority of cases were recruited., Results: A total of 13 patients fulfilled the inclusion criteria (62% women, mean age 50.9 ± 11.2 years). Six patients were discharged with good outcomes (mRS ≤ 2) and three patients died in hospital. Compared to the control group, the SARS-CoV-2 infected patients were significantly older (50.9 versus 36.7 years, p < 0.001), had a lower rate of identified CVST risk factors (23.1% versus 84.2%, p < 0.001), had more frequent cortical vein involvement (38.5% versus 10.5%, p: 0.025), and a non-significant higher rate of in-hospital mortality (23.1% versus 5.3%, p: 0.073)., Conclusion: CVST should be considered as potential comorbidity in SARS-CoV-2 infected patients presenting with neurological symptoms. Our data suggest that compared to non-SARS-CoV-2 infected patients, CVST occurs in older patients, with lower rates of known CVST risk factors and might lead to a poorer outcome in the SARS-CoV-2 infected group., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Observational cohort studies have reported a potentially increased risk of stroke in patients with epileptic seizures. Whether late-onset seizures merit primary stroke prophylaxis is not known, and more information on stroke risk is needed for the planning of RCTs. We performed a case-control study based on Swedish national registers to quantify the risk of stroke after epileptic seizures., Methods: Cases ≤100 years of age with a first-ever stroke 2001-2009 were identified through the Swedish Stroke Register, and stroke-free controls (matched for age and sex) were obtained from the Population Register. The National Patient Register provided information on diagnostic codes for seizures, epilepsy and comorbidities. 123 105 stroke cases and 250 506 controls were included., Results: Epileptic seizures prior to index stroke date were detected in 1559 (1.27 %) cases and 1806 (0.72 %) controls, yielding an odds ratio (95 % confidence interval) for stroke of 1.77 (1.65-1.89). ORs were similar in men and women, but higher below the age of 75. An onset of seizures in the year preceding stroke date resulted in a higher risk for stroke (OR = 2.21, 95 % CI = 1.79-2.72) compared to when more than 5 years had passed since the first seizure (OR = 1.57, 95 % CI = 1.43-1.72)., Conclusion: A history of epileptic seizures was associated with an increased risk of subsequent stroke. The risk seems to be particularly high in the first year following seizure diagnosis, which supports the notion that unexplained late-onset seizures may merit swift assessment of vascular risk profile. The nature of stroke prevention requires further study., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Aims: Granulocyte colony-stimulating factor (G-CSF) is a cytokine that induces proliferation and differentiation of hematopoietic precursor cells and activation of mature neutrophils. G-CSF is overexpressed in several malignant tumors and blocking its binding to the receptor can lead to significant decrease in tumor growth, vascularization and metastasis. Furthermore, targeting G-CSF receptor has shown therapeutic benefit in other diseases such as rheumatoid arthritis, progressive neurodegenerative disorder and uveitis. Camelid single-chain antibodies (nanobodies) have exceptional properties making them appropriate for tumor imaging and therapeutic application. In this study we aim to use the rational design approach to engineer a previously described G-CSF-R targeting nanobody (VHH1), to improve its affinity toward G-CSF-R., Main Methods: We redesigned the complementary determining region 3 (CDR3) domain of the VHH1 nanobody to mimic G-CSF interaction to its receptor and developed five new engineered nanobodies. Binding affinity of the engineered nanobodies was evaluated by ELISA (Enzyme-linked immunosorbent assay) on NFS60 cells., Key Findings: Enzyme-linked immunosorbent assay (ELISA) confirmed the specificity of the engineered nanobodies and ELISA-based determination of affinity revealed that two of the engineered nanobodies (1c and 5a) bind to G-CSF-R on the surface of NFS60 cells in a dose-dependent manner and with a higher potency compared to the parental nanobody., Significance: Additional studies are required to better characterize these nanobodies and assess their interaction with G-CSF-R in vitro and in vivo. These newly developed nanobodies could be beneficial in tumor imaging and therapy and make a basis for development of additional engineered nanobodies., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Activated leukocyte cell adhesion molecule (ALCAM) or CD166 is a 100 to 105 KDa transmembrane immunoglobulin which is involved in activation of T-cells, hematopoiesis, neutrophils trans-endothelial migration, angiogenesis, inflammation and tumor propagation and invasiveness through formation of homophilic and heterophilic interactions. Recently, many studies have proposed that the expression pattern of ALCAM is highly associated with the grade, stage and invasiveness of tumors. Although ALCAM is a valuable prognostic marker in different carcinomas, similar expression patterns in different tumor types may be associated with completely different prognostic states, making it to be a tumor-type-dependent prognostic marker. In addition, ALCAM isoforms provide ways for primary detection of tumor cells with metastatic potential. More importantly, this prognostic marker has shown to be considerably dependent on the cytoplasmic and membranous expression, indirect and direct regulation of post-transcriptional molecules, pro-apoptotic proteins functionalities and several other oncogenic proteins or signalling pathways. This review mainly focuses on the pathways involved in expression of ALCAM and its prognostic value of in different types of cancers and the way in which it is regulated., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Transcription factors (TFs) are proteins that are fundamental to transcription and regulation of gene expression. Each TF may regulate multiple genes and each gene may be regulated by multiple TFs. TFs can act as either activator or repressor of gene expression. This complex network of interactions between TFs and genes underlies many developmental and biological processes and is implicated in several human diseases such as cancer. Hence deciphering the network of TF-gene interactions with information on mode of regulation (activation