[Glycopolymers of Clavibacter michiganense and Pseudomonas solanacearum--interferon inducers].
A polysaccharide, being an active inductor of gamma-interferon, has been found among glycopolymers of Clavibacter michiganense. Lipopolysaccharide of Pseudomonas solanacearum is shown to display an interferonogenic activity which is analogous to that of the classical interferon inductor, lipopolysaccharide of Escherichia coli O55: B5. Besides lipid A, core oligosaccharide also contributes much to the interferonogenic activity of P. solanacearum lipopolysaccharide.


Association of the serum chemerin level with the development of diabetic retinopathy in patients with type 1 diabetes mellitus.
In patients with type 2 diabetes mellitus, the development of diabetic retinopathy (DR) correlates positively with elevated serum chemerin levels. This study was aimed at investigating the probable association between the serum chemerin level and the development of DR in patients with type 1 diabetes mellitus (T1DM). In this cross-sectional study, we included Egyptians and classified them into four groups: group 1, including healthy individuals; group 2, including patients with T1DM without DR; group 3, including patients with T1DM with non-proliferative DR (NPDR); and group 4, including patients with T1DM with proliferative DR (PDR). The assessment included best-corrected distance visual acuity assessment, slit-lamp biomicroscopy, funduscopy, fundus fluorescein angiography, and macular ocular coherence tomography. Fasting blood samples were obtained from all participants to measure serum chemerin, glycated hemoglobin (HbA1c), total cholesterol, triglyceride, and creatinine levels. Serum chemerin levels were compared among the groups, and their correlations with age, duration of diabetes, HbA1c, total cholesterol, triglyceride, and creatinine levels were analyzed. We recruited 209 participants, including 46 healthy individuals in group 1, 52 patients (T1DM and no DR) in group 2, 61 patients (T1DM and NPDR) in group 3, and 50 patients (T1DM and PDR) in group 4, with comparable mean ages and sex ratios among groups. The diabetes duration, body mass index, HbA1c, total cholesterol, triglyceride, and serum chemerin levels differed significantly among the groups (all P < 0.001), whereas the creatinine level did not (P > 0.05). The serum chemerin level was significantly higher in group 4 than in groups 3 and 2, in group 3 than in group 2, and in groups 3 and 4 than in group 1 (all P < 0.001). However, it was comparable between groups 1 and 2 (P > 0.05). It correlated with the duration of T1DM and HbA1c, total cholesterol, triglyceride, and creatinine levels but not with age. Patients with T1DM with DR showed higher serum chemerin levels than those with T1DM without DR or healthy individuals. Serum chemerin levels were higher in those with PDR than in those with NPDR. Thus, serum chemerin levels are a potential biomarker of the development and severity of DR in patients with T1DM. Nevertheless, future diagnostic accuracy studies are required to confirm these potential applications.


Effects of experimental muscle pain on electromyographic activity of masticatory muscles in the rat.
The aim of the present study was to investigate the effects of noxious chemical stimulation of a jaw muscle on postural electromyographic (EMG) activity from several masticatory muscles in lightly anesthetized rats. Unilateral injection of a substance known to induce acute muscle pain (5% NaCl) or longer duration of pain with inflammation (mustard oil) was made into the masseter muscle. The changes in EMG activity following the injection were recorded from the injected and contralateral masseter muscles and the ipsilateral digastric muscle. The algesic chemicals produced a significant but transient increase in EMG activity in all three muscles. The data from the present study and similar observations from clinical and experimental human studies suggest that increased activity from muscle nociceptors is not sufficient to produce a prolonged increase in postural EMG activity. Therefore, the development and maintenance of chronic jaw muscle pain does not appear to result from a feedback cycle mechanism.


Quantitative Assessment of COVID-19 Lung Disease Severity: A Segmentation-based Approach.
We present the use of mean Hounsfield units within lungs as a metric of disease severity for the comparison of image analysis models in patients with COPD and COVID. We used this metric to assess the performance of a novel 3D global context attention network for image segmentation that produces lung masks from thoracic HRCT scans. Results showed that the mean Hounsfield units enable a detailed comparison of our 3D implementation of the GC-Net model to the V-Net segmentation algorithm. We implemented a biomimetic data augmentation strategy and used a quantitative severity metric to assess its performance. Framing our investigation around lung segmentation for patients with respiratory diseases allows analysis of the strengths and weaknesses of the implemented models in this context.Clinical Relevance - Mean Hounsfield units within the lung volume can be used as an objective measure of respiratory disease severity for the comparison of CT scan analysis algorithms.


New and Emerging Therapies in the Management of Bladder Cancer.
The treatment landscape for bladder cancer has undergone a rapid evolution in the past five years with the approval of seven new agents. New classes of medications have improved outcomes for many patients who previously had limited treatment options, but there is still much to learn about how to optimize patient selection for these agents and the role of combination therapies. The aims of this review are to discuss these newly approved agents for bladder cancer and to feature promising drugs and combinations-including immune checkpoint inhibitors, targeted therapies, and antibody-drug conjugates-that are in development.


Expression of epidermal growth factor receptor, apomucins, matrix metalloproteinases, and p53 in rat and human cholangiocarcinoma: appraisal of an animal model of cholangiocarcinoma.
We sought to determine the expression of molecular markers in an animal model of cholangiocarcinoma compared with those in human cholangiocarcinoma. Cholangiocarcinoma is a rare disease characterized by early intrahepatic and extrahepatic spread, which seriously limits the efficacy of surgery. Establishing an experimental model to study the cholangiocarcinogenesis is desirable. Sprague-Dawley rats weighing 300 +/- 50 g were used for the study group. The animals were given 0.3% thioacetamide in tap water continuously. Thirty mass-forming peripheral cholangiocarcinoma patients also were studied. Expression of epidermal growth factor receptor (EGFR), MUC1, MUC2, MUC5AC, MMP-2, MMP-9, and p53 in both human and experimental rat cholangiocarcinoma was examined using immunohistochemistry. Using thioacetamide 0.3% as a hepatoxin to induce cholangiocarcinoma in rats, microfoci of cancerous cells were detected from 12 weeks, and all experimental rats displayed diffuse mass-forming cholangiocarcinoma after 24 weeks. EGFR was strongly expressed in 14 (47%) of 30 human cholangiocarcinoms and 24 (100%) of 24 rat cholangiocarcinomas, respectively. MUC1 was strongly expressed in all human and rat cholangiocarcinomas, whereas MUC2 and MUC5AC were focally and weakly expressed. MMP-2 and MMP-9 were strongly expressed in 22 (73%) of 30 human cholangiocarcinomas and 24 (100%) of 24 rat cholangiocarcinomas, respectively. p53 overexpression was detected in 9 (30%) of 30 human cholangiocarcinoma and none of the rat cholangiocarcinoma, respectively. The expression of EGFR, apomucins, MMPs, and p53 in rat cholangiocarcinoma was strongly homologous to human cholangiocarcinoma. Thioacetamide-induced cholangiocarcinoma in rats provides an excellent model for investigating cholangiocarcinogenesis in vivo.


Atrial Septal Defects Accelerate Pulmonary Hypertension Diagnoses in Premature Infants.
Between 4 and 16% of extremely premature infants have late pulmonary hypertension (PH) (onset >30 days of life), and infants with PH have a higher risk of tracheostomy and death. Atrial septal defects (ASD) increase pulmonary blood flow and may promote PH in at-risk infants. The objective of this study was to determine if infants with ASD develop PH sooner than those without ASD. Infants who were born at < 32 weeks' gestation, with an echocardiogram on day of life > 30, and without congenital anomalies were included. Infants with and without ASD were evaluated for the time to PH diagnosis, defined as the day of the first echocardiogram that showed PH. A multivariable model with ASD and significant variables on PH and a Cox proportional hazard model evaluating time to PH was determined. Of the 334 infants with echocardiograms, 57 had an ASD and 26% of these developed PH vs. 12% without ASD (p = 0.006). Infants with PH had lower gestational age (25.2 vs. 26.2 weeks, p = 0.005), smaller birthweight (699 vs. 816 gm, p = 0.001), and more prematurity complications than infants without PH. More PH infants had maternal African-American race (63.9 vs. 36.1%), right ventricular dysfunction (23.9 vs. 3.2%, p < 0.001), right ventricular dilation (52.1 vs. 8.6%, p < 0.001), or right ventricular hypertrophy (51.2 vs. 10.1%, p < 0.001), than infants without PH. At 150 days of life, 78.1% (95% CI 64.6-86.9%) of infants with ASD survived without PH, compared with 90.9% (95% CI 86.7-93.8%) of infants without ASD, and the unadjusted hazard for development of PH for infants with ASD was 2.37 (95% CI 1.29-4.36). When significant clinical variables were controlled, infants with ASD had a 2.44-fold (95% CI 1.27-4.68) increase in PH, compared with infants without ASD. Most PH in infants with or without ASD was diagnosed by day of life 150, but infants with ASD had an over 2-fold increased hazard for PH during their neonatal hospitalization. Premature infants with ASD should be followed closely for PH development and further studies to investigate the optimal timing of closure are needed.


Clearing the air and breathing freely: the health politics of air pollution and asthma.
This study examines the growing debate around environmental causes of asthma in the context of federal regulatory disputes, scientific controversy, and environmental justice activism. A multifaceted form of social discovery of the effect of air pollution on asthma has resulted from multipartner and multiorganizational approaches and from intersectoral policy that deals with social inequality and environmental justice. Scientists, activists, health voluntary organizations, and some government agencies and officials have identified various elements of the asthma and air pollution connection. To tackle these issues, they have worked through a variety of collaborations and across different sectors of environmental regulation, public health, health services, housing, transportation, and community development. The authors examine the role of activist groups in discovering the increased rates of asthma and framing it as a social and environmental issue; give an overview of the current knowledge base on air pollution and asthma, and the controversies within science; and situate that science in the regulatory debate, discussing the many challenges to the air quality researchers. They then examine the implications of the scientific and regulatory controversies over linking air pollution to increases in asthma. The article concludes with a discussion of how alliances between activists and scientists lead to new research strategies and innovations.


