Studies on processing, consumer survey and storage stability of a ready-to-reconstitute fish cutlet mix.
A convenience ready-to-reconstitute cutlet mix containing 30% fish protein powder was developed to improve the nutritional quality of the product. Consumer survey was based on the home use test (HUT) method. The acceptance of the fish cutlet mix (FCM) was studied using a 9-point hedonic scale ranging from 1 (extremely dislike) to 9 (extremely like). Product's characteristics and stability were studied during 6 months of storage at 27 ± 2 °C. The FCM packed in a polyethylene bag and cardboard box was stable during the storage period. There were no changes in colour, moisture gain and water activity, and TBARS values remained low. The FCM was accepted by the consumers in the study (n = 85). The average liking was high (7.5 ± 1.3) and it was influenced by frequency of fish and chicken consumption, educational level and household size. People who ate fish once a week liked the product more than other consumers. Also those with higher educational level and bigger household size. The results in this paper are important information for companies planning to develop ready-to-eat products fortified with fish proteins. The products could be means of increasing fish consumption in countries/areas where there is no tradition of consuming fresh or frozen fish.


[Rapid determination of pesticide multiresidues in porphyra by dispersive solid-phase extraction coupled with online gel permeation chromatography-gas chromatography-mass spectrometry].
A rapid method for the simultaneous identification and quantification of pesticide multiresidues in porphyra was developed using gel permeation chromatography (GPC) coupled to gas chromatography-mass spectrometry (GPC-GC/MS). Nineteen pesticides (organochlorines, organophosphoruses, triazines and pyrethroids) were selected as the target analytes. The pretreatment method was applied consisting of organic solvent extraction followed by dispersive solid-phase extraction with graphitized carbon black (GCB) and primary secondary amine (PSA) adsorbents. GPC was also employed online to remove the large molecules such as pigments and lipids. The quantitative analysis was carried out by external standard method using gas chromatography coupled with mass spectrometry in selective ion monitoring (SIM) mode. Moreover, a large volume of sample was allowed to be injected using the program of GPC programmed-temperature vaporizer of gas chromatography to improve the sensitivity of measurements. The results showed that the calibration curves were linear (r > 0.995) in the range of 10-1,000 μg/L for all the pesticides. The limits of detection (LODs) for the pesticides in porphyra were from 0.005 to 0.03 mg/kg, and the average recoveries were between 70% and 120%. The advantages of the method are simple, sensitive and shorter operation time for analysis of pesticide residues in porphyra samples.


A new method for determining the minimum inhibitory concentration of essential oils.
A new microdilution method has been developed for determining the minimum inhibitory concentration (MIC) of oil-based compounds. The redox dye resazurin was used to determine the MIC of a sample of the essential oil of Melaleuca alternifolia (tea tree) for a range of Gram-positive and -negative bacteria. Use of 0.15% (w/v) agar as a stabilizer overcame the problem of adequate contact between the oil and the test bacteria and obviated the need to employ a chemical emulsifier. A rapid version of the assay was also developed for use as a screening method. A comparison of visual and photometric reading of the microtitre plates showed that results could be assessed without instrumentation; moreover, if the rapid assay format was used, rigorous asepsis was not necessary. Accuracy of the resazurin method was confirmed by plate counting from microwells and MIC values were compared with results obtained using an agar dilution assay. The MIC results obtained by the resazurin method were slightly lower than those obtained by agar dilution.


Regulation of cyclic AMP-dependent protein kinase levels during skeletal myogenesis.
We showed previously that the levels of type I regulatory subunit of cyclic AMP-dependent protein kinase increase during differentiation of L6 skeletal myoblasts as a result of a specific decrease in its rate of degradation. Studies on the rates of degradation of the catalytic subunit show that unlike the type I regulatory subunit, catalytic subunit is degraded very slowly in myoblasts (t1/2 = 29 h) and more rapidly in myotubes (t1/2 = 14 h). As with the regulatory subunit, the degradation of catalytic subunit is increased by treatment of myoblasts with cyclic AMP analogues. These results suggest that the overall increase in the amount of type I cyclic AMP-dependent protein kinase holoenzyme during myogenesis is due to the increase in levels of mRNA for the catalytic subunit. This probably leads to an increase in the amount of catalytic subunit, which then stabilizes the regulatory subunit, thereby causing an increase in the levels of this protein also.


The multidisciplinary management of rectal cancer.
Advancements have been made in multiple aspects of diagnostic and therapeutic approaches to rectal cancer. These advances include clinical staging such as endorectal ultrasound and pelvic MRI, surgical approaches such as transanal excision, and adjuvant treatments such as new chemotherapeutic agents and refined radiotherapy techniques. Optimal patient outcomes depend on multidisciplinary involvement for tailored therapy. The successful management of rectal cancer requires a multidisciplinary approach, with treatment decisions based on precise patient evaluations by a group of clinicians, including surgeons, gastroenterologists, medical and radiation oncologists, radiologists, and pathologists. The accurate identification of patients who are candidates for combined modality treatment is particularly essential to optimize outcomes. Technical and technologic advances have led to the availability of a wide range of surgical approaches for managing rectal cancer. Concomitantly, similar critical developments and refinements have also occurred in the administration of radiation and chemotherapeutic agents. This article provides an overview of the multimodal treatment of patients who have rectal cancer, with a focus on staging, surgical techniques, and the application of chemotherapy or radiation in the adjuvant and neoadjuvant settings.


Clinical features of simian acquired immunodeficiency syndrome (SAIDS) in rhesus monkeys.
A syndrome of acquired immunodeficiency has been identified in a group of rhesus monkeys (Macaca mulatta) which died at the California Primate Research Center. Clinical evaluation of these animals revealed that 50% or more had lymphadenopathy, weight loss, and diarrhea. At least 30% had splenomegaly, fever, cutaneous abscesses and/or arthritis/myositis. Two animals had fibrosarcomas. Anemia was seen in 19 animals, lymphopenia in 14, granulocytopenia in four and thrombocytopenia in three. Hepatitis was diagnosed histopathologically in 13. Electrophoresis revealed hypoproteinemia, hypoalbuminemia and hypogammaglobulinemia. Numerous bacterial, protozoal, and viral agents were identified including cytomegalovirus and leukocyte-associated herpesvirus. Pathologic lesions included severe post-reactive depletion of lymphocytes in germinal centers and paracortical regions of lymph nodes. Clinical and pathologic changes indicate an acquired immunodeficiency syndrome which has some similarities to AIDS in humans. This disease in monkeys may provide a model for studying that disease.


Profiling of secondary metabolites in tissues from Rheum palmatum L. using laser microdissection and liquid chromatography mass spectrometry.
Evaluating the quality of herbal medicines by morphological features is a convenient, quick, and practical method compared with other methods that mostly depend on modern instruments. Here, laser microdissection and ultra-performance liquid chromatography are combined with mass spectrometry to map the distribution of secondary metabolites in cells or tissues of a herb itself for correlating its bioactive components and morphological features. The root and rhizome of Rheum palmatum L. were taken as research target, which is the Chinese medicine, Radix et Rhizoma Rhei. According to fluorescent microscopic characteristics, 12 herbal cells or tissues of Radix et Rhizoma Rhei were separated by laser microdissection. Thirty-eight compounds were identified or tentatively characterized in the microdissected tissues. (+)-Catechin, 1-O-galloyl-2-O-cinnamoyl-β-D-glucose, and emodin were found to be the major components in most of the tissues. The brown ergastic substances found in rays of normal and anomalous vascular bundles as well as the parenchymatous cells of rhizome pith and the parenchymatous cells of root xylem contained higher than average amounts of these three components and more kinds of secondary metabolites. Overall, results suggest that Radix et Rhizoma Rhei of larger size and with conspicuous "brocaded patterns" and star spots are of higher quality as they tend to have greater contents of bioactive components. The study provides quantitative and specific criteria by which the quality of Radix et Rhizoma Rhei can be judged. This research also established a new, reliable, and practical method for direct profiling and imaging of secondary metabolites in any herbal tissue.


Standardized Minnesota coding of electrocardiographic findings for purposes of cooperative research on ischaemic heart disease.
For purposes of cooperative research on multifactorial prevention of ischaemic heart disease, a standardization system was elaborated in the USSR for classification of ECG findings according to the Minnesota code. The system includes instruction about the coding rules, experimental coding, analysis of faulty codings, and finally a control test consisting in encoding several series of 200 ECG findings each. For assessing the encoder's qualification the criterion was accepted of less than 20% cases of discordance with the standard code of "ischaemic" ECG changes. It was found that after the initial instructive course it was necessary to gain experience with encoding at least 1 000 ECG to qualify the candidate for the specified expert level. The necessity is emphasized of continual surveillance of the quality of ECG classification by the encoders in different centres, and the possibility of reaching a satisfactory level of unification is declared.


[Complex treatment of patients with chronic cerebrovascular insufficiency].
Chronic cerebrovascular insufficiency is the most common manifestation of chronic diseases of the nervous system. Its main causes are hypertension and atherosclerosis. Diseases debut mainly on 5-6th decade of life. The condition prohreiyentnyy, but the degree of progression can be varied--from slow to galloping. Therefore, when studying the effectiveness of treatment programs, in our opinion, it is important to include the medical complex of different methods of reflexology.


Using Intervention Mapping to Develop a Decision Support System-Based Smartphone App (selfBACK) to Support Self-management of Nonspecific Low Back Pain: Development and Usability Study.
International guidelines consistently endorse the promotion of self-management for people with low back pain (LBP); however, implementation of these guidelines remains a challenge. Digital health interventions, such as those that can be provided by smartphone apps, have been proposed as a promising mode of supporting self-management in people with chronic conditions, including LBP. However, the evidence base for digital health interventions to support self-management of LBP is weak, and detailed descriptions and documentation of the interventions are lacking. Structured intervention mapping (IM) constitutes a 6-step process that can be used to guide the development of complex interventions. The aim of this paper is to describe the IM process for designing and creating an app-based intervention designed to support self-management of nonspecific LBP to reduce pain-related disability. The first 5 steps of the IM process were systematically applied. The core processes included literature reviews, brainstorming and group discussions, and the inclusion of stakeholders and representatives from the target population. Over a period of >2 years, the intervention content and the technical features of delivery were created, tested, and revised through user tests, feasibility studies, and a pilot study. A behavioral outcome was identified as a proxy for reaching the overall program goal, that is, increased use of evidence-based self-management strategies. Physical exercises, education, and physical activity were the main components of the self-management intervention and were designed and produced to be delivered via a smartphone app. All intervention content was theoretically underpinned by the behavior change theory and the normalization process theory. We describe a detailed example of the application of the IM approach for the development of a theory-driven, complex, and digital intervention designed to support self-management of LBP. This description provides transparency in the developmental process of the intervention and can be a possible blueprint for designing and creating future digital health interventions for self-management.


