Lipopolysaccharide-mediated regulation of hepatic transporter mRNA levels in rats.
The function of hepatic transporters is to move organic substances across sinusoidal and canalicular membranes. During extrahepatic cholestasis, transporters involved in the movement of substances from blood to bile, such as sodium/taurocholate-cotransporting polypeptide (Ntcp) and multidrug resistance protein 2 (Mrp2), are down-regulated, whereas others that transport chemicals from liver to blood, such as Mrp3, are up-regulated. Unlike extrahepatic cholestasis, where transporter expression responds to the stress of accumulating bile constituents, lipopolysaccharide (LPS)-induced intrahepatic cholestasis may be directly caused by alterations in transporter expression. The aim of this study was to quantitatively determine the effect of LPS on transporter expression and study the mechanism(s) by which LPS alters mRNA levels of major hepatic transporters in Sprague-Dawley rats. Hepatic mRNA levels of Mrp2, Mrp6, multiple drug resistance protein 1a (Mdr1a), organic anion-transporting polypeptide 1 (Oatp1), Oatp2, Oatp4, Ntcp, bile salt export pump, organic cation transporter 1 (Oct1), and organic anion transporter 3 (Oat3) were dramatically decreased, beginning approximately 6 h after LPS administration, whereas Mrp5 and Oat2 levels were unchanged. In contrast, LPS increased mRNA levels of Mrp1, Mrp3, and Mdr1b concurrently with the down-regulated transporters. Pretreatment with dexamethasone, which decreases the release of cytokines, reversed the reduction of Mdr1a, Oatp1, Oatp2, Oct1, and Ntcp mRNA following LPS administration. Furthermore, dexamethasone pretreatment also prevented the LPS-mediated increase in Mrp1, Mrp3, and Mdr1b, whereas pretreatment with aminoguanidine or gadolinium chloride, an inhibitor of inducible nitric oxide synthetase and a Kupffer cell toxicant, respectively, had no effect on the LPS-induced changes. The concurrent repression and induction of various transporters, as well as dexamethasone abatement of both LPS-mediated repression and induction, indicates that these responses may be mediated through similar pathways.


Necroptotic cell death in anti-cancer therapy.
Necroptosis is one the best-characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase-1 and receptor interacting protein kinase-3, which eventually lead to the activation of mixed lineage kinase domain-like. Necroptosis is characterized by rapid permeabilization of the plasma membrane, which is associated with the release of the cell content and subsequent exposure of damage-associated molecular patterns (DAMPs) and cytokines/chemokines. This release underlies the immunogenic nature of necroptotic cancer cells and their ability to induce efficient anti-tumor immunity. Triggering necroptosis has become especially important in experimental cancer treatments as an alternative to triggering apoptosis because one of the hallmarks of cancer is the blockade or evasion of apoptosis. In this review, we discuss recent advances in necroptosis research and the functional consequences of necroptotic cancer cell death, with focus on its immunogenicity and its role in the activation of anti-tumor immunity. Next, we discuss the molecular mechanisms of phosphatidylserine exposure during necroptosis and its role in the recognition of necroptotic cells. We also highlight the complex role of the necroptotic pathway in tumor promotion and suppression and in metastasis. Future studies will show whether necroptosis is truly a better strategy to overcome apoptosis resistance and provide the insights needed for development of novel treatment strategies for cancer.


Effects of intraluminal pH and dietary phosphate on phosphate transport in the proximal convoluted tubule.
The proximal tubule cell adjusts its phosphate absorption appropriately to meet the needs of the organism. Studies were performed to characterize some of the cellular changes involved with dietary phosphate adaptation. First, early proximal convoluted tubules were perfused with equilibrium Ringer solutions buffered to pH 7.65 or 6.5. Saturation kinetics for phosphate transport were determined at each pH value. Rats maintained on a diet of normal phosphate composition demonstrated the apparent Jmax and Km parameters about twofold greater with intraluminal pH 7.65 vs. pH 6.5. The Jmax values increased to 53.47 +/- 3.71 and 42.73 +/- 5.48 pmol X min-1 X mm-1, respectively, when the rats were placed on a phosphate-restricted diet for 5 days. By contrast, adaptation to a high dietary phosphate content resulted in diminished phosphate absorption, 8.53 +/- 1.80 and 12.87 +/- 1.61 pmol X min-1 X mm-1, for the respective pH 7.65 and 6.5 values. Second, the effect of peritubule phosphate concentration was evaluated at constant intraluminal phosphate concentrations. Unidirectional lumen-to-blood phosphate efflux was inhibited at all plasma phosphate concentrations in animals maintained on normal dietary phosphate. By contrast, rats adapted to a low phosphate diet exhibited an increase in phosphate absorption: pH 7.65, 86.21 +/- 2.63, and pH 6.5, 140.84 +/- 86.76 pmol X min-1 X mm-1 when plasma concentrations were elevated two- or three-fold from 2.4 to 6.4 mM. This was attributed to enhanced phosphate exchange on the basolateral membrane. Further hyperphosphatemic levels, above 6.4 mM, inhibited phosphate absorption. These data suggest that net phosphate absorption is determined, in part, by factors other than sodium-dependent uptake of phosphate by the brush border membrane including intracellular pH and peritubular phosphate that act in concert to control renal phosphate absorption.


Impact of removing gentamicin from an antibiotic restriction program.
Prescribing physicians at our institution were required to obtain approval from the Section of Infectious Disease for use of gentamicin sulfate and other aminoglycosides. We studied the effect of removing gentamicin from the list of restricted antibiotics, noting that gentamicin usage increased while tobramycin sulfate usage decreased during the six-month period after decontrol, compared with the previous six-month period. However, the total amount of aminoglycoside antibiotics procured by the pharmacy did not change significantly. Indications for aminoglycoside use, pretreatment evaluation of the patient (other than an initial serum creatinine determination), and rates of nephrotoxicity during treatment did not change. Decontrol of gentamicin resulted in lower aminoglycoside costs for the pharmacy without apparent compromise in patient care.


Weekday/weekend differences in OH reactivity with VOCs and CO in Baltimore, Maryland.
This study compared the first-order frequencies for OH associated with volatile organic compounds (VOCs) and CO (hereafter called OH reactivity with VOCs or CO), the product of the VOC or CO concentration, and their respective kOH value, on an average weekday with that on an average weekend day at a core urban site in Baltimore, MD. The average daytime concentrations were calculated for each of the 55 available Photochemical Assessment Monitoring Station (PAMS) VOCs using data from the Baltimore site. The data were sorted in descending order to highlight the important species based on concentration. The OH reactivity with VOCs was sorted in descending order to identify the important species based on the magnitude of the OH reactivity. A similar process was followed for the OH reactivity with CO. The contribution of the significant species to the weekday/weekend difference in OH reactivity was examined. The OH reactivity with C5H8 was the largest among the OH reactivity with the PAMS' VOCs and was the same on the weekday and weekend. The weekday/weekend difference in OH reactivity with VOCs was entirely due to differences in concentrations of the anthropogenic VOCs. The OH reactivity with VOCs was 11% larger on the weekday. When OH reactivity with CO was included, the OH reactivity was 13% larger on the weekday.


Complementation of a potato virus X mutant mediated by bombardment of plant tissues with cloned viral movement protein genes.
Microprojectile bombardment was used to examine the transport function of the 25 kDa movement protein (MP) encoded in the triple gene block of potato virus X (PVX). A 25 kDa MP-defective full-length cloned PVX genome carrying a beta-glucuronidase (GUS) reporter gene was co-bombarded with 35S promoter constructs containing either the 25 kDa MP gene of wild-type PVX, the MP gene of either of two tobamoviruses (tomato mosaic virus or crucifer tobamovirus), red clover necrotic mosaic dianthovirus (RCNMV) or brome mosaic bromovirus (BMV). When inoculated alone, the MP-defective PVX was unable to move out of the inoculated cell, as visualized by in situ staining for GUS activity. However, cell-to-cell movement of the mutant PVX genome was restored by co-inoculation with 35S constructs containing the MP cDNA of PVX, either tobamovirus or RCNMV. The BMV MP construct did not complement movement of the defective PVX. These results show that co-bombardment of cDNA of an MP-defective virus with plasmids designed to express MP of other viruses could be used as a fast and simple method for transcomplementation experiments.


A rapid electrochemical biosensor based on an AC electrokinetics enhanced immuno-reaction.
Fluorescent labelling and chromogenic reactions that are commonly used in conventional immunoassays typically utilize diffusion dominated transport of analytes, which is limited by slow reaction rates and long detection times. By integrating alternating current (AC) electrokinetics and electrochemical impedance spectroscopy (EIS), we construct an immunochip for rapid, sensitive, and label-free detection. AC electroosmosis (ACEO) and positive dielectrophoresis (DEP), induced by a biased AC electric field, can rapidly convect and trap the analyte onto an EIS working electrode within a few minutes. This allows the change of electron-transfer resistance (ΔRet) caused by the antibody-antigen (IgG-protein A) binding to be measured and quantified in real time. The measured impedance change achieves a plateau after electrokinetic concentration for only 90 s, and the detection limit is able to reach 200 pg ml⁻¹. Compared to the conventional incubation method, the electrokinetics-enhanced method is approximately 100 times faster in its reaction time, and the detection limit is reduced by 30 times. The ΔRet of the positive response is two orders of magnitude higher than the negative control, demonstrating excellent specificity for practical applications.