Antimicrobial susceptibility and susceptibility testing of Mycoplasma hominis: a review.
The determination of the minimal growth-inhibiting concentration (MIC), the minimal metabolism-inhibiting concentration (MMC), and the minimal mycoplasmacidal concentration (MCC) of various antimicrobial compounds for Mycoplasma hominis is influenced by the pH of the test media, the inoculum size, and the incubation time, although each of these factors generally do not affect the minimal concentration more than fourfold. M. hominis is resistant to beta-lactam antibiotics, vancomycin, sulfonamides, trimethoprim, and polymyxin B. There are great differences in the susceptibility of M. hominis to various macrolide antibiotics. Thus the organism is resistant to erythromycin and oleandomycin, moderately resistant to tylosin and spiramycin, susceptible to josamycin as well as to another macrolide drug, labelled M-4365G. M. hominis is also highly susceptible to the macrolide-like compound rosaramicin and to the tetracyclines (although resistant strains occur). It is susceptible to lincomycin and clindamycin, and moderately susceptible to chloramphenicol and rifampicin. The aminoglycosides have limited activity against M. hominis.


Individual variation in habituation: behaviour over time toward different stimuli in threespine sticklebacks (Gasterosteus aculeatus).
Habituation, or the relatively permanent waning of a response as a result of repeated stimulation, is a form of behavioural plasticity that allows animals to filter out irrelevant stimuli and to focus selectively on important stimuli. Individuals that fail to habituate might be at a disadvantage if they continue to respond to irrelevant stimuli; therefore, habituation can have adaptive significance. In this study we compared rates of behaviour over time toward three different ecologically-relevant stimuli (food, a male intruder and a gravid female) in threespine sticklebacks (Gasterosteus aculeatus). We detected evidence for habituation to the stimuli, and males in this study were especially aggressive toward both male and female conspecifics. Although there were some clear temporal patterns that could be detected by looking at average behaviour, not all individuals behaved in the same 'average' way. We detected substantial inter-individual variation in behaviour toward all three stimuli, inter-individual variation in rates of habituation to both male and female conspecifics, but no evidence for correlations between behaviours across stimuli (behavioural syndromes). These results suggest that individual animals vary in rates of habituation, and prompt hypotheses about the causes and consequences of variation in rates of habituation.


Neighborhood rough set reduction-based gene selection and prioritization for gene expression profile analysis and molecular cancer classification.
Selection of reliable cancer biomarkers is crucial for gene expression profile-based precise diagnosis of cancer type and successful treatment. However, current studies are confronted with overfitting and dimensionality curse in tumor classification and false positives in the identification of cancer biomarkers. Here, we developed a novel gene-ranking method based on neighborhood rough set reduction for molecular cancer classification based on gene expression profile. Comparison with other methods such as PAM, ClaNC, Kruskal-Wallis rank sum test, and Relief-F, our method shows that only few top-ranked genes could achieve higher tumor classification accuracy. Moreover, although the selected genes are not typical of known oncogenes, they are found to play a crucial role in the occurrence of tumor through searching the scientific literature and analyzing protein interaction partners, which may be used as candidate cancer biomarkers.


Characterizing Permutation-Based Combinatorial Optimization Problems in Fourier Space.
Comparing combinatorial optimization problems is a difficult task. They are defined using different criteria and terms: weights, flows, distances, etc. In spite of this apparent discrepancy, on many occasions, they tend to produce problem instances with similar properties. One avenue to compare different problems is to project them onto the same space, in order to have homogeneous representations. Expressing the problems in a unified framework could also lead to the discovery of theoretical properties or the design of new algorithms. This article proposes the use of the Fourier transform over the symmetric group as the tool to project different permutation-based combinatorial optimization problems onto the same space. Based on a previous study (Kondor, 2010), which characterized the Fourier coefficients of the quadratic assignment problem, we describe the Fourier coefficients of three other well-known problems: the symmetric and nonsymmetric traveling salesperson problem and the linear ordering problem. This transformation allows us to gain a better understanding of the intersection between the problems, as well as to bound their intrinsic dimension.


Tuberculosis innovations mean little if they cannot save lives.
The past decade has seen the emergence of new diagnostics and drugs for tuberculosis, a disease that kills over 1.8 million people each year. However, these new tools are yet to reach scale, and access remains a major challenge for patients in low and middle income countries. Urgent action is needed if we are committed to ending the TB epidemic. This means raising the level of ambition, embracing innovation, increasing financial investments, addressing implementation gaps, and ensuring that new technologies reach those who need them to survive. Otherwise, the promise of innovative technologies will never be realized.


Comparing Effects of Two Different Types of Nei-Guan Acupuncture Stimulation Devices in Reducing Postoperative Nausea and Vomiting.
To compare the effects of a relief band using transcutaneous electrical nerve stimulation with a wrist band using acupressure on the Nei-Guan acupuncture point to relieve postoperative nausea and vomiting (PONV) in patients who had undergone gynecologic surgery. A double-blinded randomized controlled trial. In total, 54 patients scheduled for gynecologic surgery under general anesthesia were included in this study. Assessments of PONV were performed 0, 2, 6, and 24 hours after discharge from the postanesthesia care unit. The severity of PONV was measured using the Rhodes' Index of Nausea, Vomiting and Retching and by recording the frequency of patient-requested antiemetic administration that is used to treat severe cases of PONV. The relief band reduced the severity of PONV and the need for antiemetic administration within the first 24 hours postsurgery. The results of this study support the use of a relief band when compared with a wrist band and with a control group to reduce PONV in women after gynecologic surgery.


Recent trends in teledermatology and teledermoscopy.
Teledermatology is a useful alternative where specialized dermatological assistance is not available and has been used successfully to support health professionals in a wide range of settings worldwide, in either an asynchronous store-and-forward format or a real-time video conferencing format. Teledermoscopy, which includes dermoscopic images in the teleconsultation, is another addition that improves remote assessments of pigmented lesions. A more recent variant is mobile teledermoscopy, which uses a smartphone to deliver the same type of service. Teledermoscopy's greatest strength may be as a triage and monitoring tool, as it can reduce the number of unnecessary referrals, wait times, and the cost of providing and receiving dermatological care. While face-to-face (FTF) care remains the gold standard for diagnosis, drawbacks of not using FTF care as the primary method can be mitigated if teleconsultants are willing to refer to FTF care whenever there is uncertainty. Teledermatology has generally been well accepted by patients and practitioners alike. Barriers to the large-scale use of teledermatology remain. Assigning medicolegal responsibility and instituting a reimbursement system are critical to promoting widespread use by medical professionals, while privacy and security features and a mechanism to link teleconsultations to patients' existing health records are essential to maximize patient benefit. Direct-to-consumer services also need attention from regulators to ensure that consumers can enjoy the benefits of telemedicine without the dangers of unregulated or untested platforms.


Designed multiple ligands: an emerging anti-HIV drug discovery paradigm.
Currently, the effect of AIDS single-target chemotherapy is severely compromised by the quick emergence of resistant HIV strains. Highly active antiretroviral therapy (HAART) combines HIV reverse transcriptase inhibitors with protease inhibitors or integrase inhibitors, and successfully suppresses HIV viral load to an undetectable level, dramatically improving the life quality of AIDS patients. However, the benefits of this approach are often compromised by poor patient compliance. Recently, there has been a move toward multicomponent drugs whereby two or more agents are coformulated in a single tablet to make dosing regimes simpler and thereby to improve patient compliance, but there are significant risks involved in the development of multicomponent drugs. Designed multiple ligands (DMLs) therapy as an emerging anti-HIV drug discovery paradigm, using a single entity to inhibit multitargets could yield improved patient compliance, thus reducing the likelihood of drug resistance. The exploration of such multifunctional ligands has proven valuable for anti-HIV leads discovery. However, presently many multifunctional scaffolds were first discovered by serendipity or screening; rational design by combining existing monofunctional scaffolds remains an enormous challenge. A key issue in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. This review of literature examples introduce numerous attractive lead compounds, capable of interfering with different stages of HIV infection and AIDS pathogenesis, which reveals trends and insights that might provide valuable clues for novel anti-HIV drug design and help medicinal chemists discover the next generation of multiple ligands.


[Contrast agent enhanced duplex ultrasonography: visualization of the hepatic artery after orthotopic liver transplantation].
A prospective study was carried out to determine whether an improved assessment of the anatomy and flow velocity in the hepatic artery could be achieved by the administration of a capillary transversing contrast agent (Levovist) in patients after orthotopic liver transplantation. In 21 (62%) of 34 patients after liver transplantation, only an insufficient visualisation of the hepatic artery was achieved. Therefore, a capillary transversing contrast agent was administered intravenously. Pre- and post-contrast peak velocity and Doppler frequency shift in the proper hepatic artery were measured and image quality of colour and spectral Doppler was assessed by a qualitative scale. Image quality, with complete visualisation of hepatic artery in 79% (precontrast 38%) of all cases, was significantly improved (p < 0.01 (Wilcoxon test)) by the administration of a contrast agent. Visualisation of the hepatic artery after orthotopic liver transplantation can be improved by the administration of Levovist. It allows a reliable measurement of peak velocity and Doppler frequency shift and helps to avoid further imaging.


Alma Ata after 40 years: Primary Health Care and Health for All-from consensus to complexity.
Forty years ago, the 134 national government members of the WHO signed the Alma Ata Declaration. The Declaration made Primary Health Care (PHC) the official health policy of all members countries. Emerging from the conference was the consensus that health was a human right based on the principles of equity and community participation. Alma Ata broadened the perception of health beyond doctors and hospitals to social determinants and social justice. In the following years implementing this policy confronted many challenges. These included: (1) whether PHC should focus on vertical disease programmes where interventions had the most possibility of success or on comprehensive programmes that addressed social, economic and political factors that influenced health improvements; (2) whether primary care and PHC are interchangeable approaches to health improvements; (3) how equity and community participation for health improvements would be institutionalised; and (4) how financing for PHC would be possible. Experiences in implementation over the last 40 years provide evidence of how these challenges have been met and what succeeded and what had failed. Lessons from these experiences include the need to understand PHC as a process rather than a blueprint, to understand the process must consider context, culture, politics, economics and social concerns, and therefore, to recognise the process is complex. PHC needs to be examined within evaluation frameworks that address complexity. Recent developments in monitoring and evaluation have begun to respond to this need. They include realist evaluation and implementation research.