vs. repression) is an important step toward understanding the regulatory pathways that underlie complex traits. There are many experimental, computational, and manually curated databases of TF-gene interactions. In particular, high-throughput ChIP-Seq datasets provide a large-scale map or transcriptional regulatory interactions. However, these interactions are not annotated with information on context and mode of regulation. Such information is crucial to gain a global picture of gene regulatory mechanisms and can aid in developing machine learning models for applications such as biomarker discovery, prediction of response to therapy, and precision medicine., Methods: In this work, we introduce a text-mining system to annotate ChIP-Seq derived interaction with such meta data through mining PubMed articles. We evaluate the performance of our system using gold standard small scale manually curated databases., Results: Our results show that the method is able to accurately extract mode of regulation with F-score 0.77 on TRRUST curated interaction and F-score 0.96 on intersection of TRUSST and ChIP-network. We provide a HTTP REST API for our code to facilitate usage. Availibility: Source code and datasets are available for download on GitHub: https://github.com/samanfrm/modex., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: We aimed to describe mesothelin (MSLN) and programmed cell death 1 ligand 1 (PD-L1) tumour overexpression amongst patients with malignant mesothelioma (MM), and their associations with survival, amongst a cohort of patients with MM in Finland., Methods: Between 2004 and 2017, 91 adults with histologically confirmed MM were identified from the Auria Biobank in Finland and followed-up using linked data from electronic health records and national statistics. Biomarker content in tumour cell membranes was determined using automated Immunohistochemistry on histological sections. Stained tumour sections were scored for MSLN and PD-L1 intensity. Adjusted associations between MSLN/PD-L1 co-expression and mortality were evaluated by estimating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression., Results: Biomarker overexpression occurred in 52 patients for MSLN and 34 patients for PD-L1 and was associated with tumour histology and certain comorbidities. Fifteen per cent of patients had a tumour that overexpressed both biomarkers; r =-0.244, p-value: 0.02. Compared with MSLN+/PD-L1+ patients, HRs (95% CIs) for death were 4.18 (1.71-10.23) for MSLN-/PD-L1+ patients, 3.03 (1.35-6.77) for MSLN-/PD-L1- patients, and 2.13 (0.97-4.67) for MSLN+/PD-L1- patients., Conclusions: Both MSLN and PD-L1 markers were independent prognostic indicators in patients with MM. Overexpression of MSLN was associated with longer survival; yet their combined expression gave a better indication of survival. The risk of death was four times higher amongst MSLN-/PD-L1+ patients than in MSLN+/PD-L1+ patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The purpose of this study was to propose a methodology for mechanical characterization of the ligaments in subject-specific models of the patellofemoral joint (PFJ) of living individuals., Method: PFJ laxity tests were performed on a healthy volunteer using a specially designed loading apparatus under biplane fluoroscopy. A three-dimensional (3D) parametric model of the PFJ was developed in the framework of the rigid body spring model using the geometrical data acquired from the subject's computed tomography and magnetic resonance images. The stiffness and pre-strains of the medial and lateral PFJ ligaments were characterized using a two-step optimization procedure which minimized the deviation between the model predictions and the calibration test results. Sensitivity analyses were performed to investigate the effect of mechanical properties of the non-characterized model components on the characterization procedure and its results., Results: The overall findings indicate that the proposed methodology is applicable and can improve the model predictions effectively. For the subject under study, ligament characterization reduced the root mean square of the deviations between the patellar shift and tilt predicted by the model and obtained experimentally for the validation laxity test (from 6.2 mm to 0.5 mm, and from 8.4° to 1.5°, respectively) and passive knee flexion test (from 1.4 mm to 0.3 mm, and from 2.3° to 1.3°, respectively). The non-characterized mechanical properties were found to have a minimal effect on the characterization procedure and its results., Conclusion: The proposed methodology can help in developing truly patient-specific models of the PFJ, to be used for personalized preplanning of the clinical interventions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Signal generation techniques for visual detection of analytes have received a great deal of attention in various sensing fields. These approaches are considered to be advantageous when instrumentation cannot be employed, such as for on-site assays, point-of-care tests, and he althcare diagnostics in resource-constrained areas. Amongst various visual detection approaches explored for non-invasive quantitative measurements, ratiometric fluorescence sensing has received particular attention as a potential method to overcome the limitations of intensity-based probes. This technique relies on changes in the intensity of two or more emission bands (induced by an analyte), resulting in an effective internal referencing which improves the sensitivity of the detection. The self-calibration, together with the unique optophysical properties of nanoparticles (NPs) have made the ratiometric fluorescent nanoprobes more sensitive and reliable, which in turn, can result in more precise visual detection of the analytes. Over the past few years, a vast number of ratiometric sensing probes using nanostructured fluorophores have been designed and reported for a wide variety of sensing, imaging, and biomedical applications. In this work, a review on the NP-based ratiometric fluorescent sensors has been presented to meticulously elucidate their development, advances and challenges. With a special emphasis on visual detection, the most important steps in the design of fluorescent ratiometric nanoprobes have been given and based on different classes of analytes, recent applications of fluorescent ratiometric nanoprobes have