Role of calmodulin in neurotransmitter synthesis.
Tyrosine 3-monooxygenase (EC 126.96.36.199) and tryptophan 5-monooxygenase (EC 184.108.40.206) are generally believed to be the rate-limiting enzymes in the biosynthesis of the neurotransmitters, catecholamines and serotonin, respectively, and therefore the regulation of their activities is of particular importance. At least three calmodulin-dependent protein kinases differed in their molecular weights and substrate specificities, designated I, II, and III in the order of decreasing molecular weight, in rat brain cytosol. Among them, calmodulin-dependent protein kinase II with a molecular weight of about 540,000 appeared to occur only in the nervous tissues. Kinase II was found, on the one hand, to phosphorylate tyrosine 3-monooxygenase and tryptophan 5-monooxygenase, leading to the activation of these monooxygenases in the presence of activator protein and, on the other hand, to phosphorylate tubulin and microtubule-associated protein 2, which results in disassembly of the microtubules that had been assembled. These results suggest the possibility that both the secretion and biosynthesis of monoamine neurotransmitters stimulated by Ca2+ influx in the nervous system may be regulated by calmodulin-dependent protein kinase II via the phosphorylation of microtubule proteins and the phosphorylation of the monooxygenases that are the rate-limiting enzymes in the biosynthesis of the neurotransmitters.


The hepatic glucagon receptor: a comparative study of the regulatory and structural properties.
Guanine nucleotide and Mg2+ ion regulation of [125I-Tyr10]monoiodoglucagon ([125I]MIG) binding to liver plasma membranes from chicken, rat, and rabbit was studied. It was found that [125I]MIG binding to chicken liver membranes was increased by the addition of Mg2+ ion, while binding to rat and rabbit liver membranes was unaffected. In the chicken liver membranes, the Mg2+ ion induced high affinity binding which was sensitive to guanine nucleotides, while the low affinity binding in the absence of Mg2+ ion was not. Maximal effects of Mg2+ ion were observed at 1 mM. Glucagon binding to rat liver membrane receptors was GTP sensitive regardless of whether Mg2+ ion was added. Glucagon binding to rabbit liver membranes was insensitive to both Mg2+ ions and GTP. This lack of GTP effect was not due to degradation of GTP; no effect of the nonhydrolyzable analog guanyl-5'-yl-imidodiphosphate was observable. Glucagon stimulation of rabbit liver adenylyl cyclase, however, was dependent on GTP, as was the case with all of the other liver adenylyl cyclases studied here. The Kact of GTP for the rabbit liver system was very similar to that for rat liver membranes. The glucagon receptor was covalently labeled with [125I]MIG using p-hydroxysuccinimidyl azidobenzoate and analyzed by sodium dodecyl sulfate-gel electrophoresis. In all cases, a major labeled band at 63,000 daltons was observed. The levels of glucagon receptor and stimulatory (Ns) and inhibitory (Ni) regulatory proteins of adenylyl cyclase were measured. The highest levels of glucagon receptor were measured in rat liver membranes, while the levels in chicken and rabbit membranes were 30-40% lower. Rabbit liver membrane had the highest levels of Ns, while rat liver membranes had 2-fold lower and chick liver membrane 4-fold lower levels than rabbit liver membranes. The levels of Ni was similar in the three systems. Thus, the ratio of Ns to glucagon receptor was highest in the rabbit. In the rat, this ratio was 3-fold lower than that in the rabbit. In the chicken membranes, the ratio was about 60% of that in the rat. These data suggest that the observed differences in effects of GTP on hormone binding can be explained by alterations in the ratio of the receptor and Ns proteins among the various species.


Isolation of a pentadentate ligand and stepwise synthesis, structures, and magnetic properties of a new family of homo- and heterotrinuclear complexes.
A neutral pentadentate ligand, di(pyrazolecarbimido)amine (Hdcadpz), and its adduct with HClO4, [H2dcadpz]+[ClO4]-, were for the first time isolated from our previously reported [Cu3(dcadpz)2(Hpz)2(ClO4)2](ClO4)2.H2O by the use of (NH4)2S to remove the CuII ions and characterized by IR, EA, UV, NMR, MS, and X-ray crystallography. Reactions of copper(II) or nickel(II) nitrate with Hdcadpz in a 1:2 molar ratio generated two mononuclear precursors of [Cu(dcadpz)2] (1) and [Ni(dcadpz)2].2/3DMF (2). Furthermore, three new linear homo- and heterotrinuclear complexes of the same motif [M{M'(dcadpz)2}M] (M=CoII, NiII, M'=CuII, NiII), [{Co(pdm)}2{Cu(dcadpz)2}](NO3)4 (3), [{Ni(pdm)}2{Cu(dcadpz)2}](NO3)4 (4), and [{Ni(MeOH)(H2O)2}2{Ni(dcadpz)2}](NO3)4 (5), were synthesized from these two precursors (pdm=2,6-pyridinedimethanol) and characterized by X-ray crystallography. Magnetic studies show that the central Cu(dcadpz)2 motif is antiferromagnetically coupled with both the terminal Co(II) atoms via the dcadpz- ligand in 3 with a J value of -5.27 cm(-1) and ferromagnetically coupled with both the terminal Ni(II) atoms in 4 with a J value of 2.50 cm(-1), while 5 behaves only as a Curie paramagnet between 2 and 300 K due to the diamagnetic character of the central square-planar Ni(II) atom.


Accelerating Biomedical Discoveries through Rigor and Transparency.
Difficulties in reproducing published research findings have garnered a lot of press in recent years. As a funder of biomedical research, the National Institutes of Health (NIH) has taken measures to address underlying causes of low reproducibility. Extensive deliberations resulted in a policy, released in 2015, to enhance reproducibility through rigor and transparency. We briefly explain what led to the policy, describe its elements, provide examples and resources for the biomedical research community, and discuss the potential impact of the policy on translatability with a focus on research using animal models. Importantly, while increased attention to rigor and transparency may lead to an increase in the number of laboratory animals used in the near term, it will lead to more efficient and productive use of such resources in the long run. The translational value of animal studies will be improved through more rigorous assessment of experimental variables and data, leading to better assessments of the translational potential of animal models, for the benefit of the research community and society.


Do extracurricular activities protect against early school dropout?
This study examined the relation between involvement in school-based extracurricular activities and early school dropout. Longitudinal assessments were completed for 392 adolescents (206 girls, 186 boys) who were initially interviewed during 7th grade and followed up annually to 12th grade. A person-oriented cluster analysis based on Interpersonal Competence Scale ratings from teachers in middle schools (i.e., 7th-8th grades) identified configurations of boys and girls who differed in social-academic competence. Early school dropout was defined as failure to complete the 11th grade. Findings indicate that the school dropout rate among at-risk students was markedly lower for students who had earlier participated in extracurricular activities compared with those who did not participate (p < .001). However, extracurricular involvement was only modestly related to early school dropout among students who had been judged to be competent or highly competent during middle school.


Wing beat kinematics of a nectar-feeding bat, Glossophaga soricina, flying at different flight speeds and Strouhal numbers.
High-speed film analysis showed that the wing beat kinematics in Glossophaga soricina change gradually with increasing flight speed, indicating that there is no sudden gait change at any particular, critical, flight speed. The flight of two adult specimens was studied over a range of flight speeds (1.23-7.52 ms(-1)) in a 30 m long flight tunnel. During the upstroke in hovering and slow flight there is a tip-reversal or supination of the handwings, which thus produce a backward flick. This backward motion successively disappears at speeds V approximately 3.2 ms(-1), above which the wingtip path becomes more vertical or directed upwards-forwards relative to the still air (the stroke plane angle increasing with flight speed as alpha=44.8V(0.29)). We found no correlations between either span ratio SR (the ratio of the wing span on the upstroke to that on the downstroke) and V, or downstroke ratio (the duration of the downstroke divided by the total stroke period) and V. On the other hand, SR decreases significantly with increasing wing beat frequency f, SR proportional to f(-0.40). The Strouhal number (St=f x amplitude/V), a dimensionless parameter describing oscillating flow mechanisms and being a predictor of the unsteadiness of the flow, decreases with the speed as St proportional to V(-1.37). Close to the theoretical minimum power speed (4-6 m s(-1)) G. soricina operates with a Strouhal number in the region 0.17<St<0.22, which is associated with efficient lift and thrust production. At slower speeds, 3.4-4 m s(-1), St is 0.25-0.4, which is still within the favourable region. But at speeds below 3 m s(-1) St becomes higher (0.5<St<0.68), indicating that unsteady effects become important, with unfavourable lift and thrust production as a result. Only at these speeds do the bats perform the backward flick during the upstroke, which may produce thrust. This may serve as a compensation in some bats and birds to increase aerodynamic performance.


Evaluation of Hydrogels Based on Oxidized Hyaluronic Acid for Bioprinting.
In this study, we evaluate hydrogels based on oxidized hyaluronic acid, cross-linked with adipic acid dihydrazide, for their suitability as bioinks for 3D bioprinting. Aldehyde containing hyaluronic acid (AHA) is synthesized and cross-linked via Schiff Base chemistry with bifunctional adipic acid dihydrazide (ADH) to form a mechanically stable hydrogel with good printability. Mechanical and rheological properties of the printed and casted hydrogels are tunable depending on the concentrations of AHA and ADH cross-linkers.


T cell control of the antibody response to the T-independent antigen, DAGG-Ficoll.
C57BL/6J nu/nu mice respond to the type 2 TI antigen DAGG-Ficoll, but not to the TD antigen SRC. A comparable difference can also be seen in vitro, but only at high spleen cell density and in the presence of selected batches of FBS. At low spleen cell density and in the absence of FBS, the DAGG-Ficoll-induced B cell response is strictly dependent on soluble helper factors or cloned specific helper T cells. The B cell response so induced requires that the T cell-depleted spleen cells be compatible in the I-A subregion of the H-2 complex. These helper factors, induced by antigen in an I-A-restricted T cell-macrophage interaction, provide helper for T cell-depleted spleen cells irrespective of their H-2 haplotype. Under conventional culture conditions, the stringent requirement for helper factors in the in vitro response to DAGG-Ficoll is obscured by FBS. In vitro culture of low numbers of spleen cells, in serum-free medium instead of FBS, provides a sensitive assay for helper factors. We have compared the helper activity for a B cell response to SRC or DAGG-Ficoll as provided by antigen-induced supernatants of various individual EA-specific T cell clones. There was a remarkable and consistent heterogeneity among individual T cell clones: their helper activity in the response to TI and TD antigens did not correlate, nor was there any correlation between helper activity and antigen-induced TCGF (interleukin 2) activity.


