Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults.
Little information is currently available on the role of the gut microflora in modulating isoflavone bioavailability or on sex differences in isoflavone metabolism and bioavailability. We sought to determine whether chronic soy consumption influences isoflavone bioavailability as judged by plasma isoflavone concentrations and modified gut microflora activities [beta-glucoside hydrolysis and equol and O-desmethylangolensin (O-DMA) production]. We also examined whether sex differences in isoflavone metabolism exist. A randomized, parallel, controlled study design was used to compare a high-soy diet (104 +/- 24 mg total isoflavones/d) with a low-soy diet (0.54 +/- 0.58 mg total isoflavones/d) in 76 healthy young adults for 10 wk. Concentrations of isoflavones and their gut microflora metabolites in the plasma, urine, and feces were significantly higher in the subjects who consumed the high-soy diet than in those who consumed the low-soy diet. Concentrations of O-DMA in plasma and urine were higher in the men than in the women. Fecal bacteria from subjects consuming both diets could convert daidzein to equol ex vivo. Fecal beta-glucosidase activity was significantly higher in the subjects who consumed the high-soy diet than in those who consumed the low-soy diet. Although interindividual variation in isoflavone metabolism was high, intraindividual variation was low. Only concentrations of O-DMA in plasma and urine appeared to be influenced by sex. Chronic soy consumption does not appear to induce many significant changes to the gut metabolism of isoflavones other than higher beta-glucosidase activity.


Toward optimal treatment in women: the effect of sex on metoprolol-diphenhydramine interaction.
The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher S-metoprolol AUC(0-infinity) and 26% and 71% lower CL/F, respectively, compared to men with the same phenotype (all Ps < .05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P < .0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P < .009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps < .05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men.


The physiology of willpower: linking blood glucose to self-control.
Past research indicates that self-control relies on some sort of limited energy source. This review suggests that blood glucose is one important part of the energy source of self-control. Acts of self-control deplete relatively large amounts of glucose. Self-control failures are more likely when glucose is low or cannot be mobilized effectively to the brain (i.e., when insulin is low or insensitive). Restoring glucose to a sufficient level typically improves self-control. Numerous self-control behaviors fit this pattern, including controlling attention, regulating emotions, quitting smoking, coping with stress, resisting impulsivity, and refraining from criminal and aggressive behavior. Alcohol reduces glucose throughout the brain and body and likewise impairs many forms of self-control. Furthermore, self-control failure is most likely during times of the day when glucose is used least effectively. Self-control thus appears highly susceptible to glucose. Self-control benefits numerous social and interpersonal processes. Glucose might therefore be related to a broad range of social behavior.


Monoclonal antibody NU-B1 reacts with novel antigen on human B cells in mantle and marginal zones distinct from known CD molecules.
To analyze the cellular antigens of human B-cell lineage, a monoclonal antibody, NU-B1, was raised using the acute lymphoblastic leukemia (ALL) cell line NALM-16 as the immunogen. NU-B1 reacted with 7.7+/-3.9% of the healthy adult peripheral blood mononuclear cells but not with neutrophils, monocytes, red blood cells or thymocytes. In order to distinguish the reaction specificity of NU-B1, two-color immunofluorescence staining using tonsillar cells was performed, and it was demonstrated that NU-B1-positive cells coexpressed CD20, which is a representative B-cell antigen. The expression of NU-B1 was highly restricted to cells of B-cell lineage when a panel of hematopoietic cell lines was examined. In a pathoimmunohistological study using human lymph node tissue, NU-B1-positive cells were localized in the mantle and marginal zones. In a clinical study, NU-B1 reacted specifically with leukemias/lymphomas of B-cell lineage: all 43 cases of ALL including common ALL and biphenotypic leukemia, all 4 cases of B-cell ALL, 6/7 B-cell type malignant lymphomas and 2/4 B-cell chronic lymphocytic leukemias. NU-B1 did not react with multiple myeloma, T-cell or myeloid leukemias/lymphomas. Immunoprecipitation of NU-B1 revealed two clear bands at 50 kDa and 42 kDa under either reducing or nonreducing conditions. Although anti-IgM treatment induced dramatic down modulation of CD79b, the NU-B1 antigen was also down modulated, but only slightly. However, crosslinking of NU-B1 did not induce tyrosine phosphorylation of intracellular proteins or the mobilization of calcium in NALM-16. The present results revealed that the antigenic determinant recognized by NU-B1 is not surface immunoglobulin chains, HLA-DR, a receptor for C3, Fc for immunoglobulin chains or any known CD molecule. We conclude that monoclonal antibody NU-B1 recognizes a novel human B-cell restricted antigen distinct from known CD molecules, and that it is a useful antibody in the immunophenotyping and classification of leukemias/lymphomas.


Reduction in p48-ISGFgamma levels confers resistance to interferon-alpha2a in MHCC97 cells.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in China and, due to the limited efficacy of currently available therapies, is responsible for a large number of deaths. IFN-alpha therapy has shown promise in the treatment of various forms of human cancer and is considered in the treatment of HCC. Previous results from our group showed that high doses of IFN-alpha exert a significant antiproliferative effect on MHCC97 human xenografts in nude mice, but not on MHCC97 cells when tested in vitro. Here we present experiments designed to characterize the molecular mechanism underlying the defective response of MHCC97 cells to IFN-alpha. Elucidation of the mechanism underlying the defective response of MHCC97 to IFN-alpha may help to explain and possibly to overcome clinical failures of this form of tumor therapy. IFN-alpha(2a) was administered between 3,000 and 10,000 IU/ml, a range strongly inhibiting proliferation in other cell lines. Gene expression profiles of MHCC97 cells were obtained before and after treatment with IFN-alpha(2a) using cDNA microarray analysis. The transcriptional activity of relevant genes responding to IFN-alpha(2a) in the cDNA microarray experiments was confirmed by RT-PCR and Northern blot analysis. Transient transfection with an expression vector was used to restore p48-ISGFgamma (IRF9) protein levels. Cell proliferation was evaluated using the MTT assay. Although IFN-alpha treatment caused the activation of several signal transduction pathways in MHCC97 cells, the lack of an antiproliferative effect was found to mainly derive from a defect in the activation of the transcription factor ISGF3 required for Jak/STATS signaling. We show that the defect in ISGF3 activation is mainly caused by the absence of one of its essential components, the protein p48-ISGFgamma from MHCC97 cells. Indeed, transient expression of p48-ISGFgamma restores sensitivity to IFN-alpha(2a). Although the mRNA levels of p48-ISGFgamma were normal in MHCC97 cells, mutations could be detected in the gene coding for the protein. We hypothesize, therefore, that these mutations alter the message or protein stability, leading to the reduced protein levels observed. Our results confirm the important role of Jak/STATS signaling in the antiproliferative effects of IFN-alpha in tumor cells and indicate that defects in ISGF3 can cause resistance to IFN-alpha(2a) treatment.


Chemokine Receptors and Phagocyte Biology in Zebrafish.
Phagocytes are highly motile immune cells that ingest and clear microbial invaders, harmful substances, and dying cells. Their function is critically dependent on the expression of chemokine receptors, a class of G-protein-coupled receptors (GPCRs). Chemokine receptors coordinate the recruitment of phagocytes and other immune cells to sites of infection and damage, modulate inflammatory and wound healing responses, and direct cell differentiation, proliferation, and polarization. Besides, a structurally diverse group of atypical chemokine receptors (ACKRs) are unable to signal in G-protein-dependent fashion themselves but can shape chemokine gradients by fine-tuning the activity of conventional chemokine receptors. The optically transparent zebrafish embryos and larvae provide a powerful in vivo system to visualize phagocytes during development and study them as key elements of the immune response in real-time. In this review, we discuss how the zebrafish model has furthered our understanding of the role of two main classes of chemokine receptors, the CC and CXC subtypes, in phagocyte biology. We address the roles of the receptors in the migratory properties of phagocytes in zebrafish models for cancer, infectious disease, and inflammation. We illustrate how studies in zebrafish enable visualizing the contribution of chemokine receptors and ACKRs in shaping self-generated chemokine gradients of migrating cells. Taking the functional antagonism between two paralogs of the CXCR3 family as an example, we discuss how the duplication of chemokine receptor genes in zebrafish poses challenges, but also provides opportunities to study sub-functionalization or loss-of-function events. We emphasize how the zebrafish model has been instrumental to prove that the major determinant for the functional outcome of a chemokine receptor-ligand interaction is the cell-type expressing the receptor. Finally, we highlight relevant homologies and analogies between mammalian and zebrafish phagocyte function and discuss the potential of zebrafish models to further advance our understanding of chemokine receptors in innate immunity and disease.


Origami paper-based sample preconcentration using sequentially driven ion concentration polarization.
Ion concentration polarization (ICP) is one of the preconcentration techniques which can acquire a high preconcentration factor. Still, the main hurdles of ICP are its instability and low efficiency under physiological conditions with high ionic strength and abundant biomolecules. Here, we suggested a sequentially driven ICP process, which enhanced the electrokinetic force required for preconcentration, enabling enrichment of highly ionic raw samples without increasing the electric field. We acquired a 13-fold preconcentration factor (PF) in human serum using a paper-based origami structure consisting of multiple layers for three-dimensional sequential ICP (3D seq-ICP). Moreover, we demonstrated a paper-based enzyme-linked immunosorbent assay (ELISA) by 3D seq-ICP using tau protein, showing a 6-fold increase in ELISA signals.