been summarized. The challenges for the future use of the technique investigated in this review have been also discussed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Effects of sub-lethal concentrations (0 (control), 0.009, 0.014, and 0.023 ppm) of the organophosphate insecticide "malathion" to rainbow trout (Oncorhynchus mykiss) after the determination of LC 50 -96 h value (0.093 ppm) were evaluated. Changes in biomarkers of neurotoxicity (acetylcholinesterase (AChE) activity), genotoxicity (DNA damage), and hematological parameters (red (RBC) and white (WBC) blood cell count, hemoglobin (Hb), hematocrit (Hct), mean cell hemoglobin (MCH), mean cell volume (MCV), and mean cell hemoglobin concentration (MCHC)) were assessed for a 15-day exposure. A significant time- and dose-dependent reduction in AChE activities of gill, muscle, brain, and liver tissues was found. However, the AChE activity was less affected by malathion concentration than by exposure time. DNA damage of erythrocytes at different malathion concentrations increased by increasing the experimental time up to the fourth day. A decrease in the count of WBC, RBC, and Hct and an increase in the number of MCH and MCV were observed by increasing malathion exposure dose and time (p < 0.05). An increase in the malathion concentration and exposure time significantly resulted in a decrease in Hb and an increase in MCHC. A significant improvement in AChE activity; DNA damage; and RBC, Hb, Hct, MCV, and MCH indices was detected during a 30-day recovery period, but the WBC count changed insignificantly. The recovery pattern based on 100% water exchange with clean water could be a successful strategy to improve the biomarker responses of rainbow trout habituating in contaminated aquatic environments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Persian sturgeon (Acipenser persicus), a commercially valuable and critically endangered fish species has been suffering considerable declines in populations in the nature due to over-fishing, habitat destruction and marine pollution during past decades. Since there were no achievements in artificial reproduction programs, genetic resource banking such as gametes and embryo cryopreservation can be a good strategy however, reported resulting gamete qualities were considerably low. In the present study, the metabolome content of Persian sturgeon spermatozoa was investigated during common straw cryopreservation and novel droplet vitrification by the use of 1 H NMR (Nuclear Magnetic Resonance) spectroscopy. Univariate (ANOVA) and multivariate (PCA) analysis showed significant differences in the metabolic profiles between cryopreserved and fresh spermatozoa samples. Adenine, creatine, creatine phosphate, glucose, guanidoacetate, lactate, N, N-dimethylglycine, and glycine levels showed no significant differences between these two cryopreservation techniques suggesting these metabolites and their corresponding enzymes and chemical pathways are so vulnerable to the temperature changes and even higher cooling rate in droplet vitrification could not conserve them. However, significant differences were found in acetate, creatinine, betaine, β-alanine and trimethylamine N-oxide suggesting better efficiency of droplet vitrification in protection of some metabolites associated to spermatozoa energetics, redox balance and hypoxia compensation compared to straw cryopreservation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Duration of endogenous estrogen exposure is apparently associated with risk of cardiovascular disease, the longer durations being more cardiovascular disease protective in women. We aimed to investigate the association of cumulative duration of endogenous estrogen exposure over women's reproductive lifespans with cardiovascular disease outcomes., Main Methods: For the purpose of the present study, of 10,192 female participants, after excluding those using HRT (n = 84), 3656 women, aged ≥30 years, who met eligibility criteria were selected and divided into three groups based on tertiles (T1, T2, T3) of exposure durations to endogenous estrogen. Cox proportional hazards regression model was used to estimate associations between exposure durations and cardiovascular disease outcomes., Key Findings: Cardiovascular events occurred in 352 participants over a median follow-up of 14.2 (13.5, 14.6) years (7.7 per 1000 person years; 95% CI: 6.9-8.5). Incidence of outcome was 10.9 per 1000 person years (CI, 9.4-12.8) in T 1 , 7.2 per 1000 person years (CI, 6.0-8.7) in T 2 , and 5.1 per 1000 person years (CI, 4.1-6.4) in T 3 . The hazard ratio of cardiovascular events in T 1 was significantly higher than that inT 3 , before and after adjustment for confounding variables. Before adjustment, women in T 2 had a 40% higher risk of CVD, compared to T 3 ; after adjustment however the risk was similar to that of women in T 3 ., Significance: Shorter durations of exposure to endogenous estrogen may increase the risk of cardiovascular diseases among these women later in life. Future studies should target women with short duration of exposure for timely screening and implementation of preventative interventions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although anti-angiogenic agents targeting VEGF have shown affordable beneficial outcomes in several human cancer types, in most pre-clinical and clinical studies, these effects are transient and followed by rapid relapse and tumor regrowth. Recently, it has been suggested that recruited bone marrow derived cells (BMDCs) to the tumor-microenvironment together with stromal cells play an important role in development of resistance to anti-VEGF therapies. Additionally, acquired resistance to anti-VEGF therapies has shown to be mediated partly through overexpression of different pro-angiogenic cytokines and growth factors including G-CSF, IL-6, IL-8, VEGF and FGF by these cells. Alongside, IL-17, a pro-inflammatory cytokine, mostly secreted by infiltrated CD4 + T helper cells, has shown to mediate resistance to anti-VEGF therapies, through recruiting BMDCs and modulating stromal cells activities including endothelial cells, tumor associated macrophages and cancer associated fibroblasts. Here, we examined the role of BMDCs, tumor stromal cells, IL-17 and their negotiation in development of resistance to anti-VEGF targeted therapies., (Copyright © 2018. Published by Elsevier Inc.)