Resveratrol Inhibits Wound Healing and Lens Fibrosis: A Putative Candidate for Posterior Capsule Opacification Prevention.
Posterior capsule opacification (PCO) is a common complication of cataract surgery. In addition to improved surgical methods and IOL designs, it is likely additional agents will be needed to improve patient outcomes. Presently no pharmacological agent is in clinical use to prevent PCO. Here we investigate the putative ability of resveratrol (RESV), a naturally occurring polyphenol, as a therapeutic agent. The human lens epithelial cell line FHL124, a human lens capsular bag model, and central anterior epithelium were used as experimental systems. Standard culture was in 5% fetal calf serum Eagle's minimum essential medium; 10 ng/mL transforming growth factor-β2 (TGFβ2) was used to induce fibrotic changes. A scratch wound assay was used to measure cell migration and the patch assay was used to assess matrix contraction by FHL124 cells. Protein expression was assessed by immunocytochemistry and Western blot and gene expression by quantitative RT-PCR. In capsular bags, cell growth across the posterior lens capsule, capsular wrinkling, and epithelial-to-mesenchymal transition were determined by image analysis. In FHL124 cells, addition of 30 μM RESV significantly impeded cell migration in a wound-healing assay. RESV significantly inhibited TGFβ2-induced expression of the myofibroblast marker alpha-smooth muscle actin (α-SMA) at both the message and protein levels, as well as significantly inhibiting matrix contraction induced by TGFβ2. In human capsular bags, 30 μM RESV significantly inhibited cell growth. TGFβ2-induced α-SMA expression and capsular wrinkling were also significantly inhibited by RESV treatment. RESV significantly suppressed expression of TGFβ2-induced genes associated with fibrotic disease, including matrix metalloproteinase-2 in FHL124 cells, capsular bags, and central anterior epithelium. RESV can counter PCO-related physiological events in two human lens model systems. RESV therefore has the potential to be used as a candidate agent for the prevention of PCO, which in turn could benefit millions of cataract patients.


Hip arthroscopy following contralateral total hip arthroplasty: a multicenter matched-pair study.
The purpose of this study was to determine if patients undergoing hip arthroscopy for labral pathology with contralateral total hip arthroplasty (THA) have a difference in revision surgeries or patient-reported outcomes (PROs) when compared with those patients undergoing hip arthroscopy for labral pathology with a native contralateral hip. A retrospective review was performed for patients that were undergoing hip arthroscopy between 2008 and 2015. Patients were included in the study group if they met the following inclusion criteria: Tönnis Grade 0 or 1, hip labral pathology, previous contralateral THA, and greater than 2-year follow-up with completion of all PROs or conversion to a THA. Exclusion criteria included the previous surgical history on ipsilateral hip, peritrochanteric or deep gluteal space arthroscopy performed concomitantly, or dysplasia [Lateral Center Edge Angle (LCEA) < 20°]. A 3:1 matched-pair study was conducted. Multiple PRO scores were recorded for both groups. There was no statistically significant difference in the modified Harris hip score, non-arthritic hip score, hip outcome score-sports specific sub-scale, visual analog pain score and patient satisfaction scores between both groups. However, the study group was noted to have six patients converted to THA (67%) at an average of 30 months post-operatively, compared with only four patients (15%) in the control group (P = 0.006). Hip arthroscopy cannot be currently recommended in patients who have undergone contralateral THA due to the high conversion to THA (67%).


Using an evidence-based approach to design large-scale programs to improve infant and young child feeding.
Global interest in scaling up nutrition outcomes has focused attention on the need for more effective programs to improve infant and young child feeding (IYCF). However there are few examples in the literature of comprehensive programs that have been systematically designed. To describe an evidence-based approach for designing large-scale yet tailored IYCF programs in varied country settings. Behavior change principles, epidemiological data, situational analysis, stakeholder consultations, formative research, and feasibility studies informed the design of IYCF programs delivered at scale in Bangladesh, Ethiopia, and Vietnam. Impact, scale, and sustainability objectives guided the choice of partners, service delivery platforms, and advocacy, systems strengthening, and communication strategies for reaching mothers and decision makers. All programs focused on the critical first 2 years of life, followed global World Health Organization and UNICEF guidelines for IYCF, and applied a common theory of change. Formative research, stakeholder consultations, trials of improved practices, and assessments of media habits were most useful for making program decisions. Opinion leader research, monitoring of the policy environment, and stakeholder analysis were key elements in the design of advocacy strategies. All programs found that setting measurable and explicit targets, strengthening systems to provide support for mothers, multichannel communication, and advocacy for opinion leaders were vital components in the design. A systematic, evidence-based collaborative approach can facilitate the design of comprehensive IYCF programs. Programs should also embed design flexibility to enable changes as new challenges and opportunities arise.


Testosterone uptake in the brainstem of a sound-producing fish.
Three nuclear areas in the medulla were implicated in the control of sound production in the oyster toadfish Opsanus tau. The sonic motor nucleus was labeled by retrograde transport of horseradish peroxidase injected into swimbladder sonic muscles, and an adjacent ventrolateral and a more anterior periventricular nucleus of the medulla were revealed by autoradiography with 3H-labeled testosterone. These androgen uptake sites occur in brainstem areas corresponding to areas predicted to contain the neural centers controlling the duration and fundamental frequency of the toadfish mating call.


Malignant transformation of phosphaturic mesenchymal tumor: a case report and literature review.
Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.


The accuracy of the physical examination for the detection of lower extremity peripheral arterial disease.
Peripheral arterial disease (PAD) is a major risk factor for adverse cardiovascular events. There has been a definite push for wider use of the ankle-brachial index (ABI) as a simple screening tool for PAD. Perhaps this has occurred to the detriment of a thorough physical examination. To assess the accuracy of the physical examination to detect clinically significant PAD compared with the ABI. PADfile, the PAD module of CARDIOfile (the Kingston Heart Clinic's cardiology database [Kingston, Ontario]), was searched for all patients who underwent peripheral arterial testing. Of 1619 patients, 1236 had all of the necessary data entered. Patients' lower limbs were divided into two groups: those with a normal ABI between 0.91 and 1.30, and those with an abnormal ABI of 0.90 or lower. Peripheral pulses were graded as either absent or present. Absent was graded as 0⁄3, present but reduced (1⁄3), normal (2⁄3) or bounding (3⁄3). Femoral bruits were graded as either present (1) or absent (0). Using the ABI as the gold standard, the sensitivity, specificity, negative predictive value (NPV), positive predictive value and overall accuracy were calculated for the dorsalis pedis pulse, the posterior tibial pulse, both pedal pulses, the presence or absence of a femoral bruit and, finally, for a combination of both pedal pulses and the presence or absence of a femoral bruit. In 1236 patients who underwent PAD testing and who underwent a complete peripheral vascular physical examination (all dorsalis pedis and posterior tibial pulses palpated and auscultation for a femoral bruit), the sensitivity, specificity, NPV, positive predictive value and accuracy for PAD were 58.2%, 98.3%, 94.9%, 81.1% and 93.8%, respectively. The clinical examination of the peripheral arterial foot pulses and the auscultation for a femoral bruit had a high degree of accuracy (93.8%) for the detection or exclusion of PAD compared with the ABI using the cut-off of 0.90 or lower. If both peripheral foot pulses are present in both lower limbs and there are no femoral bruits, the specificity and NPV of 98.3% and 94.9%, respectively, make the measurement of the ABI seem redundant. The emphasis in PAD detection should be redirected toward encouraging a thorough physical examination.


Postnatal sulfur dioxide exposure reversibly alters parasympathetic regulation of heart rate.
Perinatal sulfur dioxide exposure disrupts parasympathetic regulation of cardiovascular activity. Here, we examine the relative risks of prenatal versus postnatal exposure to the air pollutant and the reversibility of the cardiovascular effects. Two groups of animals were used for this study. For prenatal exposure, pregnant Sprague-Dawley dams were exposed to 5 parts per million sulfur dioxide for 1 hour daily throughout gestation and with their pups after birth to medical-grade air through 6 days postnatal. For postnatal exposure, dams were exposed to air, and after delivery along with their pups to 5 parts per million sulfur dioxide through postnatal day 6. ECGs were recorded from pups on postnatal day 5 to examine changes in heart rate. Whole-cell patch-clamp electrophysiology was used to examine changes in neurotransmission to cardiac vagal neurons in the nucleus ambiguus on sulfur dioxide exposure. Postnatal sulfur dioxide exposure diminished glutamatergic neurotransmission to cardiac vagal neurons by 40.9% and increased heart rate, whereas prenatal exposure altered neither of these properties. When postnatal exposure concluded on postnatal day 5, excitatory neurotransmission remained decreased through day 6 and returned to basal levels by day 7. ECGs showed that heart rate remained elevated through day 6 and recovered by day 7. On activation of the parasympathetic diving reflex, the response was significantly blunted by postnatal sulfur dioxide exposure through day 7 but recovered by day 8. Postnatal, but not prenatal, exposure to sulfur dioxide can disrupt parasympathetic regulation of cardiovascular activity. Neonates can recover from these effects within 2 to 3 days of discontinued exposure.


Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection.
Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses and the current H1N1 pandemic highlight the need for a more detailed understanding of influenza virus pathogenesis. To investigate the host transcriptional response induced by pathogenic influenza viruses, we used a functional-genomics approach to compare gene expression profiles in lungs from 129S6/SvEv mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203). Although the viruses reached similar titers in the lung and caused lethal infections, the mean time of death was 6 days for VN/1203-infected animals and 9 days for mice infected with the 1918 virus. VN/1203-infected animals also exhibited an earlier and more potent inflammatory response. This response included induction of genes encoding components of the inflammasome. VN/1203 was also able to disseminate to multiple organs, including the brain, which correlated with changes in the expression of genes associated with hematological functions and lipoxin biogenesis and signaling. Both viruses elicited expression of type I interferon (IFN)-regulated genes in wild-type mice and to a lesser extent in mice lacking the type I IFN receptor, suggesting alternative or redundant pathways for IFN signaling. Our findings suggest that VN/1203 is more pathogenic in mice as a consequence of several factors, including the early and sustained induction of the inflammatory response, the additive or synergistic effects of upregulated components of the immune response, and inhibition of lipoxin-mediated anti-inflammatory responses, which correlated with the ability of VN/1203 to disseminate to extrapulmonary organs.


Calcium and heterometallic manganese-calcium complexes supported by tripodal pyridine-carboxylate ligands: structural, EPR and theoretical investigations.
Carboxylate-bridged Mn(II)-Ca(II) complexes are potentially relevant for mimicking the first stages of the Oxygen-Evolving Complex (OEC) assembly process. Here, we report on new homonuclear Ca(II) and heteronuclear Mn(II)–Ca(II) complexes with carboxylate-functionalized tripodal tris(2-pyridylmethyl)amine ligands, the heptadentate H3tpaa, previously reported, and the new hexadentate H2tpada, containing respectively three and two carboxylate units. The mononuclear [Ca(Htpaa)(OH2)] (Ca1) and dinuclear [Ca(tpada)(OH2)2]2 (Ca2) calcium complexes, as well as the tetranuclear [{Mn(tpaa)}2{Ca(OH2)5(μ-OH2)}2][Mn(tpaa)]2 (Mn2Ca2·2Mn) and dinuclear [Mn(tpada)ClCa(OH2)2.67(MeOH)2.33]Cl (MnCa) heterometallic species have been structurally characterized; the syntheses of Ca1 and Mn2Ca2·2Mn being previously reported by us (Inorg. Chem., 2015, 54, 1283). The Mn(II) and Ca(II) are linked by two μ1,1-bridging carboxylates in MnCa, while only one μ1,3-carboxylate bridge connects each Ca2+ ion to each Mn(II) in Mn2Ca2. A variable number of water molecules (n = 1 to 7) are coordinated to Ca in all complexes, most of them being involved in hydrogen-bond networks, in analogy to what occurs in the photosystem II. All donor atoms of the tpaa3- and tpada2- ligands are coordinated to the Mn2+ ions, despite the unusually long distance between the Mn2+ ion and the tertiary amine imposed by the constraining nature of the ligands, as supported by theoretical calculations. Solid state EPR spectroscopy, in combination with DFT calculations, has also shown that the Ca2+ ion has an effect on the electronic parameters (zero field splitting) of the linked Mn(II) in the case of MnCa (μ1,1-carboxylate bridges). In Mn2Ca2 (μ1,3-carboxylate bridge) the Ca2+ ion induces only slight structural changes in the Mn coordination sphere.


Does the retinal pigment epithelium polarize the choriocapillaris?
Morphometric evaluation of choroidal capillaries from spontaneously hypertensive (SHR) rats with anatomically normal and severely dystrophic retinas reveals a marked polarization of endothelial fenestrations, endothelial cytoplasmic thickness, and endothelial cell nuclei. The mean density of fenestrations per unit endothelial length is greatest and the cytoplasmic thickness and number of nuclei is least in capillary sectors closest to the retinal pigment epithelium (RPE), with a statistically significant, continuous decrease in density of fenestrations and an increase in endothelial thickness and nuclear numbers in sectors progressively farther from the RPE. Abnormal capillaries derived from the retinal circulation and growing within the RPE also have fenestrations, but show no anatomic polarization. These results are consistent with the recently proposed hypothesis that a diffusible, trophic factor, produced by the RPE and secreted from its basal surface, modulates the structure of nearby vascular endothelial cells. However, the endothelial cells themselves probably also influence the structure of the RPE, since complex infoldings of the RPE plasma membrane, identical to those normally present in its basal surface, are also extensively present surrounding the abnormal intra-RPE capillaries.


Antibody responses to Haemophilus influenzae type B vaccines in men with human immunodeficiency virus infection.
Persons with human immunodeficiency virus (HIV) infection are at increased risk for serious infections caused by Haemophilus influenzae, yet there are few data on their antibody responses to the H. influenzae type b vaccines. We evaluated antibody responses in 248 men who were randomly assigned to receive a single dose of either the H. influenzae type b polysaccharide (PRP) vaccine or the polysaccharide-mutant diphtheria toxoid conjugate vaccine (PRP-CRM). The subjects were stratified into four groups: seronegative men (67 subjects), men with asymptomatic HIV infection (79), men with symptomatic HIV infection (47), and men with the acquired immunodeficiency syndrome (AIDS) (55). Before immunization, the subjects with AIDS had the lowest PRP-antibody titers; 40 percent had titers below the putative protective level (less than 0.15 micrograms per milliliter). In the seronegative subjects, those with asymptomatic HIV infection, and those with symptomatic HIV infection, the PRP-CRM vaccine led to a threefold greater increase in geometric mean antibody titers than did the PRP vaccine (P less than 0.01). However, the subjects with AIDS had a greater antibody response to the PRP vaccine. The antibody response of HIV-seropositive men to the PRP-CRM vaccine correlated significantly with the number of CD4 lymphocytes (r = 0.47, P less than 0.0001, as compared with r = -0.01 for the PRP vaccine). In these HIV-infected men, both vaccines elicited the dominant anti-PRP idiotype described previously in populations not infected with HIV. Immunization with the PRP-CRM conjugate vaccine early in the course of HIV infection is likely to confer protection against disease caused by H. influenzae type b.


Exploring expression data: identification and analysis of coexpressed genes.
Analysis procedures are needed to extract useful information from the large amount of gene expression data that is becoming available. This work describes a set of analytical tools and their application to yeast cell cycle data. The components of our approach are (1) a similarity measure that reduces the number of false positives, (2) a new clustering algorithm designed specifically for grouping gene expression patterns, and (3) an interactive graphical cluster analysis tool that allows user feedback and validation. We use the clusters generated by our algorithm to summarize genome-wide expression and to initiate supervised clustering of genes into biologically meaningful groups.


Factors associated with completion of childhood immunization in Malawi: a multilevel analysis of the 2015-16 Malawi demographic and health survey.
Between 2010 and 2015, the percentage of children 12-23 months of age who received full immunization in Malawi decreased from 81% to 76%, prompting us to investigate the factors associated with completion of childhood immunization in Malawi. Using data from the 2015-16 Malawi Demographic and Health Survey, generalized linear mixed models were applied on 3145 children 12-23 months of age nested within 850 communities. Complete immunization was defined as the child having received a Bacillus Calmette-Guerin, three doses of pentavalent vaccine, four doses of oral polio vaccine, three doses of pneumococcal vaccine, two doses of rotavirus vaccine and one dose of measles vaccine before their first birthday. Adjusted multilevel regression showed that children born to mothers with either none or one antenatal care visit (adjusted odds ratio [aOR] 0.56 [95% confidence interval {CI} 0.32 to 0.93]) and whose mothers had no card or no longer had a vaccination card (aOR 0.06 [95% CI 0.04 to 0.07]) were less likely to receive complete immunization. In addition, children from the poorest households (aOR 0.60 [95% CI 0.40 to 0.92]) and who resided in communities with a medium (aOR 0.73 [95% CI 0.53 to 0.98]) or high percentage (aOR 0.73 [95% CI 0.53 to 0.99]) of households that perceived the distance to the nearest health facility as a big problem had reduced odds of achieving complete immunization. Furthermore, the findings showed evidence of clustering effects of childhood complete immunization at the community level. Our findings show that a series of sociodemographic, health and contextual factors are associated with the completion of childhood vaccination. Therefore interventions that aim at increasing the completion of childhood immunization in Malawi should not only address individual needs, but should also consider contextual factors and the communities addressed in this study.


[Traces of blood. The significance of blood in criminology at the turn of the 19th century].
In late 19th and early 20th century, criminology became institutionalized as an independent branch of science. Methodologically it focused on the 'exact' methods of the natural sciences, but also it tried to integrate the methods of the humanities. This mix of methods becomes visible in the treatment of blood, which on the one hand was an object of then brand new methods of scientific analysis (identification of human blood by the biological or precipitin method), and on the other hand was analyzed as a product of the magic and superstitious mentalities of criminals. The methodical tension resulting from this epistemological crossbreeding did not disturb the criminologists, for whom the reconciliation of opposite ways of thinking and researching seemed to be possible. In this encyclopaedic analysis of blood early criminology tried to combine the anthropological exploration of vampirism with the chemical and microscopic detection of antibodies and haemoglobin, thus mirroring the positivistic optimism that was then prevalent.


Trusting our memories: dissociating the neural correlates of confidence in veridical versus illusory memories.
Although memory confidence and accuracy tend to be positively correlated, people sometimes remember with high confidence events that never happened. How can confidence correlate with accuracy but apply also to illusory memories? One possible explanation is that high confidence in veridical versus illusory memories depends on different neural mechanisms. The present study investigated this possibility using functional magnetic resonance imaging and a modified version of the Deese-Roediger-McDermott false-memory paradigm. Participants read short lists of categorized words, and brain activity was measured while they performed a recognition test with confidence rating. The study yielded three main findings. First, compared with low-confidence responses, high-confidence responses were associated with medial temporal lobe (MTL) activity in the case of true recognition but with frontoparietal activity in the case of false recognition. Second, these regions showed significant confidence-by-veridicality interactions. Finally, only MTL regions showed greater activity for high-confidence true recognition than for high-confidence false recognition, and only frontoparietal regions showed greater activity for high-confidence false recognition than for high-confidence true recognition. These findings indicate that confidence in true recognition is mediated primarily by a recollection-related MTL mechanism, whereas confidence in false recognition reflects mainly a familiarity-related frontoparietal mechanism. This account is consistent with the fuzzy trace theory of false recognition. Correlation analyses revealed that MTL and frontoparietal regions play complementary roles during episodic retrieval. In sum, the present study shows that when one focuses exclusively on high-confidence responses, the neural correlates of true and false memory are clearly different.


CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk.
Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolic activation of several procarcinogens including dietary and environmental nitrosamines, and the involvement of CYP2A6 in cancer development has been postulated. CYP2A6 phenotype was determined using caffeine as a probe drug in individuals participating in a case-control study of colorectal cancer (127 cases and 333 controls matched on age, gender, race, and geographic region). Conversion of the caffeine metabolite 1,7-dimethylxanthine (17X) to 1,7-dimethyl uric acid (17U) is catalyzed primarily by CYP2A6, and this activity can be assayed by comparison of urinary molar ratios of metabolites. Caffeine (200 mg) was administered to each participant, and a 4-5 h postadministration urine sample was collected. Urinary metabolites of caffeine were separated by high-performance liquid chromatography and quantified by comparison to authentic standards. We examined the distributions of the ratio, 17U:17X, according to subject characteristics among controls. In case-control comparisons, subjects in the medium and high tertiles of CYP2A6 activity had an increased risk of colorectal cancer compared with subjects with low activity. Odds ratios from a conditional logistic regression model for medium and high 17U:17X ratio were 2.0 (95% confidence interval, 1.1-3.7) and 2.6 (95% confidence interval, 1.5-4.5), respectively (P for trend = 0.001). CYP2A6 phenotype has not been compared previously between cancer cases and controls. We found a strong relationship between CYP2A6 activity, measured by urinary caffeine metabolite ratio, and colorectal cancer risk.


PREVALENCE AND RISK FACTORS FOR THE DEVELOPMENT OF PHYSICIAN-GRADED SUBRETINAL FIBROSIS IN EYES TREATED FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.
To assess the prevalence and incidence of and risk factors for subretinal fibrosis (SRFi) in eyes with neovascular age-related macular degeneration (nAMD) that underwent vascular endothelial growth factor inhibitor treatment for up to 10 years. A cross-sectional and longitudinal analysis was performed on data from a neovascular age-related macular degeneration registry. The presence and location of SRFi were graded by the treating practitioner. Visual acuity, lesion characteristics (type, morphology, and activity), and treatment administered at each visit was recorded. The prevalence of SRFi in 2,914 eyes rose from 20.4% at year interval 0-1 to 40.7% at year interval 9 to 10. The incidence in 1,950 eyes was 14.3% at baseline and 26.3% at 24 months. Independent characteristics associated with SRFi included poorer baseline vision (adjusted odds ratio 5.33 [95% confidence interval 4.66-7.61] for visual acuity ≤35 letters vs. visual acuity ≥70 letters, P < 0.01), baseline lesion size (adjusted odds ratio 1.08 [95% confidence interval 1.08-1.14] per 1000 µm, P = 0.03), lesion type (adjusted odds ratio 1.42 [95% confidence interval 1.17-1.72] for predominantly classic vs. occult lesions, P = 0.02), and proportion of active visits (adjusted odds ratio 1.58 [95% confidence interval 1.25-2.01] for the group with the highest level of activity vs. the lowest level of activity, P < 0.01). Subretinal fibrosis was found in 40% of eyes after 10 years of treatment. High rates of lesion activity, predominantly classic lesions, poor baseline vision, and larger lesion size seem to be independent risk factors for SRFi.


Self-Sustainable IoT-Based Remote Sensing Powered by Energy Harvesting Using Stacked Piezoelectric Transducer and Thermoelectric Generator.
We propose a self-powered remote multi-sensing system for traffic sensing which is powered by the collective energy harvested from the mechanical vibration of the road caused by the passing vehicles and from the temperature gradient between the asphalt of the road and the soil underneath. A stacked piezoelectric transducer converts mechanical vibrations into electrical energy and a thermoelectric generator harvests the thermal energy from the thermal gradient. Electrical energy signals from the stacked piezoelectric transducer and the thermoelectric generators are converted into usable DC power to recharge the battery using AC-DC and DC-DC converters working simultaneously. The multi-sensing system comprises an embedded system with a microcontroller that acquires data from the sensors and sends the sensory data to an IoT transceiver which transmits the data as RF packets to an ethernet gateway. The gateway converts the RF packets into Internet Protocol (IP) packets and sends them to a remote server. Laboratory and road-testing results showed over 98% sensory data accuracy with the system functioning solely powered by the energy harvested from the alternative energy sources. The successful maximum transmission distance obtained between the IoT, and the gateway was approximately 1 mile, which is a considerable transmission distance achieved in an urban environment. Successful operation of the self-powered multi-sensing system under both laboratory and road conditions contributes considerably to the fields of energy harvesting and self-powered remote sensing systems. The energy flow chart and efficiency for the steps in the system were found to be mechanical power from vehicles to the energy harvester of 0.25%, stacked PZT transducer efficiency was found to be 37%, and for the TEGs the efficiency is 11%. AC-to-DC and DC-to-DC converters' efficiencies were found to be 90% and 11%. The wireless communication RF transceiver efficiency was found to be 62.5%.


Submerged permanent teeth: literature review and case report.
Submerged permanent teeth pose a diagnostic as well as a treatment planning dilemma. Teeth with delayed eruption, arrested eruption, and paradoxical movement all can appear to be submerged teeth. While orthodontics may seem like the simplest solution, it often has the most frustrating results. A multidisciplinary approach often is required, utilizing surgical, orthodontic, and prosthetic components.


Lower mitotic activity in BRCA1/2-associated primary breast cancers occurring after risk-reducing salpingo-oophorectomy.
Risk-reducing salpingo-oophorectomy (RRSO) is associated with 50% reduction of BRCA1/2-associated breast cancer (BC) risk, possibly through decreased growth activity. In this pilot study, tumor characteristics and growth rates of BRCA1/2-associated primary BCs (PBCs) detected after RRSO were compared with those of PBCs originating without RRSO. From a cohort of 271 women with BRCA1/2-associated screen detected BC, we selected 20 patients with PBC detected ≥12 months after RRSO (RRSO group). Controls were 36 BRCA1/2 mutation carriers with PBC detected without RRSO (non-RRSO group) matched for age at diagnosis (± 2.5 y) and for BRCA1 or BRCA2 mutation. Pathology samples were revised for histological subtype, tumor differentiation grade, mitotic activity index (MAI), estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Tumor growth rates, expressed as tumor volume doubling times (DT), were calculated from revised magnetic resonance and mammographic images. Median age at PBC diagnosis was 52 y (range 35-67). PBCs after RRSO had lower MAIs (12 vs. 22 mitotic counts/2 mm, P = 0.02), were smaller (11 vs. 17 mm, P = 0.01), and tend to be PR-positive more often than PBCs without RRSO (38% vs. 13%, P = 0.07). Differentiation grade, ER, and HER2 status were not different. Median DT was 124 d (range 89-193) in the RRSO group and 93 days (range 54-253) in the non-RRSO group (P = 0.47). BC occurring after RRSO in BRCA mutation carriers features a lower MAI, suggesting a less aggressive biological phenotype. When confirmed in larger series, this may have consequences for BC screening protocols after RRSO.


Psychological assessment in XLMR: a proposal for setting international standards.
The need for an agreed upon set of standards for assessing individuals with XLMR was made quite evident this past year at the Fragile X and XLMR Workshop in Strasbourg. Several affected individuals from different families may have been incorrectly diagnosed as MR. Many factors can have a negative affect on IQ testing. As a result, evaluating individuals with cognitive deficits can be problematic. To be effective, psychological assessments must produce uniform results that are consistent with the definition of MR. Therefore, to foster international research in XLMR. I propose a two-stage standardized protocol. To determine which tests may be suitable. I review an assortment of instruments for psychological assessment at each stage, noting their strengths and weaknesses. Afterward, I present a set of standardized protocols based on age and language ability.


Getting New Test Results to Patients.
: New diagnostic results are constantly arriving to outpatient practices. It is imperative to effectively communicate these results and their implications to patients. We surveyed 100 patients and our clinic personnel to assess opinions regarding methods of communication in common scenarios. Response rate was 79% from patients and 75% from clinic personnel. Most patients thought letters were an appropriate way to receive normal test results (83%). They also felt medical-technician calls were appropriate for normal results (88%), medication dose changes (75%), or need for additional studies (71%). Respondents considered nurse calls acceptable in most scenarios except for new diagnoses of cancer or need for surgery; the consensus was that physicians should directly communicate to patients in these situations. Providers should take the time to discuss results with patients that lead to significant interventions, but employ support staff to disseminate information about normal results, medication dose changes, and need for additional diagnostic testing.


The International Conference on Intelligent Biology and Medicine (ICIBM) 2016: summary and innovation in genomics.
In this editorial, we first summarize the 2016 International Conference on Intelligent Biology and Medicine (ICIBM 2016) that was held on December 8-10, 2016 in Houston, Texas, USA, and then briefly introduce the ten research articles included in this supplement issue. ICIBM 2016 included four workshops or tutorials, four keynote lectures, four conference invited talks, eight concurrent scientific sessions and a poster session for 53 accepted abstracts, covering current topics in bioinformatics, systems biology, intelligent computing, and biomedical informatics. Through our call for papers, a total of 77 original manuscripts were submitted to ICIBM 2016. After peer review, 11 articles were selected in this special issue, covering topics such as single cell RNA-seq analysis method, genome sequence and variation analysis, bioinformatics method for vaccine development, and cancer genomics.