Properties of PSE-2 beta-lactamase and genetic basis for its production in Pseudomonas aeruginosa.
The properties of PSE-2 beta-lactamase have been examined by using two new PSE-2-producing plasmids, pMG33 and pMG74, as well as plasmid R151, found in Pseudomonas aeruginosa. PSE-2 beta-lactamase resembled other PSE enzymes in activity against carbenicillin, but it also resembled OXA enzymes, such as OXA-1, in rapid hydrolysis of oxacillin, cloxacillin, and methicillin and in inhibition by sodium chloride but not by cloxacillin. Antisera that inactivated TEM-1, TEM-2, OXA-1, or PSE-1 and PSE-4 beta-lactamase failed to cross-react with PSE-2, which thus appears to be immunologically distinct. The plasmids determining PSE-2 varied in geographical origin, size, transfer proficiency, and incompatibility specificity, but all determined resistance to carbenicillin, gentamicin, kanamycin, streptomycin, spectinomycin, sulfonamide, and tobramycin. From a pUZ8-R151 recombinant plasmid in Escherichia coli, the PSE-2 beta-lactamase gene could be transposed to a second plasmid in a 6.4-megadalton unit together with resistance to gentamicin, kanamycin, streptomycin, spectinomycin, sulfonamide, and tobramycin. Transposition was recA independent. We propose the designation Tn1404 for this unit, which, like transposons carrying OXA-1, PSE-1, PSE-4, and some transposons determining TEM-1, includes genes for beta-lactam, aminoglycoside, and sulfonamide resistance.


[The results and characteristics of the mupirocin (Bactroban) sanative treatment of intranasal Staphylococcus carriers in a large hospital].
The action of mupirocin as a nasal ointment (Bactroban) was studied on intranasal carriers of the hospital staphylococcal strains. The study included 37 medical workers from different and mainly problem units of the large general hospital. The tolerability of the ointment was good. After the Bactroban use no complications of the patients were recorded. The efficacy of Bacroban by the microbiological criteria in total amounted to 100 per cent. The eradication of methicillin resistant Staphylococcus aureus (MRSA) was observed in 93 per cent of the cases. A decrease of the level of the nasal passages dissemination by MRSA and methicillin resistant coagulase-negative staphylococci (MRSC) up to such low titers as 100 and 90 per cent was stated. No difference in the action of Bactroban on MRSA, MSSA and MRSC was noted. The bacteriological monitoring for 3 to 4 months revealed a change of the staphylococcal strains in 94 per cent of the cases, recolonization by the same staphylococcal strain in 19 per cent, recolonization by some another staphylococcal strains in 33 per cent and no recolonization in 14 per cent. A stable decrease of staphylococcal strains was possible with simultaneous Bactroban sanitation of all the bacterial carriers of the hospital or its isolated unit.


Construction of a polyhedral metal-organic framework via a flexible octacarboxylate ligand for gas adsorption and separation.
A flexible octacarboxylate ligand, tetrakis[(3,5-dicarboxyphenyl)oxamethyl]methane (H8X), has been used to construct a highly porous metal-organic framework (In2X)(Me2NH2)2(DMF)9(H2O)5 (1), which is comprised of octahedral and cuboctahedral cages and shows a rare (4,8)-connected scu topology. Gas adsorption studies of N2, H2 on the actived 1 at 77 K reveal a Langmuir surface area of 1707 m(2) g(-1), a BET surface area of 1555 m(2) g(-1), a total pore volume of 0.62 cm(3) g(-1), and a H2 uptake of 1.49 wt % at 1 bar and 3.05 wt % at 16 bar. CO2, CH4, and N2 adsorption studies at 195, 273, 285, and 298 K and also ideal adsorbed solution theory (IAST) calculations demonstrate that 1 has high selectivites of CO2 over CH4 and N2. The resulting framework represents a MOF with the highest gas uptakes and gas selectivities (CO2 over CH4 and N2) constructed by flexible ligands.


[Rotavirus and Campylobacter fetus jejuni associated with an outbreak of diarrhea in calves].
Rotaviruses and Campylobacter fetus jejuni are ubiquitous agents of diarrheal disease in animals and humans. Under natural conditions they do not seem to cross inter-species barriers; a zoonosis has not been documented for man. However, animal rotaviruses might contribute to the emergence of new reassortment strains in view of their segmented genome, and thus, produce new antigenic variants. On the contrary, Campylobacter fetus jejuni produces a true zoonosis. Man acquires bacilli by ingesting water and foodstuffs contaminated with feces from infected animals. In an outbreak of diarrhea in 22 calves, rotavirus was detected in 8 (36%) and Campylobacter in 6 (27%). Three (14%) calves experienced double infection. There were no human cases involved in this outbreak.


Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML).
Expression of the multidrug resistance proteins P-glycoprotein, encoded by the MDR1 gene, multidrug resistance-associated protein (MRP1) and the lung resistance-related protein or major vault protein (LRP/MVP) is associated with clinical resistance to chemotherapy in acute myeloid leukemia (AML). Recently, the breast cancer-resistant protein (BCRP), the equivalent of mitoxantrone-resistant protein (MXR) or placental ABC transporter (ABCP), was described in AML. We investigated MDR1, MRP1, LRP/MVP and BCRP mRNA expression simultaneously in 20 paired clinical AML samples from diagnosis and relapse or refractory disease, using quantitative Taqman analysis. In addition, standard assays for P-glycoprotein expression and function were performed. BCRP was the only resistance protein that was expressed at a significantly higher RNA level (median 1.7-fold, P = 0.04) at relapsed/refractory state as compared to diagnosis. In contrast, LRP/MVP mRNA expression decreased as disease evolved (P = 0.02), whereas MDR1 and MRP1 mRNA levels were not different at relapse as compared to diagnosis. Also, at the protein level no difference of MDR1 between diagnosis and relapse was found. A significant co-expression of BCRP and MDR1 was found at diagnosis (r = 0.47, P = 0.04). The present results suggest that BCRP, but not MDR1, MRP1 or LRP/MVP is associated with clinical resistant disease in AML.


A research note on the benefit of patient and public involvement in research: The experience of prostate cancer patients regarding information in radiotherapy.
To explore the inclusion of patient and public involvement (PPI) in a qualitative study on the experiences of men with prostate cancer regarding information in radiotherapy. The application of PPI to one doctoral research study is explored with respect to two perspectives: firstly, involvement of a patient reference group who informed the research design and materials, and secondly, the involvement of a public involvement in research group (PIRg) in advising the researcher during the design process. PPI is recognised as an important component of contemporary health research. PPI is becoming a common and essential requirement for high quality research projects and yet literature exploring or reporting the involvement and influence of PPI is sparse. Consideration is given to the national PPI landscape that has shaped public involvement in health research. The contribution of PPI to this study appears to have been beneficial to the development and evaluation of the study design, the self-worth of the reference group participants and demonstrates that the value of PPI in health research should not be underestimated.


Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins.
Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-rifampicin, rifabutin, and rifapentine-with antiretroviral drugs are reviewed and discussed. A rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co-infected patients whenever efavirenz cannot be used and rifabutin is not available. Despite significant pharmacokinetic interactions between antiretrovirals and antitubercular drugs, adequate clinical response of both infections can be achieved with an acceptable safety profile when the pharmacological characteristics of drugs are known, and appropriate combination regimens, dosing, and timing of initiation are used. However, more clinical research is needed for newer drugs, such as rifapentine and the recently introduced integrase inhibitor antiretrovirals, and for specific population groups, such as children, pregnant women, and patients affected by multidrug-resistant TB.


Indications and extent of central neck dissection for papillary thyroid cancer: An American Head and Neck Society Consensus Statement.
The primary purposes of this interdisciplinary consensus statement were to review the relevant indications for central neck dissection (CND) in patients with papillary thyroid cancer (PTC) and to outline the appropriate extent and relevant techniques required to accomplish a safe and effective CND. A writing group convened by the American Head and Neck Society (AHNS) Endocrine Committee was tasked with identifying the important clinical elements to consider when managing the central neck compartment in patients with PTC based on available evidence in the literature, and the group's collective experience. The position statement paper was then submitted to the full Endocrine Committee, Education Committee, and AHNS Council. This consensus statement was developed to inform the clinical decision-making process when managing the central neck compartment in patients with PTC from the AHNS. This document is intended to provide clarity through definitions as well as a basic guideline from which to manage the central neck. It is our hope that this improves the quality and reduces variation in management of the central neck, facilitates communication, and furthers research for patients with thyroid cancer. This represents, in our opinion, contemporary optimal surgical care for this patient population and is endorsed by the American Head and Neck Society. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1269-1279, 2017.


Renewal timing of long-acting depot luteinizing hormone-releasing hormone agonist (Zoladex) is critical in the treatment of hormone-dependent rat prostatic carcinoma (R3327-H).
The effects of luteinizing hormone-releasing hormone (LHRH) agonist (Zoladex) treatment on hormone-dependent rat prostate adenocarcinoma (R3327-H) were investigated based on changes in tumor volume and histology. Tumor-bearing rats were treated for 10 weeks with Zoladex in depot preparation by implantation every 2, 4, or 6 weeks. Tumor growth rate was similar in the castrated group and in the rats treated every 2 weeks with Zoladex. This growth rate was significantly slower than in animals treated with Zoladex every 6 weeks and the nontreated group. The growth rate in rats treated every 4 weeks appeared to be faster than that in the castrated animals (not significant). Changes in testosterone levels measured during Zoladex treatment correlated with tumor growth kinetics. Zoladex implantation yields effective and complete androgen deprivation only in the rats with two weekly depot renewal regimen. Tumor histology indicated that the stromal as well as the glandular epithelial cells responded to both castration and to Zoladex treatment. However, in tumors from rats treated with Zoladex every 4 and 6 weeks progressive increasing signs of restoration of normal elements, comparable to non-treated tumors were observed. These results strongly suggest that careful attention has to be paid to the timing of LHRH depot renewal in prostate cancer treatment.


Adaptation of fruit morphology to dispersal agents in a neotropical forest.
Two-thirds of 258 fruit species from Peruvian tropical forest belong to one of two classes: large orange, yellow, brown, or green fruits with a husk; or small red, black, white, blue, purple, or mixed-color fruits without a husk. The characteristics of the two fruit classes match the size, visual ability, and jaw morphology of mammals and birds, respectively, and the animals also prefer to eat one class of fruits. Thus, most plants in this forest seem to be adapted to seed dispersal by either of two distinct broad arrays of animal taxa.