Cellular Uptake of Tile-Assembled DNA Nanotubes.
DNA-based nanostructures have received great attention as molecular vehicles for cellular delivery of biomolecules and cancer drugs. Here, we report on the cellular uptake of tubule-like DNA tile-assembled nanostructures 27 nm in length and 8 nm in diameter that carry siRNA molecules, folic acid and fluorescent dyes. In our observations, the DNA structures are delivered to the endosome and do not reach the cytosol of the GFP-expressing HeLa cells that were used in the experiments. Consistent with this observation, no elevated silencing of the GFP gene could be detected. Furthermore, the presence of up to six molecules of folic acid on the carrier surface did not alter the uptake behavior and gene silencing. We further observed several challenges that have to be considered when performing in vitro and in vivo experiments with DNA structures: (i) DNA tile tubes consisting of 42 nt-long oligonucleotides and carrying single- or double-stranded extensions degrade within one hour in cell medium at 37 °C, while the same tubes without extensions are stable for up to eight hours. The degradation is caused mainly by the low concentration of divalent ions in the media. The lifetime in cell medium can be increased drastically by employing DNA tiles that are 84 nt long. (ii) Dyes may get cleaved from the oligonucleotides and then accumulate inside the cell close to the mitochondria, which can lead to misinterpretation of data generated by flow cytometry and fluorescence microscopy. (iii) Single-stranded DNA carrying fluorescent dyes are internalized at similar levels as the DNA tile-assembled tubes used here.


Biomagnification of 7Be, 234Th, and 228Ra in marine organisms near the northern Pacific coast of Japan.
Enrichment of natural radionuclides of thorium, radium and beryllium in several kinds of marine organisms was investigated near the Pacific coast of Miyagi Pref., Japan. The radioactivity of 7Be, 210Pb, 234Th, 238U, 228Ra and 137Cs was measured using gamma spectrometry. High concentrations of 234Th were observed in ascidian livers (50-400 Bq/kg dry) and excrement (2000-2900 Bq/kg dry), although the parent 238U concentrations were less than 3 Bq/kg dry. Such extreme disequilibrium between 238U and 234Th activity was observed in other organisms (barnacles, mussels and brown algae). Relatively high concentrations of 228Ra were detected in ascidian livers and were observed to decrease according to its half-life (5.75 year), suggesting disequilibrium with its parent 232Th. High concentrations (about 1900-5000 Bq/kg dry) of 7Be were detected in ascidian liver. Possible mechanisms for the observed biomagnification and bioaccumulation of these radionuclides in the organisms analyzed were proposed.


Review of 1600 water births. Does water birth increase the risk of neonatal infection?
We reviewed 1600 water births at a single institution over an 8-year period. We compared 737 primiparae deliveries in water with 407 primiparae deliveries in bed, and 142 primiparae on the delivery stool. We also evaluated the duration of labor, perineal trauma, arterial cord blood pH, postpartum maternal hemoglobin levels, and rates of neonatal infection. In 250 water deliveries we performed bacterial cultures of water samples obtained from the bath after filling and after delivery. The duration of the first stage of labor was significantly shorter with a water birth than with a land delivery (380 vs. 468 minutes, P<0.01). The episiotomy rate in all water births was lower with a water birth than with a delivery in bed or a delivery on the birthing stool (0.38%, 23%, and 8.4%, respectively). The rate of perineal tears was similar (23%, respectively). There were no differences in the duration of the second stage (34 vs. 37 minutes), arterial cord blood pH, or postpartum maternal hemoglobin levels. No woman using the water birth method required analgesics. The rate of neonatal infection was also not increased with a water birth (1.22% vs. 2.64%, respectively). Water birth appears to be associated with a significantly shorter first stage of labor, lower episiotomy rate and reduced analgesic requirements when compared with other delivery positions. If women are selected appropriately and hygiene rules are respected, water birth appears to be safe for both the mother and neonate.


The use of helical computed tomographic scan to assess bony physeal bridges.
Coronal and sagittal reformatted images of the physis obtained with the helical computed tomography (CT) scanner were studied in five children. This technique allows tomographic slices at 1.0-mm thickness and can be performed in approximately 20 s. The distal femora were studied in two children, the distal tibia in two children, and the distal radius in one child. In three children, after physeal mapping, bar resections were performed. In all cases, the location and size of the bar was accurately predicted by the map constructed from the helical CT scan. We recommend the helical CT scan to prepare physeal maps to determine the extent and location of physeal bony bars because of excellent bony detail, radiation doses one half to one quarter those of conventional tomography, and the rapidity of scanning, which bypasses the need for sedation.


Ferulic acid promoting apoptosis in human osteosarcoma cell lines.
To explore the promoting apoptosis and antitumor activities of ferulic acid (FA) in human osteosarcoma and its potential mechanism. The SaOS-2 and MG63 osteosarcoma cell lines were opted to experiment and these cells were, respectively, cultured with various concentrations of FA (0 μM, 10 μM, 20 μM, 40 μM) for 72 hours at 37°C. The viabilities of the FA treated cells were monitored by MTT. Apoptosis cells were evaluated using annexin V/PI by flow cytometry. Apoptosis proteins caspase-3, procaspase-3, Bcl-2 and Bax were detected by western blot. Expressions of apoptotic genes Bcl-2 and Bax were quantified by qPCR. The cell viabilities were critically declined in the concentration-dependent manner in FA groups (P < 0.01). The apoptosis cells were increased proportionately with the concentration of FA (P < 0.05). The procaspase-3 protein contents, and Bcl-2 mRNA and protein contents were significantly decreased while caspase-3 protein contents, and Bax mRNA and protein contents were concomitantly increased in the concentration-dependent manner in FA groups (P < 0.05). The response to FA by the SaOS-2 osteosarcoma cell was similar with the MG63 osteosarcoma cell (P > 0.05). Ferulic acid could significantly descend osteosarcoma cell viability through the promoting apoptosis pathway in which FA activates both caspase-3 and Bax and inactivates Bcl-2.


[Position statement for the diagnosis and treatment of men with benign prostate enlargement and lower urinary tract symptoms].
Benign prostate enlargement causing lower urinary symptoms is a common progressive phenomenon in adult men. Lower urinary tract symptoms may emerge during the storage, voiding, and post micturition phases, harm quality of life and may be caused by a variety of factors. The purpose of evaluation is to identify benign prostate enlargement and factors other than enlarged prostate as the cause of symptoms, and recognize the risk factors for progression of the condition. The goal of treatment is to alleviate symptoms and improve quality of life, and to prevent deterioration of symptoms and development of complications. Medical therapy is the basic approach, whereas surgery and minimally invasive procedures are reserved for patients not interested in medical therapy or for those in whom symptoms were not alleviated by means of medical therapy. In the present position statement, we present the approach to the evaluation and treatment of lower urinary tract symptoms in men with benign prostate enlargement.


Assessing whether COVID-19 patients will benefit from critical care, and an objective approach to capacity challenges during a pandemic: An Intensive Care Society clinical guideline.
This national professional society guidance lays out operational and ethical principles for decision-making during a pandemic, in the immediate context of COVID-19 in the early 2020 surge iteration but with potential ongoing relevance. It identifies the different phases of a pandemic and the implications for capacity and mutual aid within a national healthcare system, and introduces a revised CRITCON-PANDEMIC framework for shared operational responsibilities and clinical decision-making. Usual legal and ethical frameworks should continue to apply while capacity and mutual aid are available (CRITCON-PANDEMIC levels 0-3); clinicians should focus on current clinical needs and should not treat patients differently because of anticipated future pressures. In conditions of resource limitation (CRITCON-PANDEMIC 4), a structured and equitable approach is necessary and an objective Decision Support Aid is proposed. In producing this guidance, we emphasise that all patients must be treated with respect and without discrimination, because everyone is of equal value. The guidance has been put together with input from patient and public groups and aims to provide standards that are fair to everyone. We acknowledge that COVID-19 is a new disease with a partial and evolving knowledge base, and aim to provide an objective clinical decision-making framework based on the best available information. It is recognised that a factual assessment of likely benefit may take into account age, frailty and comorbidities, but the guidance emphasises that every assessment must be individualised on a balanced, case by case, basis and may inform clinical judgement but not replace it. The effects of a comorbidity on someone's ability to benefit from critical care should be individually assessed. Measures of frailty should be used with care, and should not disadvantage those with stable disability.


Phlebotomine sandflies (Diptera: Psychodidae) of the Atlantic forest in Recife, Pernambuco state, Brazil: the species coming to human bait, and their seasonal and monthly variations over a 2-year period.
In a study of the phlebotomine sandflies (Diptera: Psychodidae) in a forest reserve in Recife, Pernambuco state, north-eastern Brazil, the sandflies landing on human bait between 1.00 and 1.42 h after sunset were collected weekly for 2 years. Although 10,287 sandflies of 10 Lutzomyia species were collected, almost all (96.5%) of the sandflies caught were Lu. umbratilis. This species and several others caught are potential vectors of some of the Leishmania parasites that cause human disease. The recorded landing rate for Lu. umbratilis peaked, at the high level of 333.3 flies/person-hour, during the collections made in May 2003.The relative rarity in the collections of males of some of the species caught probably indicates that these species do not lek on their bloodmeal sources. It is likely that the sizes of the local populations of species that are not very anthrophilic, such as Lu. flaviscutellata, are much larger than indicated by the collections made on human bait.


[Surgical treatment of dermo-hypodermic sclerosis and varicose ulcer by Martorell's method].
A surgical therapy model for dermohypodermic sclerosis and varicose ulcer of the lower extremities is presented. This consists of extending the method described by Martorell in 1955 to cases of inveterate ulcer. The pre-, intra- and post-operative colour diagrams and figures presented show the validity of the method without superseding lengthier and more complex methods.


