Multiprotein HIV type 1 clade B DNA and MVA vaccines: construction, expression, and immunogenicity in rodents of the MVA component.
Recombinant modified vaccinia virus Ankara (MVA) expressing SIV or SHIV Gag-Pol and Env, alone or in conjunction with a related DNA vaccine, effectively controls immunodeficiency virus infections in nonhuman primates. Here we describe the construction, characterization, and immunogenicity of MVA/HIV 48, a candidate HIV-1 clade B Gag-Pol-Env vaccine. A novel transfer vector was designed to allow the incorporation of HIV genes regulated by vaccinia virus promoters together with a reporter gene into a single site in the MVA genome and to automatically delete the reporter after the initial isolation of the recombinant MVA. MVA/HIV 48 contains chimeric HIV-1 HXB-2/BH10 gag-pol sequences, a deletion of integrase, inactivating point mutations in reverse transcriptase, and HIV-1 ADA env sequences with a truncation of most of the cytoplasmic domain to enhance expression on the plasma membrane. Cells infected with MVA/HIV 48 expressed HIV proteins, which were processed to the expected size. The Env was inserted into the plasma membrane and was functional in a CCR5 coreceptor-dependent cell fusion assay. Moreover, virus-like particles were released into the medium and budding particles containing Env were visualized by immunoelectron microscopy. Rodents that were immunized with MVA/HIV 48 produced antibodies, which neutralized a heterologous HIV-MN strain, and Gag-specific CD8 T cells. In the accompanying paper, we show that MVA/HIV 48 provided efficient boosting of an HIV DNA vaccine.


Two dominant-acting selectable markers for gene transfer studies in mammalian cells.
We report the development of two dominant-acting genetic markers useful for monitoring gene transfer in mammalian cells that are based on prokaryotic genes encoding key steps in the synthesis of the essential amino acids, tryptophan and histidine. Under appropriate conditions, expression of these genes obviates the nutritional requirements for their respective amino acid products. Expression of the trpB gene of Escherichia coli, which encodes the beta subunit of tryptophan synthase (EC 188.8.131.52), allows mammalian cell survival and multiplication in medium containing indole in place of tryptophan. The hisD gene of Salmonella typhimurium encodes histidinol dehydrogenase (EC 18.104.22.168), which catalyzes the two-step NAD+-dependent oxidation of L-histidinol to L-histidine. In medium lacking histidine and containing histidinol, only mammalian cells expressing the hisD product survive. The selection is a double one in that the provided precursor histidinol is itself toxic to animal cells through its inhibition of histidyl-tRNA synthetase; thus, the dehydrogenase both removes an inhibitor and forms a required end product. Alternatively, the his selection may be carried out under conditions in which the dehydrogenase serves mainly to detoxify histidinol. For either the trp or his selections the substitute nutrient (indole or histidinol) is readily available, inexpensive, stable, permeable to cells, and convertible to the end product in a step controlled by a single gene. Vectors based upon murine retrovirus and papovavirus backbones have been successfully employed for both genes, allowing selection in a range of cell types, including 3T3, CV-1, and HeLa. These dominant selective schemes should provide generally useful and inexpensive alternatives to others currently in use, such as the gpt, neo, hygro, dhfr, and tk selections.


Cytoplasmic intermediate filaments are stably associated with nuclear matrices and potentially modulate their DNA-binding function.
The tight association of cytoplasmic intermediate filaments (cIFs) with the nucleus and the isolation of crosslinkage products of vimentin with genomic DNA fragments, including nuclear matrix attachment regions (MARs) from proliferating fibroblasts, point to a participation of cIFs in nuclear activities. To test the possibility that cIFs are complementary nuclear matrix elements, the nuclei of a series of cultured cells were subjected to the Li-diiodosalicylate (LIS) extraction protocol developed for the preparation of nuclear matrices and analyzed by immunofluorescence microscopy and immunoblotting with antibodies directed against lamin B and cIF proteins. When nuclei released from hypotonically swollen L929 suspension cells in the presence of digitonin or Triton X-100 were exposed to such strong shearing forces that a considerable number were totally disrupted, a thin, discontinuous layer of vimentin IFs remained tenaciously adhering to still intact nuclei, in apparent coalignment with the nuclear lamina. Even in broken nuclei, the distribution of vimentin followed that of lamin B in areas where the lamina still appeared intact. The same retention of vimentin together with desmin and glial IFs was observed on the nuclei isolated from differentiating C2C12 myoblast and U333 glioma cells, respectively. Nuclei from epithelial cells shed their residual perinuclear IF layers as coherent cytoskeletal ghosts, except for small fractions of vimentin and cytokeratin IFs, which remained in a dot-to cap-like arrangement on the nuclear surface, in apparent codistribution with lamin B. LIS extraction did not bring about a reduction in the cIF protein contents of such nuclei upon their transformation into nuclear matrices. Moreover, in whole mount preparations of mouse embryo fibroblasts, DNA/chromatin emerging from nuclei during LIS extraction mechanically and chemically cleaned the nuclear surface and perinuclear area from loosely anchored cytoplasmic material with the production of broad, IF-free annular spaces, but left substantial fractions of the vimentin IFs in tight association with the nuclear surface. Accordingly, double-immunogold electron microscopy of fixed and permeabilized fibroblasts disclosed a close neighborhood of vimentin IFs and lamin B, with a minimal distance between the nanogold particles of ca. 30 nm. These data indicate an extremely solid interconnection of cIFs with structural elements of the nuclear matrix, and make them, together with their susceptibility to crosslinkage to MARs and other genomic DNA sequences under native conditions, complementary or even integral constituents of the karyoskeleton.


Sugammadex - indications and clinical use.
Neuromuscular blocking agents are a substantial element of anaesthesia in almost every surgical field. Nevertheless, their use has been associated with rises in mortality and morbidity. Of importance are: the general health state of the patient, liver and renal function, metabolism and excretion, active metabolites, side effects of muscle relaxants and, above all, residual paralysis. Prophylaxis of insufficient block reversal consists of neuromuscular transmission monitoring using acceleromyography and pharmacologic reversal of blockade. An ideal antagonistic agent should be characterised by rapid and complete reversal of blockade, disregarding its depth and total dose of muscle relaxant, lack of side effects and 100% excretion. These criteria are met by cyclodextrine gamma - sugammadex. In contrast to anticholinergic agents, which enhance the acetylcholine amount in the postsynaptic part of the neuromuscular junction, sugammadex encapsulates myorelaxing agent removing it from the junction. Sugammadex binds specifically only muscle relaxants of aminosteroid structure. In this paper, we present the current understanding of the characteristics, dosing, indications and side effects of sugammadex.


Rates of non-AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis.
To describe the incidence of non-AIDS-defining cancers in people with HIV infection before and after the occurrence of AIDS, and to examine the association of cancer risk with immune deficiency. Cohort study involving nation-wide linkage of HIV, AIDS and cancer registry data. Association of cancer risk with immune deficiency was examined by analysing cancer risks in four periods between HIV diagnosis, AIDS and death. Linkage identified 196 cases of non-AIDS-defining cancer in 8351 people notified with HIV infection and 8118 registered with AIDS (total of 13 067 individuals). Overall, we found significantly increased rates of cancer of the lip, anus, Hodgkin's disease, myeloma and leukaemia. Of these cancers, in people with HIV infection who did not develop AIDS, or were more than 5 years prior to development of AIDS, only cancer of the anus occurred at increased rates. A significant trend of increasing relative risk of cancer with increasing time since HIV diagnosis was found for Hodgkin's disease and multiple myeloma. People with HIV with mild immune deficiency prior to AIDS were at increased risk of anal cancer, but this may reflect other risk factors. Other cancers occurred only later in the course of HIV infection. This is reassuring evidence that people with HIV who are only mildly immune deficient may not be at increased risk of non-AIDS-defining cancers, but larger studies with longer periods of follow-up are needed to confirm this.


A possible role for stable microtubules in intracellular transport from the endoplasmic reticulum to the Golgi apparatus.
The intracellular transport of secretory proteins involves at an early stage the formation of vesicles from transitional elements of the endoplasmic reticulum (ER) containing these proteins and the transfer of these vesicles to the cis-face of the Golgi apparatus. We propose that the latter transfer process does not occur by random diffusion, but is instead mediated by tracking along stable microtubules. To test this proposal, we have carried out double immunoelectron microscopic labeling experiments on frozen sections of HepG2 hepatoma cells secreting the protein human serum albumin (HSA). By a cycloheximide treatment protocol, the stage during which the transfer of newly synthesized HSA from the ER to the Golgi apparatus occurs in vivo was determined. Sections of the cells were then double immunolabeled using primary antibodies to HSA and to glu-tubulin, the latter specifically detecting stable microtubules. We observed a significantly high frequency of HSA-containing structures between the ER and the Golgi apparatus with which stable microtubules were closely associated. These results support the proposal that stable microtubules may play a critical role in directing the transfer process from the ER to the Golgi apparatus.


Multivalent supramolecular assembly with ultralong organic room temperature phosphorescence, high transfer efficiency and ultrahigh antenna effect in water.
Multivalent supramolecular assemblies have recently attracted extensive attention in the applications of soft materials and cell imaging. Here, we report a novel multivalent supramolecular assembly constructed from 4-(4-bromophenyl)pyridine-1-ium bromide modified hyaluronic acid (HABr), cucurbit[8]uril (CB[8]) and laponite® clay (LP), which could emit purely organic room-temperature phosphorescence (RTP) with a phosphorescence lifetime of up to 4.79 ms in aqueous solution via multivalent supramolecular interactions. By doping the organic dyes rhodamine B (RhB) or sulfonated rhodamine 101 (SR101) into the HABr/CB[8]/LP assembly, phosphorescence energy transfer was realized with high transfer efficiency (energy transfer efficiency = 73-80%) and ultrahigh antenna effect (antenna effect value = 308-362) within the phosphorescent light harvesting system. Moreover, owing to the dynamic nature of the noncovalent interactions, a wide-range spectrum of phosphorescence energy transfer outputs could be obtained not only in water but also on filter paper and a glass plate by adjusting the donor-acceptor ratio and, importantly, white-light emission was obtained, which could be used in the application of information encryption.