Owing to its dual role as a hormone and neurotransmitter, norepinephrine (NE) detection is of great significance to biomedical diagnosis. In the present work, we have explored intense green fluorescence of poly (norepinephrine) (PNE) nanoparticles synthesized by oxidizing NE in alkaline condition, in combination with red fluorescent bovine serum albumin-stabilized gold nanoclusters (BSA-AuNCs) for naked-eye detection of NE. The effect of sodium hydroxide on the emission behavior of NE was studied. The surface morphology and optical properties of PNE nanoparticles were characterized by UV-Vis, fluorescence, FTIR, Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) techniques. For ratiometric sensing of NE, red fluorescent BSA-AuNCs were served as an internal reference while NE delivered a new emission peak at 527 nm, resulting in a wide distinguishable color change from strong red into red, pink, orange, and green under a UV lamp. The ratiometric approach was demonstrated to be highly sensitive and selective for NE detection against even structurally similar biomolecules with a detection limit of 49 nmol L -1 . Furthermore, the proposed method was successfully applied to determine NE in urine samples., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This paper presents a three-dimensional micromechanical model of brain white matter tissue as a transversely isotropic soft composite described by the generalized Ogden hyperelastic model. The embedded element technique, with corrected stiffness redundancy in large deformations, was used for the embedment of a histology-informed probabilistic distribution of the axonal fibers in the extracellular matrix. The model was linked to a multi-objective, multi-parametric optimization algorithm, using the response surface methodology, for characterization of material properties of the axonal fibers and extracellular matrix in an inverse finite element analysis. The optimum hyperelastic characteristics of the tissue constituents, obtained based on the axonal and transverse direction test results of the corona radiata tissue samples, indicated that the axonal fibers were almost thirteen times stiffer than the extracellular matrix under large deformations. Simulation of the same tissue under a different loading condition, as well as that of another white matter tissue, i.e., the corpus callosum, in the axonal and transverse directions, using the optimized hyperelastic characteristics revealed tissue responses very close to those of the experiments. The results of the model at the sub-tissue level indicated that the stress concentrations were considerably large around the small axons, which might contribute into the brain injury., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The risk of hemorrhages after stereotactic biopsy is known to be low. Nevertheless hemorrhages in eloquent areas result in neurological deficit for the patients. Since the basal ganglia resemble a particularily high vascularized and eloquent location, which is often the source of hypertensive hemorrhages, we aimed to analyse possible risk factors for hemorrhage after stereotactic biopsy in this region., Patients and Methods: We performed a retrospective analysis including patients who underwent stereotactic biopsies of lesions in the basal ganglia between January 2012 and January 2017. 63 patients were included in this study. We accessed age, gender, histopathological diagnosis, hypertension, blood pressure intraoperative, anticoagulative medication and postoperative hemorrhage., Results: Fishers exact test revealed no significant p-values concerning anticoagulative therapy, gender, smoking and hypertension concerning postoperative hemorrhage. Wilcoxon-Mann-Whitney-Test showed no significant correlation for systolic blood pressure intraoperative, number of tissue samples and age with hemorrhage. A trend for lymphoma in correlation with postoperative hemorrhage was in patients with Lymphoma (Wilcoxon-Mann-Whitney Test)., Conclusion: Stereotactic biopsies even in eloquent areas as the basal ganglia are a safe procedure even if patients suffer under hypertension or are smoker. None of the here examined risk factors showed a significant correlation with postoperative hemorrhage. Accessing tumor tissue for histopathological diagnosis is mandatory for adequate therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A transverse-plane hyperelastic micromechanical model of brain white matter tissue was developed using the embedded element technique (EET). The model consisted of a histology-informed probabilistic distribution of axonal fibers embedded within an extracellular matrix, both described using the generalized Ogden hyperelastic material model. A correcting method, based on the strain energy density function, was formulated to resolve the stiffness redundancy problem of the EET in large deformation regime. The model was then used to predict the homogenized tissue behavior and the associated localized responses of the axonal fibers under quasi-static, transverse, large deformations. Results indicated that with a sufficiently large representative volume element (RVE) and fine mesh, the statistically randomized microstructure implemented in the RVE exhibits directional independency in transverse plane, and the model predictions for the overall and local tissue responses, characterized by the normalized strain energy density and Cauchy and von Mises stresses, are independent from the modeling parameters. Comparison of the responses of the probabilistic model with that of a simple uniform RVE revealed that only the first one is capable of representing the localized behavior of the tissue constituents. The validity test of the model predictions for the corona radiata against experimental data from the literature indicated a very close agreement. In comparison with the conventional direct meshing method, the model provided almost the same results after correcting the stiffness redundancy, however, with much less computational cost and facilitated geometrical modeling, meshing, and boundary conditions imposing. It was concluded that the EET can be used effectively for detailed probabilistic micromechanical modeling of the white matter in order to provide more accurate predictions for the axonal responses, which are of great importance when simulating the brain trauma or tumor growth., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

