Eigenvalues of autocovariance matrix: A practical method to identify the Koopman eigenfrequencies.
To infer eigenvalues of the infinite-dimensional Koopman operator, we study the leading eigenvalues of the autocovariance matrix associated with a given observable of a dynamical system. For any observable f for which all the time-delayed autocovariance exist, we construct a Hilbert space H_{f} and a Koopman-like operator K that acts on H_{f}. We prove that the leading eigenvalues of the autocovariance matrix has one-to-one correspondence with the energy of f that is represented by the eigenvectors of K. The proof is associated to several representation theorems of isometric operators on a Hilbert space, and the weak-mixing property of the observables represented by the continuous spectrum. We also provide an alternative proof of the weakly mixing property. When f is an observable of an ergodic dynamical system which has a finite invariant measure μ, H_{f} coincides with closure in L^{2}(X,dμ) of Krylov subspace generated by f, and K coincides with the classical Koopman operator. The main theorem sheds light to the theoretical foundation of several semi-empirical methods, including singular spectrum analysis (SSA), data-adaptive harmonic analysis (DAHD), Hankel DMD, and Hankel alternative view of Koopman analysis (HAVOK). It shows that, when the system is ergodic and has finite invariant measure, the leading temporal empirical orthogonal functions indeed correspond to the Koopman eigenfrequencies. A theorem-based practical methodology is then proposed to identify the eigenfrequencies of K from a given time series. It builds on the fact that the convergence of the renormalized eigenvalues of the Gram matrix is a necessary and sufficient condition for the existence of K-eigenfrequencies. Numerical illustrating results on simple low dimensional systems and real interpolated ocean sea-surface height data are presented and discussed.


[Complete primary structure of Bacillus thuringiensis extracellular ribonuclease].
Complete primary structure of an extracellular low molecular mass ribonuclease of Bacillus thuringiensis was determined using Edman degradation and mass-spectrometry analysis of individual peptides obtained after hydrolysis of the protein by cyanogen bromide and staphylococcal protease. The peptides were isolated and purified by HPLC and denaturing PAGE. The enzyme consists of 109 amino acid residues (Asp 8, Asn 6, Thr 6, Ser 10, Glu 3, Gln 1, Pro 3, Gly 9, Ala 12, Val 7, Ile 7, Leu 7, Tyr 7, Phe 4, His 1, Arg 10, Trp 3 and Lys 5) and has a molecular weight of 12182 Da. A single difference was detected between primary structures of the enzyme and an extracellular ribonuclease of B. intermedius.


Transmission networks and ectoparasite mite burdens in Oecomys paricola (Rodentia: Cricetidae).
The host contact network structure results from the movement and behaviour of hosts (e.g. degree of sociability; vagility and greater or lesser fidelity of shelters), which can generate heterogeneity in the transmission of parasites and influence the parasitic burden of individual hosts. In the current study, we tested the hypothesis that the burdens of Gigantolaelaps oudemansi mites are related to the characteristics of the transmission networks of individuals of Oecomys paricola, a solitary rodent. The study was carried out in a savannah habitat in north-eastern Brazil. In the dry season, the rodent network presented sub-groups of rodent individuals interacting with each other, whereas in the wet season, no modules were formed in the network. Mite burden was positively related to the number of connections that an individual host had with other host individuals in the dry season. The pairwise absolute difference between the mean mite burdens among individual rodents was negatively correlated with the similarities of node interactions. No relationships were observed during the wet season. There was a higher heterogeneity of mite burden among hosts in the dry season compare to that in the wet season. In solitary species, spatial organization may show seasonal variation, causing a change in the opportunities of host contacts, thereby influencing the transmission and dispersion of their ectoparasite burdens.


XFEL Microcrystallography of Self-Assembling Silver n-Alkanethiolates.
New synthetic hybrid materials and their increasing complexity have placed growing demands on crystal growth for single-crystal X-ray diffraction analysis. Unfortunately, not all chemical systems are conducive to the isolation of single crystals for traditional characterization. Here, small-molecule serial femtosecond crystallography (smSFX) at atomic resolution (0.833 Å) is employed to characterize microcrystalline silver n-alkanethiolates with various alkyl chain lengths at X-ray free electron laser facilities, resolving long-standing controversies regarding the atomic connectivity and odd-even effects of layer stacking. smSFX provides high-quality crystal structures directly from the powder of the true unknowns, a capability that is particularly useful for systems having notoriously small or defective crystals. We present crystal structures of silver n-butanethiolate (C4), silver n-hexanethiolate (C6), and silver n-nonanethiolate (C9). We show that an odd-even effect originates from the orientation of the terminal methyl group and its role in packing efficiency. We also propose a secondary odd-even effect involving multiple mosaic blocks in the crystals containing even-numbered chains, identified by selected-area electron diffraction measurements. We conclude with a discussion of the merits of the synthetic preparation for the preparation of microdiffraction specimens and compare the long-range order in these crystals to that of self-assembled monolayers.


[Indications for surgical and medical treatment of coronary artery disease (author's transl)].
The following effects in treatment of coronary artery disease are desired: 1. Elimination or improvement of angina. 2. Improvement of physical capacity. 3. Prevention of imminent complications (myocardial infarct, cardiac arrhythmias, heart failure, embolism). 4. Elimination or diminuation of risk factors. 5. Prolongation of life. - In a critical survey concerning long-term studies of patients with aorto-coronary bypass or medical treatment in the literature subtile lists of indications for surgical and conservative treatment are put up (Table II and III), illustrated by case reports. - Useful criteria for diagnosis, follow-up, and prognosis are selective coronary angiography, ventriculography as well as determination of the coronary reserve (Argon Method). Indication for aorto-coronary bypass and resection of myocardial aneurysms are presented. Principles of medical treatment are: 1. Diminuation of myocardial oxygen requirement (release of pressure, economisation of work load, recompensation, regulation of arrhythmias) and 2. improvement of myocardial oxygen supply (Diminuation of coronary perfusion resistance including prevention and treatment of atherosclerosis). Indication for various medications are discussed (nitrites, beta-adrenergic blocking agents and antihypertensive drugs, glycosides, medication for arrhythmias, coronary dilatators, anticoagulants, and lipotropic substances). Their mode of action is debated and documented by own results. Present possibilities and limits in treatment of coronary artery disease are presented.


Staphylococcus epidermidis MSCRAMM SesJ Is Encoded in Composite Islands.
Staphylococcus epidermidis is a leading cause of nosocomial infections in patients with a compromised immune system and/or an implanted medical device. Seventy to 90% of S. epidermidis clinical isolates are methicillin resistant and carry the mecA gene, present in a mobile genetic element (MGE) called the staphylococcal cassette chromosome mec (SCCmec) element. Along with the presence of antibiotic and heavy metal resistance genes, MGEs can also contain genes encoding secreted or cell wall-anchored virulence factors. In our earlier studies of S. epidermidis clinical isolates, we discovered S. epidermidis surface protein J (SesJ), a prototype of a recently discovered subfamily of the microbial surface component recognizing adhesive matrix molecule (MSCRAMM) group. MSCRAMMs are major virulence factors of pathogenic Gram-positive bacteria. Here, we report that the sesJ gene is always accompanied by two glycosyltransferase genes, gtfA and gtfB, and is present in two MGEs, called the arginine catabolic mobile element (ACME) and the staphylococcal cassette chromosome (SCC) element. The presence of the sesJ gene was associated with the left-hand direct repeat DR_B or DR_E. When inserted via DR_E, the sesJ gene was encoded in the SCC element. When inserted via DR_B, the sesJ gene was accompanied by the genes for the type 1 restriction modification system and was encoded in the ACME. Additionally, the SCC element and ACME carry different isoforms of the SesJ protein. To date, the genes encoding MSCRAMMs have been seen to be located in the bacterial core genome. Here, we report the presence of an MSCRAMM in an MGE in S. epidermidis clinical isolates.IMPORTANCES. epidermidis is an opportunistic bacterium that has established itself as a successful nosocomial pathogen. The modern era of novel therapeutics and medical devices has extended the longevity of human life, but at the same time, we also witness the evolution of pathogens to adapt to newly available niches in the host. Increasing antibiotic resistance among pathogens provides an example of such pathogen adaptation. With limited opportunities to modify the core genome, most of the adaptation occurs by acquiring new genes, such as virulence factors and antibiotic resistance determinants present in MGEs. In this study, we describe that the sesJ gene, encoding a recently discovered cell wall-anchored protein in S. epidermidis, is present in both ACME and the SCC element. The presence of virulence factors in MGEs can influence the virulence potential of a specific strain. Therefore, it is critical to study the virulence factors found in MGEs in emerging pathogenic bacteria or strains to understand the mechanisms used by these bacteria to cause infections.