In vitro accumulation and permeation of hypericin and lipophilic analogues in 2-D and 3-D cellular systems.
Previous studies have shown that hypericin is an excellent diagnostic tool for the fluorescence detection of carcinoma in situ in the human bladder. The present work was performed to get a better insight into the mechanism of cellular uptake of hypericin (HYP) using RT-112 human papillary TCC cells of the bladder. Using lipophilic hypericin acid amide derivatives like hypericin acid hexylamide (AM6), hypericin acid octylamide (AM8) and hypericin acid dodecylamide (AM12), the effect of increased lipophilicity on the binding to serum proteins was investigated, as well as the cellular accumulation and permeation, both in 2-D and 3-D cell conditions. Density-gradient ultracentrifugation of the compounds pre-incubated with fetal bovine serum (FBS) showed that HYP and to a lesser extent AM6 predominantly bind to LDL, whereas AM8 and especially AM12 preferably associate with HDL. The cellular accumulation of the compounds did not significantly differ when LDL or AcLDL was supplemented to medium, and with all compounds the highest uptake could be observed in case of medium without supplements. Using medium without supplements it was further observed that the compounds with the highest lipophilicity accumulated substantially less in RT-112 cells. We further found a significant difference in the intracellular concentration of AM8 and AM12 when LDL or FBS was supplemented to MEM, but not in case of HYP and AM6. Of particular interest, AM8 and especially AM12 showed enhanced intraspheroidal permeation in the presence of FBS. It is believed that the relative stronger binding to HDL reduces the intracellular accumulation, as seen in the 2-D conditions, and therefore increases the probability of paracellular transport in a 3-D multicellular system by passive diffusion. In conclusion the data suggest that the amount of free hypericin or its lipophilic congener determines the extent of intracellular accumulation. This concentration is both determined and limited by binding to different lipoproteins present in the medium, and by the formation of stable homoaggregates. The findings further highlight AM8 and AM12 as compounds better tailored for paracellular transport than HYP itself and therefore as potentially very interesting diagnostic tools for TCC lesions in the bladder.


Personality disorder symptom severity predicts onset of mood episodes and conversion to bipolar I disorder in individuals with bipolar spectrum disorder.
Although personality disorders (PDs) are highly comorbid with bipolar spectrum disorders (BSDs), little longitudinal research has been conducted to examine the prospective impact of PD symptoms on the course of BSDs. The aim of this study is to examine whether PD symptom severity predicts shorter time to onset of bipolar mood episodes and conversion to bipolar I disorder over time among individuals with less severe BSDs. Participants (n = 166) with bipolar II disorder, cyclothymia, or bipolar disorder not otherwise specified completed diagnostic interview assessments of PD symptoms and self-report measures of mood symptoms at baseline. They were followed prospectively with diagnostic interviews every 4 months for an average of 3.02 years. Cox proportional hazard regression analyses indicated that overall PD symptom severity significantly predicted shorter time to onset of hypomanic (hazard ratio [HR] = 1.42; p < .001) and major depressive episodes (HR = 1.51; p < .001) and conversion to bipolar I disorder (HR = 2.51; p < .001), after controlling for mood symptoms. Results also suggested that cluster B severity predicted shorter time to onset of hypomanic episodes (HR = 1.38; p = .002) and major depressive episodes (HR = 1.35; p = .01) and conversion to bipolar I disorder (HR = 2.77; p < .001), whereas cluster C severity (HR = 1.56; p < .001) predicted shorter time to onset of major depressive episodes. These results support predisposition models in suggesting that PD symptoms may act as a risk factor for a more severe course of BSDs. (PsycINFO Database Record


A retrospective study of anti-inflammatory use in dogs with pulmonary blastomycosis: 139 cases (2002-2012).
To determine the effect of anti-inflammatory medications on 30-day survival of dogs treated for pulmonary blastomycosis. Retrospective study. University teaching hospital. One hundred thirty nine client-owned dogs with confirmed pulmonary blastomycosis. The medical records of dogs diagnosed with pulmonary blastomycosis between May 2002 and October 2012 were identified. Of 139 dogs, 85 (61%) survived to 30 days, 38 (27%) were euthanized due to progressive clinical disease, 13 (10%) died secondary to respiratory or cardiac arrest, and 3 (2%) did not survive to 30 days but had an unknown cause of death. Cases were classified based on the anti-inflammatory therapy that was used: nonsteroidal anti-inflammatory drugs (NSAID), corticosteroids, both, or none. Controlling for the effects of itraconazole dose, sex, age, and pretreatment with anti-inflammatory medication, the odds for survival to 30 days was not statistically different between dogs who received no anti-inflammatory medication and the dogs who received NSAIDs (P = 0.86), corticosteroids (P = 0.65), or both (P = 0.27). The need for supplemental oxygen was associated with decreased survival (P < 0.0001). In this population of dogs with pulmonary blastomycosis, the use of anti-inflammatory medications during therapy did not impact 30-day survival; however, the need for oxygen supplementation was associated with significantly lower survival.


Comparative adrenocortical suppression in dogs with otitis externa following topical otic administration of four different glucocorticoid-containing medications.
The safety of using otic formulations is often of concern for practitioners and pet owners alike, with "safe" in this context meaning no adrenocortical suppression. This study evaluated the effect of four glucocorticoid-containing otic formulations on plasma cortisol concentrations, measured by corticotropin stimulation testing (plasma cortisol concentrations before and after corticotropin injection), in dogs presented with otitis externa. Dexamethasone tended to have larger adrenocortical suppression compared with the other three formulations (betamethasone, triamcinolone, and mometasone), but the difference was not statistically significant. The largest difference among the four drugs was observed between dexamethasone and betamethasone (P=.09).


[Case Report - Bilateral humeral intraosseous access for CPR in a 3-years-old child].
On-scene invasive emergency procedures, such as intraosseous puncture, are often unavoidable, when indicated, and present a challenge for the emergency physician. Personal, temporal or local conditions are often unsuitable. Even with regular intervention by the emergency medical service, "last resort" measures occur very infrequently, particularly in pediatric emergencies. For the first time, this case report presents the use of intraosseous access at the humeral head with children, with reference to indication, implementation, problems and risks.


The mutational landscape of a US Midwestern breast cancer cohort reveals subtype-specific cancer drivers and prognostic markers.
Female breast cancer remains the second leading cause of cancer-related death in the USA. The heterogeneity in the tumor morphology across the cohort and within patients can lead to unpredictable therapy resistance, metastasis, and clinical outcome. Hence, supplementing classic pathological markers with intrinsic tumor molecular markers can help identify novel molecular subtypes and the discovery of actionable biomarkers. We conducted a large multi-institutional genomic analysis of paired normal and tumor samples from breast cancer patients to profile the complex genomic architecture of breast tumors. Long-term patient follow-up, therapeutic regimens, and treatment response for this cohort are documented using the Breast Cancer Collaborative Registry. The majority of the patients in this study were at tumor stage 1 (51.4%) and stage 2 (36.3%) at the time of diagnosis. Whole-exome sequencing data from 554 patients were used for mutational profiling and identifying cancer drivers. We identified 54 tumors having at least 1000 mutations and 185 tumors with less than 100 mutations. Tumor mutational burden varied across the classified subtypes, and the top ten mutated genes include MUC4, MUC16, PIK3CA, TTN, TP53, NBPF10, NBPF1, CDC27, AHNAK2, and MUC2. Patients were classified based on seven biological and tumor-specific parameters, including grade, stage, hormone receptor status, histological subtype, Ki67 expression, lymph node status, race, and mutational profiles compared across different subtypes. Mutual exclusion of mutations in PIK3CA and TP53 was pronounced across different tumor grades. Cancer drivers specific to each subtype include TP53, PIK3CA, CDC27, CDH1, STK39, CBFB, MAP3K1, and GATA3, and mutations associated with patient survival were identified in our cohort. This extensive study has revealed tumor burden, driver genes, co-occurrence, mutual exclusivity, and survival effects of mutations on a US Midwestern breast cancer cohort, paving the way for developing personalized therapeutic strategies.


Design of branched and chiral solvatochromic probes: toward quantifying polarity gradients in dendritic macromolecules.
[reaction: see text] A pair of chiral, branched monomer building blocks, consisting of a solvatochromic probe and a spectroscopically inactive volume dummy, has been developed. The probe can selectively be excited, and its fluorescence characteristics provide information about local polarity. Incorporation of these monomers into high-generation polyester dendrimers should enable a detailed investigation of the polarity/density profile in dendritic architectures and ultimately allow for the realization of energy gradients from one chromophore building block only.


Physical exercise and peritoneal dialysis: An area yet to be explored.
Health-related quality of life (HRQoL) of patients suffering from chronic kidney disease (CKD) is profoundly impaired by their frailty, disability and decreased physical capacity. Especially among older patients, a high prevalence of low physical activity levels and reduced functional performance has been reported. Physical exercise training has been shown to have a beneficial impact, counteracting these same hazardous consequences of inactivity and sedentarism both on CKD and end-stage kidney disease (ESKD) patients on hemodialysis (HD) treatment. The evidence-based knowledge on the effects of physical exercise on ESKD patients undergoing Peritoneal Dialysis (PD) treatment is scarce, even though this is a continually growing population that shares the same risk factors and desired clinical outcomes as the previously mentioned groups of patients. Further investigation will be necessary to clarify whether this exercise-based approach may be suitable for the PD population. This paper's purpose is to review the available literature, including randomized controlled trials, reviews and meta-analysis results that assessed the impact of physical exercise on patients under PD treatment bearing in mind their HRQoL, physical functioning and cardiovascular parameters. Furthermore, it aims to evaluate the perceived significant barriers and limitations of the PD population in what concerns physical exercise practice and how nephrologists should address them.


Metal-Organic Synthetic Transporters (MOST): Efficient Chloride and Antibiotic Transmembrane Transporters.
We present the synthesis of two functionalized 2,4,7-triphenylbenzimidazole ligands and demonstrate the formation of their respective metal assemblies in phospholipid membranes. Anion transport experiments demonstrate the formation of metal-organic synthetic transporters (MOST) directly in phospholipid membranes. The formation of MOST in phospholipid membranes results in efficient architectures for chloride transport. We also demonstrate the insertion of these ligands and the formation of their metal-organic assemblies in bacterial membranes; the use of MOST makes the membranes of resistant bacteria more permeable to antibiotics. We also demonstrate that a combination of MOST with tetracycline lowers the sensitivity of resistant bacteria to tetracycline by 60-fold.


