The planetary biology of cytochrome P450 aromatases.
Joining a model for the molecular evolution of a protein family to the paleontological and geological records (geobiology), and then to the chemical structures of substrates, products, and protein folds, is emerging as a broad strategy for generating hypotheses concerning function in a post-genomic world. This strategy expands systems biology to a planetary context, necessary for a notion of fitness to underlie (as it must) any discussion of function within a biomolecular system. Here, we report an example of such an expansion, where tools from planetary biology were used to analyze three genes from the pig Sus scrofa that encode cytochrome P450 aromatases-enzymes that convert androgens into estrogens. The evolutionary history of the vertebrate aromatase gene family was reconstructed. Transition redundant exchange silent substitution metrics were used to interpolate dates for the divergence of family members, the paleontological record was consulted to identify changes in physiology that correlated in time with the change in molecular behavior, and new aromatase sequences from peccary were obtained. Metrics that detect changing function in proteins were then applied, including KA/KS values and those that exploit structural biology. These identified specific amino acid replacements that were associated with changing substrate and product specificity during the time of presumed adaptive change. The combined analysis suggests that aromatase paralogs arose in pigs as a result of selection for Suoidea with larger litters than their ancestors, and permitted the Suoidea to survive the global climatic trauma that began in the Eocene. This combination of bioinformatics analysis, molecular evolution, paleontology, cladistics, global climatology, structural biology, and organic chemistry serves as a paradigm in planetary biology. As the geological, paleontological, and genomic records improve, this approach should become widely useful to make systems biology statements about high-level function for biomolecular systems.


Norepinephrine Transporter in Major Depressive Disorder: A PET Study.
The norepinephrine transporter has been suggested to play a crucial role in major depressive disorder. However, norepinephrine transporter availability in major depressive disorder and its role with clinical symptoms are not known. The authors tested norepinephrine transporter availability in patients with major depressive disorder with the aim to identify any associations between test results and clinical symptoms. The present research was a cross-sectional study in which 19 patients with major depressive disorder and 19 age- and sex-matched healthy comparison subjects underwent positron emission tomography scanning to evaluate the norepinephrine transporter availability measured by the radioligand (S,S)-[18F]FMeNER-D2. Norepinephrine transporter availability in the thalamus and its subregions was quantified in terms of nondisplaceable binding potential (BPND). The authors also analyzed the association between norepinephrine transporter availability and clinical symptoms. Compared with healthy subjects, patients with major depressive disorder showed 29.0% higher BPND values in the thalamus and, in particular, 28.2% higher values in the thalamic subregion anatomically connected to the prefrontal cortex. Elevated norepinephrine transporter availability in the thalamus in patients was positively correlated with attention, as measured by the Trail Making Test, part A. These findings revealed altered norepinephrine transmission in patients with major depressive disorder, suggesting that this alteration could be related to attention in this patient population.


The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children.
There is a lack of information on prevalence, cause and consequences of slight/mild bilateral sensorineural hearing loss (SNHL) in children. We report the first systematic genetic analysis of the GJB2 gene in a population-derived sample of children with slight/mild bilateral SNHL. Hearing tests were conducted in 6240 Australian elementary school children in Grades 1 and 5. 55 children (0.88%) were found to have a slight/mild sensorineural hearing loss. 48 children with slight/mild sensorineural hearing loss and a matched group of 90 children with normal hearing participated in a genetic study investigating mutations in the GJB2 gene, coding for connexin 26, and the presence of the del(GJB6-D13S1830) and del(GJB6-D13S1854) deletions in the GJB6 gene, coding for connexin 30. Four of 48 children with slight/mild sensorineural hearing loss were homozygous for the GJB2 V37I change. The four children with homozygous V37I mutations were all of Asian background and analysis of SNPs in or near the GJB2 gene suggests that the V37I mutation arose from a single mutational event in the Asian population. Based on the prevalence of carriers of this change we conclude that V37I can be a causative mutation that is often associated with slight/mild sensorineural hearing loss. No other children in the slight/mild hearing loss group had a hearing loss related to a GJB2 mutation. One child with normal hearing was homozygous for the R127H change and we conclude that this change does not cause hearing loss. Two children of Asian background were carriers of the V37I mutation. Our data indicate that slight/mild sensorineural hearing loss due to the GJB2 V37I mutation is common in people of Asian background.