Thermo- and pH-dual responsive polymeric micelles with upper critical solution temperature behavior for photoacoustic imaging-guided synergistic chemo-photothermal therapy against subcutaneous and metastatic breast tumors.
Chemo-photothermal therapy shows great potential for inhibiting tumor growth. However, achieving maximal chemo-photothermal synergistic efficacy is challenging because of the low efficiency of controllable chemo-drug release in response to external or internal triggers. Thus, a nano-delivery system that could effectively achieve photothermal therapy and dual stimuli-responsive (heat and pH) drug release to inhibit both primary breast tumor growth and metastases is required. Methods: Herein, a thermo- and pH-responsive polymer (mPEG-PAAV) with an upper critical solution temperature (UCST) was synthesized to fabricate a DOX- and IR780-loaded micellar system. After systematic studies of the photothermal performance and controllable drug release of mPEG-PAAV micelles/IR780+DOX under NIR irradiation at different pH values, their chemo-photothermal synergetic therapy efficacies were also estimated both in in vitro and in vivo. Results: Because of the photothermal conversion of mPEG-PAAV micelle/IR780+DOX (~200 nm, 3.82 mV), high local temperature could be induced at the tumor site under NIR laser irradiation. This hyperthermia not only produced an enhanced tumor necrosis, but also broke down the micelles under the decreased pH environment, resulting in rapid DOX release and enhanced intracellular drug accumulation after NIR laser irradiation. In addition, photoacoustic imaging (PAI) of mPEG-PAAV/IR780+DOX micelle was adopted to monitor the morphology and micro-vascular distribution of the tumor tissue, which could also guide the chemo-photothermal therapy. Most importantly, the systemic administration of mPEG-PAAV micelles/IR780+DOX combined with NIR laser irradiation could simultaneously eliminate the 4T1 breast tumor and thoroughly suppress lung metastasis without any obvious adverse effects. Conclusion: Herein, a pH- and thermo-dual responsive UCST micelle system was developed for delivering IR780 and DOX, which could achieve NIR laser-controlled drug release and PA imaging guidance for chemo-photothermal synergistic therapy of both primary breast tumors and their metastases.


The experiences of students with intellectual and developmental disabilities, parents, and teachers regarding health self-advocacy program with school-home connection: a qualitative study.
Despite the importance of health as a significant indicator of quality of life, individuals with intellectual and developmental disabilities (IDD) often face low expectations, stigma, and insufficient opportunities in health care and education. In response, we developed a health self-advocacy program with a school-home connection for students with IDD to promote self-directed health care and verified its effectiveness by implementing the program for students with IDD. This study aimed to explore participants' program experiences and support needs to reduce the stigma surrounding individuals with IDD and provide implications for enhancing health self-advocacy skills. Individual and focus group interviews were conducted with 14 students, six parents, and four teachers who participated in the program. The collected data were analyzed using the constant comparative method. The following five main themes emerged: (a) the gap between perception and practice in health care; (b) advantages and influencing factors of the program; (c) challenges in program implementation; (d) outcomes of program implementation; and (e) support needs for promoting health self-advocacy. Based on these findings, implications are provided and discussed to reduce the stigma surrounding individuals with IDD and enhance health self-advocacy.


Synthesis of (Z)-(arylamino)-pyrazolyl/isoxazolyl-2-propenones as tubulin targeting anticancer agents and apoptotic inducers.
A new class of pyrazole and isoxazole conjugates were synthesized and evaluated for their cytotoxic activity against various human cancer cell lines. These compounds have shown significant cytotoxicity with lower IC50 values. FACS results revealed that A549 cells treated with these compounds arrested cells at the G2/M phase of the cell cycle apart from activating cyclin B1 protein levels. Particularly, compounds 9a and 9b demonstrated a remarkable inhibitory effect on tubulin polymerization and showed a pronounced inhibitory effect on tubulin polymerization with IC50 values of 1.28 μM and 0.28 μM respectively, whereas nocodazole, a positive control, has shown lower antitubulin activity with an IC50 value of 2.64 μM. Furthermore, these compounds induced apoptosis by loss of mitochondrial membrane potential, propidium iodide (PI) staining and the activation of caspase-3. Results of a fluorescence based competitive colchicine binding assay suggest that these conjugates bind successfully at the colchicine binding site of tubulin. These investigations reveal that such conjugates containing pyrazole with a trimethoxy phenyl ring and indole moieties have potential for the development of newer chemotherapeutic agents.


Bacillus pumilus plasmid pPL10: properties and insertion into Bacillus subtilis 168 by transformation.
Bacillus pumilus ATCC 12140 harbors 10 or more copies per chromosome of each two small plasmids. Variants of this strain were isolated which were sensitive to a killing activity produced by the plasmid-containing parent. Each of 24 such sensitive (S) variants tested lacked detectable levels of supercoiled deoxyribonucleic acid. Transduction of S variants to the Kill+ phenotype was performed using phage PBP1 propagated on a mutant of ATCC 12140, designated strain L10, that remained Kill+ but retained only a single plasmid species (plasmid pPL10; molecular weight, approximately 4.4 X 10(6), approximately 20 copies per chromosome; RHO = 1.698). Resulting Kill+ transductants of S variants contained a single plasmid species having a size and copy number comparable to that of pPL10. Transfer of pPL10 from strain L10 TO B. pumilus strain NRS 576 was accomplished by transduction with selection for the Kill+ phenotype. Strain NRS 576 naturally harbors about two copies per chromosome of a 28-million-dalton plasmid, pPL576. In Kill + transductants of NRS 576, plasmids pPL10 and pPL576 stably coexisted at a ratio of about 11 molecules of pPL10 to 1 molecule of pPL576. Therefore, pPL576 and pPL10 are compatible plasmids. B. subtilis 168 is naturally resistant to pPl10- determined killing activity. Plasmid pPl10 was therefore inserted into B-subtilis 168 by transformation, using an indirect selection procedure and a spoB mutant as recipient. The plasmid is stably maintained at an estimated 10 copies per chromosome in the spore- recipient and in spore+ transformants. pPL10 is sensitive to cleavage by the endonucleases Hind III and EcoR1.


Sustained Improvement of Arterial Stiffness and Blood Pressure after Long-Term Rosuvastatin Treatment in Patients with Inflammatory Joint Diseases: Results from the RORA-AS Study.
Patients with inflammatory joint diseases (IJD) have a high prevalence of hypertension and increased arterial stiffness. The aim of the present study was to evaluate the effect of long-term rosuvastatin treatment on arterial stiffness, measured by augmentation index (AIx) and aortic pulse wave velocity (aPWV), and blood pressure (BP) in IJD patients with established atherosclerosis. Eighty-nine statin naïve IJD patients with carotid atherosclerotic plaque(s) (rheumatoid arthritis n = 55, ankylosing spondylitis n = 23, psoriatic arthritis n = 11) received rosuvastatin for 18 months to achieve low-density lipoprotein cholesterol goal ≤1.8 mmol/L. Change in AIx (ΔAIx), aPWV (ΔaPWV), systolic BP (ΔsBP) and diastolic BP (ΔdBP) from baseline to study end was assessed by paired samples t-tests. Linear regression was applied to evaluate associations between cardiovascular disease (CVD) risk factors, rheumatic disease specific variables and medication, and ΔAIx, ΔaPWV, ΔsBP and ΔdBP. AIx, aPWV, sBP and dBP were significantly reduced from baseline to study end. The mean (95%CI) changes were: ΔAIx: -0.34 (-0.03, -0.65)% (p = 0.03), ΔaPWV: -1.69 (-0.21, -3.17) m/s2 (p = 0.03), ΔsBP: -5.27 (-1.61, -8.93) mmHg (p = 0.004) and ΔdBP -2.93 (-0.86, -5.00) mmHg (p = 0.01). In linear regression models, ∆aPWV was significantly correlated with ΔsBP and ΔdBP (for all: p<0.001). There is an unmet need of studies evaluating CVD prevention in IJD patients. We have shown for the first time that long-term intensive lipid lowering with rosuvastatin improved arterial stiffness and induced a clinically significant BP reduction in patients with IJD. These improvements were linearly correlated and may represent novel insight into the pleiotropic effects by statins. ClinicalTrials.gov NCT01389388.


Room-temperature ferromagnetism in (Zn1-xMnx)GeP2 semiconductors.
We report on the discovery of a room-temperature ferromagnetic semiconductor in chalcopyrite (Zn1-xMnx)GeP2 with Tc = 312 K. We have also observed that, at temperatures below 47 K, samples for x = 0.056 and 0.2 show a transition to the antiferromagnetic (AFM) state, so that ferromagnetism is well defined to be present between 47 and 312 K. The observation that the AFM phase is most stable at low temperatures is consistent with the predictions of full-potential linearized augmented plane wave total energy calculations and has consequences for other chalcopyrite materials.


Microglia Response During Parkinson's Disease: Alpha-Synuclein Intervention.
The discovery of the central role played by the protein alpha-synuclein in Parkinson's disease and other Lewy body brain disorders has had a great relevance in the understanding of the degenerative process occurring in these diseases. In addition, during the last two decades, the evidence suggesting an immune response in Parkinson's disease patients have multiplied. The role of the immune system in the disease is supported by data from genetic studies and patients, as well as from laboratory animal models and cell cultures. In the immune response, the microglia, the immune cell of the brain, will have a determinant role. Interestingly, alpha-synuclein is suggested to have a central function not only in the neuronal events occurring in Parkinson's disease, but also in the immune response during the disease. Numerous studies have shown that alpha-synuclein can act directly on immune cells, such as microglia in brain, initiating a sterile response that will have consequences for the neuronal health and that could also translate in a peripheral immune response. In parallel, microglia should also act clearing alpha-synuclein thus avoiding an overabundance of the protein, which is crucial to the disease progression. Therefore, the microglia response in each moment will have significant consequences for the neuronal fate. Here we will review the literature addressing the microglia response in Parkinson's disease with an especial focus on the protein alpha-synuclein. We will also reflect upon the limitations of the studies carried so far and in the therapeutic possibilities opened based on these recent findings.


Increased phonon scattering by nanograins and point defects in nanostructured silicon with a low concentration of germanium.
The mechanism for phonon scattering by nanostructures and by point defects in nanostructured silicon (Si) and the silicon germanium (Ge) alloy and their thermoelectric properties are investigated. We found that the thermal conductivity is reduced by a factor of 10 in nanostructured Si in comparison with bulk crystalline Si. However, nanosize interfaces are not as effective as point defects in scattering phonons with wavelengths shorter than 1 nm. We further found that a 5 at. % Ge replacing Si is very efficient in scattering phonons shorter than 1 nm, resulting in a further thermal conductivity reduction by a factor of 2, thereby leading to a thermoelectric figure of merit 0.95 for Si95Ge5, similar to that of large grained Si80Ge20 alloys.