An air assisted liquid-liquid microextraction by applying the solidification of a floating organic droplet method (AALLME-SFOD) coupled with a multivariate calibration method, namely partial least squares (PLS), was introduced for the fast and easy determination of Atenolol (ATE), Propanolol (PRO) and Carvedilol (CAR) in biological samples via a spectrophotometric approach. The analytes would be extracted from neutral aqueous solution into 1-dodecanol as an organic solvent, using AALLME. In this approach a low-density solvent with a melting point close to room temperature was applied as the extraction solvent. The emulsion was immediately formed by repeatedly pulling in and pushing out the aqueous sample solution and extraction solvent mixture via a 10-mL glass syringe for ten times. After centrifugation, the extractant droplet could be simply collected from the aqueous samples by solidifying the emulsion at a lower than the melting point temperature. In the next step, analytes were back extracted simultaneously into the acidic aqueous solution. Derringer and Suich multi-response optimization were utilized for simultaneous optimizing the parameters of three analytes. This method incorporates the benefits of AALLME and dispersive liquid-liquid microextraction considering the solidification of floating organic droplets (DLLME-SFOD). Calibration graphs under optimized conditions were linear in the range of 0.30-6.00, 0.32-2.00 and 0.30-1.40μg mL -1 for ATE, CAR and PRO, respectively. Other analytical parameters were obtained as follows: enrichment factors (EFs) were found to be 11.24, 16.55 and 14.90, and limits of detection (LODs) were determined to be 0.09, 0.10 and 0.08μg mL -1 for ATE, CAR and PRO, respectively. The proposed method will require neither a highly toxic chlorinated solvent for extraction nor an organic dispersive solvent in the application process; hence, it is more environmentally friendly., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of less than 15 months, emphasizing the need for better treatments. Immunotherapy as a treatment for improving or aiding the patient's own immune defense to target the tumor has been suggested for GBM. A randomized clinical trial of adoptive cell transfer using ALECSAT (Autologous Lymphoid Effector Cells Specific Against Tumor Cells) is currently ongoing in Sweden. Here we performed a paired pre-clinical study to investigate the composition and in vitro effect of ALECSAT and identify determinants for the effect using autologous GBM-derived cancer stem cells (CSC), immunocytochemistry and flow cytometry. We show a clear dose-response relationship of ALECSAT on CSC, suggesting that the number of infused cells is of importance. In addition, the in vitro effect of ALECSAT on CSC correlated significantly to the blood count of T helper (T h ) cells in the patient indicating a potential benefit of collecting cells for ALECSAT preparation at an even earlier stage when patients generally have a better blood count. The factors identified in this study will be important to consider in the design of future immunotherapy trials to achieve prolonged survival., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

According to the World Health Organization (WHO) published data in 2015; breast cancer is the most prevalent and the second leading cause of cancer death among females. As approximately 70% of breast cancer tumor cells are estrogen receptor (ER) positive, primary therapeutic agents such as Anti-estrogens were produced mostly in a way to target this receptor. Anti-estrogen therapies mostly target Estrogen receptor and block its underlying signaling pathways. Nevertheless, resistance to these agents made the condition more complicated. Recently the role of one molecule in the resistance development has been studied in some cases: ER-α36 is a 36 kDa variant of estrogen receptor molecule which is mostly absent in normal breast cells. Its interactions with epidermal growth factor receptors and ER-α66 leads in over-activation and/or over-expression of estrogen-independent pathways and suppression of estrogen-dependent pathways; they all in turn, will maintain tumor cell's growth even in the presence of tamoxifen. In this mini-review, we mainly surveyed different pathways which ER-α36 could lead to tamoxifen resistance. We also briefly mentioned how ER-α36 could switch the growth cascades from estrogen dependent into independent and make this resistance network become even more complicated., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Comparative quantitative metabolite profiling can be used for better understanding of cell functions and dysfunctions in particular circumstances such as sperm banking which is an important approach for cryopreservation of endangered species. Cryopreservation techniques have some deleterious effects on spermatozoa which put the obtained results in controversy. Therefore, in the present study, quantitative 1 H NMR (Nuclear Magnetic Resonance) based metabolite profiling was conducted to evaluate metabolite changes related to energetics and some other detected metabolites in vitrified semen of critically endangered wild Acipenser persicus. The semen was diluted with extenders containing 0, 5, 10, and 15 μM of fish antifreeze protein (AFP) type III as a cryoprotectant. Semen-extenders were vitrified and stored for two days. Based on post-thaw motility duration and motility percentage assessments, two treatments with 10 μM and 0 μM of AFP had the highest and the lowest motility percentages respectively and they were objected to 1 H NMR spectroscopy investigations in order to reveal the extremes of the metabolites dynamic range. Univariate (ANOVA) and multivariate (PCA) analysis of the resulting metabolic profiles indicated significant changes (P > 0.05) in metabolites. The level of some