[Alcohol consumption, income and education in Norway, 1993-2000].
We have studied the trend in alcohol consumption by socio-economic status in Norway over the 1993-2000 period. Have differences in consumption been stable over time, or have they levelled off? Our analysis is based on self-reported data from 6894 persons, stratified by year, sex, age, level of education, level of income, and where in Norway they lived. Bivariate and multiple analyses were performed. Alcohol consumption increased in all socio-economic groups over this period. Men consumed more than women; consumption increased with level of education and level of income. Income and level of education predicted alcohol consumption about equally well. The Oslo area had the highest consumption. Alcohol consumption has increased in all socio-economic groups. It increases with level of education and higher income; men consume more than women.


Leaf Movements of Indoor Plants Monitored by Terrestrial LiDAR.
Plant leaf movement is induced by some combination of different external and internal stimuli. Detailed geometric characterization of such movement is expected to improve understanding of these mechanisms. A metric high-quality, non-invasive and innovative sensor system to analyze plant movement is Terrestrial LiDAR (TLiDAR). This technique has an active sensor and is, therefore, independent of light conditions, able to obtain accurate high spatial and temporal resolution point clouds. In this study, a movement parameterization approach of leaf plants based on TLiDAR is introduced. For this purpose, two Calathea roseopicta plants were scanned in an indoor environment during 2 full-days, 1 day in natural light conditions and the other in darkness. The methodology to estimate leaf movement is based on segmenting individual leaves using an octree-based 3D-grid and monitoring the changes in their orientation by Principal Component Analysis. Additionally, canopy variations of the plant as a whole were characterized by a convex-hull approach. As a result, 9 leaves in plant 1 and 11 leaves in plant 2 were automatically detected with a global accuracy of 93.57 and 87.34%, respectively, compared to a manual detection. Regarding plant 1, in natural light conditions, the displacement average of the leaves between 7.00 a.m. and 12.30 p.m. was 3.67 cm as estimated using so-called deviation maps. The maximum displacement was 7.92 cm. In addition, the orientation changes of each leaf within a day were analyzed. The maximum variation in the vertical angle was 69.6° from 12.30 to 6.00 p.m. In darkness, the displacements were smaller and showed a different orientation pattern. The canopy volume of plant 1 changed more in the morning (4.42 dm3) than in the afternoon (2.57 dm3). The results of plant 2 largely confirmed the results of the first plant and were added to check the robustness of the methodology. The results show how to quantify leaf orientation variation and leaf movements along a day at mm accuracy in different light conditions. This confirms the feasibility of the proposed methodology to robustly analyse leaf movements.


Treatment of vertebrobasilar occlusion by using a coronary waterjet thrombectomy device: a pilot study.
Despite improved patient outcomes because of intraarterial fibrinolysis, vertebrobasilar thromboembolism remains a fatal disease with a death rate of more than 50%. The outcome depends on the success of recanalization. Fibrinolysis achieves recanalization in only 50%-70% of the cases. Therefore, we investigated the feasibility of using a coronary mechanical device to increase the recanalization rate. Twelve patients with acute vertebrobasilar occlusion were included in the pilot study. The older 5F and the new 4F versions of the Possis Angiojet catheter, which use a waterjet to attract, fragment, and extract the thrombus, were used. Inclusion depended on the presence of acute multisegmental intracranial or any extracranial vertebrobasilar occlusion. Exclusion criteria included coma lasting >8 hours and age >80. The Angiojet treatment did not exclude other therapeutic options. The Angiojet catheter accessed the thrombosed site in 10 of 12 patients. Combined treatment with the Angiojet and additional fibrinolysis or angioplasty resulted in a recanalization rate of 100%. Of 37 occluded vertebrobasilar segments, 30 were primarily recanalized with the Angiojet. Three symptomatic and two asymptomatic hemorrhages were detected by CT. Five of the 12 patients died. Fifty percent of all patients obtained a moderate to excellent outcome (Modified Rankin Scale 0-3). Use of the coronary Angiojet in the vertebrobasilar system is feasible. The device has the potential to increase the recanalization rate, especially in cases of extensive thrombosis, and, thus, improve patient outcomes.


FISH-eyed and genome-wide views on the spatial organisation of gene expression.
Eukaryotic cells store their genome inside a nucleus, a dedicated organelle shielded by a double lipid membrane. Pores in these membranes allow the exchange of molecules between the nucleus and cytoplasm. Inside the mammalian cell nucleus, roughly 2 m of DNA, divided over several tens of chromosomes is packed. In addition, protein and RNA molecules functioning in DNA-metabolic processes such as transcription, replication, repair and the processing of RNA fill the nuclear space. While many of the nuclear proteins freely diffuse and display a more or less homogeneous distribution across the nuclear interior, some appear to preferentially cluster and form foci or bodies. A non-random structure is also observed for DNA: increasing evidence shows that selected parts of the genome preferentially contact each other, sometimes even at specific sites in the nucleus. Currently a lot of research is dedicated to understanding the functional significance of nuclear architecture, in particular with respect to the regulation of gene expression. Here we will evaluate evidence implying that the folding of DNA is important for transcriptional control in mammals and we will discuss novel high-throughput techniques expected to further boost our knowledge on nuclear organisation.