Either ZEB1 or ZEB2/SIP1 can play a central role in regulating the Epstein-Barr virus latent-lytic switch in a cell-type-specific manner.
We previously reported that the cellular protein ZEB1 can repress expression of the Epstein-Barr virus (EBV) BZLF1 gene in transient transfection assays by directly binding its promoter, Zp. We also reported that EBV containing a 2-bp substitution mutation in the ZEB-binding ZV element of Zp spontaneously reactivated out of latency into lytic replication at a higher frequency than did wild-type EBV. Here, using small interfering RNA (siRNA) and short hairpin RNA (shRNA) technologies, we definitively show that ZEB1 is, indeed, a key player in maintaining EBV latency in some epithelial and B-lymphocytic cell lines. However, in other EBV-positive epithelial and B-cell lines, another zinc finger E-box-binding protein, ZEB2/SIP1, is the key player. Both ZEB1 and ZEB2 can bind Zp via the ZV element. In EBV-positive cells containing only ZEB1, knockdown of ZEB1 led to viral reactivation out of latency, with synthesis of EBV immediate-early and early lytic gene products. However, in EBV-positive cells containing both ZEBs, ZEB2, not ZEB1, was the primary ZEB family member bound to Zp. Knockdown of ZEB2, but not ZEB1, led to EBV lytic reactivation. Thus, we conclude that either ZEB1 or ZEB2 can play a central role in the maintenance of EBV latency, doing so in a cell-type-dependent manner.


Generation of discrete higher-order optical vortex lattice at focus.
Higher-order vortices (HOVs) extend the dimensions of optical vortex regulation, which is of great significance in optical communication and optical tweezers. Herein, we demonstrate an alternative scheme to produce a HOV in the focus plane using multiple Laguerre-Gaussian (LG) beam interference, termed a discrete higher-order optical vortex lattice (DHOVL). The modulation depth of the DHOVL exceeds 2π. In this case, the topological charge (TC) of the DHOVL is determined by the difference of the phase period between the innermost and the outermost interference beams. Compared with a conventional HOV (CHOV), the vortex exists in a form of multiple unit singularities sharing a dark core. In addition, the average orbital angular momentum per photon of the DHOVL increases with increasing TC, surpassing that of the CHOV. This work provides a novel, to the best of our knowledge, scheme to produce a HOV, which will facilitate several advanced applications, including optical micromanipulation, optical sensing and imaging, and optical fabrication.


High-Performance of Gas Hydrates in Confined Nanospace for Reversible CH4 /CO2 Storage.
The molecular exchange of CH4 for CO2 in gas hydrates grown in confined nanospace has been evaluated for the first time using activated carbons as a host structure. The nano-confinement effects taking place inside the carbon cavities and the exceptional physicochemical properties of the carbon structure allows us to accelerate the formation and decomposition process of the gas hydrates from the conventional timescale of hours/days in artificial bulk systems to minutes in confined nanospace. The CH4 /CO2 exchange process is fully reversible with high efficiency at practical temperature and pressure conditions. Furthermore, these activated carbons can be envisaged as promising materials for long-distance natural gas and CO2 transportation because of the combination of a high storage capacity, a high reversibility, and most important, with extremely fast kinetics for gas hydrate formation and release.


Dissociation of enzymatic activity from toxic properties of the most basic phospholipase A2 from Vipera russelli snake venom by guanidination of lysine residues.
The most basic phospholipase A2 VRV-PL-VIIIa purified from Russell's viper venom is a toxic enzyme. It induced neurotoxicity, myotoxicity, and oedema and was lethal to mice at 5.3 micrograms/g body weight. It also inhibited the coagulation of the human plasma. The epsilon-amino groups of lysine residues of the toxic enzyme VRV-PL-VIIIa were guanidinated with o-methylisourea. Guanidination of the enzyme did not alter the enzymatic activity markedly. The guanidinated enzyme became non-lethal in doses up to 16 micrograms/g body weight, and failed to elicit neurotoxic symptoms in experimental animals and oedema in the foot pads of mice. Also, its myotoxic and anticoagulant potencies were decreased significantly.


An example of program evaluation project in undergraduate medical education.
Revisions to existing program evaluation approaches of the Dokuz Eylul University School of Medicine (DEUSM) were made by the Medical Education Department in June 2005. After considering several evaluation models, a mixed evaluation model was developed to meet institutional needs. The general program evaluation plan was structured as areas of inquiry under the three main program evaluation questions: what are the effects of the educational program on students and graduates, what are the effects of the educational program on trainers, and is the educational program being implemented as planned. The School's first report made through its new program evaluation approach was prepared in July 2006, leading to important revisions to the educational program. This article presents DEUSM's project to revise its program evaluation approach and briefly discusses its early implementation.


Synergistetes cluster A in saliva is associated with periodontitis.
Synergistetes is a novel bacterial phylum consisting of gram-negative anaerobes. Increasing lines of evidence demonstrate that this phylum is associated with periodontal diseases. This study aimed to compare the presence and levels of Synergistetes clusters A and B, in saliva of patients with chronic periodontitis (CP), generalized aggressive periodontitis (G-AgP) and non-periodontitis subjects, and investigate their correlation with clinical parameters. Saliva was collected from patients with CP (n = 20), G-AgP (n = 21) and non-periodontitis subjects (n = 18). Full mouth clinical periodontal measurements were recorded. The numbers of Synergistetes cluster A and cluster B or the associated species Jonquetella anthropi were quantified by fluorescent in situ hybridization and microscopy. Synergistetes cluster A bacteria were detected more frequently, and at higher numbers and proportions in the two periodontitis groups, than the non-periodontitis control group. The prevalence was 27.7% in the control group, 85% in CP and 86% in G-AgP. Compared to the control group, the numbers were significantly higher by 12.5-fold in CP and 26.5-fold in G-AgP, whereas the difference between the two forms of periodontitis was not statistically significant. Within the total bacterial population, the proportion of this cluster was increased in CP and G-AgP compared to the control group, with the difference between the two forms of periodontitis being also significant. There was a positive correlation between the levels of Synergistetes cluster A in saliva and all full mouth clinical periodontal parameters. Nevertheless, Synergistetes cluster B bacteria and J. anthropi species were detected infrequently and at low levels in all the three subject groups. Synergistetes cluster A, but not cluster B, bacteria are found at higher prevalence, numbers and proportions in saliva from patients with periodontitis, than non-periodontitis subjects. These findings support the association of this cluster with periodontitis.


[Transfusion of patients with autoimmune hemolytic anemia].
Autoimmune hemolytic anemia (AIHA) is caused by the generation of autoantibodies against red cells. Sometimes, the destruction of red cells occurs in the intravascular space following the autoantibody-mediated activation of the complement cascade. More frequently, extravascular hemolysis occurs when macrophages phagocytose autoantibodies and complements bearing red cells. The direct antiglobulin test results (DAT) are usually positive. When the serum of patients with AIHA frequently reacts with all normal red cells, it is impossible to find compatible blood for transfusion. It is necessary to adsorb autoantibodies by autologous or allogeneic red cells for detecting alloantibodies in patients with AIHA. In addition, it is essential to accurately detect alloantibodies and intentionally avoid the generation of new alloantibodies for performing safer transfusion in the future. Although transfusion of phenotypically matched blood is desirable, it is challenging to obtain such blood in time. Moreover, the transfusion of partially phenotypically matched blood (ABO, D, C, E, c, e, Jka, Jkb) and the exclusion of alloantibody-related phenotype appear to be appropriate to avoid the severe transfusion reaction in the clinical setting. Furthermore, small volume, slow, and inevitable transfusion is recommended to avoid unexpected complications. In cases of cold reactive AIHAs, the application of blood warmer is recommended for transfusion.


Denitrifying capabilities of Tetrasphaera and their contribution towards nitrous oxide production in enhanced biological phosphorus removal processes.
Denitrifying enhanced biological phosphorus removal (EBPR) systems can be an efficient means of removing phosphate (P) and nitrate (NO3-) with low carbon source and oxygen requirements. Tetrasphaera is one of the most abundant polyphosphate accumulating organisms present in EBPR systems, but their capacity to achieve denitrifying EBPR has not previously been determined. An enriched Tetrasphaera culture, comprising over 80% of the bacterial biovolume was obtained in this work. Despite the denitrification capacity of Tetrasphaera, this culture achieved only low levels of anoxic P-uptake. Batch tests with different combinations of NO3-, nitrite (NO2-) and nitrous oxide (N2O) revealed lower N2O accumulation by Tetrasphaera as compared to Accumulibacter and Competibacter when multiple electron acceptors were added. Electron competition was observed during the addition of multiple nitrogen electron acceptors species, where P uptake appeared to be slightly favoured over glycogen production in these situations. This study increases our understanding of the role of Tetrasphaera-related organisms in denitrifying EBPR systems.


Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia.
Levels of hepcidin, a major regulator of iron homeostasis, may identify patients with iron deficiency anemia (IDA) who will not respond to oral iron therapy. In this study, IDA patients underwent a 14-day trial (run-in) course of ferrous sulfate therapy. Nonresponders (Hgb increase <1 g/dL with 67% compliance rate) were randomized to IV ferric carboxymaltose (FCM; two injections of 750 mg) or further oral iron for 14 days. Screening hepcidin levels were 38.4 versus 11.3 ng/mL, P = 0.0002 in nonresponders versus responders to a trial of oral iron. Hepcidin of > 20 ng/mL, showed sensitivity of 41.3%, specificity of 84.4%, and positive predictive value of 81.6% for predicting nonresponsiveness to oral iron. PPVs for ferritin> 30 ng/mL or transferrin saturation (TSAT)>15% were 59.2 and 55%, respectively. Negative predictive values for hepcidin, ferritin, and TSAT were 46.3, 22.7, and 19.7, respectively. FCM versus oral iron showed Hgb increases of ≥ 1 gm/dL in 65.3% versus 20.8% (P < 0.0001) and Hgb increases of 1.7 ± 1.3 versus 0.6 ± 0.9 g/dL (P = 0.0025), respectively. We conclude that hepcidin predicts nonresponsiveness to oral iron in patients with IDA and is superior to TSAT or ferritin for this purpose. Nonresponse to oral iron therapy does not rule out IDA, since two-thirds of patients subsequently responded to intravenous iron.