A Gene Regulatory Network Balances Neural and Mesoderm Specification during Vertebrate Trunk Development.
Transcriptional networks, regulated by extracellular signals, control cell fate decisions and determine the size and composition of developing tissues. One example is the network controlling bipotent neuromesodermal progenitors (NMPs) that fuel embryo elongation by generating spinal cord and trunk mesoderm tissue. Here, we use single-cell transcriptomics to identify the molecular signature of NMPs and reverse engineer the mechanism that regulates their differentiation. Together with genetic perturbations, this reveals a transcriptional network that integrates opposing retinoic acid (RA) and Wnt signals to determine the rate at which cells enter and exit the NMP state. RA, produced by newly generated mesodermal cells, provides feedback that initiates NMP generation and induces neural differentiation, thereby coordinating the production of neural and mesodermal tissue. Together, the data define a regulatory network architecture that balances the generation of different cell types from bipotential progenitors in order to facilitate orderly axis elongation.


Extended-release naltrexone for alcohol and opioid dependence: a meta-analysis of healthcare utilization studies.
Through improved adherence, once-monthly injectable extended-release naltrexone (XR-NTX) may provide an advantage over other oral agents approved for alcohol and opioid dependence treatment. The objective of this study was to evaluate cost and utilization outcomes between XR-NTX and other pharmacotherapies for treatment of alcohol and opioid dependence. Published studies were identified through comprehensive search of two electronic databases. Studies were included if they compared XR-NTX to other approved medicines and reported economic and healthcare utilization outcomes in patients with opioid or alcohol dependence. We identified five observational studies comparing 1,565 patients using XR-NTX to other therapies over 6 months. Alcohol dependent XR-NTX patients had longer medication refill persistence versus acamprosate and oral naltrexone. Healthcare utilization and costs was generally lower or as low for XR-NTX-treated patients relative to other alcohol dependence agents. Opioid dependent XR-NTX patients had lower inpatient substance abuse-related utilization versus other agents and $8170 lower total cost versus methadone.


Draft genome sequence of Cupriavidus sp. strain TKC, isolated from a γ-hexachlorocyclohexane-degrading community.
Cupriavidus sp. strain TKC was isolated from a microbial community enriched with γ-hexachlorocyclohexane (γ-HCH). This strain did not show γ-HCH-degrading activity but was one of the major members of the community. Here, we present the draft genome sequence of the strain TKC with a size of 7 Mb.


Tumor necrosis factor α-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163.
CD163 is expressed specifically in the monocyte/macrophage lineage, where it mediates uptake of haptoglobin-hemoglobin complexes, leading to metabolism of the oxidative heme molecule. Shedding of the CD163 ectodomain from the cell surface produces a sCD163 plasma protein, and a positive correlation is seen between the sCD163 plasma level and the severity of various infectious and inflammatory diseases. In the present analysis of the phorbol ester-induced shedding of sCD163 in CD163 cDNA-transfected HEK293 cells, we used metalloproteinase inhibitors and siRNA-mediated inhibition of metalloproteinases to identify TACE/ADAM17 as an enzyme responsible for PMA-induced cleavage of the membrane-proximal region of CD163. As TACE/ADAM17-mediated shedding of TNF-α is up-regulated in macrophages subjected to inflammatory stimuli, the present results now provide a likely explanation for the strong empirical relationship between the sCD163 plasma level and infectious/inflammatory diseases relating to macrophage activity.


Monitoring of glyphosate-DNA interaction and synergistic genotoxic effect of glyphosate and 2,4-dichlorophenoxyacetic acid using an electrochemical biosensor.
Glyphosate (GLY) is a broad-spectrum herbicide used worldwide to control broadleaf sedge, and grass weeds to control non-specific vegetation. Although it was evaluated as non-toxic agent in 20th century, its carcinogenic and genotoxic potential has being intensively investigated all over the world in the last decade. Moreover, the combination of GLY and 2,4-dichlorophenoxyacetic acid (2,4-D) has been widely applied. Although genotoxicity of GLY has been evaluated in vivo studies, there is no report in the literature for the monitoring of in vitro biointeraction of GLY and double stranded DNA, or how effect the combination of GLY and 2,4-D onto DNA. Herein, an electrochemical biosensor platform was developed for detection of the pesticide-DNA interaction by using disposable pencil graphite electrodes (PGEs). First, voltammetric detection of the interaction between GLY and DNA was investigated and the electrochemical characterization of the interaction was achieved. Taking a step further, the synergistic genotoxic effect of the mixture of GLY and 2,4-dichlorophenoxyacetic acid (2,4-D) or the mixture of their herbicide forms onto DNA could be monitored. This effect was concentration dependent, and the herbicide of GLY or the use of mixture of herbicides of GLY and 2,4-D had more genotoxic effect than analytical grade of the active molecules, GLY and 2,4-D. The single-use PGEs provided to fabricate robust, eco-friendly and time saver recognition platform for monitoring of herbicide-DNA interaction with the sensitive and reliable results. It is expected that this study will lead to be designed miniaturized lab-on-a chip platforms for on-line analysis of the pesticide-nucleic acid interactions.


Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment.
Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stem-cell-like pericytes. Although indolent, MPC may be locally aggressive with recurrent disease. The pathogenesis and diagnostic biomarkers of MPC are poorly understood. We discovered that 15% of benign MPCs (thyroid, skin; 3 of 20 samples) harbored BRAF(WT/V600E); 33.3% (1 of 3 samples) of BRAF(WT/V600E)-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAF(WT/V600E), were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAF(WT/V600E)-positive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAF(V600E) therapy with vemurafenib disrupted angiogenic and metabolic properties (~3-fold decrease) with down-regulation (~2.2-fold decrease) of some extracellular-matrix (ECM) factors and ECM-associated long non-coding RNA (LincRNA) expression, with no effects in BRAF(WT)-pericytes. Vemurafenib also inhibited (~3-fold decrease) cell viability in vitro and in BRAF(WT/V600E)-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAF(WT/V600E)-dependent thyroid MPC cell culture. Our findings identify BRAF(WT/V600E) as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAF(V600E) agents may be useful adjuvant therapy in BRAF(WT/V600E)-MPC patients. Patients with BRAF(WT/V600E)-MPC should be closely followed because of the risk for multifocality/recurrence.


Engineering input/output nodes in prokaryotic regulatory circuits.
A large number of prokaryotic regulatory elements have been interfaced artificially with biological circuits that execute specific expression programs. Engineering such circuits involves the association of input/output components that perform discrete signal-transfer steps in an autonomous fashion while connected to the rest of the network with a defined topology. Each of these nodes includes a signal-recognition component for the detection of the relevant physicochemical or biological stimulus, a molecular device able to translate the signal-sensing event into a defined output and a genetic module capable of understanding such an output as an input for the next component of the circuit. The final outcome of the process can be recorded by means of a reporter product. This review addresses three such aspects of forward engineering of signal-responding genetic parts. We first recap natural and non-natural regulatory assets for designing gene expression in response to predetermined signals - chemical or otherwise. These include transcriptional regulators developed by in vitro evolution (or designed from scratch), and synthetic riboswitches derived from in vitro selection of aptamers. Then we examine recent progress on reporter genes, whose expression allows the quantification and parametrization of signal-responding circuits in their entirety. Finally, we critically examine recent work on other reporters that confer bacteria with gross organoleptic properties (e.g. distinct odour) and the interfacing of signal-sensing devices with determinants of community behaviour.


Habituation to pain: self-report, electroencephalography, and functional magnetic resonance imaging in healthy individuals. A scoping review and future recommendations.
Habituation to pain is a fundamental learning process and important adaption. Yet, a comprehensive review of the current state of the field is lacking. Through a systematic search, 63 studies were included. Results address habituation to pain in healthy individuals based on self-report, electroencephalography, or functional magnetic resonance imaging. Our findings indicate a large variety in methods, experimental settings, and contexts, making habituation a ubiquitous phenomenon. Habituation to pain based on self-report studies shows a large influence of expectations, as well as the presence of individual differences. Furthermore, widespread neural effects, with sometimes opposing effects in self-report measures, are noted. Electroencephalography studies showed habituation of the N2-P2 amplitude, whereas functional magnetic resonance imaging studies showed decreasing activity during painful repeated stimulation in several identified brain areas (cingulate cortex and somatosensory cortices). Important considerations for the use of terminology, methodology, statistics, and individual differences are discussed. This review will aid our understanding of habituation to pain in healthy individuals and may lead the way to improving methods and designs for personalized treatment approaches in chronic pain patients.


Optimization-based methodology for the development of wastewater facilities for energy and nutrient recovery.
A paradigm shift is currently underway from an attitude that considers wastewater streams as a waste to be treated, to a proactive interest in recovering materials and energy from these streams. This paper is concerned with the development and application of a systematic, model-based methodology for the development of wastewater resource recovery systems that are both economically attractive and sustainable. With the array of available treatment and recovery options growing steadily, a superstructure modeling approach based on rigorous mathematical optimization appears to be a natural approach for tackling these problems. The development of reliable, yet simple, performance and cost models is a key issue with this approach in order to allow for a reliable solution based on global optimization. We argue that commercial wastewater simulators can be used to derive such models, and we illustrate this approach with a simple resource recovery system. The results show that the proposed methodology is computationally tractable, thereby supporting its application as a decision support system for selection of promising resource recovery systems whose development is worth pursuing.


Development of a steady-state oral microbial biofilm community using the constant-depth film fermenter.
The complexity of biofilm communities like dental plaque suggests that laboratory model biofilm growth systems may help to understand their structure and function. This study describes the use of a constant-depth film fermenter (CDFF) to investigate biofilm formation by a nine-membered community of oral bacteria. The community was grown to steady state in a chemostat incubated anaerobically. The chemostat output was fed into the CDFF incubated aerobically. Viable counts for each species from the chemostat and the CDFF at steady state showed major differences; however, all nine organisms were present under both conditions. There was evidence of succession during biofilm formation with obligately anaerobic species only establishing after several days. A steady-state biofilm community was achieved which remained stable over time. Electron microscopy showed evidence of spatial differentiation with what appeared to be Neisseria subflava dominant near the upper surface and Fusobacterium nucleatum largely confined to the middle portion.