Peptide sequences for sucrose splitting and glucan binding within Streptococcus sobrinus glucosyltransferase (water-insoluble glucan synthetase).
The gene encoding glucosyltransferase responsible for water-insoluble glucan synthesis (GTF-I) of Streptococcus sobrinus (formerly Streptococcus mutans 6715) was cloned, expressed, and sequenced. A gene bank from S. sobrinus 6715 DNA was constructed in vector pUC18 and screened with anti-GTF-I antibody to detect clones producing GTF-I peptide. Five immunopositive clones were isolated, all of which produced peptides that bound alpha-1,6 glucan. GTF-I activity was found in only two large peptides: one stretching over the full length of the GTF-I peptide and composed of about 1,600 amino acid residues (AB1 clone) and the other lacking about 80 N-terminal residues and about 260 C-terminal residues (AB2 clone). A deletion study of the AB2 clone indicated that specific glucan binding, which is essential for water-insoluble glucan synthesis, was lost prior to sucrase activity with an increase in deletion from the 3' end of the GTF-I gene. These results suggest that the GTF-I peptide consists of three segments: that for sucrose splitting (approximately 1,100 residues), that for glucan binding (approximately 240 residues), and that of unknown function (approximately 260 residues), in order from the N terminus. The primary structure of the GTF-I peptide, deduced by DNA sequencing of the AB1 clone, was found to be very similar to that of the homologous protein from another strain of S. sobrinus.


Competition in notch signaling with cis enriches cell fate decisions.
Notch signaling is involved in cell fate choices during the embryonic development of Metazoa. Commonly, Notch signaling arises from the binding of the Notch receptor to its ligands in adjacent cells driving cell-to-cell communication. Yet, cell-autonomous control of Notch signaling through both ligand-dependent and ligand-independent mechanisms is known to occur as well. Examples include Notch signaling arising in the absence of ligand binding, and cis-inhibition of Notch signaling by titration of the Notch receptor upon binding to its ligands within a single cell. Increasing experimental evidences support that the binding of the Notch receptor with its ligands within a cell (cis-interactions) can also trigger a cell-autonomous Notch signal (cis-signaling), whose potential effects on cell fate decisions and patterning remain poorly understood. To address this question, herein we mathematically and computationally investigate the cell states arising from the combination of cis-signaling with additional Notch signaling sources, which are either cell-autonomous or involve cell-to-cell communication. Our study shows that cis-signaling can switch from driving cis-activation to effectively perform cis-inhibition and identifies under which conditions this switch occurs. This switch relies on the competition between Notch signaling sources, which share the same receptor but differ in their signaling efficiency. We propose that the role of cis-interactions and their signaling on fine-grained patterning and cell fate decisions is dependent on whether they drive cis-inhibition or cis-activation, which could be controlled during development. Specifically, cis-inhibition and not cis-activation facilitates patterning and enriches it by modulating the ratio of cells in the high-ligand expression state, by enabling additional periodic patterns like stripes and by allowing localized patterning highly sensitive to the precursor state and cell-autonomous bistability. Our study exemplifies the complexity of regulations when multiple signaling sources share the same receptor and provides the tools for their characterization.


Barriers to and enablers of the implementation of an ICF-based intake tool in clinical otology and audiology practice-A qualitative pre-implementation study.
The authors are developing an intake tool based on the Brief International Classification of Functioning Disability and Health Core Set for Hearing Loss, by operationalizing its categories into a Patient Reported Outcome Measure. This study was aimed at identifying enablers and barriers to using this tool as perceived by hearing health professionals (HHPs) and patients. Focus groups and interviews were held with HHPs (ENT surgeons, N = 14; audiologists, N = 8) and patients (N = 18). Interview questions were based on the Capability-Opportunity-Motivation-Behavior (COM-B) model. Using the COM-B model and the Theoretical Domains Framework (TDF), transcript fragments were divided into meaning units, which were then categorized into capability-, opportunity- and motivation-related barriers and enablers. These were further specified into TDF domains. HHP barriers included: lack of time to use the tool (O); and fear of being made responsible for addressing any emerging problems, which may be outside the expertise of the HHP (M). Enablers included integration of the tool in the electronic patient record (O); opportunity for the patient to be better prepared for the intake visit (M); and provision of a complete picture of the patient's functioning via the tool (M). Patient' barriers included fear of losing personal contact with the HHP (M); and fear that use of the tool might negatively affect conversations with the HHP (M). Enablers included knowledge on the aim and relevance of the tool (C); expected better self-preparation (M); and a more focused intake (M). These findings suggest that an intervention is needed to enhance HHPs' knowledge, skills and motivation regarding the relevance and the clinical usefulness of the tool. Providing clear and specific information on the purpose of the tool can also enhance patient motivation. For both HHPs and patients, opportunities relating to the (digital) administration and the design of the tool provide additional targets for successful implementation.


Hexagonal image segmentation on spatially resolved transcriptomics.
Spatial transcriptomics is a rapidly evolving field that enables researchers to capture comprehensive molecular profiles while preserving information about the physical locations. One major challenge in this research area involves the identification of spatial domains, which are distinct regions characterized by unique gene expression patterns. However, current unsupervised methods have struggled to perform well in this regard due to the presence of high levels of noise and dropout events in spatial transcriptomic profiles. In this paper, we propose a novel hexagonal Convolutional Neural Network (hexCNN) for hexagonal image segmentation on spatially resolved transcriptomics. To address the problem of noise and dropout occurrences within spatial transcriptomics data, we first extend an unsupervised algorithm to a supervised learning method that can identify useful features and reduce noise hindrance. Then, inspired by the classical convolution in convolutional neural networks (CNNs), we designed a regular hexagonal convolution to compensate for the missing gene expression patterns from adjacent spots. We evaluated the performance of hexCNN by applying it to the DLPFC dataset. The results show that hexCNN achieves a classification accuracy of 86.8% and an average Rand index (ARI) of 77.1% (1.4% and 2.5% higher than those of GNNs). The results also demonstrate that hexCNN is capable of removing the noise caused by batch effect while preserving the biological signal differences.


Experimental animal models of Parkinson's disease: A transition from assessing symptomatology to α-synuclein targeted disease modification.
With the understanding that α-synuclein plays a major role in the pathogenesis of Parkinson's disease (PD), novel animal models have been developed for conducting preclinical research in screening novel disease modifying therapies. Advancements in research techniques in α-synuclein targeted disease modification have utilised methods such as viral mediated expression of human α-synuclein, as well as the inoculation of pathogenic α-synuclein species from Lewy Bodies of PD patients, for accurately modelling progressive self-propagating neurodegeneration. In applying these cutting-edge research tools with sophisticated trial designs in preclinical drug trials, a useful platform has emerged for developing candidate agents with disease modifying actions, promising a greater chance of success for clinical translation. In this article, we describe the transition of well-established animal models of PD symptomatology to newly developed models of PD pathogenesis, with specific focus on methods of viral-mediated and inoculation of pathogenic α-synuclein, that aim to aid scientific translation of neuroprotective strategies.


[The analysis of UV absorption spectrum and X-ray diffraction spectrum of Sn-doped C60 thin films].
In this article, We report our measured results of UV-Vis absorption, X-ray diffraction and scanning electron microscope for Sn-doped C60 thin film. The results show the two absorption peaks in respective short wave range of UV absorption have an apparent decline after doping Sn, and the position of three absorption peaks have a slightly shift respectively to red wave direction. The electron absorption transition of Sn-C60 film is indirect transition, and there are impurity levels in the energy band; X-ray diffraction shows that the crystal structure of Sn-C60 film is f. c. c. The film is in the form of tiny drops in nano magnitude.


Prevalence of dissociative disorders in psychiatric outpatients.
The purpose of the study was to assess the prevalence of DSM-IV dissociative disorders in an inner-city outpatient psychiatric population. Subjects were 231 consecutive admissions (84 men and 147 women, mean age=37 years) to an inner-city, hospital-based outpatient psychiatric clinic. The subjects completed self-report measures of dissociation (Dissociative Experiences Scale) and trauma history (Traumatic Experiences Questionnaire). Eighty-two patients (35%) completed a structured interview for dissociative disorders (Dissociative Disorders Interview Schedule). The 82 patients who were interviewed did not differ significantly on any demographic measure or on the self-report measures of trauma and dissociation from the 149 patients who were not interviewed. Twenty-four (29%) of the 82 interviewed patients received a diagnosis of a dissociative disorder. Dissociative identity disorder was diagnosed in five (6%) patients. Compared to the patients without a dissociative disorder diagnosis, patients with a dissociative disorder were significantly more likely to report childhood physical abuse (71% versus 27%) and childhood sexual abuse (74% versus 29%), but the two groups did not differ significantly on any demographic measure, including gender. Chart review revealed that only four (5%) patients in whom a dissociative disorder was identified during the study had previously received a dissociative disorder diagnosis. Dissociative disorders were highly prevalent in this clinical population and typically had not been previously diagnosed clinically. The high prevalence of dissociative disorders found in this study may be related to methodological factors (all patients were offered an interview rather than only those who had scored high on a screening self-report measure) and epidemiological factors (extremely high prevalence rates for childhood physical and sexual abuse were present in the overall study population).


Interaction of drug therapy with marital therapy in depressive patients.
Comparative effects of the antidepressant drug, amitriptyline hydrochloride, marital therapy, and the drug-psychotherapy interaction effects were studied in a 12-week course of treatment of outpatient depressives. Patients were assigned randomly to four treatment groups, in a 2 times 2 factorial design: (1) drug-marital therapy; (2) drug-minimal contact; (3) placebo-marital therapy; and (4) placebo-minimal contact. Both drug and marital therapy showed substantial beneficial advantages over their control conditions, but drug therapy was faster and generally superior in symptom relief and clinical improvement. Marital therapy was superior in family role task performance and perception of the marital relationship. For reducing hostility and enhancing the perception of the marital relationship, drug therapy had a better early effect, but marital therapy had superior effects by the end of treatment.