Superior efficacy of combination antibiotic therapy versus monotherapy in a mouse model of Lyme disease.
Lyme disease (LD) results from the most prevalent tick-borne infection in North America, with over 476,000 estimated cases annually. The disease is caused by Borrelia burgdorferi (Bb) sensu lato which transmits through the bite of Ixodid ticks. Most cases treated soon after infection are resolved by a short course of oral antibiotics. However, 10-20% of patients experience chronic symptoms because of delayed or incomplete treatment, a condition called Post-Treatment Lyme Disease (PTLD). Some Bb persists in PTLD patients after the initial course of antibiotics and an effective treatment to eradicate the persistent Bb is needed. Other organisms that cause persistent infections, such as M. tuberculosis, are cleared using a combination of therapies rather than monotherapy. A group of Food and Drug Administration (FDA)-approved drugs previously shown to be efficacious against Bb in vitro were used in monotherapy or in combination in mice infected with Bb. Different methods of detection were used to assess the efficacy of the treatments in the infected mice including culture, xenodiagnosis, and molecular techniques. None of the monotherapies eradicated persistent Bb. However, 4 dual combinations (doxycycline + ceftriaxone, dapsone + rifampicin, dapsone + clofazimine, doxycycline + cefotaxime) and 3 triple combinations (doxycycline + ceftriaxone+ carbomycin, doxycycline + cefotaxime+ loratadine, dapsone+ rifampicin+ clofazimine) eradicated persistent Bb infections. These results suggest that combination therapy should be investigated in preclinical studies for treating human Lyme disease.


Recent developments in filtration media and respirator technology in response to COVID-19.
The COVID-19 pandemic triggered a surge in demand for N95 or equivalent respirators that the global supply chain was unable to satisfy. This shortage in critical equipment has inspired research that addresses the immediate problems and has accelerated the development of the next-generation filtration media and respirators. This article provides a brief review of the most recent work with regard to face respirators and filtration media. We discuss filtration efficiency of the widely utilized cloth masks. Next, the sterilization of and reuse of existing N95 respirators to extend the existing stockpile is discussed. To expand near-term supplies, optimization of current manufacturing methods, such as melt-blown processes and electrospinning, has been explored. Future manufacturing methods have been investigated to address long-term supply shortages. Novel materials with antiviral and sterilizable properties with the ability for multiple reuses have been developed and will contribute to the development of the next generation of longer lasting multi-use N95 respirators. Finally, additively manufactured respirators are reviewed, which enable a rapidly deployable source of reusable respirators that can use any filtration fabric.


Development of CHARMM polarizable force field for nucleic acid bases based on the classical Drude oscillator model.
A polarizable force field for nucleic acid bases based on the classical Drude oscillator model is presented. Parameter optimization was performed to reproduce crystallographic geometries, crystal unit cell parameters, heats of sublimation, vibrational frequencies and assignments, dipole moments, molecular polarizabilities and quantum mechanical base-base and base-water interaction energies. The training and validation data included crystals of unsubstituted and alkyl-substituted adenine, guanine, cytosine, uracil, and thymine bases, hydrated crystals, and hydrogen bonded base pairs. Across all compounds, the RMSD in the calculated heats of sublimation is 4.1%. This equates to an improvement of more than 2.5 kcal/mol in accuracy compared to the nonpolarizable CHARMM27 force field. However, the level of agreement with experimental molecular volume decreased from 1.7% to 2.1% upon moving from the nonpolarizable to the polarizable model. The representation of dipole moments is significantly improved with the Drude polarizable force field. Unlike in additive force fields, there is no requirement for the gas-phase dipole moments to be overestimated, illustrating the ability of the Drude polarizable force field to treat accurately differently dielectric environments and indicating the improvements in the electrostatic model. Validation of the model was performed on the basis of the calculation of the gas-phase binding enthalpies of base pairs obtained via potential of mean force calculations; the additive and polarizable models both performed satisfactorily with average differences of 0.2 and 0.9 kcal/mol, respectively, and rms differences of 1.3 and 1.7 kcal/mol, respectively. Overall, considering the number of significant improvements versus the additive CHARMM force field, the incorporation of explicit polarizability into the force field for nucleic acid bases represents an additional step toward accurate computational modeling of biological systems.


Physical and material properties of an emulsion-based lipstick produced via a continuous process.
Water-in-oil emulsions in lipsticks could have the potential to improve moisturizing properties and deliver hydrophilic molecules to the lips. The aim of this work was to investigate the effect of a continuous process (scraped surface heat exchanger (SSHE) and pin stirrer (PS)) on the physical and material properties of an emulsion-based lipstick by altering the processing conditions of both the SSHE and PS. Emulsion formation was achieved using a SSHE and PS. Emulsions were analysed using nuclear magnetic resonance restricted diffusion (droplet size), texture analysis and rheology (mechanical properties). Results showed that a higher impeller rotational velocity (IRV) (1500 r.p.m.) and a lower exit temperature (52°C) produce the smallest droplets (~ 4 μm), due to greater disruptive forces and a higher viscosity of the continuous phase. The addition of a PS reduces the droplet size (14-6 μm) if the SSHE has a low IRV (500 r.p.m.), due to greater droplet disruption as the emulsion passes through the PS unit. Results also show that if the jacket temperature of a SSHE is 65°C, so that crystallization occurs in both process and post-production, droplets can be integrated into the network resulting in a stiffer wax network (G' - 0.12, in comparison to 0.02 MPa). This is due to small crystals creating a shell around water droplets which can form connections with the continuous network forming a structured network. The addition of a pin stirrer can disrupt a formed network reducing the stiffness of the emulsion (0.3-0.05 MPa). This work suggests the potential use of a continuous process in producing an emulsion-based lipstick, particularly when wax crystals are produced in the process. Future work should consider the moisturizing or lubricating properties of wax continuous emulsions and the release of hydrophilic compounds from the aqueous phase.


Role of paired basic residues of protein C-termini in phospholipid binding.
It is a well known phenomenon that the occurrence of several distinct amino acids at the C-terminus of proteins is non-random. We have analysed all Saccharomyces cerevisiae proteins predicted by computer databases and found lysine to be the most frequent residue both at the last (-1) and at the penultimate amino acid (-2) positions. To test the hypothesis that C-terminal basic residues efficiently bind to phospholipids we randomly expressed GST-fusion proteins from a yeast genomic library. Fifty-four different peptide fragments were found to bind phospholipids and 40% of them contained lysine/arginine residues at the (-1) or (-2) positions. One peptide showed high sequence similarity with the yeast protein Sip18p. Mutational analysis revealed that both C-terminal lysine residues of Sip18p are essential for phospholipid-binding in vitro. We assume that basic amino acid residues at the (-1) and (-2) positions in C-termini are suitable to attach the C-terminus of a given protein to membrane components such as phospholipids, thereby stabilizing the spatial structure of the protein or contributing to its subcellular localization. This mechanism could be an additional explanation for the C-terminal amino acid bias observed in proteins of several species.


Management of the psychological comorbidities of dermatological conditions: practitioners' guidelines.
Dermatological disease can be devastating for patients, and although dermatologists are focused on remedying the cutaneous manifestations of these conditions, it is easy to miss the psychological suffering lurking below. Studies reveal that psychiatric comorbidity in dermatology is highly prevalent. Undetected psychopathology can greatly decrease a patient's quality of life and even contribute significantly to the clinical severity of their skin disease. For these reasons, it is vital that practitioners learn to detect psychological distress when it is present, and it is equally essential that they understand the treatment options available for effective intervention. Without training in psychiatric diagnosis and psychopharmacology, dermatologists can easily feel overwhelmed or out of their comfort zone when faced with the need to manage such conditions, but with the negative stigma associated with psychiatric disease in general, a psychiatric referral is often refused by patients, and the dermatologist is thus left with the responsibility. Uncertainty abounds in such situations, but this review seeks to alleviate the discomfort with psychodermatological disease and share practical and impactful recommendations to assist in diagnosis and treatment. In a busy dermatology clinic, the key is effective and efficient screening, combined with a repertoire of pharmacological and non-pharmacological treatment options that can be dispersed through an algorithmic approach according to the specific findings of that screening. By implementing these recommendations into practice, dermatologists may begin to gain comfort with the management of psychocutaneous disease and, as a specialty, may expand to fill a hole in patient care that is truly significant for patients, their families, and our communities as a whole.


Beam broadening in dense scattering media.
The full 3-D integral equation for the spherically symmetric scattering of light in a medium of densely packed uniformly distributed scattering centers is solved for the case of a cylindrically symmetric laser beam (Gaussian profile) directed normally at the slab. After reduction to a 2-D problem, the discretized integral equation for the intensity (irradiance) of the scattered light is solved by a standard iteration procedure. The resulting 2-D distribution is reconverted to 3-D to obtain the r and z dependence of the irradiance. From the solution the angular distribution of backward and forward scattered light is calculated; special emphasis is placed on the radial dependence of the scattered light emerging normal to the surface in both directions. Spot sizes are defined and calculated for various values of beam radius and material parameters, nominally chosen to represent irradiation of white (translucent) biological tissue by a Nd:YAG laser. The effect of increasing the scattering coefficient on the spot profiles and radii is studied.


Androgen stimulation and laryngeal development.
Androgen-induced changes in laryngeal growth patterns were studied using a sheep animal model. Forty-eight lambs were divided into eight treatment groups. Lambs in seven of the groups were castrated at birth, while lambs in the eighth group served as an intact (noncastrated) control. Six groups were then treated with varying doses of testosterone and dihydrotestosterone, while the seventh served as a castrated, nontreated control. All animals were killed and gross dissections of the larynges were performed. Thirty-four linear and angular measurements were obtained from each larynx. The mean superior thyroid horn separation showed the most dramatic androgen-induced effect (p = 0.023). Laryngeal anterior-posterior diameter, superior thyroid horn height, posterior thyroid cartilage width, thyroid cartilage angle, and vocal process to arytenoid base distances all demonstrated positive dose-response relationships. Hypoandrogenic levels appeared to have an inhibitory effect upon laryngeal growth when compared to castrated controls.