Next generation of protein microarray support materials: evaluation for protein and antibody microarray applications.
The performance of protein and antibody microarrays is dependent on various factors, one of which is the use of an appropriate microarray surface for the immobilisation of either protein or antibody samples. We have investigated the properties of seven new surfaces in the context of both protein and antibody microarray technology. We have demonstrated the functionality of all new slide coatings and investigated the mean signal to spotted concentration ratio, determined detection limits and calculated coefficients of variation. Moreover, new concepts for slide coatings such as dendrimer and poly(ethylene glycol)-epoxy slides were evaluated and improved qualities of novel slide surfaces were observed. Optimal slide coatings for antibody and protein chips were proposed and the requirements for both technologies were discussed.


Human growth hormone as a reporter gene in regulation studies employing transient gene expression.
The human growth hormone (hGH) transient assay system described here is based on the expression of hGH directed by cells transfected with hGH fusion genes. Levels of secreted hGH in the medium, measured by a simple radioimmunoassay, are proportional to both levels of cytoplasmic hGH mRNA and the amount of transfected DNA. The system is extremely sensitive, easy to perform, and is qualitatively different from other transient expression systems in that the medium is assayed and the cells themselves are not destroyed. The hGH transient assay system is appropriate for analyses of regulation of gene expression and was utilized here to investigate the effect of the simian virus 40 enhancer on the herpes simplex virus thymidine kinase promoter and the effect of zinc on the mouse metallothionein-I promoter. The expression of hGH can also be used as an internal control to monitor transfection efficiency along with any other transient expression system. All cell types tested thus far (including AtT-20, CV-1, GC, GH4, JEG, L, and primary pituitary cells) were able to secrete hGH into the medium.


Pediatric Acute Myocarditis: Predicting Hemodynamic Compromise at Presentation to Health Care.
The clinical spectrum of pediatric acute myocarditis ranges from minimal symptoms with intact hemodynamics to rapid cardiovascular collapse and death. We sought to identify factors on initial presentation associated with subsequent hemodynamic compromise. We performed a retrospective cohort study of patients with acute myocarditis at a freestanding pediatric hospital from 2007 to 2016. We defined 2 cohorts: high-acuity patients with hemodynamic compromise defined as requiring inotropic or vasoactive medications, cardiopulmonary resuscitation, extracorporeal membrane oxygenation, ventricular assist devices, or transplant or who died and low-acuity patients without these interventions. We collected the first recorded set of vital signs, symptoms, laboratory values, and chest radiograph, electrocardiogram, and echocardiography results. Univariate analysis was performed, and 2 multivariable logistic regression models were created to discriminate between cohorts. A total of 74 patients were included: 33 high acuity and 41 low acuity. There were significant differences in demographics, symptoms, and physical examination, laboratory, electrocardiogram, and echocardiography findings between high- and low-acuity cohorts. Multivariable logistic regression models were highly discriminate in predicting those in the high-acuity cohort. The first model included presence of tachycardia, tachypnea, creatinine, and cardiomegaly on chest radiograph (area under the curve = 0.913). The second model added the presence of pericardial effusion to the above variables (area under the curve = 0.964). Models based on factors available at initial presentation with acute myocarditis are predictive of subsequent hemodynamic compromise. If our results can be validated in a multicenter study, these models may help disposition patients with suspected acute myocarditis (with those who meet model criteria being admitted to centers capable of rapidly providing extracorporeal membrane oxygenation, ventricular assist devices, and heart transplant evaluation).


Simultaneous diffuse optical and bioluminescence tomography to account for signal attenuation to improve source localization.
Photonics based pre-clinical imaging is an extensively used technique to allow for the study of biologically relevant activity typically within a small-mouse model. Namely, bioluminescent tomography (BLT) attempts to tomographically reconstruct the 3-dimensional spatial light distribution of luminophores within a small animal given surface light measurements and known underlying optical parameters. Often it is the case where these optical parameters are unknown leading to the use of a 'best' guess approach or to direct measurements using either a multi-modal or dedicated system. Using these conventional approaches can lead to both inaccurate results and extending periods of imaging time. This work introduces the development of an algorithm that is used to accurately localize the spatial light distribution from a bioluminescence source within a subject by simultaneously reconstructing both the underlying optical properties and source spatial distribution and intensity from the same set of surface measurements. Through its application in 2- and 3-dimensional, homogeneous and heterogenous numerical models, it is demonstrated that the proposed algorithm is capable of replicating results as compared to 'gold' standard where the absolute optical properties are known. Additionally, the algorithm has been applied to experimental data using a tissue mimicking block phantom, recovering a spatial light distribution that has a localization error of ∼1.53 mm, which is better than previously published results without the need of assumptions regarding the underlying optical properties or source distribution.


An Investigation of Hearing (250-20,000 Hz) in Children with Endocrine Diseases and Evaluation of Tinnitus and Vertigo Symptoms.
Introduction Despite much advancement in medicine, endocrine and metabolic diseases remain an important cause of morbidity and even mortality in children. Objective The present study was planned to investigate the evaluation of hearing that also includes high frequencies, and the presence and degree of vertigo and tinnitus symptoms in pediatric patients diagnosed with endocrine diseases such as type 1 diabetes mellitus (DM), growth hormone deficiency (GHD), obesity, idiopathic short stature, and precocious puberty Methods The present study included a patient group of 207 children patients diagnosed with endocrine disease (95 males, 112 females; mean age 9.71 years old [range 6-16 years old]) and a control group including 55 healthy children who do not have any kind of chronic disease (26 males, 29 females; mean age 9.33 years old [range 6-16 years old]). The subjects underwent a hearing test with frequencies between 250 and 20,000 Hz. The vestibular and tinnitus symptoms were evaluated with the Pediatric Vestibular Symptom Questionnaire. Results Out of 207 patients in the patient group, 5 (2.4%) had hearing loss in pure tones, 10 (4.8%) had it in high frequencies, 40 (19.3%) had tinnitus symptoms, and 18 (8.7%) had vertigo symptoms. A total of 4 out of 207 patients in the study group (1.9%), 2 out of 59 with type 1 DM patients (3.4%), 1 out of 46 with GHD (2.2%), and 1 out of 43 obesity patients (2.3%) had hearing loss, vertigo, and tinnitus symptoms. Conclusions Our results suggest that some childhood endocrine diseases can cause some changes in the inner ear, although the exact cause is unknown. Perhaps, a detailed hearing and balance examination should be a routine in a child diagnosed with an endocrine disease. We think it is necessary to work on more comprehensive patient groups and tests in the future.


Cryo-electron ptychography: Applications and potential in biological characterisation.
There is a clear need for developments in characterisation techniques that provide detailed information about structure-function relationships in biology. Using electron microscopy to achieve high resolution while maintaining a broad field of view remains a challenge, particularly for radiation-sensitive specimens where the signal-to-noise ratio required to maintain structural integrity is limited by low electron fluence. In this review, we explore the potential of cryogenic electron ptychography as an alternative method for characterising biological systems under low-fluence conditions. Using this method with increased information content from multiple sampled regions of interest potentially allows 3D reconstruction with far fewer particles than required in conventional cryo-electron microscopy. This is important for achieving higher resolution in systems where distributions of homogeneous single particles are difficult to obtain. We discuss the progress, limitations, and potential areas for future development of this approach for both single particle analysis and applications to heterogeneous large objects.


Alterations in intracellular calcium following infection of human endothelial cells with Trypanosoma cruzi.
Trypanosoma cruzi infection in cultured human umbilical vein endothelial cells increased basal cellular calcium levels from 55 to 110 nM, as monitored with the fluorescent probe, fura-2. It also influenced intracellular calcium such that consistently higher total levels were observed in response to bradykinin, angiotensin II and norepinephrine, as compared to similarly treated uninfected cells. However, bradykinin and angiotensin II-dependent increases in calcium, when considered as the absolute increment or fold elevation over basal, were significantly lower in infected endothelial cells. Infection also influenced changes in calcium levels due to agents that operate independently of plasma membrane receptors. In the presence of ionomycin, the magnitude and rate of rise of intracellular calcium were decreased; additionally the calcium peak was delayed and the subsequent decline slowed. Similar to the results with bradykinin and angiotensin II, infection decreased both the increment in and fold stimulation of intracellular calcium in response to ionomycin. In contrast, infection altered only the total calcium stimulated in response to oligomycin; neither the fold stimulation of, nor increment in intracellular calcium was affected. These results indicate that (1) infection by T. cruzi alters calcium homeostasis in endothelial cells under basal and stimulated conditions; (2) both receptor-dependent and receptor-independent mechanisms are affected by infection. The possible contribution of altered calcium homeostasis induced by T. cruzi in the pathogenesis of chagasic cardiomyopathy is considered.


Secretion of celiac disease autoantibodies after in vitro gliadin challenge is dependent on small-bowel mucosal transglutaminase 2-specific IgA deposits.
In celiac disease gluten, the disease-inducing toxic component in wheat, induces the secretion of autoantibodies which are targeted against transglutaminase 2 (TG2). These autoantibodies are produced in the small-intestinal mucosa, where they can be found deposited extracellularly below the epithelial basement membrane and around mucosal blood vessels. In addition, during gluten consumption these autoantibodies can also be detected in patients' serum but disappear from the circulation on a gluten-free diet. Interestingly, after adoption of a gluten-free diet the serum autoantibodies disappear from the circulation more rapidly than the small-intestinal mucosal autoantibody deposits. The toxicity of gluten and the secretion of the disease-specific autoantibodies have been widely studied in organ culture of small-intestinal biopsy samples, but results hitherto have been contradictory. Since the mucosal autoantibodies disappear slowly after a gluten-free diet, our aim was to establish whether autoantibody secretion to organ culture supernatants in treated celiac disease patient biopsies is related to the duration of the diet and further to the pre-existence of mucosal TG2-specific IgA deposits in the cultured biopsy samples. In the organ culture system conducted with biopsies derived from treated celiac disease patients, gliadin induced secretion of autoantibodies to culture supernatants, reduced epithelial cell height and increased the density of lamina proprial CD25+ cells. However, these changes could be demonstrated only in biopsies from short-term treated celiac disease patients, where the small-intestinal mucosal TG2-specific IgA autoantibody deposits were still present. Furthermore, in these biopsies autoantibody secretion could be stimulated fully only after a 48-hour gliadin challenge. Our results show that studies focusing on the toxic effects of gliadin in the organ culture system should be carried out with biopsy samples from short-term treated celiac disease patients who are likely still to have mucosal IgA deposits present. In addition to providing an explanation for the discrepancies in previous publications, the present study also enables further validation of the organ culture method.