Unleashing Our Potential- Pharmacists' Role in Vaccination and Public Health.
One of the greatest innovations in health care has been the development of vaccines and immunization programs that have significantly minimized the morbidity and mortality resulting from vaccine preventable diseases. While vaccines were traditionally used against infectious diseases, recent advances in technology have led to the development of vaccines for noncommunicable diseases and chronic conditions. Vaccinations are considered the most cost-effective intervention in public health that has the potential to save millions of lives every year. Despite the availability and effectiveness of vaccines for many diseases, immunization programs, and service uptake remain underused in many countries. This is mainly because of the lack of easy access to vaccinations, risk-benefit perceptions, false beliefs, and concerns about the side effects. Vaccine hesitancy-the reluctance or refusal to vaccinate, is listed as one of the top 10 threats to global health.


A framework to unlock marine bird energetics.
Energetics can provide novel insights into the roles of animals, but employing an energetics approach has traditionally required extensive empirical physiological data on the focal species, something that can be challenging for those that inhabit marine environments. There is therefore a demand for a framework through which to estimate energy expenditure from readily available data. We present the energetic costs associated with important time- and energy-intensive behaviours across nine families of marine bird (including seabirds, ducks, divers, and grebes) and nine ecological guilds. We demonstrate a worked example, calculating the year-round energetic expenditure of the great auk Pinguinus impennis under three migration scenarios, thereby illustrating the capacity of this approach to make predictions for data deficient species. We provide a comprehensive framework through which to model marine bird energetics and demonstrate the power of this approach to provide novel, quantitative insights into the influence of marine birds within their ecosystems.


Analysis of head gesture and prosody patterns for prosody-driven head-gesture animation.
We propose a new two-stage framework for joint analysis of head gesture and speech prosody patterns of a speaker towards automatic realistic synthesis of head gestures from speech prosody. In the first stage analysis, we perform Hidden Markov Model (HMM) based unsupervised temporal segmentation of head gesture and speech prosody features separately to determine elementary head gesture and speech prosody patterns, respectively, for a particular speaker. In the second stage, joint analysis of correlations between these elementary head gesture and prosody patterns is performed using Multi-Stream HMMs to determine an audio-visual mapping model. The resulting audio-visual mapping model is then employed to synthesize natural head gestures from arbitrary input test speech given a head model for the speaker. In the synthesis stage, the audio-visual mapping model is used to predict a sequence of gesture patterns from the prosody pattern sequence computed for the input test speech. The Euler angles associated with each gesture pattern are then applied to animate the speaker head model. Objective and subjective evaluations indicate that the proposed synthesis by analysis scheme provides natural looking head gestures for the speaker with any input test speech, as well as in "prosody transplant" and gesture transplant" scenarios.


The Protean Acremonium. A. sclerotigenum/egyptiacum: Revision, Food Contaminant, and Human Disease.
Acremonium is known to be regularly isolated from food and also to be a cause of human disease. Herein, we resolve some sources of confusion that have strongly hampered the accurate interpretation of these and other isolations. The recently designated type species of the genus Acremonium, A. alternatum, is known only from a single isolate, but it is the closest known relative of what may be one of the planet's most successful organisms, Acremonium sclerotigenum/egyptianum, shown herein to be best called by its earliest valid name, A. egyptiacum. The sequencing of ribosomal internal transcribed spacer (ITS) regions, actin genes, or both for 72 study isolates within this group allowed the full range of morphotypes and ITS barcode types to be elucidated, along with information on temperature tolerance and habitat. The results showed that nomenclatural confusion and frequent misidentifications facilitated by morphotaxonomy, along with misidentified early sequence deposits, have obscured the reality that this species is, in many ways, the definitive match of the historical concept of Acremonium: a pale orange or dull greenish-coloured monophialidic hyphomycete, forming cylindrical, ellipsoidal, or obovoid conidia in sticky heads or obovoid conidia in dry chains, and acting ecologically as a soil organism, marine organism, plant pathogen, plant endophyte, probable insect pathogen, human opportunistic pathogen, food contaminant, probable dermatological communicable disease agent, and heat-tolerant spoilage organism. Industrially, it is already in exploratory use as a producer of the antibiotic ascofuranone, active against trypanosomes, cryptosporidia, and microsporidia, and additional applications are in development. The genus-level clarification of the phylogeny of A. egyptiacum shows other historic acremonia belong to separate genera, and two are here described, Parasarocladium for the Acremonium radiatum complex and Kiflimonium for the Acremonium curvulum complex.


An unexpected similarity between antibiotic-resistant NDM-1 and beta-lactamase II from Erythrobacter litoralis.
NDM-1 (New Delhi metallo-beta-lactamase) gene encodes a metallo-beta-lactamase (MBL) with high carbapenemase activity, which makes the host bacterial strain easily dispatch the last-resort antibiotics known as carbapenems and cause global concern. Here we present the bioinformatics data showing an unexpected similarity between NDM-1 and beta-lactamase II from Erythrobacter litoralis, a marine microbial isolate. We have further expressed these two mature proteins in E. coli cells, both of which present as a monomer with a molecular mass of 25 kDa. Antimicrobial susceptibility assay reveals that they share similar substrate specificities and are sensitive to aztreonam and tigecycline. The conformational change accompanied with the zinc binding visualized by nuclear magnetic resonance, Zn(2+)-bound NDM-1, adopts at least some stable tertiary structure in contrast to the metal-free protein. Our work implies a close evolutionary relationship between antibiotic resistance genes in environmental reservoir and in the clinic, challenging the antimicrobial resistance monitoring.


[Research Progress of LncRNA SNHGs in Regulating the Biological Behavior of Non-small Cell Lung Cancer].
Lung cancer is one of the malignant tumors with the highest incidence and mortality rate in China, and its occurrence and development mechanism and treatment methods are the current research focuses. In recent years, the emergence of drugs targeting various tumor driver genes has significantly improved patients' survival and quality of life, setting off a wave of research on new therapeutic targets. Among them, long non-coding RNA (lncRNA) plays a crucial role in the malignant behavior of tumors, which has attracted widespread attention. Shown by a large number of studies, partial members of lncRNA small nucleolar RNA host gene (SNHG) family are aberrantly expressed in many maliglant tumors including non-small cell lung cancer (NSCLC) and participate in cell proliferation, invasion and migration, which may act as a new diagnostic and prognostic biomarker and can be a therapeutic target of NSCLC. In this review, we comprehensively summarize and explore the recent investigation of SNHGs in NSCLC in order to provide new ideas for the diagnosis and treatment of NSCLC. .


Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats.
Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans.


Maprotiline treatment in depression. A perspective on seizures.
Eleven McLean Hospital (Belmont, Mass) depressed patients who experienced seizures while receiving maprotiline hydrochloride are presented, as are data on 87 cases reported to the manufacturer (Ciba-Geigy). Most seizures occurred at high dosages, sometimes after many weeks at a stable dose, but neither rapid dosage escalation nor high drug plasma levels seemed related to seizure occurrence. Our experience suggests that a long-acting metabolite might be responsible for seizures. Ten of the 11 McLean Hospital seizures occurred in patients receiving dosages outside of the since-revised current dosage guidelines, as did 60% of the seizures reported to the company. Data in this study suggest that reductions in maximum dosage of maprotiline prescribed after the initial six weeks of treatment could result in a further decrease in risk of seizures beyond that obtained from previous alterations in regimens.


Social Media: Support for Survivors and Young Adults With Cancer
Social media use is ubiquitous among young adults. Young adults with cancer must make important decisions about where, what, and how to share information on social media. Oncology nurses are in a unique position to start conversations about the risks and benefits of social media use. This column aims to review a variety of social media platforms that may be used by young adults with cancer and provide guidance to nurses on initiating open dialogue with young adults about social media usage. .


Evaluation of group genetic ancestry of populations from Philadelphia and Dakar in the context of sex-biased admixture in the Americas.
Population history can be reflected in group genetic ancestry, where genomic variation captured by the mitochondrial DNA (mtDNA) and non-recombining portion of the Y chromosome (NRY) can separate female- and male-specific admixture processes. Genetic ancestry may influence genetic association studies due to differences in individual admixture within recently admixed populations like African Americans. We evaluated the genetic ancestry of Senegalese as well as European Americans and African Americans from Philadelphia. Senegalese mtDNA consisted of approximately 12% U haplotypes (U6 and U5b1b haplotypes, common in North Africa) while the NRY haplotypes belonged solely to haplogroup E. In Philadelphia, we observed varying degrees of admixture. While African Americans have 9-10% mtDNAs and approximately 31% NRYs of European origin, these results are not mirrored in the mtDNA/NRY pools of European Americans: they have less than 7% mtDNAs and less than 2% NRYs from non-European sources. Additionally, there is <2% Native American contribution to Philadelphian African American ancestry and the admixture from combined mtDNA/NRY estimates is consistent with the admixture derived from autosomal genetic data. To further dissect these estimates, we have analyzed our samples in the context of different demographic groups in the Americas. We found that sex-biased admixture in African-derived populations is present throughout the Americas, with continual influence of European males, while Native American females contribute mainly to populations of the Caribbean and South America. The high non-European female contribution to the pool of European-derived populations is consistently characteristic of Iberian colonization. These data suggest that genomic data correlate well with historical records of colonization in the Americas.


[Self concept and object relations of patients with affective disorders--individual centered diagnosis with the repertory-grid technique].
Significant dimensions of the self concept and the object relations of 127 depressive patients and 34 orthopaedic patients were investigated with the repertory-grid-technique. Self concept and object relations were compared by means of nomothethically used idiographic results after recovery from manifest depression. The object relations of the depressive sample were characterised by the dimension "symbiotic near"; "ambivalent" and "indifferent" partnership relationships were found much more frequently in the controls. The idiographic results contribute to a differentiation of the spectrum of affective disorders. They underline the importance of the interpersonal dimension of depression and may be used as a basis of a therapeutic orientation.