Brain activity elicited by reward and reward omission in individuals with psychopathic traits: An ERP study.
Psychopathy has been associated with behavioral adaptation deficits, which might be associated with problems in feedback and reward processing. In the present study, we examined the relation between psychopathic traits and reward processing in a passive gambling task. A total of 39 male participants who scored high (HP) and 39 male participants who scored low (LP) on the Triarchic Psychopathy Measure (TriPM), total score were tested. Feedback-related Event-Related Potentials (ERPs; i.e., P2, FRN, and P3) on predicted and unpredicted rewards and reward omissions were compared between both groups. It was found that in HP individuals, the P2 was enhanced for predicted rewards and reward omissions, but not for unpredicted stimuli. Moreover, HP individuals as compared to the LP individuals demonstrated a generally reduced P3 amplitude. The FRN amplitude, however, did not differ between the two groups. In addition, HP individuals showed enhanced reward sensitivity on the self-report level. Taken together, these findings suggest that HP individuals show enhanced sensitivity to early and reduced sensitivity to later markers of processing reinforcement learning signals, which points in the direction of compromised behavioral adaptation.


An optoelectric plantar "shear" sensing transducer: design, validation, and preliminary subject tests.
A prototype miniature plantar shear sensing transducer was developed, characterized, and tested in this study. Electro-optical components were chosen for the design because of the fast response time, low cost, small size, low power requirements, and adaptability to this application. The optoelectric circuit employed a 660 nm wavelength light source and photodiode solar cell. Signal amplification and sensitivity were adjusted to provide an output voltage proportional to light power. The sensor shell was designed to encapsulate the electro-optical sensing components while providing mechanical resistance to shear through a spring mechanism. A naval bronze was chosen for the shell due to its strength and nonreflective characteristics (alloy of copper and tin). Static and dynamic characteristics of the shear sensor were determined through a series of calibration tests. Mechanical crosstalk sensitivity ranged from 14.34 to 30.51 mV/N. This represented 1% full-scale/Newton sensitivity. Nonlinearity averaged 5.6% in the forward direction and 7.6% in the reverse direction. Overall sensor output hysteresis was 1.1 +/- 3.1% while the natural frequency of the sensor to an input shear transient was approximately 5 Hz. Temperature sensitivity was -7.0 mV/degree C or 3.5% full-scale/degree C. Testing of five adult subjects revealed peak anterior-posterior shear ranging from 6.7 kPa (posterior heel) to 51.4 kPa (great toe) and medial-lateral shear ranging from 5.4 kPa (great toe) to 43.5 kPa (first metatarsal head). Stress-time integral values ranged from 0.78 kPa-sec (posterior shear at the posterior heel) to 37.3 kPa-sec (medial shear at the posterior heel). Contact durations ranged from 0.28 sec (posterior shear at the posterior heel) to 1.25 sec (medial shear at the posterior heel). Further application of the sensor for plantar shear characterization in able-bodied subjects and those with pathology is suggested.


The HF-AF ENERGY Trial: Nicotinamide Riboside for the Treatment of Atrial Fibrillation in Heart Failure Patients.
The presence of atrial fibrillation (AF) in heart failure (HF) patients with reduced ejection fraction is common and associated with an increased risk of stroke, hospitalization and mortality. Recent research findings indicate that a reduction in nicotinamide adenine dinucleotide (NAD+) levels results in mitochondrial dysfunction, DNA damage and consequently cardiomyocyte impairment in experimental and clinical HF and AF. The HF-AF ENERGY trial aims to investigate the cardioprotective effects of the NAD+ precursor nicotinamide riboside (NR) treatment in ischemic heart disease patients diagnosed with AF. The HF-AF ENERGY trial is a prospective intervention study. The study consists of a (retrospective) 4 months observation period and a 4 months intervention period. The cardioprotective effect of NR on AF burden is investigated by remote monitoring software of implantable cardiac defibrillators (ICDs), which enables continuous atrial rhythm monitoring detection. Cardiac dimension and function are examined by echocardiography. Laboratory blood analysis is performed to determine mitochondrial function markers and energy metabolism. All the study parameters are assessed at two fixed time points (pre- and post-treatment). Pre- and post-treatment outcomes are compared to determine the effects of NR treatment on AF burden, mitochondrial function markers and energy metabolism. The HF-AF ENERGY trial investigates the cardioprotective effects of NR on AF burden and whether NR normalizes blood-based mitochondrial function markers and energy metabolites of the NAD metabolome in ischemic heart disease patients diagnosed with AF. The study outcomes elucidate whether NAD+ metabolism can be used as a future therapy for HF patients with AF.


Psychosocial impact of Peutz-Jeghers Syndrome.
Peutz-Jeghers Syndrome (PJS) is an autosomal dominant inherited cancer predisposition syndrome and gastrointestinal hamartomatous polyposis syndrome characterized by the presence of distinct perioral freckling. To date, we have not found any tool that specifically assesses the psychosocial impact of PJS on patients. We developed a PJS quality of life questionnaire using expert opinions of 3 cancer genetic counselors and a survey of patients with PJS through recruitment of participants involved in a support group over the internet. We measured and compared our questionnaire results to the widely used Center for Epidemiologic Studies and Depression Scale (CES-D) and the Short Form 36 (SF-36). We recruited 38 patients for our study. Volunteers were mailed a consent form, the self-administered CES-D, SF-36 and our developed PJS questionnaire and were instructed to return the completed questionnaires by mail. Results showed that PJS patients suffer from mild depression even though physically they did not feel impacted by their condition compared to the general population. However, having PJS caused them to alter many important life decisions. The PJS Questionnaire correlated with data obtained from analysis of CES-D, as well as the SF-36. More uniquely, it provided specific information regarding the burden of disease and quality of life in patients affected with Peutz-Jeghers syndrome. Its ability to do so for other polyposis syndrome populations remains to be studied. These results are important in developing plan of care for these patients regarding genetic counseling and surveillance strategies for PJS patients.


The Swiss Multiple Sclerosis Registry (SMSR): study protocol of a participatory, nationwide registry to promote epidemiological and patient-centered MS research.
Multiple sclerosis (MS) is one of the most frequently observed neurological conditions in Switzerland, but data sources for country-wide epidemiological trend monitoring are lacking. Moreover, while clinical and laboratory MS research are generally well established, there is a gap in patient-centered MS research to inform care management, or treatment decisions and policy making not only in Switzerland but worldwide. In light of these research gaps, the Swiss Multiple Sclerosis Society initiated and funded the Swiss Multiple Sclerosis Registry (SMSR) an open-ended, longitudinal and prospective, nationwide, patient-centered study. The SMSR recruits adult persons with a suspected or confirmed MS diagnosis who reside or receive care in Switzerland. The SMSR has established a governance structure with clear rules and guidelines. It follows a citizen-science approach with direct involvement of persons with MS (PwMS), who contribute actively to registry development, operations, and research. Main scientific goals entail the study of MS epidemiology in Switzerland, health care access and provision, as well as life circumstances and wellbeing of persons with MS. The innovative study design ("layer model") offers several participation options with different time commitments. Data collection is by means of regular surveys and medical record abstraction. Survey participation is offered in different modes (web, paper & pencil) and in the three main national languages (German, French, Italian). Participants also receive regular data feedbacks for personal use and self-monitoring, contextualized in the whole population of study participants. Data feedbacks are also used to solicit data corrections of key variables from participants. The SMSR combines the advantages of traditional and novel research methods in medical research and has recruited over 1600 PwMS in its first year. The future-oriented design and technology will enable a response not only to future technological innovations and research trends, but also to challenges in health care provision for MS. ClinicalTrials.gov NCT02980640 ; December 6, 2016; retrospectively registered.


Role of genomics in identifying new targets for cancer therapy.
The detailed map of the human genome can potentially transform future cancer therapy by merging genomics with pharmacology, thereby identifying which patients will benefit from specific therapeutic agents. Single-nucleotide polymorphisms (SNPs) provide a valuable tool for this pharmacogenetic approach to cancer therapy. The discovery of SNPs as disease markers may facilitate identification of populations at increased risk for certain cancers. In addition, SNP genetic screening may facilitate administration of appropriate treatment modalities or reveal specific genetic profiles that have importance in drug efficacy and toxicity. In addition to SNP analysis, DNA and tissue microarray analyses have the potential to transform the future of cancer therapy. For example, DNA microarrays may improve tumor classification systems as well as provide a molecular level dissection of global gene expression changes that occur in carcinogenesis. Tissue microarrays would allow one to verify candidate genes, identified from DNA microarrays, against archival tumor specimens with known clinical outcome. In addition, both microarray technologies may be combined to rapidly validate gene targets. We will review and discuss these state-of-the-art technologies including data suggesting that the combined use of these high throughput technologies will facilitate our understanding of the genetic complexities inherent in cancer and will revolutionize cancer therapy.


Human apurinic/apyrimidinic endonuclease siRNA inhibits the angiogenesis induced by X-ray irradiation in lung cancer cells.
Radiotherapy is an important and effective treatment method for non-small cell lung cancer (NSCLC). Nonetheless, radiotherapy can alter the expression of proangiogenic molecules and induce angiogenesis. Human apurinic/apyrimidinic endonuclease (APE1) is a multifunctional protein, which has DNA repair and redox function. Our previous studies indicated APE1 is also a crucial angiogenic regulator. Thus, we investigated the effect of APE1 on radiation-induced angiogenesis in lung cancer and its underlying mechanism. Tumor specimens of 136 patients with NSCLC were obtained from 2003 to 2008. The APE1 and vascular endothelial growth factor (VEGF) expression, as well as microvessel density (MVD) were observed with immunohistochemistry in tumor samples. Human lung adenocarcinoma A549 cells were treated with Ad5/F35-APE1 siRNA and/or irradiation, and then the cells were used for APE1 analysis by Western blot and VEGF analysis by RT-PCR and ELISA. To elucidate the underline mechanism of APE1 on VEGF expression, HIF-1α protein level was determined by Western blot, and the DNA binding activity of HIF-1α was detected by EMSA. Transwell migration assay and capillary-like structure assay were used to observe the migration and capillary-like structure formation ability of human umbilical veins endothelial cells (HUVECs) that were co-cultured with Ad5/F35-APE1 siRNA and (or) irradiation treated A549 cells culture medium. The high expression rates of APE1 and VEGF in NSCLC were 77.94% and 66.18%, respectively. The expressions of APE1 was significantly correlated with VEGF and MVD (r=0.369, r=0.387). APE1 and VEGF high expression were significantly associated with reduced disease free survival (DFS) time. The high expressions of APE1 and VEGF on A549 cells were concurrently induced by X-ray irradiation in a dose-dependent manner. Silencing of APE1 by Ad5/F35-APE1 siRNA significantly decreased DNA binding activity of HIF-1α and suppressed the expression of VEGF in A549 cells, moreover, significantly inhibited the endothelial cells immigration and capillary-like structure formation induced by irradiated A549 cells. Our results indicate that APE1 may play a crucial role in angiogenesis induced by irradiation. Administration of Ad5/F35-APE1 siRNA during radiotherapy could be a potent adjuvant therapeutic approach to enhance the radiotherapy response, effectively eliminate metastasis and improve the efficacy of radiotherapy for NSCLC.