Study of the perceptions of the educational environment among undergraduate medical students of Taylor's University.
This article was migrated. The article was marked as recommended. A conducive educational environment is vital to successful learning. Perception of students about their particular educational environment may vary depending on their educational background, gender, level of study, and many other factors. Awareness and understanding of the students' perception of educational environment are a key to improve our teaching and learning environment. The aim of the study was to determine the perception of undergraduate medical students of Taylor's University, Malaysia on their educational environment. A cross sectional cohort study was conducted among preclinical and clinical students simultaneously at Taylor's University, School of Medicine in July 2019. Overall total scores of perceptions (136.55 ± 19.6) and those for the subscales were very satisfactory and similar to those of other local universities as well as international universities. There was a significant difference between preclinical and clinical students in two domains; Perception of Course Organizers and Academic Self-Perception, with higher scores among clinical students in all. There was a significant difference between students with Grade 'B' and those with Grade 'C' in the mean total score and Perceptions of Atmosphere. These results, in spite of being satisfactory, urge us to seek methods of and opportunities for further enhancement of the students' education environment.


Potential characterization of free-space-wave drop demultiplexer using cavity-resonator-integrated grating input/output coupler.
A prototype free-space-wave drop demultiplexer consisting of a cavity-resonator-integrated grating input/output coupler (CRIGIC) and a different-guided-mode-coupling distributed Bragg reflector (DGM-DBR) was designed for constructing a high-density wavelength-division-multiplexing intra-board chip-to-chip optical interconnection. The CRIGIC consists of one grating coupler and two DBRs, and can vertically couple a guided wave and a free-space wave with high efficiency. A two-channel drop demultiplexer operating at around 850-nm wavelength with 5-nm channel spacing in wavelength was fabricated in a thin-film SiO2-based waveguide. The device performance was predicted theoretically, characterized experimentally, and discussed.


Use of a Questionnaire for Evaluation of Surgical Treatment of Masseter Muscle Hypertrophy: A Case Report.
Masseter hypertrophy (MH) is an uncommon natural condition that affects the facial contour. The etiology is debatable, and complaints are usually cosmetic in nature. The diagnosis is essentially clinical and aided by imaging tests. Treatment is still controversial. The literature is relatively scarce in relation to information on MH, particularly in the evaluation of outcomes. Through questionnaires, the progress was observed in the evaluation of the outcomes of aesthetic procedures. Thus, the purpose of this paper is to apply a Facelift Outcome Evaluation (FOE) questionnaire to evaluate the outcomes of surgical treatment in a case of MH. A 23-year-old male presented to the clinic complaining of bullying due to his facial aesthetics. Clinical and imaging evaluation was performed, with the creation of surgical guides. The patient answered the FOE questionnaire pre- and postoperatively, with results of 12.5 and 100.00 respectively. This subjectively shows the success of the treatment. We suggest that a questionnaire applied exclusively to masseter hypertrophy should be developed, as well as studies for the development of muscle volume measurement protocols, aiming at a more specific evaluation of the surgical outcomes.


Concentrated bovine milk whey active proteins facilitate osteogenesis through activation of the JNK-ATF4 pathway.
Concentrated fractions of low molecular weight whey proteins (1-30 kDa), that is concentrated bovine milk whey active proteins (CBP), have been found to enhance bone formation in both in vivo and clinical studies, but the underlying mechanisms are poorly understood. In this study, we found that CBP promoted osteoblastic differentiation in normal human osteoblasts, and determined the involvement of the c-jun NH2-terminal kinase (JNK)-activating transcription factor 4 (ATF4) pathway. We observed that alkaline phosphatase activity and mineralization were significantly induced by CBP treatment. In addition, mRNA expression of ATF4 was intensely elevated in CBP-treated osteoblasts, indicating that the late-phase events of differentiation were promoted. We found that CBP activated the phosphorylation of JNK and extracellular signal-regulated kinase (ERK). Furthermore, pathway analyses using the various signaling pathway-specific inhibitors revealed that JNK activation, but not ERK activation, is essential for CBP-induced mineralization and ATF4 expression. Our results indicate that the JNK-mediated ATF4 pathway is required for CBP-promotive osteogenesis.


Combined pharmacological and short-term psychodynamic psychotherapy for probable medication overuse headache: a pilot study.
We studied the effects of short-term psychodynamic psychotherapy (STPP) and pharmacological therapy in 26 consecutive patients with probable medication overuse headache (pMOH). Patients underwent a standard in-patient detoxification protocol, lasting a mean of 7 days. Eleven patients overused non-steroidal anti-inflammatory drugs (NSAIDs), five a combination of NSAIDs and triptans, four triptans, four a combination of NSAIDs, and three triptans and ergot derivates. Preventive therapy was initiated during detoxification. The STPP protocol comprised the Brief Psychodynamic Investigation (BPI) and psychoanalysis-inspired psychotherapy. All patients (groups A and B) underwent the BPI and pharmacological therapy. Half of the patients (group B) also not randomly underwent psychoanalysis-inspired psychotherapy. We found a significant interaction between time and group for headache frequency and medication intake. At 12-month follow-up, a statistically greater decrease in headache frequency and medication intake was observed in group B than in group A (P = 0.0108 and P = 0.0097, respectively). The relapse rate was much lower in group B patients at both 6 and 12 months [15.3%, odds ratio (OR) 0.11, P = 0.016, and 23%, OR 0.18, P = 0.047, respectively] than in group A. The risk of developing chronic migraine (CM) during follow-up was higher in group A than in group B at 6 (OR 2.0, P = 0.047) and 12 months (OR 2.75, P = 0.005). Our study suggests that STPP in conjunction with drug withdrawal and prophylactic pharmacotherapy relieves headache symptoms in pMOH, reducing both long-term relapses and the burden of CM.


The impact of anti-HBV treatment on the occurrence and recurrence of hepatocellular carcinoma: focus on Asian studies.
Chronic hepatitis B virus (CHB) infection can cause persistent hepatic inflammation and cirrhosis, which may lead to hepatocellular carcinoma (HCC). CHB is considered the dominant cause of HCC in Asia because of the endemic status of hepatitis B virus (HBV) infection. A persistently high viral load, long duration of infection, and cirrhosis are the major risk factors for developing HCC in CHB patients. Antiviral therapies using interferon (IFN) and nucleos(t)ide analogues (NAs) could suppress viral replication, reduce liver injury, and preserve liver function, thereby lowering the risk of developing HCC. Recurrence of HCC after therapy is closely related to high levels of HBV DNA at the initial stage. Western studies have found that persistent antiviral treatments on CHB patients could not only reduce their risk of developing HCC, but also prevent or delay HCC recurrence after liver transplantation, hepatic resection, or radiation therapies. This review will focus on Asian clinical studies, where there is a higher prevalence of CHB and HCC. The outcomes of antiviral therapies on HCC in these Asian studies were compared to those in the Western studies.


Descending thoracic aorta-to-femoral artery bypass.
Descending thoracic aorta-to-femoral artery grafts were placed in 13 patients who had abdominal aortas deemed undesirable for surgical treatment. These included seven patients in whom an infected aortic graft had been removed for primary graft infection (three) or aortoduodenal fistula (four). These patients had been treated initially with axillary-femoral grafts. In five other patients, this approach was used following failure of at least two previous aortofemoral grafts. The remaining patient was so treated following multiple complex abdominal operations. The surgical technique involves a posterolateral, seventh interspace thoracoabdominal incision with a transdiaphragmatic retroperitoneal tunnel to the left groin. There was no operative mortality. The mean follow-up of all patients was 22 months (range, one to 44 months). All grafts remained patent except one, which was removed because of ascending groin infection. Three patients died, at 24, 29, and 44 months postoperatively, respectively. Reasonable perioperative morbidity and reliable patency make this an attractive technique for the conversion of axillofemoral bypasses and, when reentry of the abdominal cavity is undesirable, laparotomy is avoided.


Reducing Health Misinformation in Science: A Call to Arms.
The public often turns to science for accurate health information, which, in an ideal world, would be error free. However, limitations of scientific institutions and scientific processes can sometimes amplify misinformation and disinformation. The current review examines four mechanisms through which this occurs: (1) predatory journals that accept publications for monetary gain but do not engage in rigorous peer review; (2) pseudoscientists who provide scientific-sounding information but whose advice is inaccurate, unfalsifiable, or inconsistent with the scientific method; (3) occasions when legitimate scientists spread misinformation or disinformation; and (4) miscommunication of science by the media and other communicators. We characterize this article as a "call to arms," given the urgent need for the scientific information ecosystem to improve. Improvements are necessary to maintain the public's trust in science, foster robust discourse, and encourage a well-educated citizenry.


Suppression of putative tinnitus-related activity by extra-cochlear electrical stimulation.
Studies on animals have shown that noise-induced hearing loss is followed by an increase of spontaneous firing at several stages of the central auditory system. This central hyperactivity has been suggested to underpin the perception of tinnitus. It was shown that decreasing cochlear activity can abolish the noise-induced central hyperactivity. This latter result further suggests that an approach consisting of reducing cochlear activity may provide a therapeutic avenue for tinnitus. In this context, extra-cochlear electric stimulation (ECES) may be a good candidate to modulate cochlear activity and suppress tinnitus. Indeed, it has been shown that a positive current applied at the round window reduces cochlear nerve activity and can suppress tinnitus reliably in tinnitus subjects. The present study investigates whether ECES with a positive current can abolish the noise-induced central hyperactivity, i.e., the putative tinnitus-related activity. Spontaneous and stimulus-evoked neural activity before, during and after ECES was assessed from single-unit recordings in the inferior colliculus of anesthetized guinea pigs. We found that ECES with positive current significantly decreases the spontaneous firing rate of neurons with high characteristic frequencies, whereas negative current produces the opposite effect. The effects of the ECES are absent or even reversed for neurons with low characteristic frequencies. Importantly, ECES with positive current had only a marginal effect on thresholds and tone-induced activity of collicular neurons, suggesting that the main action of positive current is to modulate the spontaneous firing. Overall, cochlear electrical stimulation may be a viable approach for suppressing some forms of (peripheral-dependent) tinnitus.