metabolites including acetate, adenine, creatine, creatine phosphate, lactate, betaine, sarcosine, β-alanine and trimethylamine N-oxide significantly decreased in vitrified semen while some others such as creatinine, guanidinoacetate, N, N-dimethylglycine, and glycine significantly increased. There were also significant differences between vitrified treatments in levels of creatine, creatine phosphate, creatinine, glucose, guanidinoacetate, lactate, N, N-dimethylglycine, and glycine, suggesting how fish AFP type III can be effective as a cryoprotectant., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to examine the trends of contraception use among married reproductive age women in Tehran Lipid and Glucose study between 2002 and 2011., Methods: This analysis investigated a proportion of women users and non-users of family planning, using data from 10year population-based Tehran Lipid Glucose Study from surveys conducted in 2002, 2005, 2008, and 2011. Of the 6813, 6993, 7077, and 6789 women in the four phases mentioned, 34.1%, 33.9%, 33.5% and 35% of participants in each phase preferred to use contraception. Number of participants studied were 2506 women in 2002, 2529 women in 2005, 2594 women in 2008 and 2525 women in 2011., Results: Types of methods and patterns of change in contraception differed across time. The percentage of women using traditional methods increased significantly from 25.7% in 2002 to 34.6% in 2011 (p value for trend=0.001). Accordingly, modern contraception use showed a reverse trend. From 2002 to 2011, 61.4%, 61%, 57.7%, and 51% of married women reported currently using various modern contraceptives, respectively (p value for trend=0.001). The proportion of users relying on condoms showed a significant increase during this decade, being 10.9% in 2002, 15.2% in 2005, 20% in 2008 and 21.9% in 2011. The prevalence of non-users for contraception was generally low; 12.7%, 8.2%, 8% and 14.3%, respectively from 2002 to 2011, but increased significantly across time (p=0.005) CONCLUSION: Relying on less effective contraceptive methods has increased rapidly among women in the Tehran Lipid and Glucose cohort study, a trend that could be a warning to policy makers about the possibility of higher unsafe abortion and maternal mortality/morbidity rates in the near future., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this study attempts were made to investigate the effect of extremely low frequency magnetic field (ELF-MF) on expression of glucose oxidase gene from Aspergillus niger Z-25 in Pichia pastoris GS115 at optimal environmental conditions. GOX encoding gene from A. niger was expressed in P. pastoris GS115 employing methanol inducible AOX1 promoter. From resistant transformants to high zeocin concentrations, maximum GOX expressing transformant was isolated and used throughout the study. Optimal environmental conditions for achieving maximum glucose oxidase (GOX) production was determined by varying temperature (20-30°C) and final methanol concentration from 0.25-1% (v/v). Maximum GOX production was obtained at 20°C and 0.25% (v/v) final methanol concentration. Exposure carried out at extremely low frequencies ranging from 1 to 5Hz and the field strength of 30-100mT unceasingly. Biomass, GOX, protease productions and cell viability were examined in exposed and non-exposed groups every 12h up to 96h. Among different exposure conditions, the frequency of 2.8Hz significantly increased GOX production and cell viability, decreased non-specific protease activity and improved biomass production regardless of changes in field intensity. Overall, supported by results, P. pastoris exposure to ELF-MF in certain circumstances could effectively further increase maximum production of GOX as achieved by optimized preliminary environmental parameters., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To replenish the depleting populations of sturgeon fishes especially Persian sturgeon, Acipenser persicus in the Caspian Sea, millions of Persian sturgeon fingerlings are farmed through artificial propagation and released into the Iranian river estuaries annually. Fish osmoregulation is a vital physiological process that can be affected during the release. Many Iranian river estuaries are under the influence of pesticides originating from farming activities that may affect osmoregulation. In this study, Persian sturgeon fingerlings were exposed to sublethal concentrations (0, 0.18, 0.54, 0.9mgL(-)(1)) of diazinon for 96h (short-term trial) and 12 days (long-term trial) in fresh water (FW) and then fish were exposed in brackish water (BW) for 24h. After 96h and 12 days of exposure in FW, the lower levels of plasma triidothyronine (T3), thyroxine (T4), Na(+), Cl(-), K(+), gill Na(+)/K(+)- ATPase activity and number of chloride cells were observed in exposed fish (0.54 and 0.9mgL(-)(1) diazinon) compared to control group and 0.18mgL(-)(1) diazinon treatment. Also, higher levels of plasma cortisol (except 0.18mgL(-)(1) diazinon treatment in long-term trial) were observed in diazinon exposed fish compared to control group. However, gill Na(+)/K(+)-ATPase activity and the number of chloride cells were higher in fingerlings exposed to diazinon compared than control. When fish were exposed in BW for 24h, the following changes occurred: (a) in short-term trial: increases in cortisol and Cl(-) levels (0.54mgL(-)(1) diazinon ), Na(+) (0.9mgL(-)(1) diazinon ) and gill Na(+)/K(+)-ATPase activity (0.18mgL(-)(1) diazinon ). In control group, cortisol, T4, Na(+), gill Na(+)/K(+)-ATPase activity and the number of chloride cells increased significantly. (b) In long-term trial: increases in K(+) levels in fish exposed to 0.9mgL(-)(1) diazinon, Na+ in all diazinon concentrations and decreases in chloride cells number in fish exposed to 0.18mgL(-)(1) diazinon. In control group, significant increases were observed in cortisol, T3, Na(+) and chloride cells number. Finally, gill showed many histopathological damages during exposure in FW and BW. Our results suggest that the contamination of river estuaries with diazinon may alter the osmoregulation ability of released