Effects of two conventional preoperative radiation schedules on anastomotic healing in the rat colon.
Preoperative radiotherapy (RT) is an increasingly popular form of adjunct therapy for rectal cancer; however, little is known about its effects on matrix metalloproteinase (MMP) expression in colonic anastomotic healing. Wistar rats were irradiated to a total dose of 25 or 40 Gy. Four days after the end of RT, an end-to-end colorectal anastomosis was performed. Animals were sacrificed at 1, 3, and 7 days after the anastomosis. A control group was studied similarly, but was not irradiated. No significant differences were found in peritonitis rate and anastomotic complications. The average bursting pressure and breaking strength were only reduced significantly in the rats irradiated with 40 Gy. However, the concentration and the content of hydroxyproline in anastomotic tissues were unchanged. In irradiated rats, MMP-2 and MMP-9 were significantly increased at 40 Gy, but not at 25 Gy. On the other hand, 25-Gy irradiation induced a smaller increase in the levels of the tissue inhibitors of metalloproteinase-1 compared with the controls. Anastomotic strength is adversely affected by high-dose fractionated preoperative RT. In contrast, preoperative RT at 25 Gy in five fractions over 5 days is safe with regard to the maintenance of wound strength in colorectal anastomosis.


Loneliness among cancer caregivers: A narrative review.
Providing care to a loved one with cancer places demands on caregivers that result in changes to their daily routines and disruptions to their social relationships that then contribute to loneliness. Though caregivers' psychosocial challenges have been well studied, loneliness - a determinant of health - has not been well studied in this population. This narrative review sought to describe the current evidence on loneliness among caregivers of cancer patients. We aimed to (1) define loneliness, (2) describe its prevalence, (3) describe the association between loneliness and health outcomes, (4) describe risks and consequences of loneliness among cancer caregivers, (5) identify ways to assess loneliness, and (6) recommend strategies to mitigate loneliness in this unique population. We used evidence from articles listed in PubMed, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases, book chapters, and reports. Articles were reviewed for the following inclusion criteria: (1) published in English, (2) caregivers of cancer patients, (3) loneliness as a study variable, and (4) peer-reviewed with no restriction on the timeframe of publication. Caregivers were defined as relatives, friends, or partners who provide most of the care and support for someone with cancer. Eighteen studies met inclusion criteria and were included in the analysis. Caregivers' experiences of loneliness can contribute to negative effects on one's social, emotional, and physical well-being. Social support interventions may not be sufficient to address this problem. Existing recommendations to mitigate loneliness include cognitive and psychological reframing, one-on-one and group therapy, befriending, resilience training, and technology-based interventions. Limited attention to loneliness in cancer caregivers poses a twofold problem that impacts patient and caregiver outcomes. Interventions are critically needed to address loneliness as a determinant of health in caregivers, given their pivotal role in providing care and impacting health outcomes for people with cancer.


Efficacy of methylprednisolone therapy for the injured rat spinal cord.
Currently the synthetic glucocorticosteroid methylprednisolone sodium succinate (MPSS) is the standard therapy after acute spinal cord injury (SCI) in humans based on reported neurological improvements. The mechanisms for its beneficial actions are not entirely clear, but experimental evidence suggests MPSS affords some degree of neuroprotection. As many studies with rat models of SCI have been unable to demonstrate improved behavioral outcome or tissue sparing after MPSS treatment, we chose to stereologically assess whether it alters lesion volume and tissue sparing over time, as well as long-term behavioral recovery. Adult rats subjected to contusion SCI with the NYU impactor were administered either MPSS or saline for 24 hr beginning 5 min post injury. Over time the lesion dimensions were extremely dynamic, such that by 6 weeks post injury the volumes were reduced to a third of those seen after the first week. MPSS marginally reduced lesion volumes across time vs. controls, but the amount of spared gray and white matter remained unaltered between the two groups. Behavioral results further showed that MPSS failed to improve recovery of hind-limb function. These findings add to the emerging scrutiny of MPSS as the standard therapy for acute SCI, as well as indicate the existence of a therapeutic window for tissue sparing restricted to the first several days after this type of SCI in rats. Equally important, our results caution the use of lesion volume dimensions or percent tissue sparing at the epicenter as indicators of therapeutic efficacy because neither reflects the actual amount of tissue sparing.


Chaperone-mediated in vitro assembly of Polyomavirus capsids.
The polyomavirus coat protein viral protein 1 (VP1) has the intrinsic ability to self-assemble in vitro into polymorphic capsid-like structures on addition of calcium. In contrast, polyomavirus assembly in vivo is rigorously controlled, such that virions of uniform size are formed only in the cell nucleus. During viral infection, the 72 kDa cellular chaperone heat shock cognate protein (hsc70) binds VP1 posttranslation and colocalizes with VP1 to the nucleus, thereby suggesting a role for approximately 70-kDa heat shock protein (hsp70) family chaperones in regulating the quality and location of capsid assembly. We found that, after expression of recombinant VP1 in Escherichia coli, the prokaryotic hsp70 chaperone DnaK copurified with the VP1 C-terminal domain that links pentamers in an assembled capsid. When stably bound to VP1, DnaK inhibited in vitro assembly induced by calcium. However, in the presence of ATP, the hsp70 chaperone system comprised of DnaK, DnaJ, and GrpE assembled VP1 into uniform capsids without requiring calcium. Chaperone-mediated assembly was similarly catalyzed by the eukaryotic hsc70 protein, in combination with the J-domain function of the simian virus 40 large T-antigen protein. Thus, polyomavirus capsid assembly can be recapitulated with high-fidelity in vitro using either prokaryotic or eukaryotic hsp70 chaperone systems, thereby supporting a role for cellular chaperones in the in vivo regulation of virion assembly.


Host specificity and clade dependent distribution of putative virulence genes in Moritella viscosa.
Moritella viscosa is the aetiological agent of winter-ulcer disease in farmed salmonids in the North Atlantic. Previously, two major (typical and variant) genetic clades have been demonstrated within this bacterial species, one of which is almost solely related to disease in Atlantic salmon (Salmo salar). In the present study infection trials demonstrated that 'typical' M. viscosa isolated from Norwegian Atlantic salmon was highly virulent in this fish species but resulted in lower levels of mortality in rainbow trout. 'Variant' M. viscosa isolated from rainbow trout resulted in modest mortality levels in both Atlantic salmon and rainbow trout. To investigate the possible genetic background for inter-strain virulence differences, 38 M. viscosa isolates of diverse geographical origin and host species and a number of other Moritella spp. were investigated for the presence/absence of putative virulence related homologs. All isolates were positive for DNA sequences coding for; the Type VI secretion ATPase (clpV), hemolysin co-regulated protein (hcp), bacterioferritins (bfrA and bfrB), lectin (hemG), phospholipase D (pld), multifunctional autoprocessing repeats-in-toxin (martxA), aerolysin (aer), invasin (inv), and cytotoxic necrotizing factor (cnf), with the exception of one isolate in which cnf could not be confirmed. The product of an ABC transporter metal-binding lipoprotein (mat) was consistently detected although 11 isolates, all phylogenetically related, appear to produce a truncated version. A putative insecticidal toxin complex (mitABC) was detected almost exclusively in 'typical' Atlantic salmon isolates, and our data indicate that this complex of genes is expressed and co-transcribed. Transmission electron microscopy investigation revealed pili and flagella surface structures on nine M. viscosa representing both typical and variant isolates. Our results provide strong support for the existence of host specificity/high virulence in 'typical' M. viscosa related to Atlantic salmon. The gene distribution also provides further support for the genetic division within M. viscosa, and constitutes a basis for further study of the importance of the mitABC complex in winter-ulcer pathogenesis.


Single aggressive interactions increase urinary glucocorticoid levels in wild male chimpanzees.
A basic premise in behavioural ecology is the cost-benefit arithmetic, which determines both behavioural decisions and evolutionary processes. Aggressive interactions can be costly on an energetic level, demanding increased energy or causing injuries, and on a psychological level, in the form of increased anxiety and damaged relationships between opponents. Here we used urinary glucocorticoid (uGC) levels to assess the costs of aggression in wild chimpanzees of Budongo Forest, Uganda. We collected 169 urine samples from nine adult male chimpanzees following 14 aggressive interactions (test condition) and 10 resting events (control condition). Subjects showed significantly higher uGC levels after single aggressive interactions compared to control conditions, likely for aggressors as well as victims. Higher ranking males had greater increases of uGC levels after aggression than lower ranking males. In contrast, uGC levels showed no significant change in relation to aggression length or intensity, indicating that psychological factors might have played a larger role than mere energetic expenditure. We concluded that aggressive behaviour is costly for both aggressors and victims and that costs seem poorly explained by energetic demands of the interaction. Our findings are relevant for studies of post-conflict interactions, since we provide evidence that both aggressors and victims experience a stress response to conflict.