Design of a multi-epitope protein vaccine against herpes simplex virus, human papillomavirus and Chlamydia trachomatis as the main causes of sexually transmitted diseases.
Sexually transmitted diseases (STDs) have a profound effect on reproductivity and sexual health worldwide. According to world health organization (WHO) 375 million new case of STD, including chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae, HSV, HPV has been reported in 2016. More than 30 diverse pathogenesis have identified to be transmitted through sexual intercourse. Of these, viral infections (hepatitis B, herpes simplex virus (HSV or herpes), HIV, and human papillomavirus (HPV) are incurable. However, symptoms caused by the incurable viral infections can be alleviated through treatment. Antimicrobial resistance (AMR) of sexually transmitted infections (STIs) to antibiotics has increased recent years, in this regard, vaccination is proposed as an important strategy for prevention or treatment of STDs. Vaccine against HPV 16 and 18 suggests a new approach for controlling STDs but until now, there is no prophylactic or therapeutic vaccine have been approved for HSV-2 and Chlamydia trachomatis (CT); in this reason, developing an efficient vaccine is inevitable. Recently, different combinatorial forms of subunit vaccines against two or three type of bacteria have been designed. In this study, to design a combinatorial vaccine against HSV, CT, and HPV, the E7 and L2 from HPV, glycoprotein D from HSV-2 and ompA from CT were selected as final antigens. Afterward, the immunodominant helper T lymphocytes (HTLs) and cytolytic T lymphocytes (CTLs) epitopes were chosen from aforesaid antigens. P30 (tetanus toxoid epitope) as universal T-helper were also added to the vaccine. Moreover, flagellin D1/D0 as TLR5 agonist and the RS09 as a TLR4 ligand were incorporated to N and C-terminals of peptide vaccine, respectively. Finally, all selected parts were fused together by appropriate linkers to enhance vaccine efficiency. The physicochemical, structural, and immunological properties of the designed vaccine protein were assessed. To achieve the best 3D model of the protein vaccine, modeling, refinement, and validation of modeled structures were also done. Docking evaluation demonstrated suitable interaction between the vaccine and TLR5. Moreover, molecular dynamics (MD) studies showed an appropriate and stable structure of protein and TLR5. Based on immunoinformatic analysis, our vaccine candidate could potentially incite humoral and cellular immunities, which are critical for protection against HPV, HSV-2, and chlamydia trachomatis. It should be noted that, experimental studies are needed to confirm the efficacy of the designed vaccine.


Value of exercise echocardiography in heart failure with preserved ejection fraction: a substudy from the KaRen study.
KaRen is a multicentre study designed to characterize and follow patients with heart failure and preserved ejection fraction (HFpEF). In a subgroup of patients with clinical signs of congestion but left ventricular ejection fraction (LVEF) >45%, we sought to describe and analyse the potential prognostic value of echocardiographic parameters recorded not only at rest but also during a submaximal exercise stress echocardiography. Exercise-induced changes in echo parameters might improve our ability to characterize HFpEF patients. Patients were prospectively recruited in a single tertiary centre following an acute HF episode with NT-pro-BNP >300 pg/mL (BNP > 100 pg/mL) and LVEF > 45% and reassessed by exercise echo-Doppler after 4-8 weeks of dedicated treatment. Image acquisitions were standardized, and analysis made at end of follow-up blinded to patients' clinical status and outcome. In total, 60 patients having standardized echocardiographic acquisitions were included in the analysis. Twenty-six patients (43%) died or were hospitalized for HF (primary outcome). The mean ± SD workload was 45 ± 14 watts (W). Mean ± SD resting LVEF and LV global longitudinal strain was 57.6 ± 9.5% and -14.5 ± 4.2%, respectively. Mean ± SD resting E/e' was 11.3 ± 4.7 and 13.1 ± 5.3 in those patients who did not and those who did experience the primary outcome, respectively (P = 0.03). Tricuspid regurgitation (TR) peak velocity during exercise were 3.3 ± 0.5 and 3.7 ± 0.5 m/s (P = 0.01). Exercise TR was independently associated with HF-hospitalization or death after adjustment on baseline clinical and biological characteristics. Exercise echocardiography may contribute to identify HFpEF patients and especially high-risk ones. Our study suggested a prognostic value of TR recorded during an exercise. That was demonstrated independently of the value of resting E/e'.


Reliability of self-reported health risk factors and chronic conditions questions collected using the telephone in South Australia, Australia.
Accurate monitoring of health conditions and behaviours, and health service usage in the population, using an effective and economical method is important for planning and evaluation. This study examines the reliability of questions asked in a telephone survey by conducting a test/retest analysis of a range of questions covering demographic variables, health risk factors and self-reported chronic conditions among people aged 16 years and over. A Computer Assisted Telephone Interviewing (CATI) survey on health issues of South Australians was re-administered to a random sub-sample of 154 respondents between 13-35 days (mean 17) after the original survey. Reliability between questions was assessed using Cohen's kappa and intraclass correlation coefficients. Demographic questions (age, gender, number of adults and children in the household, country of birth) showed extremely high reliability (0.97 to 1.00). Health service use (ICC = 0.90 95% CI 0.86-0.93) and overall health status (Kappa = 0.60 95% CI 0.46-0.75) displayed moderate agreement. Questions relating to self-reported risk factors such as smoking (Kappa = 0.81 95% CI 0.72-0.89) and alcohol drinking (ICC 0.75 = 95% CI 0.63-0.83) behaviour showed good to excellent agreement, while questions relating to self-reported risk factors such as time spent walking for physical activity (ICC 0.47 = 95% CI 0.27-0.61), fruit (Kappa(w) = 0.60 95% CI 0.45-0.76) and vegetable consumption (Kappa(w) = 0.50 95% CI 0.32-0.69) showed only moderate agreement. Self-reported chronic conditions displayed substantial to almost perfect agreement (0.72 to 1.00) with the exception of moderate agreement for heart disease (Kappa = 0.82 95% CI 0.57-0.99). These results show the questions assessed to be reliable in South Australia for estimating health conditions and monitoring health related behaviours using a CATI survey.


The back 2 activity trial: education and advice versus education and advice plus a structured walking programme for chronic low back pain.
Current evidence supports the use of exercise-based treatment for chronic low back pain that encourages the patient to assume an active role in their recovery. Walking has been shown it to be an acceptable type of exercise with a low risk of injury. However, it is not known whether structured physical activity programmes are any more effective than giving advice to remain active. The proposed study will test the feasibility of using a pedometer-driven walking programme, as an adjunct to a standard education and advice session in participants with chronic low back pain. Fifty adult participants will be recruited via a number of different sources. Baseline outcome measures including self reported function; objective physical activity levels; fear-avoidance beliefs and health-related quality of life will be recorded. Eligible participants will be randomly allocated under strict, double blind conditions to one of two treatments groups. Participants in group A will receive a single education and advice session with a physiotherapist based on the content of the 'Back Book'. Participants in group B will receive the same education and advice session. In addition, they will also receive a graded pedometer-driven walking programme prescribed by the physiotherapist. Follow up outcomes will be recorded by the same researcher, who will remain blinded to group allocation, at eight weeks and six months post randomisation. A qualitative exploration of participants' perception of walking will also be examined by use of focus groups at the end of the intervention. As a feasibility study, treatment effects will be represented by point estimates and confidence intervals. The assessment of participant satisfaction will be tabulated, as will adherence levels and any recorded difficulties or adverse events experienced by the participants or therapists. This information will be used to modify the planned interventions to be used in a larger randomised controlled trial. This paper describes the rationale and design of a study which will test the feasibility of using a structured, pedometer-driven walking programme in participants with chronic low back pain. [ISRCTN67030896].


Functional RNA microarrays for high-throughput screening of antiprotein aptamers.
High-throughput methods for generating aptamer microarrays are described. As a proof-of-principle, the microarrays were used to screen the affinity and specificity of a pool of robotically selected antilysozyme RNA aptamers. Aptamers were transcribed in vitro in reactions supplemented with biotinyl-guanosine 5'-monophosphate, which led to the specific addition of a 5' biotin moiety, and then spotted on streptavidin-coated microarray slides. The aptamers captured target protein in a dose-dependent manner, with linear signal response ranges that covered seven orders of magnitude and a lower limit of detection of 1 pg/mL (70 fM). Aptamers on the microarray retained their specificity for target protein in the presence of a 10,000-fold (w/w) excess of T-4 cell lysate protein. The RNA aptamer microarrays performed comparably to current antibody microarrays and within the clinically relevant ranges of many disease biomarkers. These methods should also prove useful for generating other functional RNA microarrays, including arrays for genomic noncoding RNAs that bind proteins. Integrating RNA aptamer microarray production with the maturing technology for automated in vitro selection of antiprotein aptamers should result in the high-throughput production of proteome chips.


What is the adequate sampling interval of the ECG signal for heart rate variability analysis in the time domain?
Heart rate variability (HRV) analysis is considered a simple method for investigating neurocardiac regulation. However, measures of HRV may be corrupted by technical artifacts. In order to investigate the consequences of digitization errors on the time domain parameters, HRV measures from model tachograms resampled at different rates were compared. Two 375-element tachograms from human ECG tracings were shifted to a mean of 800 ms and stretched to standard deviations (SD) of 5-120 ms in 5 ms steps. All were resampled at 1-10 ms in 1 ms steps, 10 times repetitively at each interval. The mean, SD, relative accuracy error (RAE) and relative precision error (RPE) were calculated from the mean RR-interval, SD (SDNN), root mean square of successive RR-differences (RMSSD) and the percentage of consecutive RR-interval differences greater than 50 ms (pNN50). The RAE and RPE of the mean heart rate were below 0.1%. In the series with 5 ms SD, the SDNN-RAE exceeded 30% at 10 ms SI, its RPE was lower than 2% all through. Resampling the 15 ms SD tachogram at 1, 2, 4, or 10 ms resulted in RMSSD-RAE of 0.7%, 2.5%, 7.8% and 45.1%, respectively, while its RPE remained below 5%. The pNN50 shows poor accuracy and precision. An ECG sampling interval of 1 ms is recommended for HRV analysis without interpolation in order to get accurate time domain measures even in seriously reduced-variability samples. However, a lower sampling rate may be satisfactory in cases where higher variability is expected.