Improvement of megavoltage computed tomography image quality for adaptive helical tomotherapy using cycleGAN-based image synthesis with small datasets.
Megavoltage computed tomography (MVCT) offers an opportunity for adaptive helical tomotherapy. However, high noise and reduced contrast in the MVCT images due to a decrease in the imaging dose to patients limits its usability. Therefore, we propose an algorithm to improve the image quality of MVCT. The proposed algorithm generates kilovoltage CT (kVCT)-like images from MVCT images using a cycle-consistency generative adversarial network (cycleGAN)-based image synthesis model. Data augmentation using an affine transformation was applied to the training data to overcome the lack of data diversity in the network training. The mean absolute error (MAE), root-mean-square error (RMSE), peak signal-to-noise ratio (PSNR), and structural similarity index measure (SSIM) were used to quantify the correction accuracy of the images generated by the proposed algorithm. The proposed method was validated by comparing the images generated with those obtained from conventional and deep learning-based image processing method through non-augmented datasets. The average MAE, RMSE, PSNR, and SSIM values were 18.91 HU, 69.35 HU, 32.73 dB, and 95.48 using the proposed method, respectively, whereas cycleGAN with non-augmented data showed inferior results (19.88 HU, 70.55 HU, 32.62 dB, 95.19, respectively). The voxel values of the image obtained by the proposed method also indicated similar distributions to those of the kVCT image. The dose-volume histogram of the proposed method was also similar to that of electron density corrected MVCT. The proposed algorithm generates synthetic kVCT images from MVCT images using cycleGAN with small patient datasets. The image quality achieved by the proposed method was correspondingly improved to the level of a kVCT image while maintaining the anatomical structure of an MVCT image. The evaluation of dosimetric effectiveness of the proposed method indicates the applicability of accurate treatment planning in adaptive radiation therapy.


[Clinico-radiologic aspects of calcium pyrophosphate dihydrate deposition disease].
Calcium pyrophosphate dihydrate crystal deposition disease is a clinical condition characterised by Gout-like synovitis (pseudogout), calcification on and around the joints and an arthropathy that is radiologically similar to osteoarthritis (chronic pyrophosphate arthropathy). Though all these radiological clinical aspects may coexist in the same patient this is often not the case. An examination of the X-ray data on the 68 cases studied which were diagnosed on the basis of the criteria proposed by McCarty, shows that the disease is relatively common especially in the over-fifties. When chronic pyrophosphate arthropathy is the only clinical manifestation of the disease differential diagnosis from the osteoarthrosis so common in the elderly is difficult and depends on the greater severity and progression of the joint damage that may often affect joints not subjected to weight such as the shoulder, unlike what happens in osteoarthritis.


Mexiletine: Antiarrhythmic mechanisms, emerging clinical applications and mortality.
Mexiletine, a class Ib antiarrhythmic drug, exhibits its major antiarrhythmic effect via inhibition of the fast and late Na+ currents in myocardial tissues that are dependent on the opening of Na+ channels for their excitation. Through a comprehensive examination of mexiletine's therapeutic benefits and potential risks, we aim to provide valuable insights that reinforce its role as a vital therapeutic option for patients with ventricular arrhythmias, long QT syndrome, and other heart rhythm disorders. This review will highlight the current understandings of the antiarrhythmic effects and rationales for recent off-label use and address the mortality and proarrhythmic effects of mexiletine utilizing published basic and clinical studies over the past five decades.


Humanized Anti-Carcinoembryonic Antigen Antibodies Brightly Target and Label Gastric Cancer in Orthotopic Mouse Models.
Gastric cancer poses a major therapeutic challenge. Improved visualization of tumor margins at the time of gastrectomy with fluorescent tumor-specific antibodies could improve outcomes. The present report demonstrates the potential of targeting gastric cancer with a humanized anti-carcinoembryonic antigen (CEA) antibody in orthotopic mouse models. MKN45 cells were injected subcutaneously into nude mice to establish xenograft models. Tumor fragments collected from subcutaneous models were then implanted into the greater curvature of the stomach to establish orthotopic models. For tumor labeling, a humanized anti-CEA antibody (M5A) and IgG as a control, were conjugated with the near-infrared dye IRDye800CW. Time (24-72 h) and dose (50-100 μg) response curves were performed in subcutaneous models. Orthotopic models received 50 μg of M5A-IR800 or 50 μg IgG-IR800 as a control and were imaged after 72 h. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System. In subcutaneous models, tumor to background ratios (TBRs) reached 8.85 at 72 h. Median TBRs of orthotopic model primary tumors were 6.25 (interquartile range [IQR] 6.03-7.12) for M5A-IR800 compared to 0.42 (IQR 0.38-0.54) for control. Abdominal wall metastasis median TBRs were 13.52 (IQR 12.79-13.76) for M5A-IR800 and 3.19 (IQR 2.65-3.73) for the control. Immunohistochemistry confirmed CEA expression within tumors. Humanized anti-CEA antibodies conjugated to near-infrared dyes provide specific labeling of gastric cancers in mouse models. Orthotopic models demonstrated bright and specific labeling with TBRs greater than ten times that of control. This tumor-specific fluorescent antibody is a promising potential clinical tool for improving visualization of gastric cancer margins at time of surgical resection.


Biochemistry of human converting enzyme.
Angiotensin converting enzyme (ACE, EC 126.96.36.199) was purified to homogeneity from human kidney and its specific antibody was raised in the rabbit. The antibody cross-reacted equally with human enzymes from kidney, lung, intestine, plasma and urine. Immunofluorescent and immunoelectron microscopic observation indicated that the enzyme was located on the plasma membrane and micropinocytic vesicles at the luminal site of vascular endothelium in the lung. It was also present on the brush border, intercellular and basal infolding membranes of proximal tubular epithelium, but was not detected on the distal tubular epithelium or vascular endothelium in the kidney. ACE was demonstrated immunocytologically in human alveolar macrophages and renal carcinoma tissues. The carcinoma tissue contained a possible isoenzyme of ACE differing in part immunologically from the enzyme of normal kidney.


Chylothorax complicating coronary artery by-pass grafting.
Chylothorax is a rare complication of coronary artery by-pass grafting. We present two patients who developed a left chylothorax at one week and 14 days post-coronary artery by-pass grafting. In both cases an internal mammary artery graft was harvested. Nonoperative therapy, which included adequate pleural drainage and a low fat diet, lead to successful resolution of the chylous leak in each instance.


[Effects of modification of transferrin on cytotoxicity and intracellular delivery of paclitaxel loaded PLGA nanoparticles].
To evaluate the effects of modification of transferrin on cytotoxicity and intracellular delivery of paclitaxel loaded Poly (lactide-co-glycolide) (PLGA) nanoparticle (NPs). PLGA NPs were formulated with microemulsion method, Polyvinyl alcohol (PVA) was used as surfactant (PVA NPs). Transferrin (Tf) was used to modify the NPs (Tf NPs). The cytotoxicity of paclitaxel solution and paclitaxel loaded PVA NPs and Tf NPs were measured in bladder cancer cell line J-82. The intracellular delivery of two kinds of NPs was measured. The half maximal inhibitory concentration (IC50) of paclitaxel loaded PVA NPs and Tf NPs was (44 ± 7) and (49 ± 11) ng/ml respectively and significantly lower than that of paclitaxel solution, which was (81 ± 18) ng/ml (both P < 0.05). The uptake of PVA NPs and Tf NPs by J-82 cells after 2 hours was (89 ± 19) µg/mg cellular protein and (76 ± 16) µg/mg cellular protein. The uptake of two kinds of NPs had no significantly difference. The intracellular level of NPs decreased significantly upon the withdrawal of NPs in medium. However, it became stable 2 hours later and 11.3% PVA NPs and 18.0% Tf NPs remained. The intracellular level of PVA NPs and Tf NPs had no significantly difference at any time point. NPs were distributed in cytoplasm after endocytosis. PLGA NPs can significantly improve the anti-neoplastic effect of paclitaxel on bladder cancer. However, modification of Tf does not change the intracellular dynamics.


[Diffuse interstitial pneumopathy after the treatment with gold salts of a patient with rheumatoid polyarthritis].
We present the case of a male patient with sero-negative rheumatoid arthritis, treated with gold salts, admitted for clinical symptoms and chest X-ray alterations suggesting an interstitial lung disease. This was confirmed by complex lung function tests and fiber bronchoscopy with broncho-alveolar lavage. Considerations are made about the etiology of interstitial lung disease (pulmonary determination of the rheumatoid arthritis or secondary to the gold salts therapy), about the treatment and long-term prognosis, and about the good clinical, functional and radiological evolution under treatment.


A boxer dog with chronic hypertrophic gastritis resembling Menetrier's disease in man.
Chronic hypertrophic gastritis in a 7-year-old Boxer dog is described. This gastritis resembles Menetrier's disease in man. The dog was emaciated, lethargic, vomiting and had a poor appetite over a 4-month period. There was anaemia, and the blood smear was characterized by hypochromasia, strong anisoplania and striking poikilocytosis. There was a protein loss and at a later stage of the disease, a hypoalbuminaemia. On gastroscopic examination the plicae gastricae were numerous and strongly marked; moreover, they were granulated with numerous small haemorrhages. Radiographically, the stomach had a marked folding, primarily at the greater curvature. The passage of contrast medium from the stomach into the duodenum was strongly retarded. The pathological findings included macroscopical folding caused by local gland cell hyperplasia in the body as well as the pylorus, foveolar hyperplasia and, in the fundus and in the corpus near the greater curvature, folding of the muscularis mucosae and the submucosa. A superficial gastritis was found particularly in the fundus and corpus, whereas the pyloric antrum showed a more diffuse inflammation.


Complete bony coalition of the talus and navicular: decades of discomfort.
Tarsal coalition is a congenital disturbance of hindfoot development. Talonavicular coalition is among the rarest forms of aberrant bony union of the tarsus. It frequently occurs bilaterally and in association with a number of skeletal deformities. Some patients are asymptomatic and the anomaly is discovered incidentally on plain radiographs. For others, a troublesome bony prominence will be the principle complaint and in a small proportion of patients marked foot and ankle pain with activity will prove debilitating. The authors describe the case of a 54-year-old male with bilateral foot pain spanning for nearly two decades. Symptom onset was insidious and at the time of presentation, he was limited to 10-15 min of mobilisation on flat ground.