PROBING THE IMPACT OF GAMMA-IRRADIATION ON THE METABOLIC STATE OF NEURAL STEM AND PRECURSOR CELLS USING DUAL-WAVELENGTH INTRINSIC SIGNAL TWO-PHOTON EXCITED FLUORESCENCE.
Two-photon excited fluorescence (TPEF) spectroscopy and imaging were used to investigate the effects of gamma-irradiation on neural stem and precursor cells (NSPCs). While the observed signal from reduced nicotinamide adenine dinucleotide (NADH) was localized to the mitochondria, the signal typically associated with oxidized flavoproteins (Fp) was distributed diffusely throughout the cell. The measured TPEF emission and excitation spectra were similar to the established spectra of NAD(P)H and Fp. Fp fluorescence intensity was markedly increased by addition of the electron transport chain (ETC) modulator menadione to the medium, along with a concomitant decrease in the NAD(P)H signal. Three-dimensional (3D) neurospheres were imaged to obtain the cellular metabolic index (CMI), calculated as the ratio of Fp to NAD(P)H fluorescence intensity. Radiation effects were found to differ between low-dose (≤ 50 cGy) and high-dose (≥ 50 cGy) exposures. Low-dose irradiation caused a marked drop in CMI values accompanied by increased cellular proliferation. At higher doses, both NAD(P)H and Fp signals increased, leading to an overall elevation in CMI values. These findings underscore the complex relationship between radiation dose, metabolic state, and proliferation status in NSPCs and highlight the ability of TPEF spectroscopy and imaging to characterize metabolism in 3D spheroids.


Functional brain imaging of olfactory processing in monkeys.
As a step toward bridging the gap between human and animal studies of olfactory brain systems, we report results from an fMRI study of olfaction in squirrel monkeys. High-resolution fMRI images at 3 T with 1.25 x 1.25 x 1.2 mm(3) voxels were obtained covering the whole brain using an 8-cm-diameter birdcage coil and a gradient-echo spiral pulse sequence. Data were acquired from six sedated adult males using a standard block design. All fMRI data were spatially normalized to a common template and analyzed at the individual and group levels with statistical parametric and nonparametric methods. Robust odorant-induced activations were detected in several brain regions previously implicated in conscious human olfactory processing, including the orbitofrontal cortex, cerebellum, and piriform cortex. Consistent with human data, no stimulus intensity effects were observed in any of these regions. Average signal changes in these regions exceeded 0.6%, more than three times the expected signal change based on human fMRI studies of olfaction adjusting for differences in voxel size. These results demonstrate the feasibility of studying olfaction in sedated monkeys with imaging techniques commonly used at 3 T in humans and help promote direct comparisons between humans and nonhuman primates. Our findings, for example, provide novel support for the hypothesis that the cerebellum is involved in sensory acquisition. More broadly, this study suggests that olfactory processing in sedated monkeys and nonsedated humans shares similar neural substrates both within and beyond the primary olfactory system.


Stable Magnetic Skyrmion States at Room Temperature Confined to Corrals of Artificial Surface Pits Fabricated by a Focused Electron Beam.
Stable confinement of elemental magnetic nanostructures, such as a single magnetic domain, is fundamental in modern magnetic recording technology. It is well-known that various magnetic textures can be stabilized by geometrical confinement using artificial nanostructures. The magnetic skyrmion, with novel spin texture and promise for future memory devices because of its topological protection and dimension at the nanometer scale, is no exception. So far, skyrmion confinement techniques using large-scale boundaries with limited geometries such as isolated disks and stripes prepared by conventional microfabrication techniques have been used. Here, we demonstrate an alternative technique confining skyrmions to artificial nanostructures (corrals) built from surface pits fabricated by a focused electron beam. Using aberration-corrected differential phase contrast scanning transmission electron microscopy, we directly visualized stable skyrmion states confined at a room temperature to corrals made of artificial surface pits on a thin plate of Co8Zn8Mn4. We observed a stable single-skyrmion state confined to a triangular corral and a unique transition into a triple-skyrmions state depending on the perpendicular magnetic field. Furthermore, we made an array of stable single-skyrmion states by using concatenated triangular corrals. Artificial control of skyrmion states with the present technique should be a powerful way to realize future nonvolatile memory devices using skyrmions.


Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term follow-up.
We analyzed the impact of a single Mitomycin C instillation in patients with low risk superficial bladder cancer with short and long-term follow-up. This study was conducted on 63 patients with low risk superficial bladder transitional cell carcinoma (TCC), admitted to the Urology Department, Theodor Bilharz Research Institute (TBRI) during the period from January 2002 to August 2005. All patients had a 2 cm. or less single, papillary, primary or recurrent tumor and were disease-free for more than 1 year. Patients with muscular invasion, G III tumor or bladder carcinoma in situ on pathological examination were excluded from the study. The tumor was completely resected before patients were divided randomly into 2 arms: first group who have received no further treatment (control group) and a second group with a single immediate instillation of 30 mg. Mitomycin C (mitomycin C group). Recurrences were considered early if they occurred within the first 2 years of follow-up. At 24-months follow-up, the recurrence-free interval was significantly increased and recurrence, recurrence per year and tumor per year rates were decreased in the mitomycin C group compared to the control group. Early recurrence was (16.1%) in the mitomycin C group versus (34.3%) in the control group. It was noted also that early recurrences were concentrated in the first year in the control group (18.7%) versus (3.2%) in the mitomycin C group. However, at long-term follow-up, these differences were not statistically significant (26.9%) in the mitomycin C group versus (28.6%) in the control group, and the recurrence-free interval curves were parallel. A significant relationship between early and late recurrences was found in the mitomycin C, but not in the control group. Shorter hospital stay and catheterization periods were noted in the mitomycin C group compared to the control group, but the differences were not statistically significant. These data confirm the positive effect of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer. This benefit is limited to early recurrence and is not maintained with long-term follow-up. Thus, this approach is an alternative to observation or classic long-term intravesical chemotherapy. Our study also suggests that cell implantation as a mechanism of early recurrence can be controlled or minimized with a single mitomycin C instillation.


The pathogenesis of coronary artery disease. A possible role for methionine metabolism.
Homocystinuria, an abnormality of methionine metabolism is associated with severe vascular disease in infancy and childhood. Homocysteine is formed during the metabolism of methionine and accumulations of this and of cysteine-homocysteine mixed disulfide in the plasma indicate a partial block in the methionine degradation pathway. Methionine metabolism was investigated in 25 patients aged under 50 with angiographically proved coronary artery disease and in 22 control patients, of whom 17 had normal coronary arteries at angiography and 5 were healthy volunteers. After an overnight fast, venous blood was drawn before and 4 h after oral L-methionine, 100 mg/kg. Plasma methionine levels at 4 h were not different in the two groups, but there were significant differences in the levels of cysteine-homocysteine mixed disulfide. This was detected in 5 of 22 in the noncoronary group and in higher concentration in 17 of 25 coronary patients (P less than 0-01). Age, weight, height, body-mass index, glucose tolerance, fasting serum urate, and triglycerides were not different, but serum cholesterol was higher in the coronary patients (P lessthan 0.01). These results suggest a reduced ability to metabolise homocysteine in some patients with premature coronary artery disease when this pathway is stressed.


Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model.
Cariprazine, a D3-preferring dopamine D2/D3 receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine's antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D3 receptors. Wild-type and D3-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors. Results showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D3-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D3 receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity. In combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D3 receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.


Wars, disasters and kidneys.
This paper summarizes the impact that wars had on the history of nephrology, both worldwide and in the Ghent Medical Faculty notably on the definition, research and clinical aspects of acute kidney injury. The paper briefly describes the role of 'trench nephritis' as observed both during World War I and II, supporting the hypothesis that many of the clinical cases could have been due to Hantavirus nephropathy. The lessons learned from the experience with crush syndrome first observed in World War II and subsequently investigated over many decades form the basis for the creation of the Renal Disaster Relief Task Force of the International Society of Nephrology. Over the last 15 years, this Task Force has successfully intervened both in the prevention and management of crush syndrome in numerous disaster situations like major earthquakes.


Human placental glucuronidation and transport of 3'azido-3'-deoxythymidine and uridine diphosphate glucuronic acid.
These studies were performed to characterize the contribution of the uridine diphosphate glucuronosyltransferase (UGT) enzymes to the clearance of 3'-azido-3'-deoxythymidine (AZT) in vivo and to assess the regulation of UGT activity [including the disposition of the cofactor uridine diphosphate glucuronic acid (UDPGA)] in the placenta. Transport of AZT and the cofactor UDPGA across the human placenta and the glucuronidation capacity of the placenta for AZT were assessed using a human placental cell line (JEG-3), primary cultures of villous term placenta, placental subcellular fractions, and a recirculating perfusion model. Glucuronidation of AZT was consistently observed at approximately 2% of the dose administered. High levels of AZT in cultured primary placental cells and lines caused autoinhibition of AZT metabolism. AZT crossed the perfused placenta in a bidirectional fashion and was at equilibrium after 3 h, whereas the AZT-glucuronide metabolite was excreted preferentially into the maternal compartment. In contrast, UDPGA (10 microM) was rapidly transferred from the maternal to the fetal circulation, being complete after 4 h of perfusion. AZT is transported and glucuronidated by the human placenta, but that placental metabolism of the drug is not significant for whole-body clearance. Likewise therapeutic failure of AZT (5-15%) is not due to placental obstruction of drug passage. Finally, the activity of the UGT enzymes in the placenta is not rate-limited by the supply of UDPGA cofactor, whereas the preferential transport of UDPGA toward the fetus observed here may indicate a role in fetal development.


Tumor Treating Fields - Behind and Beyond Inhibiting the Cancer Cell Cycle.
The unmet need for a safe treatment that significantly improves the overall survival, as well as the quality of life of patients with brain tumors, has urged researchers to work out new treatment modalities. About 15 years ago, it was shown that alternating electric fields significantly impair the growth of cancer cells. Recently, this potentially revolutionary approach called Tumor Treating Fields (TTFs) has been FDA-approved for the treatment of glioblastoma as well as mesothelioma. However, despite the promising reports on the potential of TTFs, the precise knowledge of the mechanisms of action is still lacking. The purpose of this review is, thus, to present the current state of research and to highlight the variety of ultrastructural effects of TTFs. Moreover, the aim is to bring to the foreground less discussed mechanisms of action of TTFs, which might develop into novel therapeutic approaches. Therefore, a systematic literature search in Ovid Medline and Embase was performed on clinical and preclinical data concerning TTFs. The alternating electric fields force cellular components to aberrant dynamics, among which the most evident is the inhibition of the mitotic spindle assembly leading to impaired cancer cell division and cell death. However, a variety of other microstructural events induced by TTFs, such as inhibition of DNA repair and cell migration, as well as an enhancement of anti- tumor immune response and membrane permeability, have been reported. In addition, apart from a suggested interference with angiogenesis, no TTF-induced effects on normal cells have been described so far.