Effects of different interventions on internet addiction: a systematic review and network meta-analysis.
Globally, Internet is a recognized form of leisure, but there are growing apprehensions about the increasing number of individuals developing an addiction to it. Recent research has focused on social issues associated with internet addiction (IA). However, the treatment of IA is currently unclear. This study aimed to explore the relationship between IA treatment outcomes and different intervention strategies through systematic review and data analysis of patients who received different intervention modes. A meta-analysis was conducted using RevMan 5.4 and Stata 14.2 on 57 literature research data from five Chinese and English databases, PubMed, Embase, Web of Science, Wanfang and CNKI. A total of 57 randomized controlled trials (RCTs) were included in this network meta-analysis involving 3538 IA patients and 13 different interventions. The network meta-analysis results demonstrated that the top four interventions were: rTMS + CBT, drug + others, rTMS, and electro-acupuncture + CBT. Our study indicated that comprehensive therapy had an optimal therapeutic effect on IA patients and rTMS + CBT ranked first among all therapeutic indicators of intervention, indicating optimal clinical effectiveness.


Metabolome Profiling of Partial and Fully Reprogrammed Induced Pluripotent Stem Cells.
Acquisition of proper metabolomic fate is required to convert somatic cells toward fully reprogrammed pluripotent stem cells. The majority of induced pluripotent stem cells (iPSCs) are partially reprogrammed and have a transcriptome different from that of the pluripotent stem cells. The metabolomic profile and mitochondrial metabolic functions required to achieve full reprogramming of somatic cells to iPSC status have not yet been elucidated. Clarification of the metabolites underlying reprogramming mechanisms should enable further optimization to enhance the efficiency of obtaining fully reprogrammed iPSCs. In this study, we characterized the metabolites of human fully reprogrammed iPSCs, partially reprogrammed iPSCs, and embryonic stem cells (ESCs). Using capillary electrophoresis time-of-flight mass spectrometry-based metabolomics, we found that 89% of analyzed metabolites were similarly expressed in fully reprogrammed iPSCs and human ESCs (hESCs), whereas partially reprogrammed iPSCs shared only 74% similarly expressed metabolites with hESCs. Metabolomic profiling analysis suggested that converting mitochondrial respiration to glycolytic flux is critical for reprogramming of somatic cells into fully reprogrammed iPSCs. This characterization of metabolic reprogramming in iPSCs may enable the development of new reprogramming parameters for enhancing the generation of fully reprogrammed human iPSCs.


Polymorphism and gene conversion in mouse alpha-globin haplotypes.
We have cloned and characterized three distinct alpha-globin haplotypes obtained from inbred strains of the mouse, Mus domesticus. We report here the complete nucleotide sequence of the six alpha-globin genes that the haplotypes contain. Our analysis of these genes and those from one other previously described haplotype indicates that recurrent gene conversion events have played a major role in their history. The pattern of nucleotide substitutions suggests that conversions have occurred both within and between haplotypes. Limited segments of coding and noncoding DNA have been involved in these gene conversion events. In two of the haplotypes, the nonallelic genes of each maintain DNA sequence identity over discrete intervals and encode the same alpha-globin polypeptide. On the other hand, the coding regions of some genes have accumulated replacement changes that result in distinct alpha-globins. In one instance, these changes appear to reflect positive selection of advantageous mutations.


Interatomic Coulombic decay as a new source of low energy electrons in slow ion-dimer collisions.
We provide the experimental evidence that the single electron capture process in slow collisions between O^{3+} ions and neon dimer targets leads to an unexpected production of low-energy electrons. This production results from the interatomic Coulombic decay process, subsequent to inner-shell single electron capture from one site of the neon dimer. Although pure one-electron capture from the inner shell is expected to be negligible in the low collision energy regime investigated here, the electron production due to this process overtakes by 1 order of magnitude the emission of Auger electrons by the scattered projectiles after double-electron capture. This feature is specific to low charge states of the projectile: similar studies with Xe^{20+} and Ar^{9+} projectiles show no evidence of inner-shell single-electron capture. The dependence of the process on the projectile charge state is interpreted using simple calculations based on the classical over the barrier model.


Muscle Fitness Changes During Childhood Associates With Improvements in Cardiometabolic Risk Factors: A Prospective Study.
The role of muscle fitness in controlling cardiometabolic risk factors during childhood is incompletely understood. A prospective observational design including 6- to 11-year-old children (n = 512) was used to study associations between 1.5-year changes in handgrip strength, standing vertical jump displacement, the short shuttle run, and a composite of these with changes in composite and single cardiometabolic risk markers. The authors modeled sequential mixed linear regressions controlling for changes in cardiorespiratory fitness, waist circumference, and other putative confounding variables. Statistically significant associations, standardized beta (95% confidence intervals), were observed between changes in composite muscle fitness -0.19 (-0.30 to -0.07), muscular strength -0.15 (-0.25 to -0.06), and agility 0.14 (0.04 to 0.23), but not muscular power -0.06 (-0.14 to 0.03) with changes in the composite risk score. In sex-stratified analysis, associations were robust in girls, but not in boys. Control for changes in cardiorespiratory fitness and waist circumference greatly attenuated associations. Changes in muscle fitness were strongly associated with changes in waist circumference in both girls -0.21 (-0.37 to -0.05) and boys -0.23 (-0.35 to -0.11) after controlling for cardiorespiratory fitness. Our data support a unique role of muscle fitness in the promotion of metabolic health and prevention of excess adipose tissue accumulation in children.


Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas.
Overall, pediatric high-grade glioma (pHGG) has a poor prognosis, in part due to the lack of understanding of the underlying biology. High-resolution 244 K oligo array comparative genomic hybridization (CGH) was used to analyze DNA from 38 formalin-fixed paraffin-embedded predominantly pretreatment pHGG samples, including 13 diffuse intrinsic pontine gliomas (DIPGs). The patterns of gains and losses were distinct from those seen in HGG arising in adults. In particular, we found 1q gain in up to 27% of our cohort compared with 9% reported in adults. A total of 13% had a balanced genetic profile with no large-scale copy number alterations. Homozygous loss at 8p12 was seen in 6 of 38 (16%) cases of pHGG. This novel deletion, which includes the ADAM3A gene, was confirmed by quantitative real-time PCR (qPCR). Loss of CDKN2A/CDKN2B in 4 of 38 (10%) samples by oligo array CGH was confirmed by fluorescent in situ hybridization on tissue microarrays and was restricted to supratentorial tumors. Only ∼50% of supratentorial tumors were positive for CDKN2B expression by immunohistochemistry (IHC), while ∼75% of infratentorial tumors were positive for CDKN2B expression (P = 0.03). Amplification of the 4q11-13 region was detected in 8% of cases and included PDGFRA and KIT, and subsequent qPCR analysis was consistent with the amplification of PDGFRA. MYCN amplification was seen in 5% of samples being significantly associated with anaplastic astrocytomas (P= 0.03). Overall, DIPG shared similar spectrum of changes to supratentorial HGG with some notable differences, including high-frequency loss of 17p and 14q and lack of CDKN2A/CDKN2B deletion. Informative genetic data providing insight into the underlying biology and potential therapeutic possibilities can be generated from archival tissue and typically small biopsies from DIPG. Our findings highlight the importance of obtaining pretreatment samples.


Arrhythmogenicity of scuba diving: Holter monitoring in a hyperbaric environment.
About 26% of diving-related fatalities are caused by cardiac disease, part of which might be associated with fatal arrhythmias. This raises the question as to whether fatal arrhythmias are being provoked by hyperbaric conditions themselves or if exercise or stress provokes the fatal arrhythmias in cases of underlying (ischemic) cardiac disease. To measure the influence of hyperbaric conditions (50 msw) on cardiac conduction and arrhythmias in professional divers by means of ECG. This is a prospective study on military divers in a hyperbaric chamber with continuous ECG monitoring using Holter registrations. Supraventricular and ventricular ectopy was registered during hyperbaric conditions. RR, PR, QRS, QT and QTc intervals were calculated at 50 msw and compared with ECGs at rest. Included were 17 male military divers who made 20 dives. A total of 10 PVCs, 45 PACs, four atrial runs and four atrial pairs were seen. Significant prolongation of the PR interval was seen and a decrease of in QRS duration at 50 msw. There was no significant change in the RR, QT and QTc intervals. In these divers, no clinically relevant arrhythmias were observed during wet dives in a recompression chamber at 50 msw. We observed a small prolongation of PR interval that is probably not clinically relevant in divers without any known conduction disorders.


Practical constraints in the kinetic plot representation of chromatographic performance data: theory and application to experimental data.
It is demonstrated that the kinetic plot representation of experimental plate height data can also account for practical constraints on the column length, the peak width, the viscous heating, and the mobile-phase velocity without needing any iterative solution routine. This implies that the best possible kinetic performance to be expected from a given tested support under any possible set of practical optimization constraints can always be found using a directly responding calculation spreadsheet template. To show how the resulting constrained kinetic plots can be used as a powerful design and selection tool, the method has been applied to a series of plate height measurements performed on a number of different commercial columns for the same component (butyl-parabene) and mobile-phase composition. The method, for example, allows one to account for the fact that the advantageous solutions displayed by the silica monolith and 5 microm particle columns in the large plate number range of the free kinetic plot are no longer accessible if applying a maximal column length constraint of Lmax = 30 cm. In the plate number range that remains accessible, the investigated sub-2 mum particle columns in any case perform (at least for the presently considered parabene separation) better than the 3.5 mum particle columns or silica monolith, especially if considering the use of system pressures exceeding 400 bar. The constrained kinetic plot method can also be used to select the best-suited column length from an available product gamma to perform a separation with a preset number of plates. One of the optimization results that is obtained in this case is that sometimes a significant gain in analysis time can be obtained by selecting a longer column, yielding the desired plate number at a larger velocity than that for a shorter column.


Aliskiren reduces myocardial ischemia-reperfusion injury by a bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanism.
Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.