Regioselective Photoisomerization/C-C Bond Formation of Asymmetric B(ppy)(Mes)(Ar): The Role of the Aryl Groups on Boron.
Asymmetric N,C-chelate organoboron compounds bearing two different aryl groups at the boron center undergo photoisomerization reactions that involve exclusively the less bulky aryl group, generating various strongly colored "dark isomers". These species thermally isomerize to 4bH-azaborepin molecules by direct hydrogen atom transfer from a borirane cycle to the pyridyl moiety and ring expansion. Mechanistic insight into these highly regioselective transformations was obtained from kinetic data and through computational studies.


Hemostatic properties of glucosamine-based materials.
Glucosamine- and N-acetyl glucosamine-containing polymers are being used in an increasing number of biomedical applications, including in products for surface (topical) hemostasis. The studies presented here investigate the relationship between the structure (conformation) and function (activation of hemostasis) of glucosamine-based materials. Several polymer systems were studied, including fibers isolated from a microalgal source containing poly-N-acetyl glucosamine polymers that are organized in a parallel, hydrogen-bonded tertiary structure and can be chemically modified to an antiparallel orientation; and gel formulation derivatives of the microalgal fibers consisting of partially deacetylated (F2 gel) and fully deacetylated (F3 gel) polymers. Comparison of the properties of the poly-N-acetyl glucosamine fiber-derived materials with chitin, chitosan, and commercial chitosan-based products are presented. Several studies were performed with the glucosamine-based materials, including (1) an analysis of the ability of materials to activate platelets and turnover of the intrinsic coagulation cascade, (2) an examination of the viscoelastic properties of mixtures of platelet-rich plasma and the glucosamine-based materials via thromboelastography, and (3) scanning electron microscopic studies to examine the morphology of the glucosamine-based materials. The results presented demonstrate that hemostatic responses to the glucosamine-based materials studied are highly dependent on their chemical nature and tertiary/quaternary structure. The unique natural microalgal fibers were found to have strongly prohemostatic activity compared to the other materials studied.


Endoplasmic reticulum stress in skin aging induced by UVB.
Aging is a normal and complex biological process. Skin is located in the most superficial layer of the body, and its degree of aging directly reflects the aging level of the body. Endoplasmic reticulum stress refers to the aggregation of unfolded or misfolded proteins in the endoplasmic reticulum and the disruption of the calcium ion balance when cells are stimulated by external stimuli. Mild endoplasmic reticulum stress can cause a series of protective mechanisms, including the unfolded protein response, while sustained high intensity stimulation leads to endoplasmic reticulum stress and eventually apoptosis. Photoaging caused by ultraviolet radiation is an important stimulus in skin aging. Many studies have focused on oxidative stress, but increasing evidence shows that endoplasmic reticulum stress plays an important role in photoaging. This paper reviews the development and mechanism of endoplasmic reticulum stress (ERS) in skin photoaging, and provides research directions for targeting the ERS pathway to slow aging.


Cognitive and behavioral effects of quetiapine in Alzheimer disease patients.
In a prospective, open-label, 12-week pilot study in outpatients with probable Alzheimer disease (AD) with psychosis or aggressive behaviors, we used the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Neuropsychiatric Inventory (NPI) to evaluate the cognitive and behavioral effects of quetiapine. After receiving doses ranging from 50 to 150 mg, patients given quetiapine showed a significant decrease of delusions, aggression, and overall behaviors based on NPI scores at 6 and 12 weeks. ADAS-cog scores did not show a significant change over 12 weeks. This study provides initial evidence that quetiapine does not significantly worsen cognition in AD outpatients.


Urinary endothelin-1 as a marker of renal damage in sickle cell disease.
Sickle cell disease (SCD) affects the kidney by acute mechanisms as well as by insidious renal medullary/papillary necrosis, resulting in tubular defects, which increase the risk of dehydration and subsequent sickle crisis. Hypoxia has been reported to stimulate endothelin-1 (ET-1) synthesis by endothelial cells and also in the renal tubule. This case-control study measured ET-1 in urine as a marker of its renal synthesis in asymptomatic SCD patients. Baseline plasma and urinary ET-1 levels were measured and followed during a water deprivation study and a subsequent administration of desmopressin. Urine and plasma levels of ET-1 were elevated in patients with SCD, compared with carefully matched African-French and African controls, and urine ET-1 excretion was associated with a marked urine-concentrating defect. Moreover, urinary ET-1 output was correlated with microalbuminuria in SCD patients. ET-1 is known to antagonize the tubular effects of vasopressin and to promote renal scarring; increased renal production of ET-1 could produce nephrogenic diabetes insipidus and dehydration in SCD patients through a combination of fibrosis and functional resistance to vasopressin. This study provides a rationale for trials with endothelin receptor antagonists in sickle cell disease nephropathy.


Perceptions of Culture of Safety in Hemodialysis Centers.
Staff members, physicians, nurse practitioners, and physician assistants from a sample of hemodialysis facilities in Network 6 (North Carolina, South Carolina, and Georgia) and Network 11 (Michigan, Minnesota, North Dakota, South Dakota, and Wisconsin) completed a 10-item assessment with modified questions from the Hospital Survey on Patient Safety Culture, with an emphasis on safety culture related to vascular access infections. A composite score was constructed, which was the average of the percent-positive scores of the items. Overall, scores were high, indicating a positive patient safety culture. Composite scores varied by role type, with nurses, patient care technicians, and other technicians reporting the lowest composite scores. Network 6 participants reported higher scores on two of the survey items. Fewer staff within a facility were associated with higher composite scores.


The nature and severity of disabilities in long-stay psychiatric in-patients in South Glamorgan.
Long-stay psychiatric in-patients in South Glamorgan were reviewed using the MRC Needs for Care assessment. The majority were middle aged or elderly and were severely disabled, with problems encompassing symptoms/behavioural difficulties, social skills, and physical health. In most, long-standing psychiatric illness was compounded by physical illness and cognitive deficits as age advanced, producing care needs that were greater than existing community services could meet.


Temperature and Photoperiod Affect the Sensitivity of Biofilms to Nickel and its Accumulation.
Whereas metal impacts on fluvial communities have been extensively investigated, effects of abiotic parameters on community responses to contaminants are poorly documented. Variations in photoperiod and temperature commonly occur over the course of a season and could affect aquatic biofilm communities and their responses to contaminants. Our objective was to characterize the influence of environmental conditions (photoperiod and temperature) on nickel (Ni) bioaccumulation and toxicity using a laboratory-grown biofilm. Environmental parameters were chosen to represent variations that can occur over the summer season. Biofilms were exposed for 7 days to six dissolved Ni treatments (ranging from 6 to 115 µM) at two temperatures (14 and 20 °C) using two photoperiods (16:8 and 12:12-h light:dark cycle). Under these different scenarios, structural (dry weight biomass and chlorophyll-a) and functional biomarkers (photosynthetic yield and Ni content) were analyzed at four sampling dates, allowing us to evaluate Ni sensitivity of biofilms over time. The results highlight the effects of temperature on Ni accumulation and tolerance of biofilms. Indeed, biofilms exposed at 20 °C accumulated 1.6-4.2-fold higher concentrations of Ni and were characterized by a lower median effect concentration value using photosynthetic yield compared with those exposed at 14 °C. In terms of photoperiod, significantly greater rates of Ni accumulation were observed at the highest tested Ni concentration for biofilms exposed to a 12:12-h compared with a 16:8-h light:dark cycle. Our study demonstrates the influence of temperature on biofilm metabolism and illustrates that environmental factors may influence Ni accumulation response and thus Ni responses of phototrophic biofilms. Environ Toxicol Chem 2022;41:1649-1662. © 2022 SETAC.


Study on Language Rehabilitation for Aphasia.
The aim is to update our clinical recommendations for evidence-based language rehabilitation of people with aphasia, based on a systematic review of the literature from 1999 to 2015. Articles referred to in this systematic review of the Medline and PubMed published in English language literatures were from 1998 to 2015. The terms used in the literature searches were aphasia and evidenced-based. The task force initially identified citations for 51 published articles. Of the 51 articles, 44 studies were selected after further detailed review. Six articles, which were not written in English, and one study related to laryngectomy rehabilitation interventions, were excluded from the study. This study referred to all the important and English literature in full. Aphasia is the linguistic disability, which usually results from injuries to the dominant hemisphere of the brain. The rehabilitation of aphasia is until in the process of being debated and researched. Evidence-based medicine (EBM), EBM based on the clinical evidence, promotes the practice of combining the clinicians' first-hand experience and the existing objective and scientific evidence encouraging making decisions based on both empirical evidence and the scientific evidence. Currently, EBM is being gradually implemented in the clinical practice as the aim of the development of modern medicine. At present, the research for the aphasia rehabilitation mainly focuses on the cognitive language rehabilitation and the intensive treatment and the precise treatment, etc. There is now sufficient information to support evidence-based protocols and implement empirically-supported treatments for linguistic disability after traumatic brain injury and stroke, which can be used to develop linguistic rehabilitation guidelines for patients with aphasia.