[Peranesthesic Anaphylactic Shocks: Contribution of a Clinical Data Warehouse].
To evaluate the performance of the collection of cases of anaphylactic shock during anesthesia in the Regional Pharmacovigilance Center of Rennes and the contribution of a query in the biomedical data warehouse of the French University Hospital of Rennes in 2009. Different sources were evaluated: the French pharmacovigilance database (including spontaneous reports and reports from a query in the database of the programme de médicalisation des systèmes d'information [PMSI]), records of patients seen in allergo-anesthesia (source considered as comprehensive as possible) and a query in the data warehouse. Analysis of allergo-anesthesia records detected all cases identified by other methods, as well as two other cases (nine cases in total). The query in the data warehouse enabled detection of seven cases out of the nine. Querying full-text reports and structured data extracted from the hospital information system improves the detection of anaphylaxis during anesthesia and facilitates access to data.


Case Report: Ensartinib for gastric epithelioid inflammatory myofibrosarcoma with STRN-ALK fusion.
Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a highly aggressive malignant subtype of inflammatory myofibroblastoma (IMT) associated with poor prognosis. IMT can occur in various parts of the body, most frequently in the lungs, followed by the mesentery, omentum, retroperitoneum, and pelvis, among other areas; however, it is exceptionally rare in the stomach. Anaplastic lymphoma kinase (ALK) is a critical driver of lung cancer development and is currently the "gold standard" target for non-small cell lung cancer treatment. However, there are few reports on the use of ALK inhibitors for EIMS, necessitating further investigation. A male patient with postoperative inflammatory myofibroblastic sarcoma of the stomach received postoperative chemotherapy and had a stable outcome. However, a repeat CT scan performed 11 months later revealed disease progression. The patient later underwent immunohistochemistry testing that indicated ALK positivity, and next-generation sequencing revealed STRN-ALK fusion. Ensartinib 225 mg qd was administered as recommended, and the patient experienced only mild pruritus and no adverse effects such as rash. Eight months after CT follow-up, the patient's subseptal soft tissue nodules had decreased, and the outcome was assessed as a partial response. The findings of this case report introduce a novel strategy for treating ALK-positive EIMS that utilizes ensartinib, a drug with previously demonstrated success in the treatment of ALK-positive cancer.


Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer's Disease.
High expression of glutaminyl cyclase (QC) contributes to the initiation of Alzheimer's disease (AD) by catalyzing the generation of neurotoxic pyroglutamate (pE)-modified β-amyloid (Aβ) peptides. Preventing the generation of pE-Aβs by QC inhibition has been suggested as a novel approach to a disease-modifying therapy for AD. In this work, a series of diphenyl conjugated imidazole derivatives (DPCIs) was rationally designed and synthesized. Analogues with this scaffold exhibited potent inhibitory activity against human QC (hQC) and good in vitro blood-brain barrier (BBB) permeability. Further assessments corroborated that the selected hQC inhibitor 28 inhibits the activity of hQC, dramatically reduces the generation of pE-Aβs in cultured cells and in vivo, and improves the behavior of AD mice.


Tocopherol deficiency reduces sucrose export from salt-stressed potato leaves independently of oxidative stress and symplastic obstruction by callose.
Tocopherol cyclase, encoded by the gene SUCROSE EXPORT DEFECTIVE1, catalyses the second step in the synthesis of the antioxidant tocopherol. Depletion of SXD1 activity in maize and potato leaves leads to tocopherol deficiency and a 'sugar export block' phenotype that comprises massive starch accumulation and obstruction of plasmodesmata in paraveinal tissue by callose. We grew two transgenic StSXD1:RNAi potato lines with severe tocopherol deficiency under moderate light conditions and subjected them to salt stress. After three weeks of salt exposure, we observed a strongly reduced sugar exudation rate and a lack of starch mobilization in leaves of salt-stressed transgenic plants, but not in wild-type plants. However, callose accumulation in the vasculature declined upon salt stress in all genotypes, indicating that callose plugging of plasmodesmata was not the sole cause of the sugar export block phenotype in tocopherol-deficient leaves. Based on comprehensive gene expression analyses, we propose that enhanced responsiveness of SnRK1 target genes in mesophyll cells and altered redox regulation of phloem loading by SUT1 contribute to the attenuation of sucrose export from salt-stressed SXD:RNAi source leaves. Furthermore, we could not find any indication that elevated oxidative stress may have served as a trigger for the salt-induced carbohydrate phenotype of SXD1:RNAi transgenic plants. In leaves of the SXD1:RNAi plants, sodium accumulation was diminished, while proline accumulation and pools of soluble antioxidants were increased. As supported by phytohormone contents, these differences seem to increase longevity and prevent senescence of SXD:RNAi leaves under salt stress.


Cochlear Fistula in Chronic Otitis Media without Cholesteatoma.
Cochlear fistula in the chronic otitis media (COM) without cholesteatoma is an extremely rare with only a few cases reported in the literature to this date. We describe a case of cochlear fistula observed in a female with COM without cholesteatoma. This report presents the first clinical case of a transtympanic iatrogenic trauma by habitual cotton swabs probably causing cochlear fistula.


[Nutritional status and factors associated with stunting in children attending public daycare centers in the Municipality of São Paulo, Brazil].
This study reports the nutritional status of children attending daycare centers in the Municipality of São Paulo, Brazil. A representative sample of 827 children under 84 months of age was evaluated. Anthropometric measurements and information on socioeconomic characteristics and morbidity were collected. The most prevalent nutritional deficit was stunting (7.0%; 95%CI: 3.60-10.40). Univariate analysis showed a significant association between stunting and age (< 24 months), OR = 2.10 (95%CI: 1.11-3.98); diarrhea one month prior to the data collection, OR = 2.84 (95%CI: 1.42-5.66); mother's or caregiver's schooling (< 3 years), OR = 3.87 (95%CI: 1.10-13.68); number of household members (> 7), OR = 3.02(95%CI: 1.46-6.22); and number of siblings (> 2) OR = 4.81 (95%CI: 1.72-13.44). In the multivariate analysis, only diarrhea one month prior to the data collection, OR = 2.54 (95%CI: 1.20-5.38) and > 2 siblings, OR = 7.40 (95%CI: 2.20-24.93), remained associated with stunting.


Progestin-binding protein in human benign prostatic hypertrophy.
Cytosols from human benign prostatic hypertrophy contained progestin-binding components which bound to R 5020, ORG 2058 and progesterone in high affinity fashion. Most of the protein bound to R 5020 was recovered in the precipitate with 0-30% saturation of ammonium sulfate. The R 5020-binding protein showed sedimentation coefficients of 3.6S and 8.4S, and was eluted in the void volume of a Sephadex G-200 column. This protein was clearly distinguished from the dihydrotestosterone-binding protein by its precipitability by ammonium sulfate, heat stability and susceptibility to delipidization. R 5020 and ORG 2058 binding were markedly inhibited by the addition of R 1881, therefore, most of the binding to progestin in cytosols from the benign prostatic hypertrophy seems to be also the sites for R 1881. Although nuclear extract by 0.4 M KCl showed R 1881 binding, the extract did not contain the R 5020-binding protein, and this suggested that the progestin-binding protein observed in the cytosols does not seem to be the steroid receptor.


Gain-of-Function Research and the Relevance to Clinical Practice.
The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded.


Jasmonic acid-isoleucine formation in grapevine (Vitis vinifera L.) by two enzymes with distinct transcription profiles.
The plant hormone jasmonic acid (JA) is essential for stress responses and the formation of reproductive organs, but its role in fruit development and ripening is unclear. Conjugation of JA to isoleucine is a crucial step in the JA signaling pathway since only JA-Ile is recognized by the jasmonate receptor. The conjugation reaction is catalyzed by JA-amido synthetases, belonging to the family of Gretchen Hagen3 (GH3) proteins. Here, in vitro studies of two grapevine (Vitis vinifera L. cv Shiraz) GH3 enzymes, VvGH3-7 and VvGH3-9, demonstrated JA-conjugating activities with an overlapping range of amino acid substrates, including isoleucine. Expression studies of the corresponding genes in grape berries combined with JA and JA-Ile measurements suggested a primary role for JA signaling in fruit set and cell division and did not support an involvement of JA in the ripening process. In response to methyl JA (MeJA) treatment, and in wounded and unwounded (distal) leaves, VvGH3-9 transcripts accumulated, indicating a participation in the JA response. In contrast, VvGH3-7 was unresponsive to MeJA and local wounding, demonstrating a differential transcriptional regulation of VvGH3-7 and VvGH3-9. The transient induction of VvGH3-7 in unwounded, distal leaves was suggestive of the involvement of an unknown mobile wound signal.


[Experimental ureteral obstruction and knockout animals].
Obstructive uropathies caused by congenital malformations of the urinary tract are relatively frequent in newborn. These obstructive lesions are the main cause for renal disease in infancy. Most of these uropathies are treated by surgical interventions restoring the drainage function of the urinary tract. Clinically these patients are cured but the question remains wether these patients will develop renal disease in adult life, since it has been recently shown in animal models that transient, neonatal and prenatal, ureteral obstruction induces significant renal deterioration later in life. Except for angiotensin converting enzyme inhibitors that slow down the progression of renal disease, no specific drugs reducing renal fibrosis exist. Animal models of ureteral obstruction have allowed to clearly identify the events leading to tubulointerstitial fibrosis. Furthermore, more recently, the use of ureteral obstruction in genetically engineered animals has shown pro- and anti-fibrotic properties of a large number of molecules. These studies using genetically engineered animals have suggested several new future promising therapeutic directions to treat renal fibrosis.