Characterization of epicardial-derived cardiac interstitial cells: differentiation and mobilization of heart fibroblast progenitors.
The non-muscular cells that populate the space found between cardiomyocyte fibers are known as 'cardiac interstitial cells' (CICs). CICs are heterogeneous in nature and include different cardiac progenitor/stem cells, cardiac fibroblasts and other cell types. Upon heart damage CICs soon respond by initiating a reparative response that transforms with time into extensive fibrosis and heart failure. Despite the biomedical relevance of CICs, controversy remains on the ontogenetic relationship existing between the different cell kinds homing at the cardiac interstitium, as well as on the molecular signals that regulate their differentiation, maturation, mutual interaction and role in adult cardiac homeostasis and disease. Our work focuses on the analysis of epicardial-derived cells, the first cell type that colonizes the cardiac interstitium. We present here a characterization and an experimental analysis of the differentiation potential and mobilization properties of a new cell line derived from mouse embryonic epicardium (EPIC). Our results indicate that these cells express some markers associated with cardiovascular stemness and retain part of the multipotent properties of embryonic epicardial derivatives, spontaneously differentiating into smooth muscle, and fibroblast/myofibroblast-like cells. Epicardium-derived cells are also shown to initiate a characteristic response to different growth factors, to display a characteristic proteolytic expression profile and to degrade biological matrices in 3D in vitro assays. Taken together, these data indicate that EPICs are relevant to the analysis of epicardial-derived CICs, and are a god model for the research on cardiac fibroblasts and the role these cells play in ventricular remodeling in both ischemic or non/ischemic myocardial disease.


Risk factors for appendiceal metastasis with epithelial ovarian cancer.
To investigate the risk factors for appendiceal metastasis of epithelial ovarian cancer and compare findings with the previous studies. One hundred and thirty-four patients with epithelial ovarian cancer were assessed in this study. All of them had undergone a surgical procedure including appendectomy. Of these, 21 (15.7%) patients who had appendiceal metastasis were analyzed as the case group and the patients with no metastasis were the controls, compared according to stage, grade, histology of tumor, preoperative Ca125 levels, presence of ascites, peritoneal cytology, diameter and site of tumor considered as risk factors. We found statistically significant differences between the groups in terms of stage, grade, right-sided tumor location, presence of ascites, diameter of tumor ≥ 10 cm and positive peritoneal cytology (p<0.05). In the logistic regression model, stage, grade, presence of ascites, right-sided location and diameter of tumor were independent risk factors. ROC curve analysis showed that stage, grade and diameter of the tumor were discriminative factors for appendiceal metastasis. In epithelial ovarian cancer, stage, grade, presence of ascites, right-sided location and large tumor size have importance for estimation of risk of appendiceal metastasis. As we compare our findings with previous studies, there is no definite recommendation for the risk factors of appendiceal metastasis in epithelial ovarian cancer and more studies are needed.


Factor XIII deficiency management: a review of the literature.
Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder estimated to affect 1 in 2 million live births. Treatment often involves prophylaxis with FXIII concentrate and is especially important in preventing intracranial hemorrhage (ICH) and maintaining pregnancy in women of childbearing age. The rarity of this condition and lack of good quality evidence has resulted in a literature largely based on case reports/case series. A review of the literature was conducted in order to provide information about the optimal management of FXIII deficiency. Articles were identified by searching MEDLINE from 1961 to June 2012. Eligible studies included details on patients with FXIII deficiency that received treatment. Information collected included dose, frequency, duration, hemostatic efficacy and adverse events. Of 606 abstracts reviewed, 43 articles, including a total of 328 patients met the selection criteria. Common bleeding manifestations included umbilical cord bleeding, ICH and hematomas. Patients were generally placed on prophylactic factor replacement therapy upon diagnosis of severe or symptomatic FXIII deficiency, which decreased and/or prevented bleeding episodes. Patients with FXIII deficiency that received prophylactic treatment successfully maintained pregnancies. Alternative treatments included the use of cryoprecipitate or frozen plasma when FXIII concentrate was not available or affordable. Recent studies of a new recombinant FXIII concentrate show promising results in regards to safety and efficacy. There are limited data to guide the optimal treatment of FXIII deficiency. Larger patient registries and international collaborations are needed to improve the evidence and enhance clinical outcomes in this rare bleeding disorder.


Awareness of Lebanese Pediatricians regarding Children's Oral Health.
Pediatricians have an important role in early identification and prevention of oral health, but they reported lack of knowledge in this field. the aim of the study is to evaluate the knowledge and attitudes of Lebanese pediatricians regarding children's oral health. A cross sectional study including 100 Lebanese pediatricians was performed. They answered 21 questions. Three variables were taken into consideration: The number of years in practice, the place and type of practice. 73.6% of pediatricians with more than 5 years in practice, 63.5% of pediatricians with an exclusive private practice and 74.7% of pediatricians working in cities/big villages believe that a child is able to brush properly his teeth before the age of 5 years. Only 27.6% of pediatricians with more than 5 years in practice, or working in cities/big villages and 12.7% of those having an exclusive private practice admit that white and black spots are signs of affected teeth. Majority of our pediatricians reported that bottle feeding is associated with early childhood caries. They do not believe that the maternal milk can harm the baby's teeth. Concerning the transmission from mother to child of the bacteria responsible for dental caries, the reported percentages were not statistically different in relation to pediatricians' years of experience, type and place of practice. Pediatricians who are academically affiliated were more likely to report that fluoride is safe compared to those practicing in the private sector (P = 0,012). The majority believe that there is a relation between systematic manifestation such as fever and eruption of primary teeth. The Lebanese pediatricians have an acceptable level of knowledge in children's oral health, but should be better informed and motivated toward dental and oral issues. Nassif N, Noueiri B, Bacho R, Kassak K. Awareness of Lebanese Pediatricians regarding Children's Oral Health. Int J Clin Pediatr Dent 2017;10(1):82-88.


Spectroscopy of BODIPY in solid phase: crystal and nanoparticles.
We compare the absorption and fluorescence spectra of single crystals and suspensions of nanoparticles with the prediction of the Frenkel theory. The single crystals of a novel synthesized fluorescent BODIPY derivative dye, adamantyl mesityl BODIPY (4,4-difluoro-3,5-di-(adamantyl)-8-mesityl-4-bora-3a,4a-diaza-s-indacene), have been prepared. Their birefringence and dichroism have been studied. The X-ray crystallography shows a monoclinic crystal with all transition moments parallel to one common plane. The refractive indices along the two neutral axes have been measured for a wavelength from 530 to 700 nm, with a difference, Δn equal to 0.11. The Frenkel exciton theory was used here to describe the coupling of the electronic excited states in the crystals. The coupling estimated by the dipolar approximation was compared with the excited state splitting calculated by TDDFT in dimers. A perfect crystal absorption spectrum is predicted. The spectral broadening that occurs at room temperature is also taken into account. The absorption spectrum of the monocrystal is reproduced without adjustable parameters. But we had to take into account the presence of optical leaks in our microspectrophotometer before comparing experiment and theory. The controlled size nanoparticles (NPs) produced by our 3D hydrodynamic focusing microfluidic system exhibit molecule like absorption. We could reproduce their absorption and fluorescence spectra assuming a strong disorder in the Frenkel model. We conclude that the nanoparticles are amorphous.


Proteomic profiling of N-linked glycoproteins identifies ConA-binding procathepsin D as a novel serum biomarker for hepatocellular carcinoma.
The aim of this study was to identify novel biomarkers for the diagnosis of, and potential therapeutic targets for, hepatocellular carcinoma (HCC). Multilectin affinity chromatography was used to enrich N-linked glycoproteins from nontumorous liver and HCC tissues followed by 2DE and protein identification by MS. Twenty-eight differentially expressed proteins were identified. Western blotting validated consistently lower concentrations of human liver carboxylesterase 1 and haptoglobin, and higher concentration of procathepsin D (pCD) in HCC tissues. Knockdown of cathepsin D (CD) expression mediated by siRNA significantly inhibited the in vitro invasion of two HCC cell lines, SNU449 and SNU473, which normally secrete high-levels of CD. Prefractionation using individual lectins demonstrated an elevation in ConA-binding glycoforms of proCD and CD in HCC tissues. In the serum of HCC patients, "ConA-binding proCD" (ConA-pCD) is significantly increased in concentration and this increase is comprised of several distinct upregulated acidic isoforms (pI 4.5-5.5). Receiver operating characteristic analysis showed that the sensitivity and specificity of serum ConA-pCD for HCC diagnosis were 85% and 80%, respectively. This is the first report that serum ConA-pCD is increased significantly in HCC and is potentially useful as a serological biomarker for diagnosis of HCC.


Studies on murine thyroiditis: new insights from organ flow cytometry.
The pathogenesis of autoimmune diseases is frequently studied in murine models, in which disease outcome is traditionally assessed by light microscopy. To determine whether digital imaging improves reliability of the histopathologic assessment, and whether flow cytometry is applicable directly on the murine thyroid, we studied 395 CBA/J mice 3 weeks after thyroglobulin immunization, and 192 nonimmunized CBA/J mice. Digital imaging significantly improved reliability of the histopathological assessment (r = 0.988, 95% confidence interval: 0.980-0.992, p < 0.0001), and flow cytometry on the murine thyroid could be performed successfully. We also found that normal thyroids contained a higher than expected number of hematopoietic cells in the interstitium. We suggest that digital imaging offers a better means of estimating disease outcome, and that flow cytometry performed at the target organ levels reflects the autoimmune pathogenesis more closely than when performed on peripheral lymphoid organs. These methods should also be applicable to other organ systems targeted by autoimmune attack, such as heart, exocrine, and other endocrine glands.