Daily omeprazole surpasses intermittent dosing in preventing relapse of oesophagitis: a US multi-centre double-blind study.
Relapse of erosive oesophagitis occurs in almost all patients if treatment is stopped after initial healing. To assess the potential of different therapeutic regimens of omeprazole to prevent relapse of erosive reflux oesophagitis after initial healing with omeprazole. Patients whose active erosive reflux oesophagitis (grade > or = 2) had healed (grade 0 or 1) after 4-8 weeks of open-label omeprazole 40 mg daily (phase I) were eligible to join a multi-centre, 6-month double-blind, placebo-controlled maintenance study (phase II), which included endoscopy, symptom assessments, serum gastrin measurements, and gastric fundic biopsies. During phase I, endoscopy was performed at weeks 0, 4, and 8. At the end of phase I, 429 of 472 patients (91%) were healed, and there were significant reductions in heartburn, dysphagia and acid regurgitation. Of the 429 patients who healed, 406 joined phase II and were randomized to one of three groups: 20 mg omeprazole daily (n = 138), 20 mg omeprazole for 3 consecutive days each week (n = 137), or placebo (n = 131). During phase II, endoscopy was performed at months 1, 3, and 6 or at symptomatic relapse. The percentages of patients still in endoscopic remission at 6 months were 11% for placebo, 34% for omeprazole 3-days-a-week, and 70% for omeprazole daily. Both omeprazole regimens were superior to placebo in preventing recurrence of symptoms (P < 0.001); however, omeprazole 20 mg daily was superior to omeprazole 20 mg 3-days-a-week (P < 0.001). Compared to baseline, omeprazole therapy resulted in no significant differences among treatment groups in the distribution of gastric endocrine cells. These results show that after healing of erosive oesophagitis with 4-8 weeks of omeprazole, relapse of oesophagitis and recurrence of reflux symptoms can be prevented in 70% of patients with a maintenance regimen of 20 mg daily, but that intermittent dosing comprising 3 consecutive days each week significantly compromises efficacy.


gamma-Glutamyl transpeptidase of human amniotic fluid.
gamma-Glutamyl transpeptidase (GGTP) activity in normal amniotic fluids and corresponding maternal sera obtained at various gestational periods was measured. The ontogenic pattern of enzyme activity in amniotic fluid is very similar to alpha fetoprotein (AFP). However, the levels of these two proteins behaved differently in corresponding maternal sera. Also, in amniotic fluids obtained from pregnancies with neural tube defects (NTD), only AFP concentration was abnormally high whereas GGTP activity was normal.


Reasons Why Post-Trial Access to Trial Drugs Should, or Need not be Ensured to Research Participants: A Systematic Review.
Background: researchers and sponsors increasingly confront the issue of whether participants in a clinical trial should have post-trial access (PTA) to the trial drug. Legislation and guidelines are inconsistent, ambiguous or silent about many aspects of PTA. Recent research highlights the potential importance of systematic reviews (SRs) of reason-based literatures in informing decision-making in medicine, medical research and health policy. PURPOSE: to systematically review reasons why drug trial participants should, or need not be ensured PTA to the trial drug and the uses of such reasons. DATA SOURCES: databases in science/medicine, law and ethics, thesis databases, bibliographies, research ethics books and included publications' notes/bibliographies. Publication selection: a publication was included if it included a reason as above. See article for detailed inclusion conditions. Data extraction and analysis: two reviewers extracted and analyzed data on publications and reasons. RESULTS: of 2060 publications identified, 75 were included. These mentioned reasons based on morality, legality, interests/incentives, or practicality, comprising 36 broad (235 narrow) types of reason. None of the included publications, which included informal reviews and reports by official bodies, mentioned more than 22 broad (59 narrow) types. For many reasons, publications differed about the reason's interpretation, implications and/or persuasiveness. Publications differed also regarding costs, feasibility and legality of PTA. LIMITATIONS: reason types could be applied differently. The quality of reasons was not measured. CONCLUSION: this review captured a greater variety of reasons and of their uses than any included publication. Decisions based on informal reviews or sub-sets of literature are likely to be biased. Research is needed on PTA ethics, costs, feasibility and legality and on assessing the quality of reason-based literature.


[A simple attachment for superficial sonography].
Electronic linear array transducers usually have a discrepant electronic (in scanning plain) and mechanical (perpendicular to scanning plain) focal zone. The "effective" focal zone can only be determined with a true cyst phantom. With transducers of medium frequency the focal zone is about 3-6 cm from the transducer surface, rendering a water path necessary for sonography of superficial organs. The considerable thickness of layer in the scanning plain of most linear array transducers affects the visualisation of superficial vessels in longitudinal direction. A simple water path attachment for small parts sonography is presented, which enables an automatic "self-indication" of palpable lesions especially in breast sonography.


Liver angiotensinogen synthesis and release during captopril treatment in sodium-depleted rats.
In vivo generation of angiotensins depends upon both plasma renin and angiotensinogen concentrations. Those factors which may influence hepatic angiotensinogen synthesis and release were examined. We have evaluated in vivo the effects of converting enzyme inhibition on several plasma renin-angiotensin system components, and, using an in vitro preparation of liver slices, we also investigated the effects of converting enzyme inhibition on the synthesis and release of hepatic angiotensinogen. Angiotensinogen concentrations were determined by two different methods. The first was an indirect enzymatic assay which measures the amount of angiotensin I liberated from plasma by an excess of renin. The second was a direct RIA that measures both angiotensinogen and its inactive residue the des-angiotensin I-angiotensinogen. The difference between the methods represents the circulating levels of des-angiotensin I-angiotensinogen. Captopril administration in sodium-depleted rats increased plasma concentrations of renin, des-angiotensin I-angiotensinogen, and angiotensin I and decreased plasma angiotensinogen concentration measured by both methods. Plasma des-angiotensin I-angiotensinogen was significantly correlated to plasma renin concentration, which suggests an increase in the consumption of angiotensinogen when the renin secretion is extremely increased. The angiotensinogen liver content and in vitro angiotensinogen release were decreased in sodium-depleted rats treated with a converting enzyme inhibitor, and these parameters were negatively correlated to in vivo plasma levels of renin, angiotensin I, and des-angiotensin I-angiotensinogen. They were positively correlated to plasma angiotensinogen concentration measured by the indirect assay. These data suggest that captopril administration during sodium depletion has two simultaneous effects: it increases angiotensinogen consumption and second, decreases angiotensinogen production and release.


The Genetic Variant I148M in PNPLA3 Is Associated With Increased Hepatic Retinyl-Palmitate Storage in Humans.
Previous studies revealed that the common sequence variant I148M in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with liver fat content and liver diseases, but not with insulin resistance. Recent data suggest that the PNPLA3 I148M variant has reduced retinyl-palmitate lipase activity in hepatic stellate cells. We hypothesized that the PNPLA3 I148M variant is associated with elevated retinyl-palmitate storage in human liver as a potential link to the clinical pathology. Design/Setting and Participants: Using HPLC, we quantified the retinoid metabolites in liver tissue extracts obtained from 42 human subjects, including 13 heterozygous and six homozygous carriers of the minor PNPLA3 I148M variant. Retinyl-palmitate is elevated in human livers of homozygous PNPLA3 I148M allele carriers Results: The PNPLA3 I148M variant was associated with a significant increase (1.4-fold) in liver fat. The content of retinyl-palmitate was elevated and the ratio of retinol/retinyl-palmitate was reduced in liver extracts obtained from homozygous PNPLA3 I148M minor allele carriers. In a multivariate model including liver fat content, these differences remained significant independent of liver fat content. The content of the minor retinyl-fatty acid esters was similarly increased in homozygous PNPLA3 I148M carriers. The increased content of hepatic retinyl-palmitate and the reduced ratio of retinol/retinyl-palmitate in PNPLA3 I148M minor allele carriers support in vitro findings of an altered retinyl-palmitate lipase activity. Our results indicate that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver, providing a possible link to chronic liver disease.


Magnetic resonance imaging of the central nervous system.
Magnetic resonance (MR) is a powerful new imaging modality which has recently become competitive with X-ray computed tomography (CT) for imaging of the central nervous system (CNS). The advantages of MR include lack of ionizing radiation and the necessity to use iodinated contrast. MR is able to image directly in the transaxial, coronal, and sagittal planes. With appropriate pulsing sequences, MR is more sensitive than CT in the detection of early disease associated with increased water content. Included in this category are multiple sclerosis, early infarcts, small tumours, and inflammatory lesions. MR is superior to CT in the posterior fossa due to beam hardening artifacts in the latter modality. In the cord, MR is useful in the evaluation of syringomyelia, spinal dysraphism, and intramedullary tumours. Due to its increased sensitivity in the detection of early disease, MR should generally be used as the initial screening procedure in the evaluation of possible intracranial disease. Current limitations of MR include longer single slice imaging times, thicker slices, inability to use contrast agents to define blood/brain barrier breakdown, and the inability to image calcification and cortical bone. Patients on cardiac monitors or on respirators and those with intracranial aneurysm clips and cardiac pacemakers are currently excluded from MR imaging.


Sustained swimming increases erythrocyte MCT1 during erythropoiesis and ability to regulate pH homeostasis in rat.
We investigated the effect of sustained swimming exercise on the increase in monocarboxylate transporter 1 (MCT1) concentration and its ability to regulate pH homeostasis in rat erythrocytes. Male Sprague-Dawley rats aged 9 weeks were divided into sedentary and swimming groups for both 1- and 3-week experiments. The exercise group swam for 30 - 60 min/day, 5 days/week. Before and 1 and 3 weeks after initiation of the exercise, blood was collected for lactate concentration measurement during pre-exercise rest and post-exercise recovery periods. On the last day of each experiment, venous blood and erythroid cells in bone marrow were collected to assay the capacity for erythropoiesis and MCT1 concentration. In the swimming group at 0 weeks (p < 0.05), 1 week (p < 0.01) and 3 weeks (p < 0.001), the blood lactate concentration post-exercise was significantly higher than at rest. The ratio of young erythrocytes to total erythrocytes was significantly higher in the 3-week swimming group than in the sedentary group (p < 0.05). The MCT1 concentration in erythrocytes was higher in the 3-week swimming group than in the sedentary group (18 %, p < 0.05), which was found in young erythrocytes (22 %, p < 0.05) when total erythrocytes were separated into young and old fractions. The MCT1 concentration in erythroid cells was higher in both the 1-week and 3-week swimming groups than in either of the sedentary groups (27 and 28 %, respectively, p < 0.05). The pH recovery of erythrocyte suspensions at 10, 15 and 20 seconds after addition of lactate to the suspension medium was significantly faster in the 3-week swimming group than in the sedentary group (p < 0.001). These findings suggest that erythrocyte MCT1 is increased during erythropoiesis in bone marrow and that the increase of the transporter facilitates, at least partly, lactate/proton co-transport due to sustained swimming exercise in rats.