[A prospective cohort study on injuries among school-age children with and without behavior problems].
To study the annual incidence of injuries and the relationship between behavior problems and injuries among school-age children. A prospective cohort study on injuries for 1-year follow-up period was conducted among 2 005 school-age children selected by cluster sampling from three primary schools in Maanshan city. They subjects were divided into two groups with or without exposure according to behavior problems rated by the Rutter Child Behavior Questionnaire at the beginning of the study. Nonparametric test was performed to analyze the differences in injuries between the two groups of children, and the influential factors for injuries were analyzed with multi-classification ordinal response variable logistic regression model. The overall incidence rate for injuries in school-age children was 42.51%, while among children with and without behavior problems were 64.87% and 38.85%, respectively. There were significant differences between the two groups (u = -6.054, P = 0.000). However, the incidence rates of injuries in school-age children with antisocial (A) behavior, neurotic (N) behavior and mixed (M) behavior were 66.99%, 67.41% and 61.40%, respectively. No significant differences were found among them (u(A,N) = -0.052, P = 0.958; u(A,M) = -0.400, P = 0.689; u(N,M) = -0.364, P = 0.716). Multivariate analysis indicated that injuries in school-age children were associated with children behavior problems, maternal age at childbirth, bad conditions during mother pregnancy, education background of mother, prevention measures for safety at home and the child accompanied to travel between school and home by adults. Behavior problems of children seemed to be the major risk factors for injuries. Children with behavior problems represented a significant risk group for injuries among school-age children. When planning intervention strategies on injuries, behavior problems should be emphasized to ensure optimal effectiveness of intervention.


Cross-cultural validation of the Inventory of School Motivation (ISM): Motivation Orientations of Navajo and Anglo students.
The Motivation Orientation scales of the Inventory of School Motivation (ISM) were validated across Navajo (n = 760) and Anglo (n = 1012) students in the U.S. Confirmatory factor analysis (CFA) supported the 8-factor structure of motivation orientations for the total sample and the Navajo and Anglo subsamples, although Navajo students did not distinguish well between the Effort and Task constructs. However, of 39 survey items, only 30 items were invariant across groups in factor loadings on respective a priori constructs. The findings show that even though the ISM Motivation Orientation scales are applicable to students of different cultural backgrounds, meaningful cross-cultural comparisons should use the 30 items that mean the same to both cultural groups; whereas studies that do not involve cross-cultural comparisons may use the complete version of the scales.


Serum omentin-1, inflammation and carotid atherosclerosis in patients with non-diabetic chronic kidney disease.
Omentin-1 is suggested to affect inversely atherosclerosis (AS). Data about omentin-1 is limited to chronic kidney disease (CKD). Our aim was to examine omentin-1 in non-diabetic CKD patients who are not dialyzed and investigate its relationships with inflammation and carotid AS. We performed a cross-sectional study in 55 non-diabetic CKD patients and 30 healthy controls. Baseline clinical and laboratory data were obtained for all participants. Serum omentin-1 and interleukin-6 (IL-6) levels were measured according to the manufacturer's instructions. Carotic plaque and intima-media thickness (IMT) were assessed by carotid ultrasonography. The homeostasis model assessment of insulin resistance index (HOMA-IR) was used to assess IR. Omentin-1 and IL-6 levels in the patient group were found to be higher than the control group; the differences were statistically significant (p = 0.01 and p = 0.04, respectively). Carotid IMT(mean) was significantly higher in the patient group (p = 0.01). Omentin-1 did not correlate with IL-6 and IMT in the patient group (p = 0.51 and p = 0.76, respectively). In subgroup analysis, omentin-1 levels in patients with carotid plaque were lower than those without carotid plaque (179.5 ± 88.1 ng/ml and 185.9 ± 67.8 ng/ml, respectively). However, the difference was not statistically significant (p = 0.47). We conclude that omentin-1 is higher in not dialyzed non-diabetic CKD and there is no correlation between omentin-1 and IL-6 or carotid IMT(mean).


Preventing Stress-Related Ill Health Among New Registered Nurses by Supporting Engagement in Proactive Behaviors-A Randomized Controlled Trial.
New registered nurses (RNs) are at risk of developing symptoms of stress-related ill health. To evaluate the effect of a 3 × 3 hour group intervention aiming to prevent symptoms of stress-related ill health among new RNs by increasing engagement in proactive behaviors. The intervention involves discussions and models of newcomer experiences and stress and the behavior change techniques reinforcing approach behaviors, systematic exposure, and action planning. A randomized parallel group trial with an active control condition. The study sample consisted of 239 new RNs participating in a transition-to-practice program for new RNs in a large county in Sweden. Participants were randomized to either the experimental intervention or a control intervention. Data on experiences of stress, avoidance of proactive behaviors, engagement in leisure activities, role clarity, task mastery, and social acceptance were collected before and after the intervention. Effects were evaluated using multilevel model analysis and regression analysis. Missing data were imputed using multiple imputation. The control group experienced a statistically significant increase in experiences of stress during the period of the study (t(194.13) = 1.98, p = .049), whereas the level in the experimental group remained stable. Greater adherence to the intervention predicted a greater effect on experiences of stress (β = -0.15, p = .039) and social acceptance (β = 0.16, p = .027). Transition-to-practice programs may benefit from adding an intervention that specifically addresses new RNs' experiences of stress to further support them as they adjust to their new professional role. However, replication studies with larger samples, more reliable measures, and longer periods of follow-up are needed.


Taxation of smokeless tobacco in India.
The role of fiscal policy, especially taxation, though has been proved to be an effective instrument of tobacco control, its application is limited in India due to several reasons. This paper examines the tax structure, price and affordability of SLT products in order to provide evidence on how to strengthen the role of fiscal policy in tobacco control. Secondary data on tax structure and revenue from tobacco products were collected from the Ministry of Finance, Government of India. In order to measure the rise of prices corresponding to the increase in tax rate, the retail price index (RPI) and Whole Price Index (WPI) of SLT products were compared with the price index for all commodities for the period 2006-2012. The affordability of tobacco products is calculated by dividing prices of tobacco products by per capita income. During the last 6 years, the tax rate on SLT has gone up leading to a rise in the prices of SLT products more than the general price rise. However, the price rise is less than the per capita income growth indicating increasing affordability. The study observed a decline in the consumption of zarda and kahini due to the price increase during 2008-2013. However, the decline in the consumption of zarda is less compared with khaini due to a very low rise in its price. The prices should be raised more than the growth in income to influence consumption. Tax administration is a major challenge for SLT products and strengthening it could enhance revenue collection from SLT products.


Comparison of the ESP and BACTEC systems for testing susceptibilities of Mycobacterium tuberculosis complex isolates to pyrazinamide.
Fifty isolates of Mycobacterium tuberculosis complex were tested for susceptibility to pyrazinamide (PZA) by the ESP (Trek Diagnostic Systems, Westlake, Ohio) and BACTEC (BD Biosciences, Sparks, Md.) test systems. Initial results showed concordance for 48 of the isolates. On retest, the two discordant isolates were resolved in favor of the ESP system. The ESP Myco susceptibility test system generates rapid, reliable PZA test results.


Management of octogenarians hospitalized for heart failure in Euro Heart Failure Survey I.
Here, the aim is to study the management of octogenarians hospitalized for heart failure in Euro Heart Failure Survey I. Heart Failure (HF) is common in older people and associated with poor outcome. We compared clinical characteristics, treatment, and short-term outcomes in 2780 octogenarians (group A, median age 85 years) and in 7912 younger patients (group B, median age 69 years) enrolled in the Euro Heart Failure Survey I. There were 37% males in group A vs. 59% in group B (P < 0.001). Co-morbidities were more common in group A. Ejection fraction was measured only in 38% in group A vs. 65% in group B (P < 0.001) and when measured was preserved in 50 vs. 40% (P < 0.001). In-hospital and 12 weeks follow-up mortality were, respectively, 13 vs. 5% (P < 0.001) and 12 vs. 6% (P < 0.001) in groups A and B. Acute cardiac conditions and co-morbidity predicted mortality, whereas the use of angiotensin-converting enzyme inhibitor (ACE-I) and beta-blockers was associated with a better outcome. ACE-I and beta-blockers were used in 50 vs. 66% (P < 0.001) and 24 vs. 42% (P < 0.001) in groups A and B, respectively, whereas diuretics, digitalis, and nitrates were more commonly used in octogenarians. Preserved systolic function, multiple co-morbidities, and high mortality are observed in octogenarians with HF. In these patients, cardiac function is assessed in only a minority and treatments known to improve prognosis in younger patients under-utilized. Overall, the management of octogenarians with HF does not follow international guidelines.


[Epidemiological aspects of human and animal rabies in the urban area of Bamako, Mali].
The district of Bamako is the political and economical capital city of Mali with 1,800,000 inhabitants. The goal of the present retrospective study was to determine the frequency of animal bites, human and animal rabies on the one hand and to determine the frequency and the nature of mad animals on the other hand from January 2000 to December 2003 (4 years). To achieve this goal, we have analysed registers and documents related to rabies in the department of prevention and fight against diseases, the central veterinary laboratory, and also at the lazaret clinic involved in caring for human rabies cases. Human rabies diagnosis has been brought up based upon the following clinical arguments: agitation and lethal hydrophobia within few days following bites by known or unknown animal. Agitation and aggressiveness followed by the animals' death within an observation period of 15 days maximum, allowed to evoke the diagnosis in animals. In Bamako an average of 1470 persons have been bitten each year. In 97.1% of the cases, the mad animal was a dog; cats (1.6%), donkeys, horses, cattle and rats (1.4%) have also been identified on a total of 5870 cases of notified human bites by animals; 10 cases of notified human rabies have been recorded. The dog has been incriminated in 6 cases of human rabies out of 10, in the 4 other cases, it has not been possible to identify the mad animal. Among the 3924 mad animals in observation at the veterinary clinic, 187 have been clinically mad that is 4.8%. The rabies virus has also been researched by direct immunofluorescence in 121 specimens of dead mad animals brain. This research has been positive in 119 cases among which 116 dogs, 2 sheep and 1 cow. Anyway the vaccinal status of people bitten by mad animals has not been clearly established. According to these results, we recommend the implementation of a national specific program to eradicate rabies in Bamako.