Long-term full-field and multifocal electroretinographic changes after treatment with ranibizumab in patients with diabetic macular edema.
To investigate changes in macular and panretinal neuroretinal functions by electroretinographic examinations in eyes with diabetic macular edema (DME) treated with intravitreal ranibizumab. Sixty-four patients with DME were included in this prospective study. Patients were treated with ranibizumab injection according to the PRN regimen for over 12 months. Before treatment, all patients underwent fundus fluorescein angiography, optical coherence tomography (OCT), best-corrected visual acuity (BCVA) assessment, full-field (ff-ERG), and multifocal electroretinography (mf-ERG). In monthly visits, BCVA and OCT were performed. Besides, mf-ERG recordings were obtained at months 3, 6, 9, and 12, and ff-ERG was performed at month 12. Fifty-eight patients completed the study. The mean age was 61.1 ± 8.5 (39-80) years. The mean number of injections was 6.19 ± 1.9. The decimal BCVA improved from 0.30 to 0.45 during the 12-month follow-up (p < 0.05). Macular thickness decreased from 413.5 μm to 329.5 μm (p < 0.05). The mf-ERG recordings in the central macular region showed improvements N1 and P1 amplitudes at months 9 and 12. There was a positive correlation between the baseline central (p < 001; r: - 0.378 and p < 0.05; r:-0.335, respectively), the second ring (p < 0.05; r: - 0.260 and p < 0.05; r: - 0.270, respectively) P1- and N1-wave amplitudes, and the BCVA at month 12. Full-field ERG recordings showed that peripheral neuroretinal responses were maintained or improved at month 12. Statistically significant improvements in BCVA and macular thickness were observed at all follow-up visits. Multifocal electroretinographic recording started to improve 6 months after the beginning of intravitreal ranibizumab treatment in eyes with DME. This improvement was significant at months 9 and 12. A significant improvement in ff-ERG was observed at month 12.


Psychoactive substances use and associated factors among Axum University students, Axum Town, North Ethiopia.
The use of substances such as alcohol, khat leaves and tobacco have long been recognized as one of the leading causes of human suffering and become one of the rising major public health and socio-economic problems worldwide. Even though substances use occurs in all segments of all societies, it is more spreading in an alarming rate among the young generation. This study aimed to establish the prevalence and associated factors of substances use among undergraduate students in Axum University. Institution based quantitative cross sectional study design was conducted among Axum University students in April 2012. A sample of 764 students was selected by using multi- stage sampling technique. Data were collected using pre- tested self- administered questionnaires. The data were cleaned, coded, entered into EPI-INFO version 3.5.1 and transferred and analysed using SPSS computer soft ware package version 20. The lifetime prevalence of khat chewing, alcohol drinking and cigarette smoking among the study participants were 28.7%, 34.5% and 9.5% respectively. Similarly, the current prevalence of khat chewing, alcohol drinking and cigarette smoking were 27.9%, 32.8% and 9.3% respectively. The commonest reasons for khat, alcohol and cigarette using were to keep alert while reading 40.6%, for relaxation 65.5% and to relief stress 37.7% respectively. Having peer friends who chew khat was strongly and positively associated with khat use [AOR: 10.18, 95%CI: (5.59, 18.54)].Family members and peer friends alcohol use were strongly associated with alcohol drinking [AOR: 2.61, 95%CI: (1.56, 4.34) and [AOR: 14, 95%CI: (8.09, 24.24)] respectively. Ever alcohol use was strongly associated with cigarette smoking [AOR: 6.54, 95%CI: (2.66, 16.05)]. This study revealed that psychoactive substances use became an urgent problem among undergraduate university students. Universities need to monitor and teach their students with special focus on fresh man students, about the health risks and socioeconomic problems associated with psychoactive substances use.


Simulated driving performance following prolonged wakefulness and alcohol consumption: separate and combined contributions to impairment.
The separate and combined effects of prolonged wakefulness and alcohol were compared on measures of subjective sleepiness, simulated driving performance and drivers' ability to judge impairment. Twenty-two males aged between 19 and 35 years were tested on four occasions. Subjects drove for 30 min on a simulated driving task under conditions determined by the factorial combination of 16 and 20 h of wakefulness and blood alcohol concentrations of 0.00 and 0.08%. The simulated driving session took place 30 min postingestion; subjects in the two alcohol conditions participated in a second 30-min driving session 90-min postingestion. Subjects made simultaneous ratings of their impairment while driving and retrospective ratings at the end of each test session. Subjective sleepiness measures were completed before and after each driving session. The combination of 20 h of prolonged wakefulness and alcohol produced significantly lower ratings of subjective sleepiness and driving performance that was worse, but not significantly so, than would be expected from the additive effects of each condition alone. Driving performance was always worse in the second driving session, during the elimination phase of alcohol metabolism, despite blood alcohol concentrations being lower than during the first driving session. There was a modest association between perceived and actual impairments in driving performance following prolonged wakefulness and alcohol. The findings suggest that the combination of prolonged wakefulness and alcohol consumption produced greater decrements in simulated driving performance than each condition alone and that drivers have only a modest ability to appreciate the magnitude of their impairment.


NxTrim: optimized trimming of Illumina mate pair reads.
Mate pair protocols add to the utility of paired-end sequencing by boosting the genomic distance spanned by each pair of reads, potentially allowing larger repeats to be bridged and resolved. The Illumina Nextera Mate Pair (NMP) protocol uses a circularization-based strategy that leaves behind 38-bp adapter sequences, which must be computationally removed from the data. While 'adapter trimming' is a well-studied area of bioinformatics, existing tools do not fully exploit the particular properties of NMP data and discard more data than is necessary. We present NxTrim, a tool that strives to discard as little sequence as possible from NMP reads. NxTrim makes full use of the sequence on both sides of the adapter site to build 'virtual libraries' of mate pairs, paired-end reads and single-ended reads. For bacterial data, we show that aggregating these datasets allows a single NMP library to yield an assembly whose quality compares favourably to that obtained from regular paired-end reads. The source code is available at https://github.com/sequencing/NxTrim


Design, data linkage, and implementation considerations in the first cooperative group led study assessing financial outcomes in cancer patients and their informal caregivers.
Few studies have assessed the financial impact of cancer diagnosis on patients and caregivers in diverse clinical settings. S1417CD, led by the SWOG Cancer Research Network, is the first prospective longitudinal cohort study assessing financial outcomes conducted in the NCI Community Oncology Research Program (NCORP). We report our experience navigating design and implementation barriers. Patients age ≥ 18 within 120 days of metastatic colorectal cancer diagnosis were considered eligible and invited to identify a caregiver to participate in an optional substudy. Measures include 1) patient and caregiver surveys assessing financial status, caregiver burden, and quality of life and 2) patient credit reports obtained from the credit agency TransUnion through a linkage requiring social security numbers and secure data transfer processes. The primary endpoint is incidence of treatment-related financial hardship, defined as one or more of the following: debt accrual, selling or refinancing home, ≥20% income decline, or borrowing money. Accrual goal was n = 374 patients in 3 years. S1417CD activated on Apr 1, 2016 and closed on Feb 1, 2019 after reaching its accrual goal sooner than anticipated. A total of 380 patients (median age 59.7 years) and 155 caregivers enrolled across 548 clinical sites. Credit data were not obtainable for 76 (20%) patients due to early death, lack of credit, or inability to match records. Robust accrual to S1417CD demonstrates patients' and caregivers' willingness to improve understanding of financial toxicity despite perceived barriers such as embarrassment and fears that disclosing financial status could influence treatment recommendations.


A hierarchical model of plumage: morphology, development, and evolution.
Plumage is a complex component of the avian phenotype. The plumage of an individual is composed of numerous hierarchically arranged developmental and morphological modules. We present a hierarchical model of plumage that provides an intellectual framework for understanding the development and evolution of feathers. Independence, covariation, and interaction among plumage modules create numerous opportunities for developmental and evolutionary diversification of feather complexity and function. The hierarchical relationships among plumage modules are characterized by both top-down and bottom-up effects in which properties of modules at one level of the hierarchy determine or influence the properties of modules at lower or higher levels of the hierarchy. Plumage metamodules are created by covariation or interaction among modules at different levels of the hierarchy.


The Effectiveness of Virtual Reality Rehabilitation in Patients with Knee and Hip Osteoarthritis.
Osteoarthritis (OA) is a common health problem leading to pain, limitation in physical function, a decrease in the quality of life and disability. OA affects 60-70% of the population above 65 years of age all over the world, and is associated with a high cost of healthcare. The main method of treatment of OA, apart from pharmacotherapy and surgery, is comprehensive rehabilitation. Advances in medical technology have resulted in the possibility of using computer-assisted interventions in rehabilitation. The present narrative review is aimed at investigating the effectiveness of virtual reality (VR) in the rehabilitation of elderly patients with knee or hip osteoarthritis, including patients after arthroplasty. This literature review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was carried out in five databases: PubMed, Medline, Web of Science, Scopus and PEDro. It includes ten randomized controlled trials focused on the application of games and biofeedback in the rehabilitation of patients with knee and hip osteoarthritis. There are no conclusive reports that interventions based on VR are more effective than standard physical therapy. Moreover, evidence regarding patients after total hip arthroplasty (THA) is very scarce. The effectiveness of VR-based rehabilitation is unclear, although interventions based on VR are promising in view of pain management, postural and proprioception training. However, this evidence is not sufficient to create clinical guidelines and further high-quality studies are needed.