Preference for Fasciocutaneous Flap Over Musculocutaneous Flap as a First-Line Option for Ischial Pressure Wound Reconstruction: A Review of 64 Cases.
The ischial pressure wound usually comprises a large, extensive defect and involves the repair of more than a small opening. Most surgeons have used a musculocutaneous flap to fill the large dead space of an ischial pressure wound. However, sacrificing muscle tissue has a potential risk of postoperative bleeding. The transferred muscle ultimately loses function as a cushion to absorb pressure. Conservation of muscle structures may be beneficial for use in future recurrence, which is common with ischial pressure wound. We compared the difference in outcome between musculocutaneous and fasciocutaneous flaps and analyzed factors affecting complications with the flaps in ischial pressure wound reconstruction. This study reviewed the results of 64 flaps in 44 patients with ischial wounds. The wounds were reconstructed with 34 musculocutaneous flaps (53%) and 30 fasciocutaneous flaps (47%). Twenty-three cases (36%) had complete healing, and 41 (64%) had complications. There was no significant difference in outcomes between fasciocutaneous and musculocutaneous flap groups. Crude logistic regression analysis showed no significant risk factors for occurrence of major complications. When fasciocutaneous flaps were used, the neighboring perforators and muscle tissues could be conserved. With a perforator-based fasciocutaneous flap, a de-epithelized distal portion of the flap could be used to fill the dead space. Therefore, the fasciocutaneous flap may have priority over the musculocutaneous flap as a first-line option for ischial pressure wound reconstruction.


[Chronic alcoholic pancreatitis: relation of pain to withdrawal and pancreatic surgery].
A group of 73 patients suffering from painful alcoholic, chronic pancreatitis, hospitalized from 1971 to 1981, has been analyzed retrospectively. The aim was to assess the effects of alcohol withdrawal and pancreatic surgery on the course of pancreatic pain. The mean number of years during which the patients complained of pain was 3.5 +/- 0.5 (m +/- SEM). At the end of follow-up, 70 p. 100 of the patients did no longer suffer, alcohol withdrawal was obtained in 45 p. 100 and surgery had been performed in 41 p. 100. Continued alcohol abuse did not prevent pain relief: 60 p. 100 of patients continuing to drink at the end of follow-up, did not suffer any longer. One year after pancreatic surgery, pain relief was more frequent, if alcohol abstinence had been obtained before surgery (p less than 0.01). Among the 53 patients followed up to 5 years after the start of pain: a) the cumulative actuarial probability of disappearance of pain was 17 p. 100 at 2 years, 52 p. 100 at 5 years, 62 p. 100 at 8 years after the start of pain. Alcohol abstinence and surgery were observed during the first five years of pain; b) the mean number of years of pain was lower among the patients who became abstinent early (less than 4 years after the beginning of pain) than among those who did not (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes.
Paraquat (PQ) promotes cell senescence in brain tissue, which contributes to Parkinson's disease. Furthermore, PQ induces heart failure and oxidative damage, but it remains unknown whether and how PQ induces cardiac aging. Here, we demonstrate that PQ induces phenotypes associated with senescence of cardiomyocyte cell lines and results in cardiac aging-associated phenotypes including cardiac remodeling and dysfunction in vivo. Moreover, PQ inhibits the activation of Forkhead box O3 (FoxO3), an important longevity factor, both in vitro and in vivo. We found that PQ-induced senescence phenotypes, including proliferation inhibition, apoptosis, senescence-associated β-galactosidase activity, and p16INK4a expression, were significantly enhanced by FoxO3 deficiency in cardiomyocytes. Notably, PQ-induced cardiac remolding, apoptosis, oxidative damage, and p16INK4a expression in hearts were exacerbated by FoxO3 deficiency. In addition, both in vitro deficiency and in vivo deficiency of FoxO3 greatly suppressed the activation of antioxidant enzymes including catalase (CAT) and superoxide dismutase 2 (SOD2) in the presence of PQ, which was accompanied by attenuation in cardiac function. The direct in vivo binding of FoxO3 to the promoters of the Cat and Sod2 genes in the heart was verified by chromatin immunoprecipitation (ChIP). Functionally, overexpression of Cat or Sod2 alleviated the PQ-induced senescence phenotypes in FoxO3-deficient cardiomyocyte cell lines. Overexpression of FoxO3 and CAT in hearts greatly suppressed the PQ-induced heart injury and phenotypes associated with aging. Collectively, these results suggest that FoxO3 protects the heart against an aging-associated decline in cardiac function in mice exposed to PQ, at least in part by upregulating the expression of antioxidant enzymes and suppressing oxidative stress.


Srebf1 Controls Midbrain Dopaminergic Neurogenesis.
Liver X receptors (LXRs) and their ligands are potent regulators of midbrain dopaminergic (mDA) neurogenesis and differentiation. However, the molecular mechanisms by which LXRs control these functions remain to be elucidated. Here, we perform a combined transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analysis of midbrain cells after LXR activation, followed by bioinformatic analysis to elucidate the transcriptional networks controlling mDA neurogenesis. Our results identify the basic helix-loop-helix transcription factor sterol regulatory element binding protein 1 (SREBP1) as part of a cluster of proneural transcription factors in radial glia and as a regulator of transcription factors controlling mDA neurogenesis, such as Foxa2. Moreover, loss- and gain-of-function experiments in vitro and in vivo demonstrate that Srebf1 is both required and sufficient for mDA neurogenesis. Our data, thus, identify Srebf1 as a central player in mDA neurogenesis.


Disrupting pre-SMA activity impairs facial happiness recognition: an event-related TMS study.
It has been suggested that the left pre-supplementary motor area (pre-SMA) could be implicated in facial emotion expression and recognition, especially for laughter/happiness. To test this hypothesis, in a single-blind, randomized crossover study, we investigated the impact of transcranial magnetic stimulation (TMS) on performances of 18 healthy participants during a facial emotion recognition task. Using a neuronavigation system based on T1-weighted magnetic resonance imaging of each participant, TMS (5 pulses, 10 Hz) was delivered over the pre-SMA or the vertex (control condition) in an event-related fashion after the presentation of happy, fear, and angry faces. Compared with performances during vertex stimulation, we observed that TMS applied over the left pre-SMA specifically disrupted facial happiness recognition (FHR). No difference was observed between the 2 conditions neither for fear and anger recognition nor for reaction times (RT). Thus, interfering with pre-SMA activity with event-related TMS after stimulus presentation produced a selective impairment in the recognition of happy faces. These findings provide new insights into the functional implication of the pre-SMA in FHR, which may rely on the mirror properties of pre-SMA neurons.


Embryonic growth and the evolution of the mammalian Y chromosome. I. The Y as an attractor for selfish growth factors.
The fitness of a mammalian zygote is affected by its probability of implantation and of postimplantation maintenance as well as the level of transplacental and transmammary uptake of resources. As with paternally expressed imprinted genes, in a species in which females are not obligately monogamous, a Y-linked sequence that can positively alter any of the above parameters could spread in a population even if it harms the prospects of other embryos. Such a selfish Y-linked gene could act as a sex ratio distorter. In contrast to autosomal imprinted loci, the patrilineal inheritance of the Y ensures that selfish Y-linked growth-promoting genes need not evolve a means to ensure correct parent-dependent expression rules. Thus, as the conditions for both their initial evolution and spread are relatively relaxed, the mammalian Y chromosome is expected to be an attractor for growth-promoting genes. Data from mice and humans indicate that, as expected and in contrast to the Y of flies, the mammalian Y harbours growth factors, sex ratio factors and multiple foetally expressed genes. The accumulation of Y-linked genes may also be explained in terms of sexual antagonism. Sexual antagonism and the model presented here are not mutually exclusive.


Bis(pyridazine-κN)bis-(seleno-cyanato-κN)zinc.
The asymmetric unit of the title compound, [Zn(NCSe)(2)(C(4)H(4)N(2))(2)], consists of one Zn(II) cation, located on a twofold rotation axis, one seleno-cyanate anion and one pyridazine ligand in general positions. The Zn(II) atom is coordinated by two N-atoms of two pyridazine ligands and two terminal N-bonded seleno-cyanate anions within a slightly distorted tetra-hedral coordination environment. In the crystal, discrete complex mol-ecules are arranged in layers parallel to the ac plane, with Zn(II)⋯Zn(II) distances of 8.0906 (6) Å along the a axis and of 9.0490 (7) or 9.3604 (7) Å along the c axis. The complex mol-ecules are further linked via weak Se⋯Se inter-actions, with Se⋯Se distances of 3.8235 (9) Å.


Size, weight, and expectations.
The size-weight illusion is well-known: if two equally heavy objects differ in size, the large one feels lighter than the small one. Most explanations for this illusion assume that because the information about the relevant attribute (weight itself) is unreliable, information about an irrelevant but correlated attribute (size) is used as well. If such reasoning is correct, one would expect that the illusion can be inverted: if size information is unreliable, weight information will be used to judge size. We explored whether such a weight-size illusion exists by asking participants to lift Styrofoam balls that were coated with glow in the dark paint. The balls (2 sizes, 3 weights) were lifted using a pulley system in complete darkness at 2 distances. Participants reported the size using free magnitude estimation. The visual size information was indeed unreliable: balls that were presented at a 20% larger distance were judged 15% smaller. Nevertheless, the judgments of size were not systematically affected by the 20% weight change (differences < 0.5%). We conclude that because the weight-size illusion does not exist, the mechanism behind the size-weight illusion is specific for judging heaviness.


Inbreeding affects fecundity of American mink (Neovison vison) in Danish farm mink.
Inbreeding is an increasing problem in farmed mink, because of limited exchange of individuals between farms. In this study, genetic relatedness within seven American mink (Neovison vison) colour strains originating from 13 different mink farms in Denmark was analysed using 21 polymorphic microsatellite loci. We detected large differences in the level of relatedness (range 0.017-0.520) within colour strains. Moreover, a very strong and highly significant negative correlation between the level of relatedness and fecundity was observed (r = 0.536, P < 0.001) [Correction added after online publication on 9 March 2011: r(2) has been changed to r]. To our knowledge, this is the first time that such a correlation has been demonstrated for commercially farmed mink.