Humpback whale "super-groups" - A novel low-latitude feeding behaviour of Southern Hemisphere humpback whales (Megaptera novaeangliae) in the Benguela Upwelling System.
Southern Hemisphere humpback whales (Megaptera novaeangliae) generally undertake annual migrations from polar summer feeding grounds to winter calving and nursery grounds in subtropical and tropical coastal waters. Evidence for such migrations arises from seasonality of historic whaling catches by latitude, Discovery and natural mark returns, and results of satellite tagging studies. Feeding is generally believed to be limited to the southern polar region, where Antarctic krill (Euphausia superba) has been identified as the primary prey item. Non-migrations and / or suspended migrations to the polar feeding grounds have previously been reported from a summer presence of whales in the Benguela System, where feeding on euphausiids (E. lucens), hyperiid amphipods (Themisto gaudichaudii), mantis shrimp (Pterygosquilla armata capensis) and clupeid fish has been described. Three recent research cruises (in October/November 2011, October/November 2014 and October/November 2015) identified large tightly-spaced groups (20 to 200 individuals) of feeding humpback whales aggregated over at least a one-month period across a 220 nautical mile region of the southern Benguela System. Feeding behaviour was identified by lunges, strong milling and repetitive and consecutive diving behaviours, associated bird and seal feeding, defecations and the pungent "fishy" smell of whale blows. Although no dedicated prey sampling could be carried out within the tightly spaced feeding aggregations, observations of E. lucens in the region of groups and the full stomach contents of mantis shrimp from both a co-occurring predatory fish species (Thyrsites atun) and one entangled humpback whale mortality suggest these may be the primary prey items of at least some of the feeding aggregations. Reasons for this recent novel behaviour pattern remain speculative, but may relate to increasing summer humpback whale abundance in the region. These novel, predictable, inter-annual, low latitude feeding events provide considerable potential for further investigation of Southern Hemisphere humpback feeding behaviours in these relatively accessible low-latitude waters.


An MEC-MFC-coupled system for biohydrogen production from acetate.
Microbial fuel cells (MFCs) are devices that use bacteria as the catalysts to oxidize organic and inorganic matter and generate current whereas microbial electrolysis cells (MECs) are a reactor for biohydrogen production by combining MFC and electrolysis. In an MEC, an external voltage must be applied to overcome the thermodynamic barrier. Here we report an MEC-MFC-coupled system for biohydrogen production from acetate, in which hydrogen was produced in an MEC and the extra power was supplied by an MFC. In this coupled system, hydrogen was produced from acetate without external electric power supply. At 10 mM of phosphate buffer, the hydrogen production rate reached 2.2 +/- 0.2 mL L(-1) d(-1), the cathodic hydrogen recovery (RH2) and overall systemic Coulombic efficiency (CEsys) were 88 to approximately 96% and 28 to approximately 33%, respectively, and the overall systemic hydrogen yield (Y(sysH2)) peaked at 1.21 mol-H2 mol-acetate(-1). The hydrogen production was elevated by increasing the phosphate buffer concentration, and the highest hydrogen production rate of 14.9 +/- 0.4 mL L(-1) d(-1) and Y(sysH2) of 1.60 +/- 0.08 mol-H2 mol-acetate(-1) were achieved at 100 mM of phosphate buffer. The performance of the MEC and the MFC was influenced by each other. This MEC-MFC-coupled system has a potential for biohydrogen production from wastes, and provides an effective way for in situ utilization of the power generated from MFCs.


Enhancing EFL students' critical thinking skills using a technology-mediated self-study approach: EFL graduates and labor market in perspective.
This research project bridges the gap between Saudi Vision 2030 and labor market needs by strengthening English as a Foreign Language (EFL) students' critical thinking skills. The increasing unemployment rates may not be due to insufficient vacancies in the labor market, but graduates' lack of the general abilities deemed vital to meet the labor market needs. With employability in mind, this study reiterates that graduates should ideally be advanced specialists, critical researchers, creative initiators, and active communicators to be more competitive and contribute to the prosperity of their nation. Therefore, this research employs a quasi-experimental design (time series design) to investigate how effectively students' critical thinking skills are enriched using a video-mediated self-study program through Telegram. Studies in this respect, regarding the Saudi EFL context, are limited. Therefore, this research employed a video-mediated self-study program through Telegram on learning critical thinking skills for EFL students majoring in English or Translation. The data collection included a pre-and post-test on critical thinking skills and a semi-structured interview. The findings showed that students improved their critical thinking skills due to the training program compared to their performance before the treatment at a low level. Besides, the participants evaluated learning critical thinking skills from thinking ways, feelings, benefits, motivation, challenges and problems, and suggestions. In light of the findings, recommendations were presented.


Epidemiology of West Nile infection in Volgograd, Russia, in relation to climate change and mosquito (Diptera: Culicidae) bionomics.
In 1999, there was the large outbreak of West Nile fever (WNF) in Southern Russia (>500 cases in the Volgograd Province). In 2000-2004, the WNF incidence rate decreased steadily to zero, but a new outbreak occurred in 2007 (64 cases). The analysis of historical climate data for Volgograd from 1900 to present showed that the years 1999 and 2007 were the hottest ones due to a very mild "winter" (Dec.-Mar.) and a hot "summer" (June-Sep.). There are up to 15 potential WNF vectors in Volgograd, but only Culex pipiens and Culex modestus are abundant in late summer, both in urban and rural settings. Only these species are naturally attracted to and feed on both humans and birds. The RNA of pathogenic WN virus genovariant was found by reverse transcriptase polymerase chain reaction only in Culex mosquitoes at the infection rate of about 0.04%. So these species may be considered as potential WNF "bridge vectors" between birds and humans as well as main vectors in sylvatic avain cycle. Their abundance in an epidemic season was higher in the years with a mild winter and a hot summer, so this phenomenon may serve as a connecting link between a climate and WNF epidemiology. These findings give some hints on the predisposing factors for WNF epidemic as well as the possibility to predict WNF outbreaks in the temperate climate zones.


Evidence of a central inhibition of growth hormone secretion by calcitonin gene-related peptide.
The effects of intracerebroventricular or intracarotid injection of synthetic rat calcitonin gene-related peptide (CGRP) on growth hormone (GH) secretion induced by various stimuli in male rats were examined. CGRP (2.5 or 5 micrograms/rat intracerebroventricularly, i.c.v.) was administered 10 min before beta-endorphin (0.5 microgram/rat i.c.v.) or morphine (1 mg/kg intracarotidly, i.a.) or clonidine (0.25 mg/kg i.a.) or GH-releasing hormone (GHRH1-40; 2 micrograms/kg i.a.). When injected peripherally, CGRP (10 micrograms/rat, i.a.) was administered 5 min before morphine or GHRH. To investigate the possible involvement of somatostatin (SRIF) in the inhibition of GH secretion by CGRP, the effect of the peptide on GHRH-induced GH release was also examined in rats with hypothalamic SRIF depletion obtained by pretreatment (4 h before) with cysteamine (300 mg/kg subcutaneously). Blood samples for hormone determination were drawn from freely moving rats at various times before and after drug treatment. The intracerebroventricular administration of CGRP (5 micrograms/rat) significantly inhibited GH secretion induced by all the stimuli used. In rats with SRIF depletion CGRP did not modify the stimulation of GH by GHRH. When CGRP was administered intracarotidly, even the dose of 10 micrograms/rat did not reduce the GH release induced by GHRH or morphine. The effects of intracerebroventricular CGRP on basal or beta-endorphin-induced prolactin release were also examined. When given intracerebroventricularly, the peptide did not modify prolactin secretion. The present results indicate that CGRP has a central inhibitory role in the control of GH secretion, probably through a stimulation of SRIF release.


CASE REPORT: Serial Cases of False-Positive Flow-Cytometry T Cell Crossmatch Associated With Anti-Blood Type Antibodies in Patients Undergoing ABO-Incompatible Kidney Transplantation.
A positive flow-cytometry T cell crossmatch (FTXM) has important prognostic implications, even when the complement-dependent cytotoxicity crossmatch is negative. Recent studies have shown that ABO incompatibility is associated with positive FTXM, but the underlying mechanism remains poorly understood. In five ABO blood type O recipients of kidneys from wives with type B, FTXM was positive but complement-dependent cytotoxicity crossmatch was negative. Application of a solid-phase technique (LABScreen) revealed no case with antibodies to donor-specific human leukocyte antigen. After removal of type B antibodies from patient sera, FTXM was negative for all five patients. In one tested case, the eluate prepared from the donor's T lymphocyte agglutinated only type B red blood cells, implying the existence of blood type B substances on donor T lymphocytes. False-positive FTXM reflects blood type B substrates bound to T lymphocytes. Repeat FTXM after incubation with donor-type red blood cells (to adsorb anti-ABO antibodies) was negative. This phenomenon explains the discrepancy between FTXM and solid-phase bead assays. Demonstration of type B substances on donor T lymphocytes is necessary before absolute test validity is confirmed. False-positive FTXM may be associated with type B antibodies bound to T lymphocytes when a blood type O recipient receives tissue from a type B donor. This phenomenon explains the false-positive FTXM observed in the setting of ABO-incompatible kidney transplantation.


Cyclospora infection in adults infected with HIV. Clinical manifestations, treatment, and prophylaxis.
To determine the prevalence and clinical manifestations of Cyclospora in Haitians infected with human immunodeficiency virus (HIV) who have diarrhea and to evaluate therapy and prophylaxis. Cohort study. From 1990 to 1993, stool samples were collected from adults seropositive for HIV who had had diarrhea for at least 3 weeks. A clinic in Haiti. Stool samples were examined for enteric protozoa after acid-fast staining. Patients with Cyclospora infection were treated with trimethoprimsulfamethoxazole (160 mg and 800 mg, respectively) given orally four times a day for 10 days. After completion of therapy, patients were evaluated weekly and re-treated if clinical and parasitologic recurrences occurred, followed by trimethoprim-sulfamethoxazole prophylaxis three times a week. 804 of 2400 patients (33%) seropositive for HIV had a history of chronic or intermittent diarrhea; 502 of these 804 patients (62%) currently had diarrhea, and 450 patients each provided two stool specimens for examination. Enteric protozoa identified included Cryptosporidium (30%), Isospora belli (12%), Cyclospora species (11%), Giardia lamblia (3%), and Entamoeba histolytica (1%). Forty-three patients with diarrhea and Cyclospora infection were studied; their symptoms were indistinguishable from those seen in patients with isosporiasis or cryptosporidiosis. In all patients, diarrhea ceased and results from stool examinations were negative within 2.5 days after beginning oral trimethoprim-sulfamethoxazole therapy. Recurrent symptomatic cyclosporiasis developed in 12 of 28 patients (43%) followed for 1 month or more, but it also responded promptly to trimethoprim-sulfamethoxazole therapy. These 12 patients received trimethoprim-sulfamethoxazole three times a week as secondary prophylaxis, with only a single recurrence after 7 months. Cyclospora infection is common in Haitian patients with HIV infection, responds to trimethoprim-sulfamethoxazole therapy, and has a high recurrence rate that can be largely prevented with long-term trimethoprim-sulfamethoxazole prophylaxis.