Multiplexed Quantitative Proteomics Reveals Proteomic Alterations in Two Rodent Traumatic Brain Injury Models.
In many cases of traumatic brain injury (TBI), conspicuous abnormalities, such as scalp wounds and intracranial hemorrhages, abate over time. However, many unnoticeable symptoms, including cognitive, emotional, and behavioral dysfunction, often last from several weeks to years after trauma, even for mild injuries. Moreover, the cause of such persistence of symptoms has not been examined extensively. Recent studies have implicated the dysregulation of the molecular system in the injured brain, necessitating an in-depth analysis of the proteome and signaling pathways that mediate the consequences of TBI. Thus, in this study, the brain proteomes of two TBI models were examined by quantitative proteomics during the recovery period to determine the molecular mechanisms of TBI. Our results show that the proteomes in both TBI models undergo distinct changes. A bioinformatics analysis demonstrated robust activation and inhibition of signaling pathways and core proteins that mediate biological processes after brain injury. These findings can help determine the molecular mechanisms that underlie the persistent effects of TBI and identify novel targets for drug interventions.


Impact of RING and BRCT domain mutations on BRCA1 protein stability, localization and recruitment to DNA damage.
Mutations within the tumor suppressor BRCA1 cause the majority of hereditary breast and ovarian cancers. The BRCA1 protein is an important regulator of DNA double-strand break repair, and BRCA1-deficient cells are highly sensitive to ionizing radiation. Furthermore, BRCA1 function may contribute to enforcement of the G(2) cell cycle checkpoint. E3-ubiquitin ligase activity is the only known enzymatic activity of BRCA1, which is mediated by the N-terminal RING finger domain. The C-terminal BRCT repeat domain, which mediates protein-protein interactions, is the only other identified structural domain. By investigating cancer-linked mutations within each domain, we demonstrate that truncation of the BRCT domain greatly impairs the stability and nuclear localization of BRCA1 protein. A missense mutation within the RING domain does not affect these biochemical properties. However, both mutant forms of BRCA1 fail to colocalize in nuclear foci with the known BRCA1-interacting proteins BARD1 and BACH1, which are important for DNA repair. This failure occurs despite the continued ability of the RING mutant protein to interact with BACH1 and the ability of the BRCT mutant to interact with BARD1. Furthermore, neither mutant form of BRCA1 is recruited into DNA damage-associated foci marked by gamma-H2AX. Therefore, our data suggest that both the RING and BRCT domains of BRCA1 are required for an early step in the function of BRCA1 during DNA repair: recruitment to the sites of DNA damage.


Mechanistic insights into antitumor effects of new dinuclear cis Pt(II) complexes containing aromatic linkers.
The primary objective was to understand more deeply the molecular mechanism underlying different antitumor effects of dinuclear Pt(II) complexes containing aromatic linkers of different length, {[cis-Pt(NH(3))(2)Cl](2)(4,4'-methylenedianiline)}(2+) (1) and {[cis-Pt(NH(3))(2)Cl](2)(alpha,alpha'-diamino-p-xylene)}(2+) (2). These complexes belong to a new generation of promising polynuclear platinum drugs resistant to decomposition by sulfur nucleophiles which hampers clinical use of bifunctional polynuclear trans Pt(II) complexes hitherto tested. Results obtained with the aid of methods of molecular biophysics and pharmacology reveal differences and new details of DNA modifications by 1 and 2 and recognition of these modifications by cellular components. The results indicate that the unique properties of DNA interstrand cross-links of this class of polynuclear platinum complexes and recognition of these cross-links may play a prevalent role in antitumor effects of these metallodrugs. Moreover, the results show for the first time a strong specific recognition and binding of high-mobility-group-domain proteins, which are known to modulate antitumor effects of clinically used platinum drugs, to DNA modified by a polynuclear platinum complex.


Prevalence of restless legs syndrome and associated factors in an otherwise healthy population: results from the Danish Blood Donor Study.
Restless legs syndrome (RLS) is a neurological sensorimotor disorder characterized by uncomfortable sensations in the legs. RLS often occurs as a comorbid condition. Besides an increased risk of iron deficiency, blood donors are considered to be generally healthy. Blood donors are therefore an ideal population for studying factors associated with RLS occurrence, herein the role of iron. It is suggested that RLS is linked to sex, age, low socioeconomic status, unhealthy lifestyle, and iron deficiency. The objective of this study is therefore to estimate the RLS prevalence and identify associated biological, sociodemographic, economic, and lifestyle factors in a population of blood donors. A total of 13,448 blood donors enrolled in the Danish Blood Donor Study from May 2015 to May 2016. RLS cases were identified using the validated Cambridge-Hopkins RLS-questionnaire. Logistic regression models were applied to assess the relationship between RLS and data on socially related factors collected using questionnaires and population registers. In this study, 7.2% women and 4.5% men were classified with RLS. RLS was associated with: female sex, high age, smoking, frequent alcohol consumption, and low education. RLS-related symptoms were associated with obesity, parity and donation intensity three years prior to inclusion among women. RLS was not related to: reduced plasma ferritin, employment status, and income. RLS is a frequent disorder in otherwise healthy individuals. The associations discovered in this study can be utilized in preventing or reducing RLS symptoms.


Mechanisms underlying proglucagon gene expression.
The proglucagon gene (gcg) encodes a number of peptide hormones that are of cell-type specifically expressed in the pancreatic islets, the distal ileum and the large intestine, as well as certain brain neuronal cells. These hormones are important in controlling blood glucose homeostasis, intestinal cell proliferation, and satiety. More importantly, the major hormone generated in the pancreas (i.e. glucagon) exerts opposite effects to the ones that are produced in the intestines (i.e. glucagon-like peptide-1 (GLP-1) and GLP-2). To understand the mechanisms underlying cell-type-specific gcg expression may lead to the identification of novel drug targets to control endogenous hormone production for therapeutic purposes. Extensive in vitro examinations have shown that more than a half dozen of homeodomain (HD) proteins are able to interact with the gcg gene promoter and activate its expression. In vivo 'knock-out' mouse studies, however, cannot demonstrate the role of some of them (i.e. Cdx-2, Brn-4, and Nkx6.2) in the development of pancreatic islet alpha-cells, suggesting that these HD proteins may exert some redundant functions in the genesis of gcg-producing cells. Investigations have also revealed that gcg expression is controlled by both protein kinase A and Epac signaling pathways in response to cAMP elevation, and cell-type specifically controlled by insulin and the effectors of the Wnt signaling pathway. This review summarizes our current understanding on the mechanisms underlying gcg transcription and presented my interpretations on how the interactions between different signaling networks regulate gcg expression.


Polarized distribution of renal natriuretic peptide receptors in normal physiology and ischemia.
The polarized expression of guanylyl cyclase-coupled natriuretic peptide receptors, types A (GC-A) and B (GC-B), was measured in inner medullary collecting ducts (IMCD) of normal and ischemic rat kidneys, as well as in IMCD cells. Exposure of normal rat kidney medulla to an anti-GC-A antibody demonstrated a propensity of receptor staining on the cellular basal membrane. The polarization of GC-A receptors was lost in the ischemic kidney. The maximal binding capacity of 125I-atrial natriuretic factor (ANF) to the basal membrane of the inner medullary cell line mIMCD-K2 was five times greater than that to the apical membrane. ANF or C-type natriuretic peptide (CNP) added to the basal side of cultured cells resulted in guanosine 3',5'-cyclic monophosphate formation that was greater than when applied to the apical side. Depletion of ATP stores in cultured cells was followed by an increase of 125I-ANF binding to apical cellular membranes. Similar results were obtained when receptor guanylyl cyclase activity was assayed. In conclusion, these results suggest that functional GC-A and GC-B receptors are present predominantly on the basal membrane of IMCD. However, depletion of cellular ATP stores such as in ischemia is followed by a partial loss of polarization.


[Proceedings: Experimental endocarditis. Experimental basis and prophylaxis].
A simple model has been developed for the production of bacterial endocarditis in rabbits. The principle depends on the insertion of a polyethylene catheter into the venous or arterial system so that the tip rests in the heart cavity in which endocarditis is to be established. After catheter placement, intravenous injection of any one of a variety of microorganisms regularly produces infective endocarditis. The characteristics of the infection in rabbits are similar to those observed in infective endocarditis in man. The production of streptococcus viridans infections in previously immunized animals leads to the development of diffuse glomerulonephritis. Translating antibiotic doses on a weight basis, prophylactic antibiotic treatment programs recommended in man have been shown to be ineffective in rabbits. If the activity of antibiotics in this model infection in rabbits can be assumed to be comparable to that in man, it is necessary that we reconsider the currently accepted recommendation for prophylaxis and treatment of infective endocarditis in man.


HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression?
The prevalence of the most severe forms of HIV-associated neurocognitive disorders (HAND) is decreasing due to worldwide availability and high efficacy of antiretroviral treatment (ART). However, several grades of HIV-related cognitive impairment persist with effective ART and remain a clinical concern for people with HIV (PWH). The pathogenesis of these cognitive impairments has yet to be fully understood and probably multifactorial. In PWH with undetectable peripheral HIV-RNA, the presence of viral escapes in cerebrospinal fluid (CSF) might explain a proportion of cases, but not all. Many other mechanisms have been hypothesized to be involved in disease progression, in order to identify possible therapeutic targets. As potential indicators of disease staging and progression, numerous biomarkers have been used to characterize and implicate chronic inflammation in the pathogenesis of neuronal injuries, such as certain phenotypes of activated monocytes/macrophages, in the context of persistent immune activation. Despite none of them being disease-specific, the correlation of several CSF cellular biomarkers to HIV-induced neuronal damage has been investigated. Furthermore, recent studies have been evaluating specific microRNA (miRNA) profiles in the CSF of PWH with neurocognitive impairment (NCI). The aim of the present study is to review the body of evidence on different biomarkers use in research and clinical settings, focusing on PWH on ART with undetectable plasma HIV-RNA.


[Nutritional and metabolic factors as risk factors for cardiovascular diseases in an adult population in the city of Maracibo, Estado Zulia, Venezuela].
To analyze the nutritional and metabolic risk factors for Cardiovascular Diseases (CVD) present in a group of people in the city of Maracaibo a study was performed with 209 volunteers (145 women and 64 men) between 20 and 89 years of age who underwent: a) Anthropometric Evaluation: Body Mass Index (BMI) and Waist-to-Hip Ratio (WHR) and Physical Examination: Systolic (SBP) and Diastolic Blood Pressure (DBP); b) Dietetic Evaluation (24 hours recall), and c) Biochemical Evaluation: Glycemia (GLYC), Triglycerides (TG), Total Cholesterol (CHOL), HDL-C, LDL-C and VLDL-C, applying enzymatic methods. It was also investigated, their Age, Family History of Metabolic Alterations (FHMA), physical activity, smoking habits and alcohol consumption. More than 50% of the individuals showed a BMI > 25; 64% of women showed a WHR value > 0.8; 34 and 28% of men and women respectively had a high fat ingestion (HFI); 36% of men had hypertriglyceridemia and high levels of VLDL-C; 41% of women and 30% of men showed decreased HDL-C. A high frequency of FHMA was found in 85% of women and 78% of men followed by sedentary life in 64% of men and 79% of women. The age significantly (p < 0.05) affected the values for WHR, SBP, DBP, GLYC, CHOL, TG, HDL-C, LDL-C and VLDL-C. The dietetic evaluation showed a diet that was low in calories, high in protein, normal in fat and low in carbohydrates. It is concluded that the population elected for this study might be considered under a high risk for CVD, since both nutritional and metabolic factors, as well as the other risk factors analyzed, were present in a high percentage of the individuals studied.


Rephine.r: a pipeline for correcting gene calls and clusters to improve phage pangenomes and phylogenies.
A pangenome is the collection of all genes found in a set of related genomes. For microbes, these genomes are often different strains of the same species, and the pangenome offers a means to compare gene content variation with differences in phenotypes, ecology, and phylogenetic relatedness. Though most frequently applied to bacteria, there is growing interest in adapting pangenome analysis to bacteriophages. However, working with phage genomes presents new challenges. First, most phage families are under-sampled, and homologous genes in related viruses can be difficult to identify. Second, homing endonucleases and intron-like sequences may be present, resulting in fragmented gene calls. Each of these issues can reduce the accuracy of standard pangenome analysis tools. We developed an R pipeline called Rephine.r that takes as input the gene clusters produced by an initial pangenomics workflow. Rephine.r then proceeds in two primary steps. First, it identifies three common causes of fragmented gene calls: (1) indels creating early stop codons and new start codons; (2) interruption by a selfish genetic element; and (3) splitting at the ends of the reported genome. Fragmented genes are then fused to create new sequence alignments. In tandem, Rephine.r searches for distant homologs separated into different gene families using Hidden Markov Models. Significant hits are used to merge families into larger clusters. A final round of fragment identification is then run, and results may be used to infer single-copy core genomes and phylogenetic trees. We applied Rephine.r to three well-studied phage groups: the Tevenvirinae (e.g., T4), the Studiervirinae (e.g., T7), and the Pbunaviruses (e.g., PB1). In each case, Rephine.r recovered additional members of the single-copy core genome and increased the overall bootstrap support of the phylogeny. The Rephine.r pipeline is provided through GitHub (https://www.github.com/coevoeco/Rephine.r) as a single script for automated analysis and with utility functions to assist in building single-copy core genomes and predicting the sources of fragmented genes.


[Molecular phylogenetic study of the systematic position of Baikalian oligochaetes in the system Clitellata].
Phylogenetic relationships within the class Clitellata were examined using nucleotide sequences of nuclear 18S ribosomal RNA gene fragments. In the analysis, the already determined sequences for the individual species representing the class members Hirudinea, Acanthobdellida, Branchiobdellida, and Oligochaeta were included. Furthermore, newly determined sequences of the thirteen representatives of the family Lumbriculidae. including 12 Baikalian endemic species, were analyzed. The hypothesis on the close relatedness of these four groups of Clitellata was supported. Leeches, branchiobdellidans, and lumbriculides form three independent parallel branches of evolution. These results were consistent with the hypothesis on the role of the family Lumbriculidae as a connecting link, or the transition form between the parasitic and free-living groups of Clitellata. At the same time, these data refute the suggestion that Lumbriculidae could be the ancestral lineage of other Oligochaeta. Moreover, polymorphic group of Baikalian lumbriculides clustered independently from the other representatives of the family, pointing to the uniqueness of the Baikalian fauna of oligochaetes, which was formed within relatively closed system of this ancient lake.


Multiple Environmental Stressors Induce an Adaptive Maternal Effect.
AbstractEvolution of adaptation requires predictability and recurrence of functional contexts. Yet organisms live in multifaceted environments that are dynamic and ever changing, making it difficult to understand how complex adaptations evolve. This problem is particularly apparent in the evolution of adaptive maternal effects, which are often assumed to require reliable and discrete cues that predict conditions in the offspring environment. One resolution to this problem is if adaptive maternal effects evolve through preexisting, generalized maternal pathways that respond to many cues and also influence offspring development. Here, we assess whether an adaptive maternal effect in western bluebirds is influenced by maternal stress pathways across multiple challenging environments. Combining 18 years of hormone sampling across diverse environmental contexts with an experimental manipulation of the competitive environment, we show that multiple environmental factors influenced maternal corticosterone levels, which, in turn, influenced a maternal effect on aggression of sons in adulthood. Together, these results support the idea that multiple stressors can induce a known maternal effect in this system. More generally, they suggest that activation of general pathways, such as the hypothalamic-pituitary-adrenal axis, may simplify and facilitate the evolution of adaptive maternal effects by integrating variable environmental conditions into preexisting maternal physiological systems.


Tracing the geographic origins of weedy Ipomoea purpurea in the southeastern United States.
Ipomoea purpurea (common morning glory) is an annual vine native to Mexico that is well known for its large, showy flowers. Humans have spread morning glories worldwide, owing to the horticultural appeal of morning glory flowers. Ipomoea purpurea is an opportunistic colonizer of disturbed habitats including roadside and agricultural settings, and it is now regarded as a noxious weed in the Southeastern US. Naturalized populations in the Southeastern United States are highly polymorphic for a number of flower color morphs, unlike native Mexican populations that are typically monomorphic for the purple color morph. Although I. purpurea was introduced into the United States from Mexico, little is known about the specific geographic origins of US populations relative to the Mexican source. We use resequencing data from 11 loci and 30 I. purpurea accessions collected from the native range of the species in Central and Southern Mexico and 8 accessions from the Southeastern United States to infer likely geographic origins in Mexico. Based on genetic assignment analysis, haplotype composition, and the degree of shared polymorphism, I. purpurea samples from the Southeastern United States are genetically most similar to samples from the Valley of Mexico and Veracruz State. This supports earlier speculation that I. purpurea in the Southeastern United States was likely to have been introduced by European colonists from sources in Central Mexico.


Cotransfection of TrkA and p75(NTR) in neuroblastoma cell line (IMR-32) promotes differentiation and apoptosis of tumor cells.
To assess the effects of both TrkA and p75(NTR) on nerve growth factor (NGF)-induced differentiation of neuroblastoma cells. Retroviral vectors were constructed to express the high affinity NGF receptor (TrkA) and low affinity NGF receptor (p75(NTR)). Neuroblastoma cell line IMR-32 was transfected by the vectors expressing either TrkA or p75(NTR) or both by using lipofectmine trade mark reagent separately or cotransfected at the same time. Southern blot, Northern blot, RT-PCR and flow cytometry were used to determine the success of the transfection. MTT technique was to monitor the cell proliferation. Colony formation in soft agar and tumor forming assay in nude mice were used to test the biological characteristics of the tumor cells. Terminal-deoxynucleotidytransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay was used to test the apoptosis of the tumor cells. Stable transformant cell lines expressing TrkA, p75(NTR) or both genes were established. Studies on these transformant cell lines have shown different NGF responses. The p75(NTR) transfection only resulted in the mild differentiation response, and transfection of TrkA gene caused remarkable neurite extension, up-regulation of neurofilament and decreased expression of N-myc oncogene after NGF treatment. The cotransfection of the two genes into this cell line resulted in the more rapid and more apparent morphological changes than single TrkA transfected cells after NGF treatment. The cotransfected cells underwent apoptosis after withdrawal of NGF. The results indicate that coexpression of both low- and high-affinity NGF receptors are not only more efficient in restoration of NGF-induced differentiation pathway, but also be able to activate the pro-apoptotic activity of low-affinity NGF receptor and make the tumor cells become NGF-dependent and irreversibly differentiated.