The associations of implant and patient factors with migration of the tibial component differ by sex : a radiostereometric study on more than 400 total knee arthroplasties.
Thresholds of acceptable early migration of the components in total knee arthroplasty (TKA) have traditionally ignored the effects of patient and implant factors that may influence migration. The aim of this study was to determine which of these factors are associated with overall longitudinal migration of well-fixed tibial components following TKA. Radiostereometric analysis (RSA) data over a two-year period were available for 419 successful primary TKAs (267 cemented and 152 uncemented in 257 female and 162 male patients). Longitudinal analysis of data using marginal models was performed to examine the associations of patient factors (age, sex, BMI, smoking status) and implant factors (cemented or uncemented, the size of the implant) with maximum total point motion (MTPM) migration. Analyses were also performed on subgroups based on sex and fixation. In the overall group, only fixation was significantly associated with migration (p < 0.001). For uncemented tibial components in males, smoking was significantly associated with lower migration (p = 0.030) and BMI approached significance (p = 0.061). For females with uncemented components, smoking (p = 0.081) and age (p = 0.063) approached significance and were both associated with increased migration. The small number of self-reported smokers in this study warrants cautious interpretation and further investigation. For cemented components in females, larger sizes of tibial component were significantly associated with increased migration (p = 0.004). No factors were significant for cemented components in males. The migration of uncemented tibial components was more sensitive to patient factors than cemented implants. These differences were not consistent by sex, suggesting that it may be of value to evaluate female and male patients separately following TKA. Cite this article: Bone Joint J 2022;104-B(4):444-451.


A new 3,4-seco-lupane triterpenene glycosyl ester from the leaves of Eleutherococcus sessiliflorus.
A new minor 3,4-seco-lupane triterpenene glycosyl ester, named sessiloside-A1 (1), along with three known 3,4-seco-lupane triterpenenes were isolated from the which alcohol extract of the leaves of Eleutherococcus sessiliflorus (Rupr. & Maxim.) S.Y. Hu by silica gel column chromatography, and their structures were determined by spectroscopic methods (UV, IR, NMR and HRMS). Compound 1 was elucidated to be β-D-glucopyranosyl ester of chiisanogenin. At the same time, a new efficient two-step enzymatic hydrolysis method was established to transform chiisanoside (2) → divaroside (3) → 1.


Characterization of glucose transporter isoforms in the adult and developing human eye.
The expression of glucose transporter isoforms (Glut 1, Glut 3, Glut 4, and Glut 5) in the human eye was investigated at various ages ranging between 8 weeks gestation (first trimester) and adult using Western blot and immunohistochemical analyses. Glut 1 and Glut 3 expression and cellular localization patterns were similar to those of human brain. Glut 1 (50-kilodalton protein) was expressed by epithelial cells (retinal pigmented epithelium, choroidal, iridial, and pars planus), which form the blood-eye barrier, retinal Mueller cells, the lens fiber cells, iridial microvascular endothelial cells, and to a lesser extent by the outer segments of the photoreceptor cells in the adult eye. This pattern was conserved throughout development and was evident as early as 8 weeks gestation. In addition, the endothelial cells of vitreous hyaloid vessels expressed Glut 1 at 8 weeks gestation. Glut 3 (50 to 55-kilodalton protein) immunoreactivity was observed only in the adult inner synaptic layer of the retina. Neither Glut 4 nor Glut 5 was expressed in any occular tissue at any age examined. These results suggest that Glut 1 is the main glucose transporter of the human eye and that it is ontogenically conserved. In contrast, Glut 3 is associated with selective neuronal processes, and its expression is developmentally altered.


Melting of Tantalum at Multimegabar Pressures on the Nanosecond Timescale.
Tantalum was once thought to be the canonical bcc metal, but is now predicted to transition to the Pnma phase at the high pressures and temperatures expected along the principal Hugoniot. Furthermore, there remains a significant discrepancy between a number of static diamond anvil cell experiments and gas gun experiments in the measured melt temperatures at high pressures. Our in situ x-ray diffraction experiments on shock compressed tantalum show that it does not transition to the Pnma phase or other candidate phases at high pressure. We observe incipient melting at approximately 254±15 GPa and complete melting by 317±10 GPa. These transition pressures from the nanosecond experiments presented here are consistent with what can be inferred from microsecond gas gun sound velocity measurements. Furthermore, the observation of a coexistence region on the Hugoniot implies the lack of significant kinetically controlled deviation from equilibrium behavior. Consequently, we find that kinetics of phase transitions cannot be used to explain the discrepancy between static and dynamic measurements of the tantalum melt curve. Using available high pressure thermodynamic data for tantalum and our measurements of the incipient and complete melting transition pressures, we are able to infer a melting temperature 8070_{-750}^{+1250} K at 254±15 GPa, which is consistent with ambient and a recent static high pressure melt curve measurement.


Determination of Water Vapor Pressure Over Corrosive Chemicals Versus Temperature Using Raman Spectroscopy as Exemplified with 85.5% Phosphoric Acid.
A method to determine the water vapor pressure over a corrosive substance was developed and tested with 85.5 ± 0.4% phosphoric acid. The water vapor pressure was obtained at a range of temperatures from ∼25 ℃ to ∼200 ℃ using Raman spectrometry. The acid was placed in an ampoule and sealed with a reference gas (either hydrogen or methane) at a known pressure (typically ∼0.5 bar). By comparing the Raman signals from the water vapor and the references, the water pressure was determined as a function of temperature. A considerable amount of data on the vapor pressure of phosphoric acid are available in the literature, to which our results could successfully be compared. A record value of the vapor pressure, 3.40 bar, was determined at 210 ℃. The method required a determination of the precise Raman scattering ratios between the substance, water, and the used reference gas, hydrogen or methane. In our case the scattering ratios between water and reference ν1 Q-branches were found to be 1.20 ± 0.03 and 0.40 ± 0.02 for H2 and CH4, respectively.


Considerations regarding the development of individual nonclinical test strategies in the European Community.
The wish of pharmaceutical companies to be given the most binding possible preclinical test programmes for a new product, and the tendency of authorities to regulate to a great extent the preclinical testing of new drugs (especially at a multinational level), has led to differing requirements and practices in preclinical testing in different areas of the world. These differing requirements and practices have of necessity brought in their wake varying scientific criteria, with particular regard to animal protection, ethical standards, as well as imposing apparently unjustified extra financial costs. In order to improve this situation, the development of drug-specific preclinical test strategies is proposed in a drafted E. C. Note for Guidance, which incorporates already existing drug-testing guidelines and method recommendations. This draft Note for Guidance points to general methods of analysing problems and reaching decisions and thus appears to be worthy of recommendation as practical and desirable. It requires the co-operation of drug producers and supervisory authorities at a high scientific and ethical level. With regard to the state-of-the art and the socio-political background, the fulfillment of these requirements would appear not only to be appropriate but also imperative. To put them into practice would contribute enormously to the improvement of drug development and to de-emotionalization of the public debate. Therefore, comments on these draft guidelines from societies and associations are urgently sought and awaited with keen interest.


Positive correlation between degree of parasitemia, interferon titers, and natural killer cell activity in Plasmodium falciparum-infected children.
Natural killer (NK) cell activity and interferon levels have been measured in the peripheral blood of children acutely ill with Plasmodium falciparum infection. The NK cell levels were found to be raised in the malaria-infected children, with a positive correlation between the degree of parasitemia and lytic activity. Comparatively high titers of antiviral activity was discovered in sera from the majority of P. falciparum-infected children, again positively correlating with the degree of parasitemia and NK levels. The characteristics of the antiviral factor indicated alpha-type interferon to be the dominating agent involved. Addition of exogenous interferon in vitro potentiated the NK levels of PBL from normal children while having no significant impact on cells from malaria-infected children.


Pharmacokinetics of benzo[a]pyrene in the rat.
Groups of 4 male Wistar rats were dosed intravenously with 14C-labeled benzo[a]pyrene dissolved in an Emulphor/water vehicle at 3 different dose levels and killed at 1 of 15 specific time intervals from 5 min to 32 h after dosing. 14C-Radiolabel concentration-time data were obtained for blood, brain, adipose, heart, kidney, liver, lung, spleen, and testes. Benzo[a]pyrene concentration-time data were obtained for blood, adipose, kidney, liver, and lung. Appropriate mathematical models were fitted to these data and to the data for metabolites derived as the residuals from 14C-radiolabel minus benzo[a]pyrene difference, where applicable. Nonlinear kinetics were found for 14C-radiolabel in liver, while the data from lung for both 14C-radiolabel and for benzo[a]pyrene per se supported the binding of benzo[a]pyrene in that tissue.


Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease.
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively. We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified. We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas. 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05-1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation. Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought. CRD42019132045.


[Methodical abdominal palpation: the history of the development of the method].
Despite the development of instrumental and laboratory methods, objective examination of a patient is an important diagnostic doctors tool, especially at the first contact with the patient and in outpatient practice. The physician Frantz Glnard (18481920) [France] and russian professors Vasily P. Obraztsov (18511920) and Theodor Georg (Fyodor) Hausmann (18681944) developed methodical abdominal palpation, which entered clinical practice a little more than a hundred years ago. Their brief biographies and scientific achievements are review, and the contribution of each of them to the creation of the abdomens palpation is discussed in the article. For the first time, some aspects of F.O. Hausmanns biography from archival sources are present and clarify.


Pulmonary Neuroendocrine Tumors: Part II. Treatment.
Pulmonary neuroendocrine tumors that arise from Kulchitzky cells of the bronchial mucosa consist of a spectrum of histologic features leading to a variable prognosis. Although typical carcinoid represents the most benign course, small-cell cancer has the grimmest outcome. Therefore, differentiating the spectrum of neuroendocrine tumors helps one not only to determine the prognosis, but also to guide the treatment options. In this part, we aim to discuss the treatment options in pulmonary neuroendocrine tumors except for small-cell lung cancer.


Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects.
Cumulating evidence for the involvement of mitochondrial dysfunction in psychiatric disorders leaves little to no doubt regarding the involvement of this pathology in mood disorders. However, mitochondrial abnormalities are also observed in a wide range of disorders spanning from cancer and diabetes to various neurodegenerative and neurodevelopmental disorders such as Parkinson's, Alzheimer's, Huntington's, autism, and amyotrophic lateral sclerosis. The apparent lack of specificity questions the role of mitochondrial dysfunction in psychiatric disorders, in general, and in mood disorders, in particular. Is mitochondrial dysfunction a general phenomenon, simplistically rendering brain cells to be more vulnerable to a variety of disease-specific perturbations? Or is it an epiphenomenon induced by various disease-specific factors? Or possibly, the severity and the anatomical region of the dysfunction are the ones responsible for the distinct features of the disorders. Whichever of the aforementioned ones, if any, is correct, "mitochondrial dysfunction" became more of a cliché than a therapeutic target. In this review, we summarize current studies supporting the involvement of mitochondrial dysfunction in different psychiatric disorders. We address the question of specificity and causality of the different findings and provide an alternative explanation for some of the aforementioned questions.