Pre- and post-surgery treatments in rectal cancer: a long-term single-centre experience.
Our study evaluated long-term survival outcomes in rectal cancer patients treated with preoperative radiotherapy, and the impact on survival of concomitant and postoperative adjuvant chemotherapy (ctx), among other prognostic factors. The study included 196 patients [median age: 58 years (range: 20-86 years); 63.0% men] with locally advanced rectal carcinoma and, in some cases, resectable liver metastasis. Rates of distant metastasis and local recurrence and of 5-year distant metastasis-free survival (dmfs) and overall survival (os) were determined. The 5-year os rate was 57.0%, with a median duration of 81.5 months (95% confidence interval: 73.7 months to 89.4 months), and the 5-year dmfs rate was 54.1%, with a median duration of 68.4 months (95% confidence interval: 40.4 months to 96.4 months). Prognostic factors for higher os and dmfs rates were downstaging (p = 0.013 and p = 0.005 respectively), radiotherapy dose (50 Gy vs. 56 Gy or 45-46 Gy, both p = 0.002), and concomitant ctx use (p = 0.004 and p = 0.001) and type (5-fluorouracil-leucovorin-folinic acid vs. tegafur-folinic acid, p = 0.034 and p = 0.043). Adjuvant ctx after neoadjuvant long-term concomitant chemoradiotherapy (ccrt) and surgery was associated with better 5-year os rates for postoperative T0-T3 disease (p = 0.003) and disease at all lymph node stages (p = 0.001). Our findings revealed a favourable survival outcome with long-term fractionated irradiation and concomitant 5-fluorouracil-based ctx, achieving 5-year os and dmfs rates of 57.0% and 54.1% respectively. Preoperative administration of radiotherapy (50 Gy) and postoperative adjuvant ctx were associated with a significant survival benefit. Radiation doses above 50 Gy and the interval between ccrt and surgery had no significant effect on survival.


Emerging Advances to Transform Histopathology Using Virtual Staining.
In an age where digitization is widespread in clinical and preclinical workflows, pathology is still predominantly practiced by microscopic evaluation of stained tissue specimens affixed on glass slides. Over the last decade, new high throughput digital scanning microscopes have ushered in the era of digital pathology that, along with recent advances in machine vision, have opened up new possibilities for Computer-Aided-Diagnoses. Despite these advances, the high infrastructural costs related to digital pathology and the perception that the digitization process is an additional and nondirectly reimbursable step have challenged its widespread adoption. Here, we discuss how emerging virtual staining technologies and machine learning can help to disrupt the standard histopathology workflow and create new avenues for the diagnostic paradigm that will benefit patients and healthcare systems alike via digital pathology.


Topology-Based Functionalization of Robust Chiral Zr-Based Metal-Organic Frameworks for Catalytic Enantioselective Hydrogenation.
The design and development of robust and porous supported catalysts with high activity and selectivity is extremely significant but very challenging for eco-friendly synthesis of fine chemicals and pharmaceuticals. We report here the design and synthesis of highly stable chiral Zr(IV)-based MOFs with different topologies to support Ir complexes and demonstrate their network structures-dependent asymmetric catalytic performance. Guided by the modulated synthesis and isoreticular expansion strategy, five chiral Zr-MOFs with a flu or ith topology are constructed from enantiopure 1,1'-biphenol-derived tetracarboxylate linkers and Zr6, Zr9, or Zr12 clusters. The obtained MOFs all show high chemical stability in boiling water, strongly acidic, and weakly basic aqueous solutions. The two flu MOFs featuring the dihydroxyl groups of biphenol in open and large cages, after sequential postsynthetic modification with P(NMe2)3 and [Ir(COD)Cl]2, can be highly efficient and recyclable heterogeneous catalysts for hydrogenation of α-dehydroamino acid esters with up to 98% ee, whereas the three ith MOFs featuring the dihydroxyl groups in small cages cannot be installed with P(NMe2)3 to support the Ir complex. Incorporation of Ir-phosphorus catalysts into Zr-MOFs leads to great enhancement of their chemical stability, durability, and even stereoselectivity. This work therefore not only advances Zr-MOFs as stable supports for labile metal catalysts for heterogeneous asymmetric catalysis but also provides a new insight into how highly active chiral centers can result due to the framework topology.


Structural analysis of the Escherichia coli K-12 hisT operon by using a kanamycin resistance cassette.
We constructed a series of recombinant plasmids containing a kanamycin resistance (Kmr) cassette upstream from, within, and downstream from hisT, which encodes the tRNA modification enzyme pseudouridine synthase I. These Kmr insertions were then crossed directly into the bacterial chromosome. We determined growth characteristics, assayed in vivo hisT expression, and mapped in vivo hisT operon transcripts for the Kmr insertion mutants. We also analyzed polypeptides synthesized in minicells from plasmids containing Kmr cassettes. The combined results from these experiments demonstrate new features concerning the structure and expression of the complex operon that contains hisT. We show that the minimum size of the operon is approximately 3,500 base pairs and that it contains at least four genes, which are arranged in the order usg-2 (pdxB), usg-1, hisT, and dsg-1 and encode polypeptides with apparent molecular masses of 42,000, 45,000, 31,000, and 17,000 daltons, respectively. Of these genes, only the functions of usg-2 (pdxB) and hisT are known, and genetic evidence suggests that these two genes do not require usg-1 or dsg-1 for function, usg-2 (pdxB) is required for growth of bacteria on minimal medium at 37 degrees C. In contrast, the three genes at the end of the hisT operon are dispensable and form a transcription unit that is expressed from a relatively strong internal promoter. The phenotypes of the Kmr insertion mutants and results from gene expression experiments further confirm the position of the internal promoter and locate additional genetic signals in the DNA sequence around hisT. The experiments reported here also indicate several interesting properties of the Kmr cassette as a tool for probing complex operons.


Ultrasensitive Detection of Biomarkers by Using a Molecular Imprinting Based Capacitive Biosensor.
The ability to detect and quantitate biomolecules in complex solutions has always been highly sought-after within natural science; being used for the detection of biomarkers, contaminants, and other molecules of interest. A commonly used technique for this purpose is the Enzyme-linked Immunosorbent Assay (ELISA), where often one antibody is directed towards a specific target molecule, and a second labeled antibody is used for the detection of the primary antibody, allowing for the absolute quantification of the biomolecule under study. However, the usage of antibodies as recognition elements limits the robustness of the method; as does the need of using labeled molecules. To overcome these limitations, molecular imprinting has been implemented, creating artificial recognition sites complementary to the template molecule, and obsoleting the necessity of using antibodies for initial binding. Further, for even higher sensitivity, the secondary labeled antibody can be replaced by biosensors relying on the capacitance for the quantification of the target molecule. In this protocol, we describe a method to rapidly and label-free detect and quantitate low-abundant biomolecules (proteins and viruses) in complex samples, with a sensitivity that is significantly better than commonly used detection systems such as the ELISA. This is all mediated by molecular imprinting in combination with a capacitance biosensor.


Blood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma.
Infiltrating tumor-associated macrophages (TAM) are known to impede immunotherapy against glioblastoma (GBM), however, TAMs are heterogeneous, and there are no clear markers to distinguish immunosuppressive and potentially immune-activating populations. Here we identify a subset of CD169+ macrophages promoting an anti-tumoral microenvironment in GBM. Using single-cell transcriptome analysis, we find that CD169+ macrophages in human and mouse gliomas produce pro-inflammatory chemokines, leading to the accumulation of T cells and NK cells. CD169 expression on macrophages facilitates phagocytosis of apoptotic glioma cells and hence tumor-specific T cell responses. Depletion of CD169+ macrophages leads to functionally impaired antitumor lymphocytes and poorer survival of glioma-bearing mice. We show that NK-cell-derived IFN-γ is critical for the accumulation of blood monocyte-derived CD169+ macrophages in gliomas. Our work thus identifies a well-distinguished TAM subset promoting antitumor immunity against GBM, and identifies key factors that might shift the balance from immunosuppressive to anti-tumor TAM.


Improvement of tactile discrimination performance and enlargement of cortical somatosensory maps after 5 Hz rTMS.
Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to investigate mechanisms of brain functions and plasticity, but also as a promising new therapeutic tool. The effects of rTMS depend on the intensity and frequency of stimulation and consist of changes of cortical excitability, which often persists several minutes after termination of rTMS. While these findings imply that cortical processing can be altered by applying current pulses from outside the brain, little is known about how rTMS persistently affects learning and perception. Here we demonstrate in humans, through a combination of psychophysical assessment of two-point discrimination thresholds and functional magnetic resonance imaging (fMRI), that brief periods of 5 Hz rTMS evoke lasting perceptual and cortical changes. rTMS was applied over the cortical representation of the right index finger of primary somatosensory cortex, resulting in a lowering of discrimination thresholds of the right index finger. fMRI revealed an enlargement of the right index finger representation in primary somatosensory cortex that was linearly correlated with the individual rTMS-induced perceptual improvement indicative of a close link between cortical and perceptual changes. The results demonstrate that repetitive, unattended stimulation from outside the brain, combined with a lack of behavioral information, are effective in driving persistent improvement of the perception of touch. The underlying properties and processes that allow cortical networks, after being modified through TMS pulses, to reach new organized stable states that mediate better performance remain to be clarified.