Regulation of human mast cell tryptase. Effects of enzyme concentration, ionic strength and the structure and negative charge density of polysaccharides.
Tryptase was previously shown to undergo rapid inactivation under physiological conditions unless stabilized by the presence of heparin. The current study shows that increasing the concentration of free tryptase enhances the preservation of enzymic activity, consistent with dissociation of the tetramer, rather than autodegradation, as the mechanism of inactivation. Heparin glycosaminoglycan fragments of Mr greater than 5700 are necessary for complete stabilization of tryptase activity. This stabilizing effect depends upon negative charge density rather than carbohydrate composition. Thus, keratan sulphate or hyaluronic acid were no better than physiological buffer alone; chondroitin monosulphates and heparan sulphate each prolonged the t1/2 about 20-fold over buffer alone; chondroitin sulphate E prolonged the t1/2 69-fold; and dextran sulphate and heparin provided complete stabilization of tryptase activity for 120 min. Poly-D-glutamic acid prolonged the t1/2 55-fold. In each case the loss of tryptase activity followed apparent first-order kinetics. Increasing the NaCl concentration from 0.01 M to 1.0 M increased the stability of free tryptase. In contrast, increasing the NaCl concentration in the presence of stabilizing polysaccharides decreased the stability of tryptase until dissociation of tryptase from each polysaccharide presumably occurred; thereafter tryptase stability increased as did that of free tryptase. The effect of salt concentration on heparin-stabilized tryptase activity (as opposed to stability) was also evaluated. The mast cell proteoglycans heparin and chondroitin sulphate E, by virtue of containing the naturally occurring glycosaminoglycans of highest negative charge density, may play a major role in the regulation of mast cell tryptase activity in vivo.


A latent class growth analysis of school bullying and its social context: the self-determination theory perspective.
The contribution of social context to school bullying was examined from the self-determination theory perspective in this longitudinal study of 536 adolescents from 3 secondary schools in Hong Kong. Latent class growth analysis of the student-reported data at 5 time points from grade 7 to grade 9 identified 4 groups of students: bullies (9.8%), victims (3.0%), bully-victims (9.4%), and typical students (77.8%). There was a significant association between academic tracking and group membership. Students from the school with the lowest academic performance had a greater chance of being victims and bully-victims. Longitudinal data showed that all 4 groups tended to report less victimization over the years. The victims and the typical students also had a tendency to report less bullying over the years, but this tendency was reversed for bullies and bully-victims. Perceived support from teachers for relatedness significantly predicted membership of the groups of bullies and victims. Students with higher perceived support for relatedness from their teachers had a significantly lower likelihood of being bullies or victims. The findings have implications for the theory and practice of preventive interventions in school bullying.


Life threatening self starvation; a case report.
Obsessive compulsive disorders are a complex group that can have a variety of manifestations. Many authors now describe an obsessive compulsive spectrum disorder where many other specific diagnostic entities such as trichotillomania, tic disorders and body dysmorphic disorder are considered to be related and linked disorders. We report a case of a twenty two year old Sri Lankan male who presented with life threatening self starvation due to severe obsessive compulsive disorder. The diagnosis was not considered till late due to the atypical presentation of the patient. While his symptoms bordered on a delusional psychosis, a decision was made to treat him as for obsessive compulsive disorder with behavioural therapy which was successful in the end. In analysis of a patient with severe anorexia, the psychological causes should not be forgotten. In fact, if the feeding pattern of the patient was observed at the beginning, unnecessary investigating and life threatening worsening of the condition could have been avoided.


Interleukin-1 polymorphisms are associated with the inflammatory response in human muscle to acute resistance exercise.
Inflammation appears to play an important role in the repair and regeneration of skeletal muscle after damage. We tested the hypothesis that the severity of the inflammatory response in muscle after an acute bout of resistance exercise is associated with single nucleotide polymorphisms (SNPs) previously shown to alter interleukin-1 (IL-1) activity. Using a double-blind prospective design, sedentary young men were screened (n = 100) for enrolment (n = 24) based upon having 1 of 4 haplotype patterns composed of five polymorphic sites in the IL-1 gene cluster: IL-1A (+4845), IL-1B (+3954), IL-1B (-511), IL-1B (-3737) and IL-1RN (+2018). Subjects performed a standard bout of resistance leg exercise and vastus lateralis biopsies were obtained pre-, and at 24, and 72 h post-exercise. Inflammatory marker mRNAs (IL-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha)) and the number of CD68(+) macrophages were quantified. Considerable variation was observed in the expression of these gene products between subjects. At 72 h post-exercise, IL-1beta had increased in a number of subjects (n = 10) and decreased (n = 4) or did not change (n = 10) in others. Inflammatory responses were significantly associated with specific haplotype patterns and were also influenced by individual SNPs. Subjects with genotypes 1.1 at IL-1B (+3954) or 2.2 at IL-1B (-3737) had approximately a 2-fold higher median induction of several markers, but no increase in macrophages, suggesting that cytokine gene expression is elevated per macrophage. The IL-1RN (+2018) SNP maximized the response specifically within these groups and was associated with increased macrophage recruitment. This is the first report that IL-1 genotype is associated with the inflammation of skeletal muscle following acute resistance exercise that may potentially affect the adaptations to chronic resistance exercise.


Factors that prevent physicians reporting adverse events.
The purpose of this paper is to explore the reasons why Greek doctors are reluctant to report adverse events. The paper is an exploratory study using the adverse events questionnaire, administered to 209 doctors in 14 major Athens hospitals, comprising university as well as tertiary. The questionnaire showed a high degree of internal consistency (Cronbach's alpha 0.84), which revealed a four-factor solution, explaining 67.4 per cent of the variance. Three dominant reasons for not reporting, with which almost or more than 50 per cent of doctors strongly or slightly agreed, were identified as no tradition for bringing up adverse events and a belief that bringing up adverse events will not lead to any improvement and workload. Factors that dissuade doctors from bringing up adverse events may be projected not only by cultural aspects such as professional, national and organisational cultures but also by healthcare structural issues such as safety systems, rules and procedures, and relevant acts and regulations. The study has several noteworthy limitations. First, doctors' response was poor, which might conceal sample bias problems. Second, the present study identified four factors but the fourth factor was not well defined. The study provides an understanding why physicians fail to report adverse events so that systems can be introduced and cultures developed, which make this easier.


Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells.
Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.


Cardiovascular dysautonomia of patients with end-stage renal disease and type I or type II diabetes.
End-stage renal disease and diabetes mellitus are known to cause autonomic dysfunctions that are responsible for poor outcomes. Studies suggest that 24-hour heart rate variability with power spectral analysis is more sensitive to early changes in autonomic function than laboratory-evoked measures. To evaluate cardiovascular autonomic function in patients (a) awaiting kidney or pancreas-kidney transplantation, (b) without diabetes (NonDM), (c) with Type I insulin dependent diabetes mellitus (IDDM), and (d) with Type II noninsulin dependent diabetes mellitus (NIDDM), and to compare the results of the laboratory-evoked cardiovascular autonomic tests with those from 24-hour heart rate variability monitoring with power spectral analysis. This cross-sectional study examined autonomic function in prekidney transplant patients with and without diabetes (N=96), comparing laboratory-evoked measures to 24-hour measures. The nondiabetic group had a normal change in heart rate with deep breathing, Valsalva ratio, and change in systolic blood pressure with tilt. Both diabetic groups had poorer values for all measures of heart rate variability; demonstrated abnormal changes in heart rate with deep breathing and borderline Valsalva ratios; demonstrated a greater decrease in circadian rhythmicity; and had lower SDNNS, pNN50s, and rMSSDs than the nondiabetic group. Results showed that 24-hour measures are more sensitive, that patients with end-stage renal disease and diabetes regardless of type experience significantly poorer function than do patients without diabetes, and that these values approach those associated with sudden cardiac death.


Temporal Trends in Telehealth Availability in Mental Health Treatment Settings: Differences in Growth by State Rurality, 2015-2020.
We sought to investigate temporal trends in telehealth availability among outpatient mental health treatment facilities and differences in the pace of telehealth growth by state urbanicity and rurality. We used the National Mental Health Services Survey (2015-2020) to identify outpatient mental health treatment facilities in the US (N = 28,989 facilities; 2015 n = 5,018; 2020 n = 4,889). We used logistic regression to model telehealth, predicted by time, state rurality (1 to 10% rural, 10 to < 20%, 20 to < 30%, or [Formula: see text] 30%), and their interaction, and adjusted for relevant covariates. We estimated the predicted probability of telehealth based on our model. We estimated effects with and without data from 2020 to assess whether the rapid and widespread adoption of telehealth during the COVID-19 pandemic changed the rural/urban trajectories of telehealth availability. We found that telehealth grew fastest in more urban states (year*rurality interaction p < 0.0001). Between 2015 and 2020, the predicted probability of telehealth in more urban states increased by 51 percentage points (from 9 to 61%), whereas telehealth in more rural states increased by 38 percentage points (from 23 to 61%). Predicted telehealth also varied widely by state, ranging from more than 75% of facilities (RI, OR) to below 20% (VT, KY). Health systems and new technological innovations must consider the unique challenges faced by urban populations and how best practices may be adapted to meet the growing urban demand. We framed our findings around the need for policies that minimize barriers to telehealth.


Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells.
COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2 inhibitors, e.g., in combination with radiotherapy or endoradiotherapy, represents an interesting treatment option. Based on our own findings that nitric oxide (NO)-releasing and celecoxib-derived COX-2 inhibitors (COXIBs) showed promising radiosensitizing effects in vitro, we herein present the development of a series of eight novel NO-COXIBs differing in the peripheral substitution pattern and their chemical and in vitro characterization. COX-1 and COX-2 inhibition potency was found to be comparable to the lead NO-COXIBs, and NO-releasing properties were demonstrated to be mainly influenced by the substituent in 4-position of the pyrazole (Cl vs. H). Introduction of the N-propionamide at the sulfamoyl residue as a potential prodrug strategy lowered lipophilicity markedly and abolished COX inhibition while NO-releasing properties were not markedly influenced. NO-COXIBs were tested in vitro for a combination with single-dose external X-ray irradiation as well as [177Lu]LuCl3 treatment in HIF2α-positive mouse pheochromocytoma (MPC-HIF2a) tumor spheroids. When applied directly before X-ray irradiation or 177Lu treatment, NO-COXIBs showed radioprotective effects, as did celecoxib, which was used as a control. Radiosensitizing effects were observed when applied shortly after X-ray irradiation. Overall, the NO-COXIBs were found to be more radioprotective compared with celecoxib, which does not warrant further preclinical studies with the NO-COXIBs for the treatment of pheochromocytoma. However, evaluation as radioprotective agents for healthy tissues could be considered for the NO-COXIBs developed here, especially when used directly before irradiation.


Critical Casimir interactions and colloidal self-assembly in near-critical solvents.
A binary solvent mixture close to critical demixing experiences fluctuations whose correlation length, ξ, diverges as the critical point is approached. The solvent-mediated (SM) interaction that arises between a pair of colloids immersed in such a near-critical solvent can be long-ranged and this so-called critical Casimir interaction is well-studied. How a (dense) suspension of colloids will self-assemble under these conditions is poorly understood. Using a two-dimensional lattice model for the solvent and hard disks to represent the colloids, we perform extensive Monte Carlo simulations to investigate the phase behaviour of this model colloidal suspension as a function of colloid size and wettability under conditions where the solvent reservoir is supercritical. Unlike most other approaches, where the solvent is modelled as an implicit background, our model employs an explicit solvent and treats the suspension as a ternary mixture. This enables us to capture important features, including the pronounced fractionation of the solvent in the coexisting colloidal phases, of this complex system. We also present results for the partial structure factors; these shed light on the critical behaviour in the ternary mixture. The degree to which an effective two-body pair potential description can describe the phase behaviour and structure of the colloidal suspension is discussed briefly.


Can multiaxial diagnosis predict future use of psychiatric hospitalization?
Demographic and diagnostic intake data on about 10,000 patients at a public psychiatric facility were used to assess whether information recorded on various DSM-III axes could predict the frequency of patients' psychiatric hospitalizations over a follow-up period. Compared with patients who had been hospitalized only once or not at all, patients with three or more hospitalizations during the study period were more likely to be single and black and to come from lower social classes. They were more likely to have an axis I diagnosis of an alcohol-related disorder, a substance use disorder, or a psychotic disorder. When samples from the patient groups were matched on key demographic variables and primary axis I diagnosis, the multiaxial resources of DSM-III were not helpful in predicting future use of hospitalization. The results reinforce the importance of axis I diagnosis and demographic characteristics in assessing course and prognosis.


Feasibility and cost of FH cascade screening in Belgium (BEL-CASCADE) including a novel rapid rule-out strategy.
Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.


Prevalence of Anemia in Type 2 Diabetic Patients.
The aim of the study was to determine the prevalence of anemia in patients with type 2 diabetes and to assess the risk of anemia according to gender, age and glycemic control. The study group comprised of patients with type 2 diabetes attending Outpatient Diabetic Department of Amiri Hospital (Al-Asimah Capital area) from January 1, 2016 to December 31, 2017. Patients were divided into groups according to glycemic status and gender. Glycated hemoglobin (HbA1C) values and hemoglobin (Hb) levels were evaluated. The presence of anemia was defined by an Hb level < 13.0 g/dL for men and < 12.0 g/dL for women. The prevalence of anemia is significantly greater in diabetic females (38.5%) than in diabetic males (21.6%) and in poorly controlled diabetics (33.46%) than those with glycemic status under control (27.9%) (P < 0.05). The average age of patients with anemia was found to be 60.69 ± 0.198 years and the average age of patients without anemia was found to be 54.07 ± 0.121 years. This indicates that the risk of anemia increases with age. Screening for anemia at the time of diagnosis of diabetes, diabetic medication compliance, awareness of the risk of anemia and other complications in the diabetic patients helps in reducing the prevalence of anemia in diabetic population.


Selective removal of erythromycin by magnetic imprinted polymers synthesized from chitosan-stabilized Pickering emulsion.
Magnetic imprinted polymers (MIPs) were synthesized by Pickering emulsion polymerization and used to adsorb erythromycin (ERY) from aqueous solution. The oil-in-water Pickering emulsion was stabilized by chitosan nanoparticles with hydrophobic Fe3O4 nanoparticles as magnetic carrier. The imprinting system was fabricated by radical polymerization with functional and crosslinked monomer in the oil phase. Batches of static and dynamic adsorption experiments were conducted to analyze the adsorption performance on ERY. Isotherm data of MIPs well fitted the Freundlich model (from 15 °C to 35 °C), which indicated heterogeneous adsorption for ERY. The ERY adsorption capacity of MIPs was about 52.32 μmol/g at 15 °C. The adsorption kinetics was well described by the pseudo-first-order model, which suggested that physical interactions were primarily responsible for ERY adsorption. The Thomas model used in the fixed-bed adsorption design provided a better fit to the experimental data. Meanwhile, ERY exhibited higher affinity during adsorption on the MIPs compared with the adsorption capacity of azithromycin and chloramphenicol. The MIPs also exhibited excellent regeneration capacity with only about 5.04% adsorption efficiency loss in at least three repeated adsorption-desorption cycles.


Report of the Dutch experience with the Ross procedure in 343 patients.
Limited information is available on outcome after autograft aortic valve replacement, in particular with respect to the durability of the autograft and of the allograft used to reconstruct the right ventricular outflow tract. A retrospective follow-up study of all patients who underwent a Ross procedure in the Netherlands since 1988 was done to obtain an overview of the Dutch experience with this procedure. From 1988 to January 2000, 348 Ross procedures were performed in nine centers in the Netherlands. Pre-operative, peri-operative and follow-up data from 343 patients in seven centers (99% of all Dutch autograft patients) were collected and analyzed. Mean patient age was 26 years (SD 14, range 0-58) and male/female ratio was 2.1. Bicuspid valve or other congenital heart valve disease was the most common indication for operation. The root replacement technique was used in 95% of patients and concomitant procedures were done in 12%. Hospital mortality was 2.6% (N=9). Mean follow-up was 4 years (median 3.8, SD 2.8, range 0-12.5). Overall cumulative survival was 96% at 1 year (95% confidence interval (CI) 94-98%) and 94% at 5 and 7 post-operative years, respectively (95% CI 91-97%). At last follow-up, 87% of the surviving patients was in New York Heart Association (NYHA) class I. Independent predictors of overall mortality were pre-operative NYHA class IV/V and longer perfusion time. Autograft reoperation had to be performed in 14 patients and reintervention on the pulmonary allograft in 10 patients. Freedom from any valve-related reintervention was 88% at 7 years (95% CI 81-94%). The Dutch experience with the Ross procedure is favorable, with low operative mortality and good mid-term results. Although both the autograft in aortic position and the allograft in the right ventricular outflow tract have a limited durability, this has not yet resulted in considerable reoperation rates and associated morbidity and mortality.


Inhibitors of the calcineurin/NFAT pathway.
The well known calcium-sensitive phosphatase calcineurin is implicated in many eukaryotic activation and developmental programmes, including lymphocyte activation, heart-valve morphogenesis, angiogenesis, and neural and muscle development. The importance of this phosphatase is graphically illustrated by the observation that the immunosuppressive actions of the microbial drugs Cyclosporin A (CsA) and FK506 arise from their inhibition of calcineurin. As substrates of calcineurin, transcription factors of the NFAT family play an essential role in lymphocyte activation, and it follows that their function is also inhibited by CsA and FK506. Although the use of these drugs has been crucial for the success of organ transplantation, their therapeutic use is associated with severe side effects. There is, therefore a need to develop better, less toxic immunosuppressive agents. In recent years, a number of endogenous calcineurin inhibitor proteins have been identified that bind calcineurin and block its phosphatase activity. In some cases the calcineurin interaction domains of these proteins, or their corresponding docking sites on calcineurin, have been described. However, their mode of action and regulatory mechanisms are not completely known. In a more recent development, specific amino acidic sequences implicated in the interaction between calcineurin and NFAT have been identified. It is of special interest that specific disruption of this pathway has been obtained through the expression of peptides based on some of these sequences. A more profound analysis of these issues could open up new perspectives in immunosuppressive therapy; promising compounds with features of endogenous calcineurin inhibitors (and thus likely to have fewer toxic effects than CsA and FK506), or selective blockers of calcineurin-NFAT interactions that would not alter the functioning of other calcineurin substrates.


Stable and uniform multiwavelength erbium-doped fiber laser using nonlinear polarization rotation.
A novel and simple technique, based on nonlinear polarization rotation (NPR) effect, to generate stable multiwavelength oscillations in an erbium-doped fiber laser is proposed and successfully demonstrated. The NPR effect effectively induced intensity- and wavelength-dependent loss to alleviate mode competition caused by homogeneous gain broadening in erbium-doped fibers. Up to 28-wavelength lasing operation with wavelength spacing of 0.8 nm has been achieved. The outputs had uniform power distributions, and the power fluctuation in each wavelength is smaller than 0.2 dB within a period of an hour.