Representation of item position in immediate serial recall: Evidence from intrusion errors.
In immediate serial recall, participants are asked to recall novel sequences of items in the correct order. Theories of the representations and processes required for this task differ in how order information is maintained; some have argued that order is represented through item-to-item associations, while others have argued that each item is coded for its position in a sequence, with position being defined either by distance from the start of the sequence, or by distance from both the start and the end of the sequence. Previous researchers have used error analyses to adjudicate between these different proposals. However, these previous attempts have not allowed researchers to examine the full set of alternative proposals. In the current study, we analyzed errors produced in 2 immediate serial recall experiments that differ in the modality of input (visual vs. aural presentation of words) and the modality of output (typed vs. spoken responses), using new analysis methods that allow for a greater number of alternative hypotheses to be considered. We find evidence that sequence positions are represented relative to both the start and the end of the sequence, and show a contribution of the end-based representation beyond the final item in the sequence. We also find limited evidence for item-to-item associations, suggesting that both a start-end positional scheme and item-to-item associations play a role in representing item order in immediate serial recall.


Treatment of steinstrasse by transureteral lithotripsy.
Extracorporeal shock wave lithotripsy (SWL) is an essential treatment for urinary calculi, but Post-SWL steinstrasse is a potential complication, especially in large-burden calculi. Our purpose was to evaluate the efficacy of transureteral lithotripsy (TUL) in the treatment of steinstrasse caused by SWL. Twenty-four patients with steintrasse following SWL were treated by TUL. The length of steinstrasse varied from 1.5 cm to 6 cm. The patients were followed up after TUL and failed treatment was considered if the steinstrasse was not cleared within 6 weeks. Fourteen patients (58.3%) became stone free, of whom 8 had a double-J stent before SWL. Partial response was seen in 6 patients (25.0%). The remained 4 patients (16.7%) with failed TUL underwent open ureterolithotomy. One patient developed nonfunctioning kidney during the follow-up. Transureteral lithotripsy was successful in 6 out 8 patients with type 1, 8 out of 12 with type 2, and none of those with type 3 steinstrasse. All of the successful cases of TUL were in the patients with lower ureteral calculi. Successful treatment of steinstrasse by TUL can be achieved in less than two-thirds of the cases. Type and location of steinstrasse may influence the outcomes. This complication seems sometimes to be troublesome and may even cause kidney loss.


Exploring Object Discrimination in Zebrafish: Behavioral Performance and Scopolamine-Induced Cognitive Deficits at Different Retention Intervals.
The object discrimination test allows the testing of different memory retention periods. However, few behavioral endpoints have been measured in fish species such that retention is often assessed using a single parameter (time spent in object area). Here, we aimed to explore the object discrimination test in zebrafish by assessing their behavioral performance after 1 or 24 h retention interval periods. To characterize putative interaction-like behaviors, fish were tested in the absence or presence of scopolamine (1 h before test session). Zebrafish were habituated for 3 consecutive days in the experimental tank, and training session was performed for 10 min using two identical nonpreferred objects (black cube or sphere). After the retention intervals, a familiar object was replaced by a novel object (test session, 10 min). Fish were also exposed to the novel tank diving test to assess locomotion and anxiety-like behaviors. At 1 h retention interval, animals performed more circular-like investigation near the familiar object, whereas 24 h after training session, a prominent rapid investigation was observed when animals explore the nonfamiliar object. Because scopolamine abolished these phenotypes, as well as the increased time spent in the novel object area during the test without changing locomotion and anxiety-related parameters, the behavioral responses described here may predictively reflect interaction-like behaviors involved in object discrimination memory in zebrafish models.


Intramural intestinal gas in adults.
It is important that a routine search be done roentgenographically for intramural intestinal gas. Several different patterns may be present, but unfortunately, classification of the findings is not helpful in predicting either the cause, or the presence, of gangrene. Also, the clinical circumstances in which intramural intestinal gas is discovered are important--if seen in a patient with acute pain in the abdomen, panmural gangrene is nearly always present and early operation desirable. However, if first discovered in the early postoperative period, a more selective approach is possible. Although many of the patients with intramural intestinal gas died, approximately one-quarter will survive. Hopefully, more timely recognition of intramural intestinal gas will allow earlier surgical intervention in some patients with ischemia of the intestine.


The role of the outer membrane in formaldehyde tolerance in Escherichia coli VU3695 and Halomonas sp. MAC.
To investigate the mechanism of formaldehyde tolerance in Gram-negative bacteria, two formaldehyde-tolerant strains, Escherichia coli VU3695 and Halomonas sp. MAC (DSM 7328), and formaldehyde-sensitive revertants obtained by ethidium bromide or novobiocin treatment were studied. The presence of high levels of formaldehyde dehydrogenase activity alone proved insufficient to confer tolerance to high formaldehyde concentrations, as shown by high activity displayed by formaldehyde-sensitive revertants of Halomonas MAC. Moreover, formaldehyde-tolerant strains also proved to be tolerant to high concentrations of acetaldehyde and glutaraldehyde, which are not oxidized by formaldehyde dehydrogenase. Treatment with sublethal concentrations of EDTA rendered the resistant strains highly sensitive to formaldehyde without affecting the activity of formaldehyde dehydrogenase. Comparison of the outer membrane proteins of formaldehyde-resistant strains with those of their sensitive revertants showed the presence of at least one additional high molecular mass protein in the tolerant strains. It is concluded that formaldehyde tolerance in the bacteria studied depends on the composition and structure of the outer membrane.


Respiratory muscle pressures in non-CF bronchiectasis: repeatability and reliability.
Respiratory muscle strength is used diagnostically in clinical practice and as an outcome measure in clinical trials in various chronic lung diseases. There is limited data on its repeatability in people with non-CF bronchiectasis. The aim of the present study was to assess the repeatability of maximal inspiratory (P( I)max) and expiratory pressures (P(E)max) in a group of patients with stable, moderate-to-severe non-CF bronchiectasis. Twenty participants with stable moderate-to-severe non-CF bronchiectasis were recruited. Respiratory muscle strength measurements (three maximal inspiratory and expiratory pressures) were made on 2 separate days. A standard protocol was used, including practice tests, before obtaining three technically acceptable and reproducible readings with a difference of 10% or less between values. ClinicalTrials.gov: NCT00487149. The mean (SD) age of the non-CF bronchiectasis group was 63 (9) years. Maximal inspiratory pressures were repeatable with mean (SD) for highest P(I)max, Test 1 and Test 2, 75.90 (20) and 79.40 (19) cmH(2)O, and limits of agreement (mean difference +/- 2SD) -3.50 +/- 20 cmH(2)O, (p = 0.14). Maximal expiratory pressures differed significantly with mean (SD) for highest P(E)max, Test 1 and Test 2, 102.25 (27) and 112.30 (32) cmH(2)O, and limits of agreement (mean difference +/- 2SD) -10.10 +/- 35 cmH(2)O, (p = 0.02). The intraclass correlation coefficient (95% CI) for highest P(I)max and P(E)max was 0.93 (95% CI 0.82 to 0.97) and 0.90 (95% CI 0.76 to 0.96), respectively. Maximal inspiratory pressure measurements were repeatable during a period of clinical stability in moderate-to-severe non-CF bronchiectasis, suggesting this may be a useful outcome measure in non-CF bronchiectasis. Once a baseline has been established, a second visit is not required. P(E)max was not a repeatable measure and further study is necessary to ascertain how much practice testing is required to obtain an accurate value.


The Effect of Consuming Carbohydrate With and Without Protein on the Rate of Muscle Glycogen Re-synthesis During Short-Term Post-exercise Recovery: a Systematic Review and Meta-analysis.
Rapid restoration of muscle glycogen stores is imperative for athletes undertaking consecutive strenuous exercise sessions with limited recovery time (e.g. ≤ 8 h). Strategies to optimise muscle glycogen re-synthesis in this situation are essential. This two-part systematic review and meta-analysis investigated the effect of consuming carbohydrate (CHO) with and without protein (PRO) on the rate of muscle glycogen re-synthesis during short-term post-exercise recovery (≤ 8 h). Studies were identified via the online databases Web of Science and Scopus. Investigations that measured muscle glycogen via needle biopsy during recovery (with the first measurement taken ≤ 30 min post-exercise and at least one additional measure taken ≤ 8 h post-exercise) following a standardised exercise bout (any type) under the following control vs. intervention conditions were included in the meta-analysis: part 1, water (or non-nutrient beverage) vs. CHO, and part 2, CHO vs. CHO+PRO. Publications were examined for methodological quality using the Rosendal scale. Random-effects meta-analyses and meta-regression analyses were conducted to evaluate intervention efficacy. Overall, 29 trials (n = 246 participants) derived from 21 publications were included in this review. The quality assessment yielded a Rosendal score of 61 ± 8% (mean ± standard deviation). Part 1: 10 trials (n = 86) were reviewed. Ingesting CHO during recovery (1.02 ± 0.4 g·kg body mass (BM)-1 h-1) improved the rate of muscle glycogen re-synthesis compared with water; change in muscle glycogen (MGΔ) re-synthesis rate = 23.5 mmol·kg dm-1 h-1, 95% CI 19.0-27.9, p < 0.001; I2 = 66.8%. A significant positive correlation (R2 = 0.44, p = 0.027) was observed between interval of CHO administration (≤ hourly vs. > hourly) and the mean difference in rate of re-synthesis between treatments. Part 2: 19 trials (n = 160) were reviewed. Ingesting CHO+PRO (CHO: 0.86 ± 0.2 g·kg BM-1 h-1; PRO: 0.27 ± 0.1 g·kg BM-1 h-1) did not improve the rate of muscle glycogen re-synthesis compared to CHO alone (0.95 ± 0.3 g·kg BM-1 h-1); MGΔ re-synthesis rate = 0.4 mmol·kg dm-1 h-1, 95% CI -2.7 to 3.4, p = 0.805; I2 = 56.4%. Athletes with limited time for recovery between consecutive exercise sessions should prioritise regular intake of CHO, while co-ingesting PRO with CHO appears unlikely to enhance (or impede) the rate of muscle glycogen re-synthesis. Registered at the International Prospective Register of Systematic Reviews (PROSPERO) (identification code CRD42020156841 ).