Genetic diversity of the pandemic influenza A (H1N1) virus in Saudi Arabia.
Pandemic influenza A (H1N1) virus emerged and spread globally in the spring of 2009. Saudi Arabia also witnessed a severe H1N1 pandemic virus epidemic with considerable morbidity and mortality in different parts of the kingdom beginning in June 2009. The influenza A(H1N1)pdm09 virus was detected in samples collected between May 2009 and November 2010 from Makkah region. This study provides data on the viral diagnosis and genetic diversity of hemagglutinin (HA) and neuraminidase (NA) genes of influenza A (H1N1)pdm09 virus from Saudi Arabia. Nasopharyngeal swabs from 100 clinically infected patients in the peak of the outbreak were collected from Makkah region and processed for viral diagnosis by viral culture and real-time polymerase chain reaction (PCR). HA and NA genes of 10 selected samples were sequenced and analyzed. A total of 100 samples were collected; only 10 samples were found to be positive for influenza A virus infection by real-time PCR. Nucleotide sequence analysis of the HA and NA genes of influenza A (H1N1) from Saudi Arabia showed significant similarities with selected isolates. The phylogenetic tree constructed for both HA and NA genes formed close clusters with selected reference isolates. Nucleotide sequence analysis and phylogenetic relationships of the HA and NA genes of influenza A (H1N1) virus from Saudi Arabia with selected reference isolates indicates that they were genetically close and most probably originated from influenza A(H1N1)pdm09.


Analysis of problem types and difficulty among older stroke caregivers.
Stroke onset causes disruption of family roles as caregiving tasks are assumed. The current study presents a qualitative and quantitative analysis of the problems of 123 older, spousal stroke caregivers. Problems were coded into 14 categories; frequencies of occurrence and difficulty were also analyzed. Differences in problem difficulties were examined by race, gender, years caregiving, and care receiver's functional level, depression, burden, and loneliness. Noncompliance was the least frequent but most difficult problem type. Lack of social involvement was the most frequent problem type and the most difficult for the more depressed, burdened, and lonely caregivers. This increase in problem specificity and detail of analysis has provided direction for clinical application in counseling the spouses of stroke survivors on how to manage the stress of their new life role.


Multiomic Approaches for Cancer Biomarker Discovery in Liquid Biopsies: Advances and Challenges.
Cancer is a complex and heterogeneous disease that poses a significant threat to global health. Early diagnosis and treatment are critical for improving patient outcomes, and the use of liquid biopsies has emerged as a promising approach for cancer detection and monitoring. Traditionally, cancer diagnosis has relied on invasive tissue biopsies, the collection of which can prove challenging for patients and the results of which may not always provide accurate results due to tumor heterogeneity. Liquid biopsies have gained increasing attention as they provide a non-invasive and accessible source of cancer biomarkers, which can be used to diagnose cancer, monitor treatment response, and detect relapse. The integration of -omics technologies, such as proteomics, genomics, and metabolomics, has further enhanced the capabilities of liquid biopsies by introducing precision oncology and enabling the tailoring of treatment for individual patients based on their unique tumor biology. In this review, we will discuss the challenges and advances in the field of cancer liquid biopsies and the integration of -omics technologies for different types of liquid biopsies, including blood, tear, urine, sweat, saliva, and cerebrospinal fluid.


Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome.
The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/β-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in β-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of β-catenin were inactivated in the Mef2c-AHF-Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, β-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS.


Red Blood Cell Dysfunction Induced by High-Fat Diet: Potential Implications for Obesity-Related Atherosclerosis.
High-fat diet (HFD) promotes endothelial dysfunction and proinflammatory monocyte activation, which contribute to atherosclerosis in obesity. We investigated whether HFD also induces the dysfunction of red blood cells (RBCs), which serve as a reservoir for chemokines via binding to Duffy antigen receptor for chemokines (DARC). A 60% HFD for 12 weeks, which produced only minor changes in lipid profile in C57/BL6 mice, markedly augmented the levels of monocyte chemoattractant protein-1 bound to RBCs, which in turn stimulated macrophage migration through an endothelial monolayer. Levels of RBC-bound KC were also increased by HFD. These effects of HFD were abolished in DARC(-/-) mice. In RBCs from HFD-fed wild-type and DARC(-/-) mice, levels of membrane cholesterol and phosphatidylserine externalization were increased, fostering RBC-macrophage inflammatory interactions and promoting macrophage phagocytosis in vitro. When labeled ex vivo and injected into wild-type mice, RBCs from HFD-fed mice exhibited ≈3-fold increase in splenic uptake. Finally, RBCs from HFD-fed mice induced increased macrophage adhesion to the endothelium when they were incubated with isolated aortic segments, indicating endothelial activation. RBC dysfunction, analogous to endothelial dysfunction, occurs early during diet-induced obesity and may serve as a mediator of atherosclerosis. These findings may have implications for the pathogenesis of atherosclerosis in obesity, a worldwide epidemic.


Observing the intrinsic linewidth of a quantum-cascade laser: beyond the Schawlow-Townes limit.
A comprehensive investigation of the frequency-noise spectral density of a free-running midinfrared quantum-cascade laser is presented for the first time. It provides direct evidence of the leveling of this noise down to a white-noise plateau, corresponding to an intrinsic linewidth of a few hundred hertz. The experiment is in agreement with the most recent theory on the fundamental mechanism of line broadening in quantum-cascade lasers, which provides a new insight into the Schawlow-Townes formula and predicts a narrowing beyond the limit set by the radiative lifetime of the upper level.


Ureaplasma bacteremia in very low birth weight infants in Brazil.
To determine the prevalence of Ureaplasma urealyticum and Ureaplasma parvum bacteremia in very low birth weight (VLBW) infants and to evaluate the associated factors. Ninety-five VLBW newborns with gestational age ≤32 weeks were included in the study conducted between March 2009 and July 2010. DNA was extracted from the blood samples collected during the first 72 hours of life, and U. urealyticum and/or U. parvum were identified by polymerase chain reaction. The newborns were followed up until hospital discharge. The prevalence of U. urealyticum and/or U. parvum bacteremia was 12.6% (12 cases): 5 (5.2%) for U. urealyticum, 5 (5.2%) for U. parvum, and 2 (2.1%) for both. Based on the univariate analysis, the presence of Ureaplasma was associated with clinical chorioamnionitis and spontaneous preterm labor. Preeclampsia and small for gestational age were associated with lower incidence of Ureaplasma. When spontaneous preterm labor was present, the prevalence of Ureaplasma bacteremia was 25%. Only spontaneous preterm labor was a statistically significant factor after step-by-step logistic regression analysis (P = 0.006), with 9-fold increase in chance of neonatal Ureaplasma bacteremia. Ureaplasma bacteremia is common in VLBW infants, especially among those born after preterm labor.


Pyomyositis presenting as septic arthritis. A report of 2 cases.
Two cases of pyogenic infection of skeletal muscle presented in a fashion that initially suggested a diagnosis of septic arthritis. One infection was caused by Staphylococcus aureus, but the other was caused by Streptococcus pyogenes, which is rarely implicated in pyomyositis. We note that the number of reported cases of pyomyositis in temperate climates has increased in recent years.


Distinct functions of Crumbs regulating slit diaphragms and endocytosis in Drosophila nephrocytes.
Mammalian podocytes, the key determinants of the kidney's filtration barrier, differentiate from columnar epithelial cells and several key determinants of apical-basal polarity in the conventional epithelia have been shown to regulate podocyte morphogenesis and function. However, little is known about the role of Crumbs, a conserved polarity regulator in many epithelia, for slit-diaphragm formation and podocyte function. In this study, we used Drosophila nephrocytes as model system for mammalian podocytes and identified a conserved function of Crumbs proteins for cellular morphogenesis, nephrocyte diaphragm assembly/maintenance, and endocytosis. Nephrocyte-specific knock-down of Crumbs results in disturbed nephrocyte diaphragm assembly/maintenance and decreased endocytosis, which can be rescued by Drosophila Crumbs as well as human Crumbs2 and Crumbs3, which were both expressed in human podocytes. In contrast to the extracellular domain, which facilitates nephrocyte diaphragm assembly/maintenance, the intracellular FERM-interaction motif of Crumbs is essential for regulating endocytosis. Moreover, Moesin, which binds to the FERM-binding domain of Crumbs, is essential for efficient endocytosis. Thus, we describe here a new mechanism of nephrocyte development and function, which is likely to be conserved in mammalian podocytes.


A general survey of blood and tissue parasites of some rodents in Arbil province, Iraq.
In a survey of blood and tissue parasites from 233 mice and rats, consisting of 105 specimens of house mice (Mus musculus), 99 black rats (Rattus rattus), and 29 Norway rats (Rattus norvegicus), collected from different localities of Arbil province, northern Iraq, Trypanosoma lewisi was found in 7 (7.07%) of 99 R. rattus and in 5 (17.86%) of 29 R. norvegicus, while Trypanosoma musculi was found in 4 (3.80%) of 105 M. musculus and this is the first record of this trypanosome from rodents in Iraq. During the preparation of tissue impression smears we came across 2 specimens of Fasciola hepatica in the livers of 2 R. norvegicus and the incidence of infection was 6.89%. Examination of other organs revealed no parasites. F. hepatica which is recorded, in the present study, for the first time from rodents in Iraq, is of particular importance since it infects both humans and domestic animals.


Velocity encoding versus acceleration encoding for pressure gradient estimation in MR haemodynamic studies.
Many methods have been proposed to extract pressure gradient maps from magnetic resonance (MR) images. They were based on the resolution of the haemodynamic model of Navier-Stokes and needed the flow acceleration to be known. Most used velocity data acquisition and computed acceleration from temporal and spatial derivatives of the velocity field. However, MR sequences have been developed in order to acquire the acceleration field directly. Here we compared direct MR measurements of acceleration field components with those calculated from MR velocity acquisitions. Two experimental phantoms were used to separately evaluate the inertial and convective components of the acceleration. Mathematical simulation of the convective phantom further explained the origin of the noise generated by the spatial and temporal derivatives of the velocity data, and the misregistration artefacts due to MR sequences. We found that direct measurement of the acceleration field generates less noise and fewer artefacts than calculation from velocity derivatives.