Food deprivation reduces sensitivity of liver Igf1 synthesis pathways to growth hormone in juvenile gopher rockfish (Sebastes carnatus).
Growth hormone (Gh) regulates growth in part by stimulating the liver to synthesize and release insulin-like growth factor-1 (Igf1), which then promotes somatic growth. However, for fish experiencing food limitation, elevated blood Gh can occur even with low circulating Igf1 and slow growth, suggesting that nutritional stress can alter the sensitivity of liver Igf1 synthesis pathways to Gh. Here, we examined how recent feeding experience affected Gh regulation of liver Igf1 synthesis pathways in juvenile gopher rockfish (Sebastes carnatus) to illuminate mechanisms underlying the nutritional modulation of Igf1 production. Juvenile gopher rockfish were maintained under conditions of feeding or complete food deprivation (fasting) for 14 d and then treated with recombinant sea bream (Sparus aurata) Gh or saline control. Gh upregulated hepatic igf1 mRNA levels in fed fish but not in fasted fish. The liver of fasted rockfish also showed a lower relative abundance of gene transcripts encoding teleost Gh receptors 1 (ghr1) and 2 (ghr2), as well as reduced protein levels of phosphorylated janus tyrosine kinase 2 (pJak2) and signal transducer and activator of transcription 5 (pStat5), which function to induce igf1 gene transcription following Gh binding to Gh receptors. Relative hepatic mRNA levels for suppressors of cytokine signaling (Socs) genes socs2, socs3a, and socs3b were also lower in fasted rockfish. Socs2 can suppress Gh activation of Jak2/Stat5, and fasting-related variation in socs expression may reflect modulated inhibitory control of igf1 gene transcription. Fasted rockfish also had elevated liver mRNA abundances for lipolytic hormone-sensitive lipase 1 (hsl1) and Igf binding proteins igfbp1a, -1b and -3a, reduced liver mRNAs encoding igfbp2b and an Igfbp acid labile subunit-like (igfals) gene, and higher transcript abundances for Igf1 receptors igf1ra and igf1rb in skeletal muscle. Together, these findings suggest that food deprivation impacts liver Igf1 responsiveness to Gh via multiple mechanisms that include a downregulation of hepatic Gh receptors, modulation of the intracellular Jak2/Stat5 transduction pathway, and possible shifts in Socs-inhibitory control of igf1 gene transcription, while also demonstrating that these changes occur in concert with shifts in liver Igfbp expression and muscle Gh/Igf1 signaling pathway components.


Optically induced long-period fiber gratings for guided mode conversion in few-mode fibers.
We propose and demonstrate guided mode conversion by an optically induced long-period fiber grating (OLPG). The beating of two guided modes excited by a nanosecond pulsed laser beam is used to induce a refractive index grating via the Kerr effect. This grating converts a counter-propagating continuous-wave beam from the LP(01) to the LP(11) mode. Numerical simulations using a beam propagation method show that a full conversion is possible. Experimentally, a mode conversion with an efficiency of about 50% is firstly demonstrated.


Fatty Acid-binding Proteins 1 and 2 Differentially Modulate the Activation of Peroxisome Proliferator-activated Receptor α in a Ligand-selective Manner.
Nuclear hormone receptors (NHRs) regulate the expression of proteins that control aspects of reproduction, development and metabolism, and are major therapeutic targets. However, NHRs are ubiquitous and participate in multiple physiological processes. Drugs that act at NHRs are therefore commonly restricted by toxicity, often at nontarget organs. For endogenous NHR ligands, intracellular lipid-binding proteins, including the fatty acid-binding proteins (FABPs), can chaperone ligands to the nucleus and promote NHR activation. Drugs also bind FABPs, raising the possibility that FABPs similarly regulate drug activity at the NHRs. Here, we investigate the ability of FABP1 and FABP2 (intracellular lipid-binding proteins that are highly expressed in tissues involved in lipid metabolism, including the liver and intestine) to influence drug-mediated activation of the lipid regulator peroxisome proliferator-activated receptor (PPAR) α. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARα activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARα. Nuclear accumulation of FABP on drug binding is driven largely by reduced nuclear egress rather than an increased rate of nuclear entry. Importin binding assays indicate that nuclear access occurs via an importin-independent mechanism. Together, the data suggest that specific drug-FABP complexes can interact with PPARα to effect nuclear accumulation of FABP and NHR activation. Because FABPs are expressed in a regionally selective manner, this may provide a means to tailor the patterns of NHR drug activation in a tissue-specific manner.


Patient, Family, and Clinician Perspectives on End-of-Life Care Quality Domains and Candidate Indicators for Adolescents and Young Adults With Cancer.
End-of-life care quality indicators specific to adolescents and young adults (AYAs) aged 12 to 39 years with cancer have not been developed. To identify priority domains for end-of-life care from the perspectives of AYAs, family caregivers, and clinicians, and to propose candidate quality indicators reflecting priorities. This qualitative study was conducted from December 6, 2018, to January 5, 2021, with no additional follow-up. In-depth interviews were conducted with patients, family caregivers, and clinicians and included a content analysis of resulting transcripts. A multidisciplinary advisory group translated priorities into proposed quality indicators. Interviews were conducted at the Dana-Farber Cancer Institute, Kaiser Permanente Northern California, Kaiser Permanente Southern California, and an AYA cancer support community (lacunaloft.org). Participants included 23 AYAs, 28 caregivers, and 29 clinicians. Stage IV or recurrent cancer. Care priorities. Interviews were conducted with 23 patients (mean [SD] age, 29.3 [7.3] years; 12 men [52%]; 18 White participants [78%]), 28 family caregivers (23 women [82%]; 14 White participants [50%]), and 29 clinicians (20 women [69%]; 13 White participants [45%]). Caregivers included 22 parents (79%), 5 spouses or partners (18%), and 1 other family member (4%); the 29 clinicians included 15 physicians (52%), 6 nurses or nurse practitioners (21%), and 8 social workers or psychologists (28%). Interviews identified 7 end-of-life priority domains: attention to physical symptoms, attention to quality of life, psychosocial and spiritual care, communication and decision-making, relationships with clinicians, care and treatment, and independence. Themes were consistent across the AYA age range and participant type. Although some domains were represented in quality indicators developed for adults, unique domains were identified, as well as AYA-specific manifestations of existing domains. For example, quality of life included global quality of life; attainment of life goals, legacy, and meaning; support of personal relationships; and normalcy. Within communication and decision-making, domains included communication early in the disease course, addressing prognosis and what to expect at the end of life, and opportunity for AYAs to hold desired roles in decision-making. Care and treatment domains relevant to cancer therapy, use of life-prolonging measures, and location of death emphasized the need for preference sensitivity rather than a standard path. This finding differs from existing adult indicators that propose that late-life chemotherapy, intensive measures, and hospital death should be rare. The findings of this qualitative study suggest that AYAs with cancer have priorities for care at the end of life that are not fully encompassed in existing indicators for adults. Use of new indicators for this young population may better reflect patient- and family-centered experiences of quality care.


Metformin and respiratory chain complex I: the last piece of the puzzle?
Metformin is the most widely prescribed drug used to treat patients affected by Type 2 diabetes. Metformin has also been shown to prevent some forms of cell death; however, evidence suggests that it may have anti-neoplastic properties. All of these effects have been attributed to complex I inhibition, but the mechanism by which metformin leads to complex I inhibition is not fully understood. Although it has been reported that the incubation of functionally isolated complex I in the presence of high concentrations of metformin led to its inhibition, much lower concentrations of metformin have been shown to inhibit complex I in intact cells. In a recent issue of the Biochemical Journal, Bridges, Jones, Pollak and Hirst [(2014) Biochem. J. 462, 475-487] studied for the first time the effect of metformin on purified complex I. They report that millimolar concentrations of metformin directly inhibit complex I activity in a non-competitive manner. They also specify that the binding of metformin to complex I depends on its conformation. To explain the difference in concentration required to inhibit complex I in intact cells and on isolated enzyme, Bridges et al. (2014) propose that metformin concentrates within mitochondria in intact cells. Albeit theoretically plausible, this attractive hypothesis is not directly tested by Bridges et al. (2014) Moreover, although sparse, the current literature does not support this hypothesis.


Prevention of postcataract endophthalmitis: evidence-based medicine.
To provide a summary of current peer-reviewed publications on the methods of prophylaxis against postcataract endophthalmitis. Preoperative application of povidone-iodine remains the standard protocol for the prevention of postoperative endophthalmitis. More recent evidence suggests that intracameral cefuroxime administered at the conclusion of surgery significantly reduces the risk of endophthalmitis. However, its clinical use has been limited because of a lack of commercially available antibiotic indicated for intraocular injection. Although topical antibiotic application continues to be a controversial topic with respect to the types of antibiotic prescribed and dosage, most ophthalmologists do prescribe an antibiotic for the perioperative period. Resistance against antibiotics, including the very popular classes of fluoroquinolones, is rising. Most notably, methicillin resistance continues to increase over time. Prevention of postcataract endophthalmitis remains a difficult topic to study given the low incidence. In addition to appropriate wound construction, a combination of povidone-iodine and antibiotics provide a reasonable approach in reducing the risk of this rare but serious infection.


Ribosomal acidic phosphoproteins P1 and P2 are not required for cell viability but regulate the pattern of protein expression in Saccharomyces cerevisiae.
Saccharomyces cerevisiae strains with either three inactivated genes (triple disruptants) or four inactivated genes (quadruple disruptants) encoding the four acidic ribosomal phosphoproteins, YP1 alpha, YP1 beta, YP2 alpha, and YP2 beta, present in this species have been obtained. Ribosomes from the triple disruptants and, obviously, those from the quadruple strain do not have bound P proteins. All disrupted strains are viable; however, they show a cold-sensitive phenotype, growing very poorly at 23 degrees C. Cell extracts from the quadruple-disruptant strain are about 30% as active as the control in protein synthesis assays and are stimulated by the addition of free acidic P proteins. Strains lacking acidic proteins do not have a higher suppressor activity than the parental strains, and cell extracts derived from the quadruple disruptant do not show a higher degree of misreading, indicating that the absence of acidic proteins does not affect the accuracy of the ribosomes. However, the patterns of protein expressed in the cells as well as in the cell-free protein system are affected by the absence of P proteins from the particles; a wild-type pattern is restored upon addition of exogenous P proteins to the cell extract. In addition, strains carrying P-protein-deficient ribosomes are unable to sporulate but recover this capacity upon transformation with one of the missing genes. These results indicate that acidic proteins are not an absolute requirement for protein synthesis but regulate the activity of the 60S subunit, affecting the translation of certain mRNAs differently.