Shape irregularity of the intracranial aneurysm lumen exhibits diagnostic value.
Morphological irregularity is linked to intracranial aneurysm wall instability and manifests in the lumen shape. Yet there is currently no consent on how to assess shape irregularity. The aims of this work are to quantify irregularity as perceived by clinicians, to break down irregularity into morphological attributes, and to relate these to clinically relevant factors such as rupture status, aneurysm location, and patient age or sex. Thirteen clinicians and 26 laypersons assessed 134 aneurysm lumen segmentations in terms of overall perceived irregularity and five different morphological attributes (presence/absence of a rough surface, blebs, lobules, asymmetry, complex geometry of the parent vasculature). We examined rater agreement and compared the ratings with clinical factors by means of regression analysis or binary classification. Using rank-based aggregation, the irregularity ratings of clinicians and laypersons did not differ statistically. Perceived irregularity showed good agreement with curvature (coefficient of determination R2 = 0.68 ± 0.08) and was modeled very accurately using the five morphological rating attributes plus shape elongation (R2 = 0.95 ± 0.02). In agreement with previous studies, irregularity was associated with aneurysm rupture status (AUC = 0.81 ± 0.08); adding aneurysm location as an explanatory variable increased the AUC to 0.87 ± 0.09. Besides irregularity, perceived asymmetry, presence of blebs or lobules, aneurysm size, non-sphericity, and curvature were linked to rupture. No association was found between morphology and any of patient sex, age, and history of smoking or hypertension. Aneurysm size was linked to morphology. Irregular lumen shape carries significant information on the aneurysm's disease status. Irregularity constitutes a continuous parameter that shows a strong association with the rupture status. To improve the objectivity of morphological assessment, we suggest examining shape through six different morphological attributes, which can characterize irregularity accurately.


Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins with Potential Anticancer Effects.
Coumarins are the secondary metabolites of some plants, fungi, and bacteria. Coumarins and the hybrid molecules of coumarins are the compounds which have been widely studied for their potential anticancer effects. They belong to benzopyrone chemical class, more precisely benzo-α-pyrones, where benzene ring is fused to pyrone ring. In nature, coumarins are found in higher plants like Rutaceae and Umbelliferae and some essential oils like cinnamon bark oil, cassia leaf oil and lavender oil are also rich in coumarins. The six main classes of coumarins are furanocoumarins, dihydrofuranocoumarins, pyrano coumarins, pyrone substituted coumarins, phenylcoumarins and bicoumarins. As well as their wide range of biological activities, coumarins and the hybrid molecules of coumarins are proven to have an important role in anticancer drug development due to the fact that many of its derivatives have shown an anticancer activity on various cell lines. Osthol, imperatorin, esculetin, scopoletin, umbelliprenin, angelicine, bergamottin, limettin, metoxhalen, aurapten and isopimpinellin are some of these coumarins. This review summarizes the anticancer effects of coumarins and their hybrid molecules including the novel pharmaceutical formulations adding further information on the topic for the last ten years and basically focusing on the structureactivity relationship of these compounds in cancer.


[Echographic diagnosis of calculous lesions of the bile ducts].
The author presented methods and results of ultrasonic diagnosis of concrements in intrahepatic (4), lobar (5), cystic (24) and common bile (20) ducts. In technically difficult cases the starting point of an acoustic shadow route was the only sign permitting concrement localization in the duct. Indirect signs of occluding choledocholithiasis were dilatated lumen of intrahepatic and proximal (with respect to the site of occlusion) extrahepatic ducts, a concrement filled cavity and the tense gall bladder wall, the absence of echographic signs of tumor involvement of the peritoneal cavity organs. The dilatation of the ducts and gall bladder cavity were more noticeable in patients with a long history of cholestasis. The lamination of the gall bladder content into zones of different echogenicity, the filling of the dilatated ducts with the content of inhomogeneous acoustic transparency indicated the complication of occluding choledocholithiasis by purulent cholangitis.


Saccharomyces boulardii in acute childhood diarrhoea: a randomized, placebo-controlled study.
To evaluate the efficacy of the probiotic yeast Saccharomyces boulardii (S. boulardii) as an adjuvant to oral rehydration solution (ORS) in shortening the duration of acute infectious gastroenteritis in children less than 2 years old in ambulatory care. In a period of 1 year, 100 outpatients between 3 and 24 months old presenting with acute mild to moderate diarrhoea of less than 7 days duration, were included in a double-blind, randomized, placebo-controlled trial evaluating the efficacy of S. boulardii administered for 6 days. Twelve children were lost in follow-up; the data of 88 children could be analysed (44 in the placebo and 44 in the S. boulardii group). Seventy-two patients were followed for one month (37 in the placebo and 35 in the S. boulardii group) allowing the calculation of the duration of diarrhoea. The mean duration of diarrhoea was 6.16 days (range 2-13 days) in the placebo group and 4.70 days (range 2-10 days) in the S. boulardii group (p<0.05). On the 4th day, the patients in the S. boulardii group passed 2.5+/-1.4 stools/day versus 3.5+/-1.8 in the placebo group (p<0.001). The risk of having diarrhoea lasting more than 7 days was lower in the S. boulardii group (3/44 versus 12/44; RR 0.25; 95% CI 0.1-0.8). In no patient diarrhoea persisted longer than 14 days. A statistically significant difference was observed in the number of stools on the 4th and 7th day favouring the subgroup that received early treatment (within the first 48 h of the onset of diarrhoea). The administration of antibiotics before inclusion did not make any difference. S. boulardii as an adjuvant to ORS in ambulatory care in children less than 2 years old with mild or moderate acute diarrhoea decreased the duration of diarrhoea, accelerated recovery and reduced the risk of prolonged diarrhoea. The data also indicate increased efficacy if S. boulardii is administered within the first 48 h of the onset of diarrhoea.


N-Acetylcysteine Resolves Placental Inflammatory-Vasculopathic Changes in Mice Consuming a High-Fat Diet.
The mechanism by which poor maternal nutrition can affect the long-term health of offspring is poorly understood. In mice, we previously found that maternal high-fat diet (HFD) exposure results in reduced fetal growth regardless of maternal genotype. We tested our hypothesis that maternal HFD-induced inflammation contributes to metabolic disease susceptibility of the offspring via alterations in the placenta. The effect of maternal genotype, diet, and treatment with the anti-inflammatory compound N-acetylcysteine (NAC) on placental morphologic features was investigated. Placentas from wild-type dams maintained on a HFD but not those heterozygous (+/-) for Glut4 (Slc2a4) on the same diet had an increase in decidual inflammation and vasculopathy occurring together. NAC administration resulted in amelioration of HFD-induced decidual vasculopathy independent of offspring genotype and sex. Consistent with these morphologic improvements, placentas from HFD dams treated with NAC had decreased mRNA and immunostaining of IL-1β and monocyte chemoattractant protein-1, decreased mRNA of inflammatory genes, and increased mRNA of Vegfa. These results strongly suggest consumption of an HFD results in vascular changes in placenta reflected by alterations in expression of pivotal vascular developmental markers and inflammatory genes all of which are ameliorated by NAC. These placental changes play a key role in the increased programed metabolic disease of HFD-exposed offspring.


Neurostimulation for traumatic brain injury.
Traumatic brain injury (TBI) remains a significant public health problem and is a leading cause of death and disability in many countries. Durable treatments for neurological function deficits following TBI have been elusive, as there are currently no FDA-approved therapeutic modalities for mitigating the consequences of TBI. Neurostimulation strategies using various forms of electrical stimulation have recently been applied to treat functional deficits in animal models and clinical stroke trials. The results from these studies suggest that neurostimulation may augment improvements in both motor and cognitive deficits after brain injury. Several studies have taken this approach in animal models of TBI, showing both behavioral enhancement and biological evidence of recovery. There have been only a few studies using deep brain stimulation (DBS) in human TBI patients, and future studies are warranted to validate the feasibility of this technique in the clinical treatment of TBI. In this review, the authors summarize insights from studies employing neurostimulation techniques in the setting of brain injury. Moreover, they relate these findings to the future prospect of using DBS to ameliorate motor and cognitive deficits following TBI.


Direct interactions between the Paf1 complex and a cleavage and polyadenylation factor are revealed by dissociation of Paf1 from RNA polymerase II.
The Paf1 complex (Paf1, Ctr9, Cdc73, Rtf1, and Leo1) is normally associated with RNA polymerase II (Pol II) throughout the transcription cycle. However, the loss of either Rtf1 or Cdc73 results in the detachment of the Paf1 complex from Pol II and the chromatin form of actively transcribed genes. Using functionally tagged forms of the Paf1 complex factors, we have determined that, except for the more loosely associated Rtf1, the remaining components stay stably associated with one another in an RNase-resistant complex after dissociation from Pol II and chromatin. The loss of Paf1, Ctr9, or to a lesser extent Cdc73 or Rtf1 results in reduced levels of serine 2 phosphorylation of the Pol II C-terminal domain and in increased read through of the MAK21 polyadenylation site. We found that the cleavage and polyadenylation factor Cft1 requires the Pol II-associated form of the Paf1 complex for full levels of interaction with the serine 5-phosphorylated form of Pol II. When the Paf1 complex is dissociated from Pol II, a direct interaction between Cft1 and the Paf1 complex can be detected. These results are consistent with the Paf1 complex providing a point of contact for recruitment of 3'-end processing factors at an early point in the transcription cycle. The lack of this connection helps to explain the defects in 3'-end formation observed in the absence of Paf1.


Splinting for carpal tunnel syndrome: prognostic indicators of success.
To identify (combinations of) prognostic indicators for the long term success of splinting in patients with electrophysiologically confirmed idiopathic carpal tunnel syndrome (CTS). This study was conducted within the framework of a randomised controlled trial on the efficacy of splinting and surgery for CTS. Patients randomised to splinting received a wrist splint, which they had to wear during the night for at least six weeks. To assess the long term success, patients were asked to indicate whether there was any improvement 12 months after randomisation. Potential prognostic indicators included variables from the history taking and physical examination, self administered questionnaires on severity of symptoms, and electrodiagnostic studies. Multiple logistic regression was used to identify (combinations of) prognostic indicators. Of the 89 patients randomised to splinting, 83 attended the follow up measurement at 12 months, of whom 60 reported improvement. However, 34 patients had received one or more additional types of treatment during the follow up period and were therefore considered as treatment failures for splinting, resulting in a final success rate of 31% for splinting (26 of 83 patients). Only two prognostic indicators could be identified, namely a short duration of CTS complaints (one year or less) and a score of 6 or less for severity of paraesthesia at night at baseline. For patients to whom both factors applied, the predicted probability of treatment success, according to the model, was 62%. The overall percentage of patients who were correctly classified by the model was 78% (95% CI 69% to 87%).