Stable expression of Shigella dysenteriae serotype 1 O-antigen genes integrated into the chromosome of live Salmonella oral vaccine vector Ty21a.
Typhoid fever and shigellosis cause high morbidity and mortality worldwide, yet no anti-Shigella vaccine is currently available. However, to protect against typhoid fever, an approved vaccine, based on the attenuated Salmonella enterica serovar Typhi strain Ty21a is available. We have investigated Ty21a as a live oral vaccine vector for expression of heterologous foreign antigens to protect against other diseases (e.g. shigellosis, anthrax, and plague). Shigella LPS is a potent vaccine antigen for serotype-specific protection against Shigellae. We previously reported the construction of a Ty21a derivative expressing S. sonnei O-antigen by insertion of a large (∼12.5 kb) operon comprising the S. sonnei O-antigen biosynthetic genes into a targeted site within the Ty21a chromosome using modified λ red recombineering methods. In the current study, S. dysenteriae 1 O-antigen biosynthetic genes from 2 separate genetic loci, rfp and rfb were assembled and inserted into the Ty21a chromosome by λ red-mediated recombineering to construct strain Ty21a-Sd. To obtain a high level of heterologous LPS expression, the native upstream promoter was replaced with the constitutive lpp promoter, which resulted in Ty21a-Sdl with enhanced heterologous LPS expression. Both Ty21a-Sd and Ty21a-Sdl elicited significant serum antibody responses in mice against both Ty21a and this heterologous Shigella LPS, and conferred protection against virulent S. dysenteriae 1 challenge. This work represents progress toward the goal of a safe and effective vaccine against Shigella.


High-level resistance to gentamicin in clinical isolates of Streptococcus (Enterococcus) faecium.
During a 14-month period beginning in July 1986, three distinct clinical isolates of Streptococcus (Enterococcus) faecium demonstrating high-level resistance (MIC, greater than 2,000 micrograms/ml) to gentamicin, kanamycin, tobramycin, and streptomycin were recovered from individual patients at one institution. Combinations of ampicillin with any of these agents failed to show bactericidal synergism. By filter-mating techniques, high-level gentamicin resistance could be transferred into a susceptible recipient of the same species at frequencies as high as 1 x 10(-4); transfer into Streptococcus faecalis JH2-7 occurred at lower frequencies (less than 2 x 10(-7). Aminoglycoside substrate profile analysis of clinical isolates as well as of laboratory-derived cured strains and transconjugants revealed 2"-aminoglycoside phosphotransferase and 3'-aminoglycoside phosphotransferase (III) phosphorylating enzymes, AAC-6' acetylating activity above that attributable to the intrinsic activity characteristic of S. faecium, and a streptomycin adenylylating enzyme. All three isolates carried a 51-megadalton plasmid. Curing of this plasmid or conjugative transfer into susceptible recipients was associated with the loss or acquisition of high-level gentamicin resistance, respectively. Loss of high-level gentamicin resistance was also observed when curing techniques resulted in a decrease in the size of this plasmid equivalent to a 10-megadalton deletion. Transferable, high-level resistance to gentamicin and other aminoglycosides, which was previously recognized in S. faecalis, has now emerged in clinical isolates of S. faecium, with the attendant concerns for possible spread.


Patient characteristics and outcomes by GN subtype in ESRD.
Outcomes-based research rarely focuses on patients with ESRD caused by GN. The hypotheses were that the GN subtype would clinically discriminate patient groups and independently associate with survival after ESRD therapy initiation. Data were extracted from the US Renal Data System for adult patients with incident (1996-2011) ESRD attributed to six GN subtypes: FSGS, IgA nephropathy (IgAN), membranous nephropathy, membranoproliferative glomeruonephritis, lupus nephritis (LN), and vasculitis. ESRD attributed to diabetes and autosomal dominant polycystic kidney disease served as non-GN comparators. Unadjusted and adjusted mortality hazard ratios (aHRs) with 95% confidence intervals (95% CIs) were estimated using Cox regression (reference, IgAN). Models sequentially adjusted for sociodemographic (model 2), comorbidity/laboratory (model 3), and ESRD treatment modality (model 4) variables. Among 84,301 patients with ESRD attributed to GN, the median age ranged from 39 (LN) to 66 (vasculitis) years, male sex ranged from 18% (LN) to 68% (IgAN), and black race ranged from 7% (IgAN) to 49% (LN). Patients with IgAN had the fewest comorbidities and lowest use of hemodialysis (70.1%). After a median follow-up of 2.5 (interquartile range, 1.0-4.9) years, crude mortality was lowest in IgAN (3.7 deaths/100 person years). Compared to IgAN, adjusted mortality was highest in LN (model 4 aHR=1.75; 95% CI, 1.68 to 1.83) and in diabetes (aHR=1.73; 95% CI, 1.67 to 1.79), and was also higher in all other GN subtypes (membranous nephropathy: aHR=1.23; 95% CI, 1.17 to 1.29; FSGS: aHR=1.37; 95% CI, 1.32 to 1.42; membranoproliferative GN: aHR=1.38; 95% CI, 1.31 to 1.45; vasculitis: aHR=1.51; 95% CI, 1.45 to 1.58) and in autosomal dominant polycystic kidney disease (aHR=1.22; 95% CI, 1.18 to 1.27). This study exposes substantial heterogeneity across GN subtypes at ESRD therapy initiation and identifies independent associations between GN subtype and post-ESRD mortality. These survival discrepancies warrant further study, and the utility of current research practice to group GN subtypes together when evaluating ESRD outcomes should be questioned.


Carrier function in anti-hapten immune responses. II. Specific properties of carrier cells capable of enhancing anti-hapten antibody responses.
Transfer of live lymphoid cells from BGG-immunized strain 2 guinea pigs into syngeneic animals primed with DNP-OVA prepares the recipients for a markedly enhanced secondary anti-DNP antibody response upon challenge with DNP-BGG. This phenomenon has been demonstrated when the recipients were challenged 1 day after cell transfer, but it was considerably more striking when an interval of 6 days was allowed between transfer of cells and challenge with antigen. As demonstrated in the preceding paper (6), BGG preimmunization enhanced anti-DNP antibody responses to challenge with DNP-BGG. An analysis of the characteristics of substances to which preimmunization was effective in enhancing subsequent anti-hapten responses was made. It was shown that preimmunization of strain 13 guinea pigs with a copolymer of glutamic acid and lysine (GL), to which these animals are genetically unable to accord an immune response, failed to prepare them for an enhanced anti-DNP response to DNP-GL. Tolerance to BGG specifically abrogated the capacity of subsequent BGG immunization to prepare DNP-OVA primed rabbits for an enhanced anti-DNP response to DNP-BGG. Sensitization of animals to haptens by preimmunization with hapten-protein conjugates failed to prepare them for enhanced primary or secondary antibody responses to other determinants associated with that hapten on a different carrier. These studies indicate that the enhancing effect of carrier preimmunization reflects a cooperative interaction between lymphoid cells specific for carrier and cells specialized for haptenic determinants. Furthermore, the capacity of a substance to behave as a carrier requires more than its possession of a variety of antigenic determinants.


Steady-state current-voltage relationship of the Na/K pump in guinea pig ventricular myocytes.
Whole-cell currents were recorded in guinea pig ventricular myocytes at approximately 36 degrees C before, during, and after exposure to maximally effective concentrations of strophanthidin, a cardiotonic steroid and specific inhibitor of the Na/K pump. Wide-tipped pipettes, in combination with a device for exchanging the solution inside the pipette, afforded reasonable control of the ionic composition of the intracellular solution and of the membrane potential. Internal and external solutions were designed to minimize channel currents and Na/Ca exchange current while sustaining vigorous forward Na/K transport, monitored as strophanthidin-sensitive current. 100-ms voltage pulses from the -40 mV holding potential were used to determine steady-state levels of membrane current between -140 and +60 mV. Control experiments demonstrated that if the Na/K pump cycle were first arrested, e.g., by withdrawal of external K, or of both internal and external Na, then neither strophanthidin nor its vehicle, dimethylsulfoxide, had any discernible effect on steady-state membrane current. Further controls showed that, with the Na/K pump inhibited by strophanthidin, membrane current was insensitive to changes of external [K] between 5.4 and 0 mM and was little altered by changing the pipette [Na] from 0 to 50 mM. Strophanthidin-sensitive current therefore closely approximated Na/K pump current, and was virtually free of contamination by current components altered by the changes in extracellular [K] and intracellular [Na] expected to accompany pump inhibition. The steady-state Na/K pump current-voltage (I-V) relationship, with the pump strongly activated by 5.4 mM external K and 50 mM internal Na (and 10 mM ATP), was sigmoid in shape with a steep positive slope between about 0 and -100 mV, a less steep slope at more negative potentials, and an extremely shallow slope at positive potentials; no region of negative slope was found. That shape of I-V relationship can be generated by a two-state cycle with one pair of voltage-sensitive rate constants and one pair of voltage-insensitive rate constants: such a two-state scheme is a valid steady-state representation of a multi-state cycle that includes only a single voltage-sensitive step.


Association between serum γ-glutamyltranspeptidase and atherosclerosis: a population-based cross-sectional study.
The purpose of this study was to determine the relationship between serum γ-glutamyltranspeptidase (GGT) and brachial-ankle pulse wave velocity (baPWV) as an indicator for atherosclerosis in Japanese men and women after adjusting for fatty liver. A cross-sectional study. A health check-up centre in Japan. 912 Japanese men and women aged 24-84 years recruited from people who received a medical health check-up programme with a standardised questionnaire and an automatic waveform analyser to measure baPWV. We measured serum GGT concentrations and baPWV. Fatty liver was diagnosed by standardised criteria using abdominal ultrasonography. The postmenopausal state was defined as beginning 1 year after the cessation of menses. In women, log2 GGT was positively associated with baPWV (β=0.11, 95% CI 0.02 to 0.19, p<0.05), independent of age, body mass index, systolic blood pressure, fasting plasma glucose, triglycerides, estimated glomerular filtration rate, fatty liver, menopausal state and parameters of lifestyles. However, in men, the positive association of log2 GGT with baPWV was not significant (β=-0.04, 95% CI -0.10 to 0.03, p=0.28) in multivariable linear regression analyses. The serum GGT level was associated with baPWV, independently of covariates including fatty liver or menopausal state just in women, but not in men.