Behavioral characterization and genetic analysis of the Drosophila melanogaster larval response to light as revealed by a novel individual assay.
A new assay was designed, named checker, that measures the individual response to light in the fruitfly Drosophila melanogaster larva. In this assay the Drosophila larva apparently modulates its pattern of locomotion when faced with a choice between a dark and lit environment by orienting its movement towards the dark environment. We show that, in this assay, a response to light can be measured as an increase in residence time in the dark versus the lit quadrant. Mutations that disrupt phototransduction in the adult Drosophila abolish the larval response to light, demonstrating that this larval visual function is similar to that of the adult fly. Similarly, no response to light was detected in strains where the larval visual system (photoreceptors and target area) was disrupted by a mutation in the homeobox containing gene sine oculis (so) gene. Ablation of photoreceptors by the targeted expression of the cell death gene hid under the control of the photoreceptor-specific transcription factor glass (gl) abolishes this response entirely. Finally, we demonstrate that this response to light can be mediated by rhodopsins other than the blue absorbing Rh1.


Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation.
The aim of this study was to determine the efficacy, safety, and immunosuppressant adherence in 125 stable liver transplant (LT) patients converted from twice-daily tacrolimus (TAC BID) to once-daily TAC (TAC OD). Tacrolimus trough levels, laboratory parameters, metabolic disorders, selected patient reported outcomes, and adverse events were assessed. Mean TAC trough level concentration was 6.1 ± 2.3 ng/ml at study entry, decreased to 5.5 ± 2.1 ng/ml (P = 0.016) and 5.5 ± 2.2 ng/ml (P = 0.019) after 1 and 2 weeks, respectively, and tended to equal the baseline value during further follow-up. At week 1, TAC concentrations were lower in 62.4% of patients and higher in 36.0% when compared with baseline. Renal and cardiovascular risk factors remained stable and no rejection episodes occurred over 12 months. Adverse events were consistent with the safety profile known from previous studies with TAC BID. Nonadherence measured by the "Basel Assessment of Adherence Scale to Immunosuppressives" was evident in 66.4% at study entry and decreased to 30.9% postconversion (P < 0.0001). Prevalence of nonadherence at baseline was significantly higher in patients converted >2 years after LT and in those ≤60 years of age. Conversion to TAC OD is safe, enhances immunosuppressant adherence and should be accompanied by a close TAC level monitoring during the initial period.


Electrochemical impacts complement light scattering techniques for in situ nanoparticle sizing.
We show that the electrochemical particle-impact technique (or 'nano-impacts') complements light scattering techniques for sizing both mono- and poly-disperse nanoparticles. It is found that established techniques - Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) - can accurately measure the diameters of '30 nm' silver particles assuming spherical shapes, but are unable to accurately size a smaller '20 nm' sample. In contrast, nano-impacts have a high accuracy (<5% error in effective diameters) and are able to size both individual '20 nm' and '30 nm' silver NPs in terms of the number of constituent atoms. Further study of a '20 nm and 30 nm' bimodal sample shows that the electrochemical technique resolves the two very similar sizes well, demonstrating accurate sizing regardless of particle size polydispersity, whereas due to inherent limitations of light scattering measurements this is not possible for DLS and NTA. Electrochemical sizing is concluded to offer significant attractions over light scattering methods.


Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages.
Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization.


New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials.
To evaluate the efficacy and safety of new oral anticoagulants (NOACs) in elderly adults. Meta-analyses of randomized clinical trials (RCTs). PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 1, 2001, through March 30, 2013. Elderly population (≥ 75) in RCTs comparing NOACs (rivaroxaban, apixaban, and dabigatran) with conventional therapy. Two authors reviewed the trials, and odds ratios (ORs) were calculated using a random effects model. Ten RCTs included 25,031 elderly participants. Risk of major or clinically relevant bleeding was not significantly different between NOACs and conventional therapy in elderly adults (OR = 1.02, 95% confidence interval = 0.73-1.43). Similar results were observed when comparing NOACs and pharmacologically active agents. In atrial fibrillation (AF) trials, NOACs were more effective than conventional therapy in prevention of stroke or systemic embolism in an elderly population with AF. In non-AF trials, NOACs also had a significantly lower risk of venous thromboembolism (VTE) or VTE-related death than conventional therapy in elderly adults. Analysis for individual NOACs showed that the NOAC was noninferior or more effective than conventional therapy for efficacy and safety outcomes. In participants of clinical trials aged 75 and older, NOACs did not cause excess bleeding and were associated with equal or greater efficacy than conventional therapy.


Luminescence and binding studies on tRNA-Phe.
The phenylalanine transfer RNA of baker's yeast (tRNA(Phe)) contains a base Y of unknown molecular structure next to the anticodon triplet. Since the base Y fluoresces at room temperature (lambda(max) = 431 nm), its emission properties offer a unique tool for studying conformational and binding properties of tRNA(Phe). The results obtained by these experiments include the following: (1) The quantum yield of fluorescence of Y in tRNA(Phe) (phiF) is 0.07 +/- 0.01 at high Mg(2+) concentrations (>10(-2)M) and about half that at 10(-3)M or less, indicating a [Mg(2+)]-dependent conformational change of the anticodon loop. (2) The fluorescence of Y isolated from tRNAPhe (Y(+)) is red-shifted by 15 nm compared to Y in tRNA(Phe) which suggests a stacked (more hydrophobic) environment for Y in the intact anticodon loop. phiF of Y(+) is 0.035. (3) The solvent isotope effect phiF(D(2)O)/phiF(H(2)O) is 1.5 for tRNA(Phe) and 1.9 for Y(+) i.e., Y in tRNA is still hydrated. (4) The temperature dependence of phiF in a polar glass shows that quenching occurs only at temperatures at which the glass has sufficiently low viscosity to permit solvent shell relaxation in the excited state. The low-temperature (80 degrees K) fluorescence is blue shifted (lambda(max) = 409 nm) and the phosphorescence has a decay time of 1.5 seconds, a threshold at 392 nm and a spectral shape like that of guanine. (5) In the presence of 10(-2)M Mg(2+) penta-uridylate, which contains the codon triplet, a small blue shift and a decrease in phiF are observed. This shift can be used to establish the formation of a binary complex between the codon and the anticodon with an association constant of 4 x 10(2)M(-1), approximately. A similar complex is formed with poly-uridylate but not with poly-cytidylate. In the absence of Mg(2+) the binary complex is not formed.


Magnetic response of split ring resonators (SRRs) at visible frequencies.
In this paper, we report on a substantial shift in the response of arrays of similarly sized Split Ring Resonators (SRRs), having a rectangular U-shaped form--and made respectively of aluminium and of gold. We also demonstrate that it is possible to obtain the polarization dependent LC peak in the visible spectrum--by using SRRs based on aluminium, rather than gold. The response of metallic SRRs scales linearly with size. At optical frequencies, metals stop behaving like nearly perfect conductors and begin displaying characteristically different behaviour, in accord with the Drude model. The response at higher frequencies, such as those in the visible and near infra-red, depends both on their size and on the individual properties of the metals used. A higher frequency limit has been observed in the polarization dependent response (in particular the LC resonance peak) of gold based SRRs in the near infrared region. By using aluminium based SRRs instead of gold, the higher frequency limit of the LC resonance can be further shifted into the visible spectrum.


Antithyroid Drug Therapy for Graves' Disease and Implications for Recurrence.
Graves' disease (GD) is the most common cause of hyperthyroidism worldwide. Current therapeutic options for GD include antithyroid drugs (ATD), radioactive iodine, and thyroidectomy. ATD treatment is generally well accepted by patients and clinicians due to some advantages including normalizing thyroid function in a short time, hardly causing hypothyroidism, and ameliorating immune disorder while avoiding radiation exposure and invasive procedures. However, the relatively high recurrence rate is a major concern for ATD treatment, which is associated with multiple influencing factors like clinical characteristics, treatment strategies, and genetic and environmental factors. Of these influencing factors, some are modifiable but some are nonmodifiable. The recurrence risk can be reduced by adjusting the modifiable factors as much as possible. The titration regimen for 12-18 months is the optimal strategy of ATD. Levothyroxine administration after successful ATD treatment was not recommended. The addition of immunosuppressive drugs might be helpful to decrease the recurrence rate of GD patients after ATD withdrawal, whereas further studies are needed to address the safety and efficacy. This paper reviewed the current knowledge of ATD treatment and mainly focused on influencing factors for recurrence in GD patients with ATD treatment.


Cellular heterogeneity in normal and neoplastic human urothelium: a study using murine monoclonal antibodies.
To assist in the description of the cellular heterogeneity present in normal and neoplastic urothelium, a panel of monoclonal antibodies (MoAbs) was raised against human transitional cell carcinoma (TCC) of the urinary bladder. All immunizations were carried out using whole cells and membrane preparations from well differentiated human TCCs. Two fusions produced 145 hybridomas. Following primary screening by ELISA and secondary screening with immunohistochemistry, three useful antibodies were identified. MoAb 35.48 binds to all cell layers of the normal urothelium and well differentiated tumours, but not to the majority of poorly differentiated tumours. MoAb 21.48 binds preferentially to the basal cell layer of normal urothelium and to some well differentiated papillary TCCs, but poorly differentiated tumours exhibit diffusely positive staining. MoAb 21.48 also shows cross-reactivity with basal cell layers of other epithelia. MoAb 5.48 binds preferentially to the superficial cell layers of normal urothelium and well differentiated TCCs, but exhibits less binding in poorly differentiated tumours with loss of the preferential superficial staining. Quantitative flow cytometric studies indicate that MoAb 5.48 binds to a cell-surface antigen which is present on significantly fewer cells of poorly differentiated tumours than on either normal urothelium (P less than 0.05), or well differentiated tumours (P = 0.05).