First-principle calculation of solar cell efficiency under incoherent illumination.
Because of the temporal incoherence of sunlight, solar cells efficiency should depend on the degree of coherence of the incident light. However, numerical computation methods, which are used to optimize these devices, fundamentally consider fully coherent light. Hereafter, we show that the incoherent efficiency of solar cells can be easily analytically calculated. The incoherent efficiency is simply derived from the coherent one thanks to a convolution product with a function characterizing the incoherent light. Our approach is neither heuristic nor empiric but is deduced from first-principle, i.e. Maxwell's equations. Usually, in order to reproduce the incoherent behavior, statistical methods requiring a high number of numerical simulations are used. With our method, such approaches are not required. Our results are compared with those from previous works and good agreement is found.


Performance characteristics of Allele-Specific PCR (ASPCR) in detecting drug resistance mutations among non-B HIV-1 Variants.
Allele-Specific Polymerase Chain Reaction (ASPCR) is an affordable point-mutation assay whose validation could improve the detection of HIV-1 drug resistance mutations (DRMs) in resource-limited settings (RLS). We assessed the performance of ASPCR onforty-four non-B HIV-1 plasma samples from patients who were ARV treated in failure in N'Djamena-Chad. Viral RNA was reverse-transcribed and amplified using LightCycler® FastStart DNA MasterPLUS SYBR Green I. Detection of six major DRMs (K70R, K103N, Y181C, M184V, T215F, T215Y) was evaluated on Roche LightCycler®480 automated system (with dilutions 0.01-100%). ASPCR-results were compared to Sanger-sequencing (gold-standard). Correlations of mutation curves were excellent (R2 >0.97); all DRMs were detected with desirable mutant/wild-type threshold differences (ΔCt≥9) except K70R(ΔCtK70R=6; ΔCtK103N=13; ΔCtM184V=9; ΔCtT215F=12; ΔCtT215Y=12; ΔCtY181C=9) and positive controls were below required thresholds. Also, ASPCR reproducibility on DRMs was assessed by using dilutions of intra-assay and inter-assay coefficient of variations respectively with a threshold of less than 50(i.e.<0.50 variation) which are;: K70R (0.02-0.28 vs. 0.12-0.37), K103N (0.08-0.42 vs. 0.12-0.37), Y181C (0.12-0.39 vs. 0.31-0.37), M184V (0.13-0.39 vs. 0.23-0.42), T215F (0.05-0.43 vs. 0.04-0.45) and T215Y (0.13-0.41 vs. 0.19-0.41). DRM detection-rate by ASPCR vs Sanger was respectively: M184V (63.6% vs. 38.6%); T215F (18.1% vs. 9.1%); T215Y (6.8% vs. 2.3%); K70R (4.5% vs. 2.3%). K103N (22.7% vs. 13.6%); Y181C (13.6% vs. 11.4%). Correlations of mutation curves were excellent (R2 >0.97); all DRMs were detected with desirable mutant/wild-type threshold differences (ΔCt≥9) except K70R(ΔCtK70R=6; ΔCtK103N=13; ΔCtM184V=9; ΔCtT215F=12; ΔCtT215Y=12; ΔCtY181C=9) and positive controls were below required thresholds. Also, ASPCR reproducibility on DRMs was assessed by using dilutions of intra-assay and inter-assay coefficient of variations respectively with a threshold of less than 50(i.e.<0.50 variation) which are;: K70R (0.02-0.28 vs. 0.12-0.37), K103N (0.08-0.42 vs. 0.12-0.37), Y181C (0.12-0.39 vs. 0.31-0.37), M184V (0.13-0.39 vs. 0.23-0.42), T215F (0.05-0.43 vs. 0.04-0.45) and T215Y (0.13-0.41 vs. 0.19-0.41). DRM detection-rate by ASPCR vs Sanger was respectively: M184V (63.6% vs. 38.6%); T215F (18.1% vs. 9.1%); T215Y (6.8% vs. 2.3%); K70R (4.5% vs. 2.3%). K103N (22.7% vs. 13.6%); Y181C (13.6% vs. 11.4%). ASPCR appears more efficient for detecting DRMs on diverse HIV-1 non-B circulating in RLS like Chad.


Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson's disease.
Nanomedicine-based anti-neuroinflammation strategy has become a promising dawn of Parkinson's disease (PD) treatment. However, there are significant gaps in our understanding of the therapeutic mechanisms of antioxidant nanomedicines concerning the pathways traversing the blood-brain barrier (BBB) and subsequent inflammation mitigation. Here, we report nanozyme-integrated metal-organic frameworks with excellent antioxidant activity and chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for the treatment of PD. These chiral nanozymes are synthesized by embedding ultra-small platinum nanozymes (Ptzymes) into L-chiral and D-chiral imidazolate zeolite frameworks (Ptzyme@L-ZIF and Ptzyme@D-ZIF). Compared to Ptzyme@L-ZIF, Ptzyme@D-ZIF shows higher accumulation in the brains of male PD mouse models due to longer plasma residence time and more pathways to traverse BBB, including clathrin-mediated and caveolae-mediated endocytosis. These factors contribute to the superior therapeutic efficacy of Ptzyme@D-ZIF in reducing behavioral disorders and pathological changes. Bioinformatics and biochemical analyses suggest that Ptzyme@D-ZIF inhibits neuroinflammation-induced apoptosis and ferroptosis in damaged neurons. The research uncovers the biodistribution, metabolic variances, and therapeutic outcomes of nanozymes-integrated chiral ZIF platforms, providing possibilities for devising anti-PD drugs.


Toward Tunable Protein-Driven Hydrogel Lens.
Despite the significant progress in protein-based materials, creating a tunable protein-activated hydrogel lens remains an elusive goal. This study leverages the synergistic relationship between protein structural dynamics and polymer hydrogel engineering to introduce a highly transparent protein-polymer actuator. By incorporating bovine serum albumin into polyethyleneglycol diacrylate hydrogels, the authors achieved enhanced light transmittance and conferred actuating capabilities to the hydrogel. Taking advantage of these features, a bilayer protein-driven hydrogel lens that dynamically modifies its focal length in response to pH changes, mimicking the adaptability of the human lens, is fabricated. The lens demonstrates durability and reproducibility, highlighting its potential for repetitive applications. This integration of protein-diverse biochemistry, folding nanomechanics, and polymer engineering opens up new avenues for harnessing the wide range of proteins to potentially propel various fields such as diagnostics, lab-on-chip, and deep-tissue bio-optics, advancing the understanding of incorporating biomaterials in the optical field.


Application of motor learning in neurorehabilitation: a framework for health-care professionals.
Learning motor skills is an essential part of most rehabilitation processes. Facilitating and supporting motor learning is particularly challenging in neurological rehabilitation: patients who suffer from neurological diseases experience both physical limitations and difficulties of cognition and communication that affect and/or complicate the motor learning process. Therapists (e.g. physiotherapists and occupational therapists) who work in neurorehabilitation are therefore continuously searching for the best way to facilitate patients during these intensive learning processes. To support therapists in the application of motor learning, a framework was developed, integrating knowledge from the literature and the opinions and experiences of international experts. This article presents the framework, illustrated by cases from daily practice. The framework may assist therapists working in neurorehabilitation in making choices, implementing motor learning in routine practice, and supporting communication of knowledge and experiences about motor learning with colleagues and students. The article discusses the framework and offers suggestions and conditions given for its use in daily practice.


Motion integration for ocular pursuit does not hinder perceptual segregation of moving objects.
When confronted with a complex moving stimulus, the brain can integrate local element velocities to obtain a single motion signal, or segregate the elements to maintain awareness of their identities. The integrated motion signal can drive smooth-pursuit eye movements (Heinen and Watamaniuk, 1998), whereas the segregated signal guides attentive tracking of individual elements in multiple-object tracking tasks (MOT; Pylyshyn and Storm, 1988). It is evident that these processes can occur simultaneously, because we can effortlessly pursue ambulating creatures while inspecting disjoint moving features, such as arms and legs, but the underlying mechanism is unknown. Here, we provide evidence that separate neural circuits perform the mathematically opposed operations of integration and segregation, by demonstrating with a dual-task paradigm that the two processes do not share attentional resources. Human observers attentively tracked a subset of target elements composing a small MOT stimulus, while pursuing it ocularly as it translated across a computer display. Integration of the multidot stimulus yielded optimal pursuit. Importantly, performing MOT while pursuing the stimulus did not degrade performance on either task compared with when each was performed alone, indicating that they did not share attention. A control experiment showed that pursuit was not driven by integration of only the nontargets, leaving the MOT targets free for segregation. Nor was a predictive strategy used to pursue the stimulus, because sudden changes in its global velocity were accurately followed. The results suggest that separate neural mechanisms can simultaneously segregate and integrate the same motion signals.


Effects of renin-angiotensin system blockade on the islet morphology and function in rats with long-term high-fat diet.
The renin-angiotensin system (RAS) has an important role in the endocrine pancreas. Multiple researches have shown that even in the insulin resistance phase, there are many abnormalities in islets morphology and function. This study aimed at investigating the effects of RAS blockade on the islets function in rats with long-term high-fat diet and its mechanisms. Wistar rats with 16-week high-fat diet were randomly divided into perindopril intervention group (FP, n = 15) and telmisartan intervention group (FT, n = 15). After 8-week intervention, insulin sensitivity and islets function were detected by hyperinsulinemic euglycemic clamp and intravenous glucose tolerance test (IVGTT), respectively. The pancreases were stained by immunohistochemistry technique to qualitatively and/or quantitatively analyze the relative content of insulin (IRC), NF-KB, uncoupling protein 2 (UCP2) and caspase-3 in islets. The apoptosis of islet cells was detected by TUNEL. The expression of angiotensin II receptor 1 (AT1R), interleukin-1β (IL-1β), hypoxia-inducing factor (HIF)-1α and CHOP mRNA in the islets was detected by reverse transcription polymerase chain reaction (RT-PCR). Compared with normal control group (NC, n = 15), the glucose infusion rate (GIR), area under the insulin curve (AUCI) of 0-10 min and IRC were decreased in high-fat control group (FC, n = 15). The relative content of NF-KB, UCP-2 and caspase-3 was increased significantly with the increased number of apoptotic cells in unit islets area. The relative expression of AT1R, IL-1β, HIF-1α and CHOP was also increased evidently (all P < 0.01). After intervention, the GIR, AUCI of 0-10 min and IRC were all increased obviously with the decreased relative concentration of NF-KB, UCP-2, caspase-3 and the number of apoptotic cell in unit islets area. The relative expression of AT1R, IL-1β, HIF-1α and CHOP mRNA was reduced significantly (all P < 0.01 or P < 0.05). There were no significant differences between groups FP and FT. So we concluded that blockade of RAS may protect islet function of rats with long-term high-fat diet via downregulation of islets inflammation, oxidative stress, endoplasmic reticulum stress and apoptosis, which have tight relationship with each other.