A tunable notch filter using microelectromechanical microring with gap-variable busline coupler.
A microelectromechanical tunable notch filter using silicon-photonic freestanding waveguides is proposed, and the basic characteristics are experimentally investigated. The proposed filter is composed of a wavelength-tunable silicon microring resonator and a busline switch. The tunable microring consists of freestanding single-mode waveguides and air-gap directional waveguide couplers. The optical path length of the microring is varied physically by a displacement of electrostatic comb-drive actuator. The busline switch consists of a gap-variable waveguide coupling mechanism, which enables coupling the tunable microring with the busline by another electrostatic comb-drive actuator. During the wavelength tuning of microring, the busline can be disconnected from the microring. Therefore, the proposed device operates as a hitless wavelength-selective switch if they are connected in series. The waveguides are 320 nm in width and 340 nm in thickness. The resonant wavelength shift of the microring is 9.96 nm at the voltage of 26 V with the actuator displacement of 1.0 μm. The coupling to busline is adjusted from the switch-off state at the gap of 600 nm to the switch-on state corresponding to the critical coupling condition at the gap of 383 nm. The whole size of the wavelength-tunable filter with hitless mechanism is about 150 μm by 80 μm. Due to the capacitive operation of the comb-drive actuators, the power consumption is negligibly small.


Atomic resolution structure of serine protease proteinase K at ambient temperature.
Atomic resolution structures (beyond 1.20 Å) at ambient temperature, which is usually hampered by the radiation damage in synchrotron X-ray crystallography (SRX), will add to our understanding of the structure-function relationships of enzymes. Serial femtosecond crystallography (SFX) has attracted surging interest by providing a route to bypass such challenges. Yet the progress on atomic resolution analysis with SFX has been rather slow. In this report, we describe the 1.20 Å resolution structure of proteinase K using 13 keV photon energy. Hydrogen atoms, water molecules, and a number of alternative side-chain conformations have been resolved. The increase in the value of B-factor in SFX suggests that the residues and water molecules adjacent to active sites were flexible and exhibited dynamic motions at specific substrate-recognition sites.


Neutrophil gelatinase-associated lipocalin as an early marker of acute kidney injury in patients with traumatic brain injury.
Recent studies have shown that urinary neutrophil gelatinase-associated lipocalin (NGAL) is rapidly up-regulated early after murine renal injury, and in patients after cardiac surgery or patients critically ill with multiple trauma. In this study, we evaluated urinary NGAL levels as a potential biomarker of early acute kidney injury (AKI) in patients with severe traumatic brain injury (TBI). All patients with severe TBI admitted to our neurosurgical intensive care unit from March to September 2011 were enrolled prospectively. Urinary NGAL was measured using a chemiluminescent microparticle immunoassay upon admission and at 24 and 48 hours after TBI. The presence of AKI was defined by the Acute Kidney Injury Network (AKIN) criteria. Using AKIN criteria, a total of 13 patients were identified with AKI, an incidence of 24%. Those who subsequently developed AKI had a striking rise in urinary NGAL early after TBI and a sustained increase over the entire duration of the study. The urinary NGAL level of the AKI group was significantly higher than the group without AKI at all time points. Using a cutoff value of 53.9 ng/mL, the area under the receiver-operating characteristic curve for urinary NGAL at 48 hours was 0.876 with a sensitivity of 0.69 and specificity of 0.95. Increased urinary NGAL is associated with an increased occurrence of AKI in patients with severe TBI. It is possible that urinary NGAL could provide a screening tool for AKI immediately after severe TBI, and this may in turn allow early intervention to ameliorate the adverse effects of AKI.


[Effect on the immobilization-induced stress on the immune response in mice with various behavioral stereotypes].
CBA and C57BL/6J mice with aggressive and submissive types of zoo-social behavior fixed during 10-day confrontation testing demonstrated different immune response to immobilization stress. In aggressive mice with confrontation experience stress resulted in a decrease in the immune response in comparison with aggressive inexperienced mice. Therewith, the immune response of CBA mice did not differ from the control level (the immunized mice without experience of victories and defeats), and in C57BL/6 mice the immune response was two times lower than in the control. In contrast to the control and aggressive mice, stress did not suppress the immune response in submissive animals. It is suggested that stress-induced changes in the immune response depend on zoo-social rank of an individual underlain by a particular neurochemical pattern of the brain.


An oral absorbent, AST-120, restores vascular growth and blood flow in ischemic muscles in diabetic mice via modulation of macrophage transition.
Background Diabetes has a pronounced effect on the peripheral vasculature. The accumulation of advanced glycation end products (AGEs) is regarded as the crucial mechanism responsible for vascular damage in diabetes, but it is not easy to be avoided from food. In this study, we aimed to investigate the effects of an oral absorbent, AST-120, on the accumulation of AGEs and changes in blood flow recovery in diabetic mice. Methods The mice were divided into four groups, wild-type (WT) mice without treatment, WT mice treated with 5% AST-120 mixed into pulverized chow, streptozotocin-induced diabetes mellitus (DM) mice, and DM mice treated with 5% AST-120. Six weeks after hind-limb ischemia surgery, blood flow reperfusion, histology, plasma AGE, and cytokine were examined. Bone marrow cells were cultured and derived into macrophages to evaluate the effects of AGEs on macrophage polarization. Results Plasma AGEs were significantly increased in diabetic mice. AST-120 could bind to AGEs and reduced their plasma concentrations. Histological analysis revealed fewer collateral vessels with corresponding impairment of blood flow recovery in diabetic mice. In these mice, AGE-positive and AGE receptor-positive macrophages were numerous in ischemic limbs compared with non- diabetic mice. In diabetic mice, macrophages in ischemic tissues demonstrated greater M1 polarization than M2 polarization; this pattern was reversed in the AST-120 treatment group. The change in macrophage polarization was associated with the corresponding expression of pro-inflammatory cytokines in the ischemic tissues. In cell cultures, AGEs triggered the transformation of bone marrow-derived macrophages into the M1 phenotype. The alterations in the polarization of macrophages were reversed after treatment with AST-120. Conclusions Oral administration of AST-120 decreased the serum levels of AGEs in diabetic mice and improved neovascularization of ischemic limbs. This benefit may be due to, at least partially, the alterations in macrophage polarization and the associated changes in inflammatory cytokines.


[Effects of selenium on soybean chloroplast ultra-structure and microelement content of soybean leaves under continuous cropping stress].
Pot and field experiments were carried out to study the effect of low Se concentration on soybean chloroplast ultra-structure and on Mg, Fe, Mn and contents in soybean leaves under continuous cropping stress. The results showed that Se could certainly increase the contents of Mg, Fe and Mn in soybean leaves when the application rate of Se was below 0.50 mg.kg-1 in pot experiment, and below 300 g.hm-2 in field experiment. In pot experiment, Se concentration positively correlated with Mg and Fe contents in soybean leaves, but the relationship between Mn and Se was hardly to be quantified. Transmission electron microscopic observation indicated that under continuous cropping stress, application of Se could hold the soybean chloroplast membrane structure in good condition. When Se was not applied, the chloroplast swelled, and its grana disappeared, and even, transformed into etioplast. These experiments indicated that application of low Se could alleviate peroxidative stress resulting from continuous cropping, and keep the soybean grow normally.


Fertilization potential and polyspermy prevention in the egg of the nemertean, Cerebratulus lacteus.
We investigated the electrical properties of the egg of the nemertean worm Cerebratulus, and found evidence that an electrically-mediated polyspermy block operates for a period of about 1 hr after fertilization. At fertilization, in natural or artificial sea water, the membrane potential shifts from its resting level of about -66 mV to a peak of about +43 mV, and in most cases remains greater than 0 mV for more than 1 hr. The average potential during the first 30 min is +22 +/- 8 mV (SD, n = 12). When the external Na+ concentration is reduced from 486 to 51 mM (choline substituted) the fertilization potential amplitude is reduced; the average potential during the first 30 min is -27 +/- 21 mV (SD, n = 5). Eggs inseminated in 51 mM Na+ sea water become polyspermic, indicating that polyspermy prevention depends on an electrically-mediated mechanism. The electrical block is required for about 60 min, since transfer to 51 mM Na+ sea water during this period results in polyspermy. During the first hour following fertilization, the egg is also developing a permanent, nonelectrical block; the degree of polyspermy which results upon transfer to low Na+ sea water decreases progressively with time. The permanent block appears to be at the level of the egg plasma membrane or glycocalyx, since the egg envelope is not a barrier to sperm penetration, nor does its removal induce polyspermy. Electron micrographs show no obvious changes in the morphology of the extracellular layers, plasma membrane or cortex of the egg after fertilization.


Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis: Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer data base data.
The objective of the current study was to identify independent clinical and pathologic variables that were predictive of lymph node involvement in patients with squamous cell carcinoma of the penis in a multicenter series with the intent to select patients who were suitable to undergo immediate inguinal lymphadenectomy. Data were analyzed from 175 patients who underwent surgery for penile carcinoma in 11 urologic centers participating in the Gruppo Uro-Oncologico del Nord-Est (Northeast Uro-Oncological Group) Penile Cancer Data Base. Pathologically positive lymph nodes were defined as the presence of histologically confirmed lymph node metastasis in patients who underwent either immediate or delayed inguinal and/or pelvic lymphadenectomy. Patients who had clinically positive lymph nodes with cytologically positive fine-needle aspiration results and who had not undergone lymphadenectomy were censored. Overall, lymph-node involvement was observed in 71 of 175 patients (40.6%) included in the analyses. After analyzing the whole group of patients, the following variables were identified as independent predictors of pathologic lymph node metastasis: clinical lymph node status, pathologic stage of the primary tumor, venous and lymphatic embolizations, and histologic grade. In the subgroup of patients with clinically negative lymph nodes, tumor thickness, histologic grade, lymphatic and venous embolizations, infiltration of both corpus spongiosum and urethra, and pathologic stage of the primary tumor (according to the 1997 TNM classification system) were predictive of lymph node involvement on univariate analysis. The generated logistic regression model showed that venous and/or lymphatic embolizations and infiltration of the corpus spongiosum and/or urethra were independent predictors of pathologic lymph node metastasis in patients with clinically negative lymph nodes. Venous and/or lymphatic embolizations played relevant roles as predictors of pathologic lymph node involvement in patients with penile neoplasia and should be considered important parameters in determining which patients with clinically negative lymph nodes should undergo immediate lymphadenectomy.