Persian sturgeon fingerlings, which could lead to a failure in their restocking program in the Caspian Sea., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Current research has focused on the preparation of Zinc-clinoptilolite/Graphene Oxide (Zn-Clin/GO) hybrid nanostructure and investigating its biocompatibility for the first time. As prepared samples were characterized by X-ray diffraction (XRD), Scanning electron microscopy (SEM), Thermo gravimetric analysis (TGA) and Fourier transform infrared (FT-IR). In order to use it as a drug carrier two important factors were investigated: cytocompatibility of nanocomposites and their drug loading capacity. The results showed that the prepared nanocomposite is cytocompatible and its high loading capacity and slow release performance for Doxorubicin (DOX), as a cancer drug, proved that it can be used as a drug carrier. At last in-vitro toxicity of DOX loaded nanocomposite was compared with pure DOX., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Acute psychosocial stress stimulates transient increases in circulating pro-inflammatory plasma cytokines, but little is known about stress effects on anti-inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level. Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120min after stress DNA binding activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF-κB, its inhibitor IκBα, and of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1ß, IL-6, and IL-10. Compared to non-stress, acute stress induced significant and rapid increases in NF-κB-BA and delayed increases in plasma IL-6 and mRNA of IL-1ß, IL-6, and IκBα (p's<.045). In the stress group, significant increases over time were also observed for NF-κB mRNA and plasma IL-1ß and IL-10 (p's<.055). NF-κB-BA correlated significantly with mRNA of IL-1β (r=.52, p=.002), NF-κB (r=.48, p=.004), and IκBα (r=.42, p=.013), and marginally with IL-6 mRNA (r=.31, p=.11). Plasma cytokines did not relate to NF-κB-BA or mRNA levels of the respective cytokines. Our data suggest that stress induces increases in NF-κB-BA that relate to subsequent mRNA expression of pro-inflammatory, but not anti-inflammatory cytokines, and of regulatory-cytoplasmic-proteins. The stress-induced increases in plasma cytokines do not seem to derive from de novo synthesis in circulating blood cells., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The prevalence of mental disorders in Iran approximates to that of other countries. This study evaluates mental health status and its related factors among underprivileged women in Shiraz, Iran., Methods: This research was conducted between June, 2010 and November, 2012, and comprised 2108 women who participated in the Shiraz Women's Health Cohort Study. The questionnaire used in the study was completed by trained general practitioner and included demographic information and the 28-item version of the General Health. The t-test, chi-square test and multivariate logistic regression model were used for statistical analysis. A P-value <0.05 was considered significant., Results: The mean age of the participants was 49.7±10.6 years. According to the General Health Questionnaire, the most prevalent mental disorder was social dysfunction observed in 1643 (77.9%) participants followed by somatic symptoms found in 1308 (62%) subjects. Mental disorders were most prevalent among married women (63.8%, P=0.004). Participants holding high school diploma or university degree (141; 52.4%) comprised the smallest proportion of subjects with mental disorders (P=0.01). Of a total 265 participants whose husband were in prison, 171 (64.5%) exhibited mental disorders, presenting the greatest proportion of women with mental disorders. Logistic regression analysis showed an association between mental health status and participants' level of education, number of children and marital status, based on the General Health Questionnaire total score., Conclusions: The results of this study showed a considerably higher prevalence of mental disorders among Iranian women in comparison with the general population. Therefore policymakers should pay greater attention to the mental health status of underprivileged Iranian women., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: It has previously been reported that increased level of serum heat shock proteins (Hsps) antibody in patients with metabolic syndrome. It is possible that the expression of Hsp and inflammatory markers can be affected by cupping and traditional Chinese medicine. There is a little data investigating the effects of cupping on markers of inflammation and Hsp proteins, hence, the objective of this study was evaluation of the effects of wet cupping on serum high-sensitivity C-reactive protein (hs-CRP) and Hsp27 antibody titers in patients with metabolic syndrome., Subjects and Methods: Serum Hs-CRP and Hsp27 antibody titers were assessed in samples from 126 patients with metabolic syndrome (18-65 years of age) at baseline, and after 6 and 12 weeks after treatment. One hundred and twenty-six patients were randomly divided into the experimental group treated with wet cupping combined with dietary advice, and the control group treated with dietary advice alone using a random number table. Eight patients in case group and five subjects in control groups were excluded from the study. Data were analyzed using SPSS 15.0 software and a repeated measure ANCOVA., Results: Serum hs-CRP titers did not change significantly between groups (p>0.05) and times (p=0.27). The same result was found for Hsp27 titers (p>0.05)., Conclusion: Wet-cupping on the interscapular region has no effect on serum hs-CRP and Hsp27 patients with metabolic syndrome., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Body mass index (BMI) is used worldwide as an indirect measure of nutritional status and has been shown to be associated with mortality. Controversy exists over the cut points associated with lowest mortality, particularly in older populations. In patients suffering from dementia, information on BMI and mortality could improve decisions about patient care., Objectives: The objective was