De novo transcription of multiple Hox cluster genes takes place simultaneously in early Xenopus tropicalis embryos.
hox genes are found as clusters in the genome in most bilaterians. The order of genes in the cluster is supposed to be correlated with the site of expression along the anterior-posterior body axis and the timing of expression during development, and these correlations are called spatial and temporal collinearity, respectively. Here we studied the expression dynamics of all hox genes of the diploid species Xenopus tropicalis in four Hox clusters (A-D) by analyzing high-temporal-resolution RNA-seq databases and the results showed that temporal collinearity is not supported, which is consistent with our previous data from allotetraploid X enopus laevis Because the temporal collinearity hypothesis implicitly assumes the collinear order of gene activation, not mRNA accumulation, we determined for the first time the timing of when new transcripts of hox genes are produced, by detecting pre-spliced RNA in whole embryos with reverse transcription and quantitative PCR (RT-qPCR) for all hoxa genes as well as several selected hoxb, hox c and hoxd genes. Our analyses showed that, coinciding with the RNA-seq results, hoxa genes started to be transcribed in a non-sequential order, and found that multiple genes start expression almost simultaneously or more posterior genes could be expressed earlier than anterior ones. This tendency was also found in hoxb and hoxc genes. These results suggest that temporal collinearity of hox genes is not held during early development of Xenopus.


Oxide nanocrystal based nanocomposites for fabricating photoplastic AFM probes.
We report on the synthesis, characterization and application of a novel nanocomposite made of a negative tone epoxy based photoresist modified with organic-capped Fe(2)O(3) nanocrystals (NCs). The mechanical properties of the nanocomposite drastically improve upon incorporation of a suitable concentration of NCs in the polymer, without deteriorating its photolithography performance. High aspect ratio 3D microstructures made of the nanocomposite have been fabricated with a uniform surface morphology and with a resolution down to few micrometres. The embedded organic-capped Fe(2)O(3) NCs drastically increase the stiffness and hardness of the epoxy based photoresist matrix, making the final material extremely interesting for manufacturing miniaturized polymer based mechanical devices and systems. In particular, the nanocomposite has been used as structural material for fabricating photoplastic Atomic Force Microscopy (AFM) probes with integrated tips showing outstanding mechanical response and high resolution imaging performance. The fabricated probes consist of straight cantilevers with low stress-gradient and high quality factors, incorporating sharp polymeric tips. They present considerably improved performance compared to pure epoxy based photoresist AFM probes, and to commercial silicon AFM probes.


Assessment of deep learning-based auto-contouring on interobserver consistency in target volume and organs-at-risk delineation for breast cancer: Implications for RTQA program in a multi-institutional study.
To quantify interobserver variation (IOV) in target volume and organs-at-risk (OAR) contouring across 31 institutions in breast cancer cases and to explore the clinical utility of deep learning (DL)-based auto-contouring in reducing potential IOV. In phase 1, two breast cancer cases were randomly selected and distributed to multiple institutions for contouring six clinical target volumes (CTVs) and eight OAR. In Phase 2, auto-contour sets were generated using a previously published DL Breast segmentation model and were made available for all participants. The difference in IOV of submitted contours in phases 1 and 2 was investigated quantitatively using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). The qualitative analysis involved using contour heat maps to visualize the extent and location of these variations and the required modification. Over 800 pairwise comparisons were analysed for each structure in each case. Quantitative phase 2 metrics showed significant improvement in the mean DSC (from 0.69 to 0.77) and HD (from 34.9 to 17.9 mm). Quantitative analysis showed increased interobserver agreement in phase 2, specifically for CTV structures (5-19 %), leading to fewer manual adjustments. Underlying IOV differences causes were reported using a questionnaire and hierarchical clustering analysis based on the volume of CTVs. DL-based auto-contours improved the contour agreement for OARs and CTVs significantly, both qualitatively and quantitatively, suggesting its potential role in minimizing radiation therapy protocol deviation.


Influence of colors on habituation of visual evoked potentials in patients with migraine with aura and in healthy volunteers.
To investigate whether colored glasses influence the habituation of visual evoked potentials. We have previously shown that during pattern-reversal stimulations lasting 2 minutes the amplitude of the visual evoked potential increases in migraine with and without aura between attacks, whereas it decreases in healthy volunteers. Red light was found to increase visually evoked EEG fast activity only in children with migraine with aura. Wearing rose-tinted glasses for 4 months decreased attack frequency in parallel with a reduction of the visually evoked EEG fast activity. We compared the change in amplitude of the visual evoked potential using five different tinted glasses in 12 patients with migraine with aura and in 10 healthy volunteers. During continuous stimulation at 3.1 Hz, five blocks of 50 responses were sequentially averaged using red, yellow, green, blue, and grey glasses and without glasses in a random order and analyzed in terms of latencies and N1-P1 amplitudes. Amplitude changes were calculated for each block by comparison with the first block in every condition and analyzed statistically using Zerbe's method. In healthy volunteers, the visual evoked potential amplitude increased with red glasses compared to without glasses (P = .05) or with green glasses (P = .03). In patients with migraine with aura, no significant difference was detected using colored glasses. Our findings in healthy volunteers are in line with earlier reports of increased excitability of the human visual cortex when exposed to red light. The lack of such a pattern in patients with migraine with aura suggests that the visual cortex is interictally hypoexcitable rather than hyperexcitable, which is consistent with studies of transcranial magnetic stimulation.


High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.
High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. STN HFS did not affect the dopamine lesion-mediated overexpression of enkephalin mRNA or the decrease in substance P in the ipsilateral striatum. The lesion-induced increases in intraneuronal glutamate decarboxylase 67 kDa isoform (GAD67) mRNA levels on the lesion side were reversed by STN HFS in the substantia nigra, partially antagonized in the entopeduncular nucleus but unaffected in the globus pallidus. The stimulation did not affect neuropeptide or GAD67 mRNA levels in the side contralateral to the dopamine lesion or in intact animals. These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.


An instrument to monitor physiological and environmental parameters associated with heat stress on an ambulatory subject.
This paper outlines the development and construction of an instrument for use on an ambulatory subject which monitors selected physiological and environmental parameters that are a reflection of the degree of physiological strain associated with heat stress. The resulting instrument is rugged, reliable, and uses existing practical technology for in-the-field ambulatory monitoring, and provides minimal restriction to subject movement. The physiological parameters monitored (heart rate and skin temperature) were selected following examination of systemic, skin, and psychoneurotic heat disorders, with the environmental parameters (wind velocity, ambient temperature and relative humidity) based on existing heat stress indices' correlation with physiological parameters. A microprocessor is utilized for data acquisition, mathematical computation and long term storage, and software for downloading the data to a large mainframe computer is provided. Following calibration of the transduction circuits, the instrument was assembled and tested. Improvements are required to obtain the reliability originally envisaged. Additional field trials would see the collection of data to establish criteria to determine the values of the parameters monitored enabling prediction of the onset of heat stress in hot, humid environments.


IMP3, a Promising Prognostic Marker in Clear Cell Renal Cell Carcinoma.
Insulin-like growth factor II mRNA-binding protein 3 (IMP3) has been reported as a prognostic biomarker in various cancers. To validate IMP3 as a prognostic biomarker in renal cell carcinoma (RCC), we investigated the expression of IMP3, p53, and Ki-67, and their associations with clinicopathologic outcomes. We studied 148 clear cell RCCs (CCRCCs) from patients who underwent radical nephrectomy. The expression levels of IMP3, p53, and Ki-67 were assessed by immunohistochemical staining and the clinical and pathologic parameters were retrospectively reviewed. Twenty-nine percent of CCRCCs expressed IMP3. Forty-one percent of IMP3-immunopositive tumors developed metastases, while only 11.4% of IMP3-negative tumors developed metastases (p<.001). A Kaplan-Meier curve showed that patients with IMP3-immunopositive tumors had lower metastasis-free survival and cancer-specific survival than did those with IMP3-immunonegative tumors (p<.001 and p<.001, respectively). Expression of high Ki-67 proliferation index was also associated with a higher metastatic rate. In the multivariate Cox regression analysis, pT stage and IMP3-positivity were independently associated with disease-specific survival. IMP3 is an independent prognostic biomarker for patients with CCRCC to predict metastasis and poor outcome.


Hysteroscopy for Abnormal Uterine Bleeding and Fibroids.
Operative hysteroscopy is a safe and effective minimally invasive treatment option for submucosal and intramural leiomyomas. We discuss preoperative evaluation, fluid management, postoperative complications, preventative measures, and hysteroscopic outcomes. Technical instructions and tips for successful hysteroscopy, as well as the various equipment options most commonly utilized in the United States, are also reviewed.


A New Model Incorporating Axillary Ultrasound After Neoadjuvant Chemotherapy to Predict Non-Sentinel Lymph Node Metastasis in Invasive Breast Cancer.
Few models with good discriminative power have been introduced to predict the risk of non-sentinel lymph node (non-SLN) metastasis in breast cancer after neoadjuvant chemotherapy (NAC). We aimed to develop a new and simple model for predicting the probability of non-SLN metastasis in breast cancer and facilitate the selection of patients who could avoid unnecessary axillary lymph node dissection following NAC. A total of 298 patients diagnosed with invasive breast cancer, who underwent SLN biopsy after completing NAC and subsequently breast surgery, were included and classified into the training set (n=228) and testing set (n=70). Univariate and multivariate analyses were used to select factors that could be determined prior to breast surgery and significantly correlated with non-SLN metastasis in the training set. A logistic regression model was developed based on these factors and validated in the testing set. Nodal status before NAC, post-NAC axillary ultrasound status, SLN number, and SLN metastasis number were independent predictors of non-SLN metastases in breast cancer after NAC. A predictive model based on these factors yielded an area under the curve of 0.838 (95% confidence interval: 0.774-0.902, p< 0.001) in the training set. When applied to the testing set, this model yielded an area under the curve of 0.808 (95% confidence interval: 0.609-1.000, p= 0.003). A new and simple model, which incorporated factors that could be determined prior to breast surgery, was developed to predict non-SLN metastasis in invasive breast cancer following NAC. Although this model performed excellently in internal validation, it requires external validation before it can be widely utilized in the clinical setting.