Educational Curricula and Programs in Adolescent Medicine for Health Workers in Low- and Middle-Income Countries: A Scoping Review.
Adolescent medicine (AM) has been increasingly recognized as critically important to the health of individuals during their transition to adulthood. On a global scale, AM is often underprioritized and underfunded. In low- and middle-income countries (LMICs), education and AM training is developing, and AM physicians often are from general medicine backgrounds. The objective of our scoping review was to identify existing training curricula and educational tools designed to teach AM skills to health care workers in LMICs. We followed PRISMA guidelines for scoping reviews for article identification and inclusion. Online databases, including MEDLINE, Embase, CINAHL, and Scopus, were used to identify papers. We included studies that took place in a LMIC, were available in English, and described any of the following: published educational curricula in AM, education-based intervention for HCWs that focused on AM, or a training opportunity in AM located in a LMIC. Our review includes 14 publications: 5 published curricula and 9 articles describing educational interventions or training opportunities in AM in LMICs. Curricula were relatively consistent in the topics included, although they varied in implementation and teaching strategies. The scholarly articles described educational materials and identified a number of innovative strategies for training programs. Our review found existing high-quality AM curricula designed for LMICs. However, there is limited published data on their implementation and utilization. There is a continued need for funding and implementation of education in AM in resource-constrained settings.


Renoprotective effects of losartan in renal transplant recipients. Results of a retrospective study.
Chronic allograft nephropathy is the main cause of late graft loss and nonimmunological factors, including hypertension and proteinuria, the principal etiological factors. In this context, blockage of the renin-angiotensin system could be helpful. The aim of the present study was to review the renoprotective efficacy of losartan in a large group of renal transplant patients undergoing long-term follow-up. A retrospective analysis of 276 renal transplant patients treated with losartan was performed. The indication for losartan was arterial hypertension in 163 patients, proteinuria in 37 patients and hypertension plus proteinuria in the remaining 76 patients. Clinical and biochemical parameters before starting losartan treatment (-6 months, -3 months and at baseline) and 3, 6, 9, 12, 18 and 24 months after the introduction of losartan were analyzed. Arterial hypertension significantly decreased after the introduction of losartan (p = 0.000). Serum creatinine was significantly decreased by losartan therapy, and changes in the serum creatinine slope (1/sCr) before and after losartan were statistically significant. Proteinuria markedly decreased after the introduction of losartan. Clinical and biochemical tolerance of losartan was excellent in most patients and only 9 out of the 276 patients (3%) treated with losartan discontinued the drug because of an adverse event. During follow-up, only 3 patients required substitutive treatment with dialysis due to progressive deterioration of renal function in the context of chronic allograft nephropathy. Losartan demonstrated high efficacy as a renoprotective agent in renal transplant patients and could be useful in the treatment and prevention of chronic allograft nephropathy.


Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study.
To see whether sudden unexpected death in chronic heart failure is preceded by intraindividual worsening in inflammation and in ECG criteria. Prospective cohort study conducted in the community. 34 patients with chronic heart failure were studied. Their mean (SD) age was 68 (8) years, 29 were men, mean (SD) left ventricular ejection fraction was 29 (9)%, and they were in New York Heart Association functional class II (n = 20), III (n = 11), and IV (n = 3). The patients were examined monthly over 24 months, with sequential measurement of C reactive protein and neutrophil counts and 24 hour ambulatory ECG monitoring measuring heart rate variability, mean heart rate, and arrhythmias. Intraindividual changes in these parameters were related to subsequent cardiac deaths. During follow up, nine patients died: five patients had a sudden unexpected death (SUD) and four died of progressive heart failure (PHF). There were significant intraindividual changes in neutrophil counts (p = 0.02), C reactive protein (p = 0.039), and heart rate variability (p < or = 0.018) in those who died of SUD and PHF. In contrast no significant changes were seen in ventricular extrasystoles, ventricular tachycardia episodes, brain natriuretic peptide, or aldosterone in the SUD group, but all of these parameters did increase as expected in those who died of PHF. This is preliminary evidence that SUD may be preceded by intraindividual increases in both inflammation and autonomic dysfunction. Both may be causal in genesis but, even if they are not, intraindividual increases in either may be convenient markers to identify patients at high risk of impending SUD. Larger studies are needed to confirm the observation from this pilot study.


The receptor binding domain of botulinum neurotoxin serotype A (BoNT/A) inhibits BoNT/A and BoNT/E intoxications in vivo.
The receptor binding domain of botulinum neurotoxin (BoNT), also designated the C terminus of the heavy chain (H(C)), is a promising vaccine candidate against botulism. In this study, a highly efficient expression system for the protein was developed in Escherichia coli, which provided yields that were 1 order of magnitude higher than those reported to date (350 mg H(C) per liter). The product was highly immunogenic, protecting mice from a challenge with 10(5) 50% lethal dose (LD(50)) after a single vaccination and generating a neutralizing titer of 49.98 IU/ml after three immunizations. In addition, a single boost with HC increased neutralizing titers by up to 1 order of magnitude in rabbits hyperimmunized against toxoid. Moreover, we demonstrate here for the first time in vivo inhibition of BoNT/A intoxication by H(C)/A, presumably due to a blockade of the neurotoxin protein receptor SV2. Administration of HC/A delayed the time to death from 10.4 to 27.3 h in mice exposed to a lethal dose of BoNT/A (P = 0.0005). Since BoNT/A and BoNT/E partially share SV2 isoforms as their protein receptors, the ability of H(C)/A to cross-inhibit BoNT/E intoxication was evaluated. The administration of H(C)/A together with BoNT/E led to 50% survival and significantly delayed the time to death for the nonsurviving mice (P = 0.003). Furthermore, a combination of H(C)/A and a subprotective dose of antitoxin E fully protected mice against 850 mouse LD(50) of BoNT/E, suggesting complementary mechanisms of protection consisting of toxin neutralization by antibodies and receptor blocking by H(C)/A.


Genomic rearrangements of hMSH6 contribute to the genetic predisposition in suspected hereditary non-polyposis colorectal cancer syndrome.
Germline mutations in mismatch repair genes, mainly in hMLH1, hMSH2, and hMSH6, predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. A substantial fraction of these mutations exists in genomic rearrangements of hMSH2 and hMLH1. In contrast, genomic rearrangements have not been reported in hMSH6. Out of 15 HNPCC or HNPCC-like patients who developed tumours with loss of hMSH6 protein expression, we selected three patients who still had no germline mutations after gene sequencing. Genomic DNA of these patients was analysed using PCR based relative quantification of hMSH6 fragments. Indicated exon deletions and amplifications were characterised by long range PCR and sequencing. Genomic rearrangements were identified in two of the three patients. Breakpoint analyses showed an Alu repeat mediated deletion of 13.0 kb affecting the promoter region, exon 1, and exon 2 in one patient, and a duplication of 4.9 kb containing 1.6 kb of the 3' end of exon 4 and exon 5, integrated into intron 5, in the other patient. Although genomic rearrangements of hMSH6 only play a small role in the spectrum of all mutations predisposing to HNPCC, our results suggest that up to 10-20% of patients with hMSH6 negative tumours harbour germline rearrangements in this gene.


Psychometric validation of the Childhood Trauma Questionnaire-Short Form (CTQ-SF) in a Danish clinical sample.
The Childhood Trauma Questionnaire - Short Form (CTQ-SF) is a widely utilized self-report instrument in the assessment and characterization of childhood trauma. Yet, research on the instrument's psychometric properties in clinical samples is sparse, and the Danish version of the CTQ-SF has not been previously evaluated in clinical samples. To examine the structural validity, internal consistency reliability, and multi-method convergent validity of the CTQ-SF in a heterogenous clinical sample from Denmark. The study was based on data from four Danish clinical samples (N = 393): 1) Outpatients diagnosed with personality disorders, 2) Patients commencing psychiatric treatment for non-affective first-episode psychosis, 3) Patients diagnosed with first-episode or prolonged depression recruited from general practitioners and an outpatient mood disorder clinic, and 4) detained delinquent boys. Confirmatory factor analysis was used to explore structural validity. Also, we calculated internal consistency and multi-method convergent validity with interview-based ratings of adverse parenting. Confirmatory factor analyses indicated that the five-factor structure described in CTQ-SF manual with three error correlated items best fitted the data, as compared to various other models. Coefficients of congruence also supported factorial similarity across countries (i.e. US substance abuser and a mixed Brazilian sample). Internal consistency reliability was acceptable and comparable to estimates previously published. Multi-method convergent validity associations further corroborated the validity of the CTQ-SF. These findings provide support for the reliability and validity of the Danish version of the CTQ-SF in clinical samples.


Effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairment in rats.
The role of kappa opioid receptor agonists in learning and memory is controversial. In the present study, the effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairments in rats were investigated. Scopolamine (3.3 mumol/kg s.c.), a muscarinic cholinergic antagonist, and mecamylamine (40 mumol/kg s.c.), a nicotinic cholinergic antagonist, significantly impaired learning and memory in rats in a step-through type passive avoidance test. Administration of U-50,488H (0.17 or 0.51 mumol/kg s.c.) 25 min before the acquisition trial reversed the impairment of learning and memory induced by scopolamine and mecamylamine. Although low doses of scopolamine (0.17 mumol/kg) and mecamylamine (12 mumol/kg) had no effect, concurrent administration of both antagonists induced impairment of learning and memory. Scopolamine significantly increased acetylcholine release in the hippocampus as determined by in vivo brain microdialysis. On the other hand, mecamylamine significantly decreased acetylcholine release. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, whereas it only partially blocked the increase of acetylcholine induced by scopolamine. On the other hand, an endogenous kappa opioid receptor agonist, dynorphin A (1-13), did not block the increase in acetylcholine release induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine (4.9 nmol/rat i.c.v.), a selective kappa opioid receptor antagonist. U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA receptors by dizocilpine ((+)-MK-801). These results suggest that U-50,488H reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release induced by mecamylamine via the kappa receptor-mediated opioid neuronal system.