to explore the association between BMI and mortality risk in an incident dementia cohort., Design: Cohort study based on SveDem, the Swedish Quality Dementia Registry; 2008-2011., Setting: Specialist memory clinics, Sweden., Participants: A total of 11,398 patients with incident dementia with data on BMI (28,190 person-years at risk for death)., Main Outcome Measures: Hazard ratios and 95% confidence intervals for mortality associated with BMI were calculated, controlling for age, sex, dementia type, results from Mini-Mental State Examination, and number of medications. BMI categories and linear splines were used., Results: Higher BMI was associated with decreased mortality risk, with all higher BMI categories showing reduced risk relative to patients with BMI of 18.5 to 22.9 kg/m(2), whereas underweight patients (BMI <18.5 kg/m(2)) displayed excess risk. When explored as splines, increasing BMI was associated with decreased mortality risk up to BMI of 30.0 kg/m(2). Each point increase in BMI resulted in an 11% mortality risk reduction in patients with BMI less than 22.0 kg/m(2), 5% reduction when BMI was 22.0 to 24.9 kg/m(2), and 3% risk reduction among overweight patients. Results were not significant in the obese weight range. Separate examination by sex revealed a reduction in mortality with increased BMI up to BMI 29.9 kg/m(2) for men and 24.9 kg/m(2) for women., Conclusion: Higher BMI at the time of dementia diagnosis was associated with a reduction in mortality risk up to and including the overweight category for the whole cohort and for men, and up to the normal weight category for women., (Copyright © 2014 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to investigate the toxicity effects of acute and sublethal of Roundup® as a glyphosate-based herbicide on acetylcholinesterase (AChE) activity and several hematological and biochemical parameters of Cyprinus carpio. The LC₅₀-96 h of Roundup® to C. carpio was found to be 22.19 ppm. Common carp was subjected to Roundup® at 0 (control), 3.5, 7 and 14 ppm for 16 days, and the AChE activity is verified in tissues of gill, muscle, brain and liver. After 5 days, a significant decrease was observed in the AChE activity of muscle, brain and liver tissues. Besides, a time- and dose-dependent increase in mean cell hemoglobin (MCH) and mean cell volume (MCV) was observed. In contrast, a significant decrease was found in the quantities of hemoglobin (Hb), hematocrit (HCT) and, red (RBC) and white (WBC) blood cell count. Also, the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in Roundup® treated groups were significantly higher than the controlled group at experimental periods. However, the level of alkaline phosphatase (ALP) had a significant reduction behavior during the sampling days. It seems that the changes in hematological and biochemical parameters as well as AChE activity could be used as efficient biomarkers in order to determine Roundup® toxicity in aquatic environment., (© 2013 Elsevier Inc. All rights reserved.)

The present study is the first report on optimization of recovery conditions of fishes exposed to pesticides using response surface methodology-central composite rotatable design (RSM-CCRD). The sub-lethal toxicity bioassay of Roundup® (2 ppm ~10 percent LC₅₀, 96 h) in common carp (1, 4, 9, 16, 25, 35 and 40 day) was investigated. After exposure for 16 days to Roundup®, some the fishes were introduced to herbicide-free water. The effects of four recovery parameters including time (5-25 d), temperature (18-26 °C), water exchange rate (WER, 10-30), and salinity (0-8 ppt) on the levels of biomarkers of genotoxicity (DNA damage), neurotoxicity (acetylcholinesterase activity (AChE)), and the serum alanine (ALT) and aspartate (AST) aminotransferase in plasma were studied. The polynomial equations were significantly fitted for all response variables with high R² values (>0.95), which revealed no indication of lack of fit. The optimum conditions for the maximum AChE activity (37.14 nmol/min/mg protein) and the minimum levels of DNA damage (8.00 percent tail DNA), ALT (27.0 IU/L) and AST (91.0 IU/L) were time of 20 d, temperature of 20 °C, WER of 25 and water salinity of 6 ppt. Thus, a promising improvement for the recovery trend of fishes exposed to Roundup® stress was obtained under the optimized conditions using RSM-CCRD., (© 2013 Elsevier Inc. All rights reserved.)

Background: Studying the kinematics of the ACL deficient (ACLD) knees, during different physiological activities and muscle contraction patterns, can improve our understanding of the joint's altered biomechanics due to ACL deficiency as well as the efficacy and safety of the rehabilitations exercises., Methods: Twenty-five male volunteers, including 11 normal and 14 unilateral ACLD subjects, participated in this study. The kinematics of the injured knees of the ACLD subjects was compared with their intact knees and the healthy group during passive flexion and isometric leg press with the knees flexed from full extension to 45° flexion, with 15° intervals. An accurate registration algorithm was used to obtain the three dimensional kinematical parameters, from magnetic resonance images., Results: The ACL deficiency mainly altered the tibial anterior translation, and to some extent its internal rotation, with the change in other parameters not significant. During leg press, the anterior translation of the ACLD knees was significantly larger than that of the normal knees at 30° flexion, but not at 45°. Comparison of the anterior translations of the ACLD knees during leg press with that of the passive flexion revealed improved consistency (CVs changed from 1.2 and 4.0 to 0.6 and 0.6, at 30° and 45° flexion, respectively), but considerable larger translations (means increased by 6.2 and 4.9mm, at 30° and 45° flexion, respectively)., Conclusion: The simultaneous contraction of the quadriceps and hamstrings during leg press, although reduces the knee laxity, cannot compensate for the loss of the ACL to restore the normal kinematics of the joint, at least during early flexion., (Copyright © 2012 Elsevier B.V. All rights reserved.)