Synthesis and in vitro evaluation of charge reversal photoresponsive quinoline tethered mesoporous silica for targeted drug delivery.
We developed excellent charge reversal photoresponsive nanoparticles for targeted delivery of the anticancer drug chlorambucil. The charge reversal photoresponsive nanoparticles were constructed using two main ingredients, namely folic acid decorated mesoporous silica and quinoline chromophore. The newly synthesized quinoline chromophore performed three important roles, i.e., (i) fluorescent chromophore for cell imaging, (ii) phototrigger for regulated release of anticancer drug, and (iii) charge reversal based on its zeta potential for nuclear localization. Furthermore, folic acid decorated mesoporous silica facilitated active internalization of the drug inside the cancer cells. In vitro biological studies reveal that our photoresponsive DDS could deliver the anticancer drug chlorambucil into the tumor cells, killing the cancer cells by both one photon (≥365 nm) and two photon (675 nm) irradiation.


The Popularity of Outcome Measures for Hip and Knee Arthroplasties.
The optimal methods of determining outcomes following hip and knee arthroplasty remain controversial. The objectives of this study were to determine the most frequently used outcome measures in randomized controlled trials (RCT) and study protocols registered with clinical trials registries (CTR) on hip and knee arthroplasty. A systematic search strategy was undertaken to identify the outcome measures used in RCT and CTR following joint arthroplasty. Databases searched included Embase, Ovid MEDLINE (including In-Process), Cochrane Central Register of Controlled Trials, CINAHL Plus, clinicaltrials.gov, ISRCTN registry, and ANZCTR. Differences in the use of outcome measures between RCT and CTR were assessed using logistic regression. There were 291 RCT and 113 CTR on hip arthroplasty and 452 RCT and 184 CTR on knee arthroplasty that met the inclusion criteria. The most popular outcome measures were the Harris Hip Score and the Knee Society Score. Multiple outcome measures were used in greater than 50% of the included studies. The Oxford Hip Score, Oxford Knee Score, EuroQol-5D, and Knee Injury and Osteoarthritis Outcome Score (all P < .001) were used in significantly more CTR than RCT. There is a clear preference for the use of the Harris Hip Score and Knee Society Score, contrary to existing international guidelines and reviews on the topic. Both measures require clinician input, which potentially influences their validity and increases their overall administration cost. Some patient-reported outcome measures, such as the Oxford Hip and Knee Scores, EuroQol-5D, and KOOS, appear to be increasing in popularity.


Retinoblastoma susceptibility genes contain 5' sequences with a high propensity to form guanine-tetrad structures.
Retinoblastoma susceptibility genes contain significant runs of oligoguanine at their 5' ends. Oligonucleotides having these sequences underwent complex formation in the presence of sodium ions, in which there was association of four strands. Formation of this structure was completely prevented if guanine was replaced by 7-deazaguanine, indicating the importance of guanine N7 in the formation of the complex. Complex formation lead to protection of guanine N7 against methylation by dimethyl sulphate, but thymine bases located between oligoguanine blocks were reactive to osmium tetroxide. There was also some sensitivity to S1 nuclease to the 5' side of the oligoguanine block. The results show that the G-rich regions of the mouse and human retinoblastoma susceptibility genes have a propensity to undergo tetraplex formation of the kind demonstrated in the immunoglobulin switch region.


Comparison of tetracycline action on Staphylococcus aureus and Escherichia coli by microbial kinetics.
Cultures of tetracycline-treated Staphylococcus aureus exhibited monophasic steady-state growth curves similar to that observed for tetracycline-treated Escherichia coli. Apparent growth rate constants of the respective drug-treated cultures showed the same formal dependence on drug concentration, which was linear at a low concentration but asymptotically approached zero at higher concentration levels and implied the saturation of a limited number of receptor sites engaged in microbial protein synthesis. The relative potency of tetracycline action of S. aureus/E. coli was 6.50:1 at 37.5 degrees C and pH 7.05. This is attributed to relative differences in drug permeation and/or binding affinity for biophase receptors in the respective organisms. It is concluded from kinetic dependencies of growth inhibition of the cultures that tetracycline has the same mode of action on S. aureus and E. coli. It is bacteriostatic at concentrations below the minimal inhibitory concentration level but bactericidal at the higher concentration levels.


IGG practice guidelines on germ cell tumor in adult male patients.
Germ cell tumors are rare neoplasms that affect young males. Nearly 99% of patients with localized stage I disease and nearly 80% of patients with metastatic disease can be cured. Even patients who relapse following chemotherapy can achieve a long-term survival in approximately 30-40% of cases. The main objective in early stages and in good prognosis patients has changed in recent years, and it has become of major importance to reduce treatment-related morbidity without compromising the excellent long-term survival rate. In poor prognosis patients, there is a correlation between the experience of the treating institution and the long-term clinical outcome of the patients, particularly when the most sophisticated therapies are needed. So far, of utmost importance is the information from updated practice guidelines for the diagnosis and treatment of germ cell tumors. The Italian Germ cell cancer Group (IGG) has developed the following clinical recommendations, which identify the current standards in diagnosis and treatment of germ cell tumors in adult males.


Competition between the conditioned rewarding effects of cocaine and novelty.
Access to novelty might provide an alternative learning history that competes with conditioned drug reward. We tested this suggestion in rats using a place conditioning procedure with cocaine and novelty. In Experiment 1, rats were conditioned with cocaine to prefer one side of an apparatus. In a subsequent phase, cocaine exposure continued; however, on the unpaired side, separate group of rats had access to novel objects, cocaine injections, or saline with no objects. Pairings with novel objects or cocaine shifted a preference away from the cocaine-paired environment during drug-free and drug-challenge tests. Experiment 2 tested novelty's impact when cocaine exposure was discontinued. The identical procedures were used except drug exposure ceased on the cocaine-paired side during the second phase. Both groups expressed a preference for the cocaine compartment. This preference was maintained for rats that did not have novel objects; however, rats that experienced novelty spent similar amounts of time in both compartments during both tests. Overall, the conditioned rewarding effects of novelty competed with those of cocaine as evidenced by a change in choice behaviors motivated by drug reward.


Mechanistic Assessment of PD-1H Coinhibitory Receptor-Induced T Cell Tolerance to Allogeneic Antigens.
PD-1H is a recently identified cell surface coinhibitory molecule of the B7/CD28 immune modulatory gene family. We showed previously that single injection of a PD-1H agonistic mAb protected mice from graft-versus-host disease (GVHD). In this study, we report two distinct mechanisms operate in PD-1H-induced T cell tolerance. First, signaling via PD-1H coinhibitory receptor potently arrests alloreactive donor T cells from activation and expansion in the initiation phase. Second, donor regulatory T cells are subsequently expanded to maintain long-term tolerance and GVHD suppression. Our study reveals the crucial function of PD-1H as a coinhibitory receptor on alloreactive T cells and its function in the regulation of T cell tolerance. Therefore, PD-1H may be a target for the modulation of alloreactive T cells in GVHD and transplantation.


Effects of changes in motor unit size on transmitter release at the frog neuromuscular junction.
The dependence of transmitter release and synaptic effectiveness on the size of a neuron's peripheral field was studied using neuromuscular junctions in sartorius muscles of adult frogs (Rana pipiens). The size of the peripheral field (motor unit size) was reduced by crushing the sartorius nerve and surgically removing half of the muscle fibers. Synapses thus formed were compared with those formed when crushed nerves reinnervated intact whole muscles, as well as with synapses in normal unoperated muscles. Indirect observations suggested that all motor axons participated in reinnervation and that motor unit size was indeed smaller in half-muscles. Synaptic safety margins, as measured by the sensitivity of nerve stimulus-evoked twitching to low Ca2+, were substantially higher in muscles with reduced motor units. These higher safety margins were due to enhanced evoked transmitter release. In Ringer solution containing Mg2+ and lowered Ca2+, total evoked release and evoked release per unit nerve terminal length were approximately 2-fold higher in muscles with reduced motor units, when studied 7 to 18 weeks postoperatively. A similar difference was seen when unblocked release was measured in a normal physiological solution, after blocking excitation-contraction coupling and muscle fiber action potential generation with formamide. Miniature endplate potential frequency in half-muscles was 2 to 3 times higher than in controls when tested in normal physiological solution, but was not significantly different in low Ca2+, Mg2+-containing solution. By 34 weeks postoperatively, there was no longer a difference in evoked release, even though the difference in motor unit size persisted.(ABSTRACT TRUNCATED AT 250 WORDS)


MicroRNA profiling of benign and malignant pheochromocytomas identifies novel diagnostic and therapeutic targets.
MicroRNAs (miRNAs) are small RNAs ( approximately 22 bp) that post-transcriptionally regulate protein expression and are found to be differentially expressed in a number of human cancers. There is increasing evidence to suggest that miRNAs could be useful in cancer diagnosis, prognosis, and therapy. We performed miRNA microarray expression profiling on a cohort of 12 benign and 12 malignant pheochromocytomas and identified a number of differentially expressed miRNAs. These results were validated in a separate cohort of ten benign and ten malignant samples using real-time quantitative RT-PCR; benign samples had a minimum follow-up of at least 2 years. It was found that IGF2 as well as its intronic miR-483-5p was over-expressed, while miR-15a and miR-16 were under-expressed in malignant tumours compared with benign tumours. These miRNAs were found to be diagnostic and prognostic markers for malignant pheochromocytoma. The functional role of miR-15a and miR-16 was investigated in vitro in the rat PC12 pheochromocytoma cell line, and these miRNAs were found to regulate cell proliferation via their effect on cyclin D1 and apoptosis. These data indicate that miRNAs play a pivotal role in the biology of malignant pheochromocytoma, and represent an important class of diagnostic and prognostic biomarkers and therapeutic targets warranting further investigation.


Clinical diagnoses associated with histologic findings of fibrotic tissue and new bone in the inner ear.
Fibrotic tissue or new bone occurs following inner ear inflammation, fracture, or surgery. The prevalence is unknown and was investigated using the National Temporal Bone, Hearing and Balance Pathology Resource Registry database. A search yielded 264 temporal bones with diagnoses of otosclerosis, tumor, Meniere's disease, meningitis, labyrinthitis, chronic otitis media, autoimmune disease, temporal bone fracture, or sensorineural hearing loss. All autoimmune cases contained some new bone, whereas only 20% to 30% of the labyrinthitis/meningitis cases were reported to contain new bone. Otosclerosis, Meniere's disease, and otitis media had relatively few cases containing new bone. Although new bone may derive from surgical trauma, it is also likely to be a result of the disease process. It seems that all these disease processes may contain a common feature that acts as a stimulus to induce fibrosis or bone growth in the inner ear.