Harmful effect of ERβ on BCRP-mediated drug resistance and cell proliferation in ERα/PR-negative breast cancer.
The role of estrogen receptor β (ERβ) in breast cancer is still under investigation. Various studies have provided evidence that ERβ behaves as a tumor suppressor in breast cancer, whereas some studies of estrogen receptor α (ERα) negative breast cancer reported a positive correlation between high ERβ expression and poor prognostic phenotypes, such as induced proliferation, invasion and metastasis. In the present immunohistochemistry study of 99 ERα/progesterone receptor (PR)-negative breast cancer samples, nuclear expression of ERβ was positively associated with membranous expression of breast cancer resistance protein (BCRP), Ki67 (proliferation marker) and tumor size. Moreover, both endogenous and exogenous ERβ upregulated BCRP expression which induced BCRP-mediated drug resistance and enhanced proliferation of ERα-/PR- breast cancer cells in the presence of 17β-estradiol, whereas these effects were reversed by additional use of tamoxifen (TAM). In addition, the regulation of BCRP via specific binding between ERβ and estrogen response element (ERE) was demonstrated in an electrophoretic mobility shift assay. Overall, our findings manifest that ERβ might act as a tumor promoter of cell proliferation and BCRP-mediated drug resistance in ERα-/PR- breast cancer. TAM routinely used for patients with ERα+/PR+, ERα+/PR- and ERα-/PR+ breast cancer might also be effective in ERα-/PR- but ERβ+ breast cancer. Therefore, the detection of ERβ in clinic is valuable and should not be neglected in breast cancer, especially for the ERα-/PR- phenotype.


A practical approach to detection and treatment of depression in Parkinson disease and dementia.
To review the available evidence for the detection and management of depression in Parkinson disease (PD) and dementia. Depression is a common comorbidity in those with PD or dementia, and leads to increased morbidity. There are several available and accurate tools for the detection of depression in PD (e.g., Geriatric Depression Scale) and dementia (e.g., Cornell Scale for Depression in Dementia). Treatment of depression depends on patient preference, severity of depression, comorbidities, and available resources. Despite variable evidence, the use of nonpharmacologic strategies to manage depression is suggested. Pharmacologic management is guided by modest evidence in PD and dementia, but also informed by the management of late-life depression (LLD). There is evidence to guide the diagnosis and management of depression in PD or dementia. However, more research is required in this field to better inform clinical decision-making.


The development of a short measure of physical function for knee OA KOOS-Physical Function Shortform (KOOS-PS) - an OARSI/OMERACT initiative.
To develop a short measure of physical function for knee osteoarthritis (OA) using multi-national data from individuals with varying degrees of severity of knee OA. Rasch analysis, based on the partial credit model, was conducted on Knee injury and Osteoarthritis Outcome Score and Western Ontario McMaster Universities' Osteoarthritis Index data from individuals with knee OA, ranging from community to pre-total knee replacement samples from five countries. Fit of the data to the Rasch model was evaluated by overall model fit and item-level fit statistics (chi(2), size of residual, F-test). Invariance across age, gender and country was evaluated. Unidimensionality was evaluated by factor analysis of residuals. The derived short measure was further tested for fit through re-analyses in individual sub-samples. A nomogram converting raw summed scores to Rasch-derived interval scores was developed. Thirteen data sets were included (n=2145), with an age range of 26-95 years, and a male/female ratio of 1:1.4. The final model included seven of the original 22 items. From easiest to most difficult, the items (logit) were as follows: rising from bed (1.366), putting on socks/stockings (1.109), rising from sitting (0.537), bending to the floor (0.433), twisting/pivoting on injured knee (-0.861), kneeling (-1.292) and squatting (-1.292). Sub-sample analyses confirmed findings. Based on the use of accepted Rasch-based measurement methods and the compliment of countries, languages and OA severity represented in this study, our seven item short measure of physical function for knee OA is likely generalizable and widely applicable. This measure has potential for use as the function component in an OA severity scoring system.


Early-Onset Mild Type Leukoencephalopathy Caused by a Homozygous EARS2 Mutation.
Childhood leukoencephalopathies are a broad class of diseases, which are extremely rare. The treatment and classification of these disorders are both challenging. Nearly half of children presenting with a leukoencephalopathy remain without a specific diagnosis. Leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) is a newly described childhood leukoencephalopathy caused by mutations in the gene encoding a mitochondrial aminoacyl-tRNA synthetase specific for glutamate, EARS2 Magnetic resonance images show a characteristic leukoencephalopathy with thalamic and brain stem involvement. Here, we report a different clinical course of LTBL supported by typical MRI features in a Turkish patient who presented with a history of failure to walk. The EARS2 gene mutation analysis identified a c.322C>T transition, predicting a p.R108W change. This is the first reported early-onset mild type LTBL caused by a homozygous EARS2 mutation case in the literature.


Volumetric-modulated arc radiotherapy for pancreatic malignancies: dosimetric comparison with sliding-window intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy.
Volumetric-modulated arc radiotherapy (VMAT) is an iteration of intensity-modulated radiotherapy (IMRT), both of which deliver highly conformal dose distributions. Studies have shown the superiority of VMAT and IMRT in comparison with 3-dimensional conformal radiotherapy (3D-CRT) in planning target volume (PTV) coverage and organs-at-risk (OARs) sparing. This is the first study examining the benefits of VMAT in pancreatic cancer for doses more than 55.8 Gy. A planning study comparing 3D-CRT, IMRT, and VMAT was performed in 20 patients with pancreatic cancer. Treatments were planned for a 25-fraction delivery of 45 Gy to a large field followed by a reduced-volume 8-fraction external beam boost to 59.4 Gy in total. OARs and PTV doses, conformality index (CI) deviations from 1.0, monitor units (MUs) delivered, and isodose volumes were compared. IMRT and VMAT CI deviations from 1.0 for the large-field and the boost plans were equivalent (large field: 0.032 and 0.046, respectively; boost: 0.042 and 0.037, respectively; p > 0.05 for all comparisons). Both IMRT and VMAT CI deviations from 1.0 were statistically superior to 3D-CRT (large field: 0.217, boost: 0.177; p < 0.05 for all comparisons). VMAT showed reduction of the mean dose to the boost PTV (VMAT: 61.4 Gy, IMRT: 62.4 Gy, and 3D-CRT: 62.3 Gy; p < 0.05). The mean number of MUs per fraction was significantly lower for VMAT for both the large-field and the boost plans. VMAT delivery time was less than 3 minutes compared with 8 minutes for IMRT. Although no statistically significant dose reduction to the OARs was identified when comparing VMAT with IMRT, VMAT showed a reduction in the volumes of the 100% isodose line for the large-field plans. Dose escalation to 59.4 Gy in pancreatic cancer is dosimetrically feasible with shorter treatment times, fewer MUs delivered, and comparable CIs for VMAT when compared with IMRT.


Heme biosynthesis in a chicken hepatoma cell line (LMH): comparison with primary chick embryo liver cells (CELC).
5-Aminolevulinic acid synthase (ALA synthase), the rate-controlling enzyme of hepatic heme biosynthesis, is feed-back repressed by heme. In the liver, chemicals such as barbiturates markedly induce ALA synthase, especially in the presence of partial defects of heme biosynthesis. The inducibility and regulation of ALA synthase have been investigated using a variety of models, including intact animals and liver cell culture systems. A widely used model that closely approximates what occurs in vivo and in humans is that of primary cultures of chick embryo liver cells (CELCs). However, CELCs have some limitations: the cells obtained are somewhat heterogeneous; isolation and culture must be repeated every week resulting in weekly variations; and cells are short-lived limiting the feasibility of time-course and transfection studies. The aim of this study was to determine if LMH cells, a chick hepatoma cell line, are a good model comparable to that of CELCs. In both cells similar patterns of response of, ALA synthase activities and mRNA levels, and of porphyrin accumulation were obtained following treatments known to affect heme biosynthesis. Similarly, heme repressed ALA synthase mRNA levels in both cell types and ALA synthase activities in LMH cells. We conclude that LMH cells are a useful model for the study of hepatic heme biosynthesis and regulation of ALA synthase.


Identification of a novel potent CDK inhibitor degrading cyclinK with a superb activity to reverse trastuzumab-resistance in HER2-positive breast cancer in vivo.
CDK12 is overexpressed in HER2-positive breast cancers and promotes tumorigenesis and trastuzumab resistance. Thus CDK12 is a good therapeutic target for the HER2-positive breast tumors resistant to trastuzumab. We previously reported a novel purine-based CDK inhibitor with an ability to degrade cyclinK. Herein, we further explored and synthesized new derivatives, and identified a new potent pan-CDK inhibitor degrading cyclinK (32e). Compound 32e potently inhibited CDK12/cyclinK with IC50 = 3 nM, and suppressed the growth of the both trastuzumab-sensitive and trastuzumab-resistant HER2-positive breast cancer cell lines (GI50's = 9-21 nM), which is superior to a potent, clinical pan-CDK inhibitor dinaciclib. Moreover, 32e (10, 20 mg/kg, ip, twice a week) showed a dose-dependent inhibition of tumor growth and a more dramatic anti-cancer effect than dinaciclib in mouse in vivo orthotopic breast cancer model of trastuzumab-resistant HCC1954 cells. Kinome-wide inhibition profiling revealed that 32e at 1 μM exhibits a decent selectivity toward CDK-family kinases including CDK12 over other wildtype protein kinases. Quantitative global proteomic analysis of 32e-treated HCC1954 cells demonstrated that 32e also showed a decent selectivity in degrading cyclinK over other cyclins. Compound 32e could be developed as a drug for intractable trastuzumab-resistant HER2-positive breast cancers. Our current study would provide a useful insight in designing potent cyclinK degraders.