Multicomponent Pt-Based Zigzag Nanowires as Selectivity Controllers for Selective Hydrogenation Reactions.
The selective hydrogenation of α, β-unsaturated aldehyde is an extremely important transformation, while developing efficient catalysts with desirable selectivity to highly value-added products is challenging, mainly due to the coexistence of two conjugated unsaturated functional groups. Herein, we report that a series of Pt-based zigzag nanowires (ZNWs) can be adopted as selectivity controllers for α, β-unsaturated aldehyde hydrogenation, where the excellent unsaturated alcohol (UOL) selectivity (>95%) and high saturated aldehyde (SA) selectivity (>94%) are achieved on PtFe ZNWs and PtFeNi ZNWs+AlCl3, respectively. The excellent UOL selectivity of PtFe ZNWs is attributed to the lower electron density of the surface Pt atoms, while the high SA selectivity of PtFeNi ZNWs+AlCl3 is due to synergy between PtFeNi ZNWs and AlCl3, highlighting the importance of Pt-based NWs with precisely controlled surface and composition for catalysis and beyond.


Outcomes of Surgical Management of Supracondylar Periprosthetic Femur Fractures.
Fracture location is an important consideration in managing supracondylar periprosthetic femur fractures. The outcomes of locked plating and intramedullary (IM) nail fixation were therefore compared based on fracture location, being above or at/below the total knee arthroplasty (TKA) flange. Fifty-seven patients were identified from surgical records as being treated for supracondylar periprosthetic femur fracture with either a locking plate (n = 38) or IM nail (n = 19). Based on fracture location, either above or at/below the TKA flange, both groups were assessed for time to full weight bearing, time to radiographic union, number of postoperative complications, subsequent surgery, transfusion requirements, as well as range of motion, pain, and instability at most recent follow-up. Radiographs were reviewed to assess fracture alignment with comparisons made immediately postoperative to most recent. Mean follow-up for IM nail and locking plate fixation was 13.9 and 15.6 months, respectively. There was no statistical difference between groups in the mean time to fully weight bear, the incidence of postoperative pain, range of motion, use of gait aids, time to full radiographic union, or the overall radiographic alignment of a healed fracture (P > .05). Comparison based on fracture location yielded similar outcomes. Nonunion was only demonstrated in the IM nail cohort, particularly for fractures below the TKA flange (n = 2). The use of either IM nail or locking plate fixation for supracondylar periprosthetic fractures provides comparable clinical outcomes. Caution is recommended in using IM nails for fractures below the flange where limited fixation may increase the risk of nonunion.


Spinal and paraspinal lesions: the role of stereotactic body radiotherapy.
Stanford University has a long legacy of contributions to the field of radiation therapy. The Cyberknife image-guided robotic radiosurgery is the latest in a series of radiation advancements that allows for improved treatment of tumors. Here we present a decade of experience in using robotic radiosurgery to treat 295 spinal and paraspinal lesions including spinal metastases, benign intradural tumors, and arteriovenous malformations. Our analysis of clinical outcomes confirms the promise of this technology in terms of efficacy and safety.


In vivo evaluation of vaccine efficacy against challenge with a contemporary field isolate from the α cluster of H1N1 swine influenza virus.
Influenza A virus vaccines currently contain a mixture of isolates that reflect the genetic and antigenic characteristics of the currently circulating strains. This study was conducted to evaluate the efficacy of a trivalent inactivated swine influenza virus vaccine (Flusure XP) in pigs challenged with a contemporary α-cluster H1N1 field isolate of Canadian swine origin. Pigs were allocated to vaccinated, placebo, and negative-control groups and monitored for respiratory disease for 5 d after challenge. On the challenge day and 5 d after challenge the serum of the vaccinated pigs had reciprocal hemagglutination inhibition antibody titers 40 for all the vaccine viruses but ≤ 20 for the challenge virus. Gross lesions were present in the lungs of all pigs that had been inoculated with the challenge virus, but the proportion of lung tissue consolidated did not differ significantly between the placebo and vaccinated pigs. However, the amount of virus was significantly reduced in the nasal secretions, lungs, and bronchoalveolar lavage fluid in the vaccinated pigs compared with the placebo pigs. These results indicate that swine vaccinated with Flusure XP were partially protected against experimental challenge with a swine α-cluster H1N1 virus that is genetically similar to viruses currently circulating in Canadian swine.


Aperture-array acquisition scheme for optical links in atmospheric turbulence.
Spatial acquisition is essential for the establishment of atmospheric optical links. The detection probability in the acquisition process can be degraded by atmospheric-turbulence-induced scintillation. We present an aperture-array acquisition scheme to suppress this scintillation noise. The aperture array is composed of N receiving elements, each containing an aperture to receive the optical signal, an optical filter to reject the background radiation, and a charge-coupled device (CCD) to detect the optical signal. The mathematical model of the long-term average detection probability (LTADP) for the aperture-array acquisition is derived based on the lognormal distribution in turbulent atmosphere, when the CCD sample time is shorter than scintillation characteristic time. In this case, the average signal count and the detection probability in the CCD sample time are both random variables; therefore, the probability density of the average signal count needs to be considered and the LTADP can be calculated based on this probability density. The simulation results show that this aperture-array acquisition scheme can suppress scintillation effectively and enhance the LTADP when the one-aperture signal-to-noise ratio is fixed.


Differentiating agents regulate cathepsin B gene expression in HL-60 cells.
We utilized HL-60 cells as a model system to examine the regulation of ctsb gene expression by differentiating agents. Inducers of monocytic differentiation [phorbol ester (PMA), calcitriol (D3), and sodium butyrate (NaB)] and inducers of granulocytic differentiation [all-trans retinoic acid (RA) and 9-cis retinoic acid (9-cis RA)] increase ctsb mRNA levels in a dose-dependent manner as determined by Northern blot hybridization. D3 and retinoids exert additive effects, suggesting that these agents act in part through distinct pathways. Actinomycin D decay experiments indicate that D3, NaB, RA, and 9-cis RA do not alter mRNA stability. In contrast, PMA markedly increases the half-life of ctsb mRNA. In transient transfection assays, PMA and NaB both stimulate transcription of the luciferase reporter gene placed under the control of ctsb promoter fragments. Thus, inducers of HL-60 cell differentiation can regulate the expression of the ctsb gene at both transcriptional and posttranscriptional levels.


Electron microscopic observations on platelet aggregation induced by cationized ferritin.
Washed and gel-filtered human platelets were dose-dependently aggregated by the addition of cationized ferritin (CF). Ca++ and plasma factors were not necessary to induce the aggregation. Immediately after the addition of CF, CF particles were attached to the surface of platelets that showed discoid form, as observed electron microscopically. Some platelets were connected to each other through the CF particles located on their membranes. After the addition of CF, the following was observed: at 15 sec after, platelets showed a round form and were aggregated to each other; at 3 min after, centralization of granules was clearly seen and the aggregates increased their size during the time course; at 3-5 min after, the CF-connected aggregates were found locally. Around the aggregates, other platelets were aggregated, though not through the membrane-located CF. Observing with a lumiaggregometer, the aggregation showed a biphasic curve associated with adenosine triphosphate (ATP) release. The second part of aggregation curve was inhibited by PGI2, PGE1, aspirin, N-ethylmaleimide, and apyrase. The first part of the aggregation curve was inhibited only by heparin. Neuraminidase treatment also inhibited the aggregation dose-dependently. These findings suggest that neutralization of the platelet surface negative charge by a positively charged macromolecule can trigger platelet aggregation, which is followed by the release reaction.


Primary prophylaxis of variceal bleeding in liver cirrhosis: failure to learn from past experience.
In patients with cirrhosis of liver, variceal bleeding is the most serious complication, with a mortality of up to 50%. Primary prophylaxis of variceal bleeding with shunt surgery or endoscopic variceal sclerotherapy was attempted and then abandoned, as higher rates of complications and mortality were observed. Endoscopic variceal ligation is now being recommended for primary prophylaxis in some centers, as it has fewer complications than sclerotherapy. But this has been done with inadequate evaluation of the cost-effectiveness of variceal ligation. Propranolol therapy is also being widely used for a selected group of patients (large varices with cherry red spots), despite its several limitations and side effects, to reduce frequency of bleeding but without improving survival. Is primary prophylaxis of variceal bleeding cost-effective? The cost involved needs to be accurately assessed in different countries.


Agreement in human interpretation of analog thallium myocardial perfusion images.
To assess the agreement of human interpretation of analog thallium myocardial perfusion images, four experienced interpreters evaluated 100 images on two occasions using a form designed to limit reader variability. A high intraobserver agreement (agreement by same observer at separate times) of 89--93% was found when films were interpreted as normal or abnormal (a dichotomous decision). Interobserver agreement for a majority grouping of observers (three or four) was 75% for an abnormal and 68% for a normal interpretation. However, agreement ranged from 11--79% when interpreters were asked to read the anatomic location of defects. Posterior and lateral wall defects were interpreted with the least amount of agreement. These results indicate that caution must be taken when interpreting defect location. Using a scale of 1--10 to grade the severity of a defect, correlations of 0.82--0.86 were found when reading defects in the lateral and anterior projections. Higher correlations, from 0.86--0.94, were found in left anterior oblique views. Use of reporting forms with specific criteria, multiple observers at one occasion, and/or computer processing may improve agreement. A brief review of the agreement of cardiology testing procedures is also presented.