Reliability of the BCCT.core software in evaluation of breast cosmesis - A systematic review.
Breast cancer conservative treatment software (BCCT.core) has the potential to provide objective results using digital photographs, thus increasing the reliability, limiting the subjective interpretation and standardising the evaluation of breast cosmesis in patients. The aim of this systematic review was to summarise the empirical evidence regarding the agreement between the BCCT.core and other methods used by health professionals and patients to assess breast cosmesis. The Ovid MEDLINE, Embase, CINAHL, PsycINFO and Scopus databases were systematically searched for studies comparing the agreement between BCCT.core and other methods used to assess breast cosmesis. A total of 14 studies involving 2703 patients were included in the review. In studies where patients undertook self-assessment, the percentage agreement ranged from 69.2% to 74.8% and the kappa values ranged from slight (k = 0.12) to fair agreement. There was a low correlation between the BCCT.core and the Harvard scale when patients assessed cosmetic outcomes using photographs of their breasts (r = 0.165). A 75% and 42.8% agreement was reported in studies where clinicians assessed breast cosmesis by directly visualising the patients' breasts and photographs, respectively. Assessment of breast cosmesis by the expert panel using patient photographs reported a percentage agreement ranging from 25% to 83%. The results of this systematic review demonstrated an overall agreement of fair to moderate between the BCCT.core and the subjective scales used to assess breast cosmesis. However, clinician experience and patient values should be considered in clinical decision-making.


Lung injury mediated by antibodies to endothelium. I. In the rabbit a repeated interaction of heterologous anti-angiotensin-converting enzyme antibodies with alveolar endothelium results in resistance to immune injury through antigenic modulation.
To study the effects of relatively long-term interaction of antibodies with surface antigens of lung endothelium, rabbits were intravenously injected for a maximum of 4 d with goat anti-rabbit lung angiotensin-converting enzyme (Gt anti-RbACE) antibodies. On day 1 69%, on day 2 13%, and on days 3 and 4 of injection none of the rabbits developed lethal pulmonary edema. By immunofluorescence microscopy, deposits of GtIgG, frequently in association with RbC3, were found along the endothelium of alveolar capillary walls in all rabbits studied on day 1, in 57% on day 2, in 33% on day 3, and in none of them on day 4. While in vitro anti-ACE antibodies bound in a linear pattern to the lung endothelium, the binding pattern in vivo was distinctly granular. The in vivo interaction of antibodies with ACE also redistributed ACE in a granular pattern along capillary walls. In contrast to the granular deposition of injected anti-ACE IgG and F(ab')2 fragments of anti-ACE IgG, Fab fragments of anti-ACE IgG localized, without fixing C3, in a linear pattern along the endothelium of lung capillaries and did not modify the normal distribution of ACE. However, when the injection of Fab fragments of Gt anti-RbACE IgG was followed by an injection of Rb anti-GtIgG serum, granular deposits of Gt Fab fragments, RbIgG and RbC3 were seen along alveolar capillary walls. Biochemical measurement of ACE activity in lung homogenates provided data in agreement with those obtained by immunofluorescence microscopy, showing diminished activity to none on day 4, with some return of ACE activity on day 5, 24 h after the last injection of antibody, and normal values on day 21. The results obtained indicate that divalent antibodies to an antigen expressed on the plasma membrane of rabbit lung endothelial cells promotes a rapid redistribution of antigenic receptors, fixation of complement and, in surviving rabbits, disappearance of the antigen from the endothelial cells that are no longer susceptible to immune injury. In vivo "immunologic enzymectomy" induced by a ligand-surface antigen interaction is an example of antigenic modulation. These events may have an important role in the pathogenesis of inflammatory lesions induced by antibodies reacting with antigens expressed on the plasma membrane of cells in the lung and in other organs.


Proton magnetic resonance spectroscopy (H-MRS) studies of schizophrenia.
Proton magnetic resonance spectroscopy ((1)H-MRS) is a noninvasive technique that can quantify biochemical compounds in the brain. (1)H-MRS has been used to investigate neural structures implicated in the pathology of schizophrenia. The majority of research has revealed reduced N-acetylaspartate (NAA), an index of neuronal integrity, in frontal and temporal regions of medicated and chronically ill patients with schizophrenia. This review summarizes basic principles of (1)H-MRS, studies of frontal, temporal, subcortical, and cerebellar regions in schizophrenia. Technical and study design limitations are also discussed.


Cardiovascular and All-Cause Mortality Risk by Coronary Artery Calcium Scores and Percentiles Among Older Adult Males and Females.
Coronary calcium is a marker of coronary atherosclerosis and established predictor of cardiovascular risk in general populations; however, there are limited studies examining its prognostic value among older adults (≥75 years) and even less regarding its utility in older males compared with females. Accordingly, we sought to examine the prognostic significance of both absolute and percentile coronary calcium scores among older adults. The multicenter Coronary Artery Calcium Consortium consists of 66,636 asymptomatic patients without cardiovascular disease. Participants ages ≥75 were included in this study and stratified by sex. Multivariable Cox regression models were constructed to assess cardiovascular and all-cause mortality risk by Agatston coronary calcium scores and percentiles. Among 2,474 asymptomatic patients (mean age 79 years, 10.4-year follow-up), prevalence of coronary artery calcium was 92%. For both sexes, but in females more so than males, higher coronary calcium score and percentiles were associated with increased cardiovascular and all-cause mortality risk. Those at the lowest coronary calcium categories (0-9 and <25 percentile) had significantly lower risk of cardiovascular and all-cause mortality relative to the rest of the population. Multivariable analyses of traditional cardiovascular risk factors and coronary artery calcium variables revealed that age and coronary calcium were the strongest independent predictors for adverse outcomes. Both coronary artery calcium scores and percentiles are strongly predictive of cardiovascular and all-cause mortality among older adults, with greater risk-stratification among females than males. Both low coronary artery calcium scores 0-9 and <25th percentile define relatively low risk older adults.


A role for choroidal lymphatics during recovery from form deprivation myopia?
The choroid of the chick swells markedly during recovery from experimentally induced myopia. It has been demonstrated previously that the lymphatic sinusoids of the choroid contribute most to the expansion. This raises important questions about the particular ultrastructural changes occurring in choroidal lymphatics as a means of understanding the role these vessels might play in emmetropization. Thirteen hatchling chicks were monocularly occluded for 2 weeks to induce myopia and then allowed normal visual experiences during recovery for periods of 0 to 72 h before sacrifice. Electron microscopic analysis detailed the temporal progression of vascular changes and provides qualitative evidence for edema in the extravascular space. Quantitative analysis showed that the frequency of open junctions between lymphatic endothelial cells (an indicator of passive fluid transfer) increased over the 3 days of recovery. Lymphatic fenestrations (an indicator of active fluid transfer) were rare in both nondeprived eyes and in form-deprived eyes at the time of occluder removal, but increased in density significantly over the first 24 h of recovery before returning to control levels by 72 h. The number of lymphatic endothelial caveolae did not change significantly during recovery, nor did the number of fenestrations along the walls of choriocapillaris vessels. The walls of the lymphatics of the chick choroid open to allow greater fluid transfer during re-emmetropization than normal; the lymphatics may play an important role in the maintenance of chorioretinal fluid balance and homeostasis.


Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy.
Thirty patients with insulin-dependent diabetes mellitus (IDDM) who had advanced background retinopathy were randomized to unchanged conventional treatment (UCT) or to continuous subcutaneous insulin infusion (CSII). They were followed prospectively for 2 yr. The mean blood glucose and hemoglobin A1C (HbA1C) were significantly lower in the CSII group than in the UCT group. The mean blood glucose and HbA1C did not change from the first to the second year in either of the treatment groups in spite of less frequent home-monitoring of blood glucose and less frequent outpatient visits during the second year. Four patients in the CSII group and five in the UCT group developed proliferative retinopathy. However, a marginally significant trend was found toward more frequent improvement of retinal morphology in the CSII group (47%) than in the UCT group (13%). Beat-to-beat variation was found to deteriorate significantly with UCT compared with a nonsignificant improvement with CSII therapy. Vibration sense was unchanged in both treatment groups. It is concluded that near-normal blood glucose levels can be maintained with CSII therapy in spite of less frequent home-monitoring of blood glucose and outpatient visits. Furthermore, established background retinopathy may progress to proliferative retinopathy in spite of 2 yr of near-normal blood glucose levels. However, a marginally significant trend toward more frequent improvement of retinal morphology was found among CSII-treated patients compared with conventionally treated patients. Large-scale, prospective, randomized studies are needed to confirm these results.


In vitro digestibility of goat milk and kefir with a new standardised static digestion method (INFOGEST cost action) and bioactivities of the resultant peptides.
The hydrolysis degrees of goat milk and kefir during simulated gastrointestinal digestion and some bioactivities of the resulting peptides after fermentation and digestion were studied. A static in vitro digestion method by the COST FA1005 Action INFOGEST was used and goat milk and kefir were partially hydrolyzed during the gastric phase and had above 80% hydrolysis after duodenal digestion. There were no differences between the digestibility of goat milk and kefir (p > 0.05). Goat milk and kefir displayed about 7-fold antioxidant activity after digestion (p < 0.05). Fermentation showed no effect on the calcium-binding capacity of the samples (p > 0.05), however, after in vitro digestion calcium-binding capacity of the goat milk and kefir increased 2 and 5 fold, respectively (p < 0.05). Digested goat milk and kefir showed a higher dose-dependent inhibitory effect on α-amylase compared to undigested samples (p < 0.05). α-Glucosidase inhibitory activities and in vitro bile acid-binding capacities of the samples were not determined at the studied concentrations.