The effect of docosahexaenoic acid on aggression in elderly Thai subjects--a placebo-controlled double-blind study.
Docosahexaenoic acid (DHA) administration controls extraggression (aggression against others) in young subjects under psychological stress. However, it is not known whether its administration affects extraggression of elderly subjects. Forty Thai subjects of 50-60 years of age (22 males and 18 females) were recruited from Silpakorn University and nearby villages. They were allocated to the control and DHA groups in a double-blind fashion, and took 10 mixed plant oil capsules and 10 DHA capsules (1.5g DHA/day) for 2 months, respectively. Extraggression was measured with a psychological test (PF Study) at the beginning and end of the study. Just prior to the PF Study at the end of the study, subjects were asked to watch a stressful videotape as a stressor component. The average DHA intake from food was 150-160mg/day. In the group of university employees, extraggression did not change over time with placebo, whereas extraggression significantly decreased (31 +/- 13 to 24 +/- 13%, P = 0.04 by the paired-t test, P = 0.04 by ANOVA). In the group of villagers, there was no significant difference between the control and DHA groups in extraggression. The DHA administration favorably controlled extraggression in at least elderly white-collar workers. The daily intake of 150-160 mg/day of DHA was not enough to control extraggression.


MicroRNA-382-5p Targets Nuclear Receptor Subfamily 3 Group C Member 1 to Regulate Depressive-Like Behaviors Induced by Chronic Unpredictable Mild Stress in Rats.
Depression is an emotional disorder characterized by depression, lack of pleasure, and cognitive and sleep disorders. It is a systemic disease with a complex pathogenesis. In this study, we will be focused to investigate their associations and the exact functional mechanisms of miR-382-5p and NR3C1 in depression. We measured the expressions of microRNA-382-5p (miR-382-5p) and NR3C1 in the hippocampus by chronic unpredictable mild stress (CUMS). Depression behavior test including novelty-suppressed feeding test (NSFT), sucrose preference test (SPT), and forced swim test (FST) on rats have been conducted to examine the roles and functions of miR-382-5p and NR3C1 on depression-like behaviors by lentivirus vectors. Up-regulation of miR-382-5p and down-regulation of NR3C1 were observed in rats' hippocampus induced by CUMS. miR-382-5p targeted NR3C1 and inhibited the expressions of NR3C1 in rats' hippocampus. miR-382-5p could significantly change the depression behaviors induced by CUMS. NR3C1 downstream BDNF and p-TrkB were also oppositely associated with miR-382-5p in rats' hippocampus. Through our experiments and analysis, we found that the associations between miR-382-5p and NR3C1 could affect the depression-like behaviors.


Clinical validation of methods of diagnosis of neuropathy in a field study of United Kingdom sheep dippers.
To investigate the reproducibility of measured indices of chronic peripheral neuropathy from a field study of sheep dippers when compared with similar measurements carried out in a clinical setting. A stratified random sample of field study subjects was invited to attend a clinic. Neuropathy was measured both in the field and at the clinic with a modified version of a standard symptoms questionnaire and quantitative sensory thresholds for hot, cold, and vibration. These were combined into a classification of the likelihood of neuropathy with a neuropathy scoring system. Indicators of sensory abnormality were based on comparison of sensory thresholds to age dependent reference values derived from an external reference group. Only 51% of subjects were assigned similar classifications in the field and clinic based on the neuropathy scoring system. Of the component indices, grouped symptom scores, with 65% of subjects showing exact agreement, proved to be more reproducible than quantitative sensory test indicators. There were biases in the comparison of field and clinic measurements of hot and vibration sensations, but no evidence of greater variation between individual people in sensory thresholds in the field relative to at the clinic. The neuropathy scoring system proved to be of limited reproducibility, due in a large part to the lack of reproducibility of the indicators of sensory test abnormality caused by inadequate temperature control. However, the symptoms score and measured sensory thresholds could be used separately as indices of neuropathy in exposure-response analyses.


The basic mechanism of inotropic action of digitalis glycosides.
A broad survey of the experimental literature suggests that the only unifying concept of digitalis action is that these drugs, at pharmacologically relevant doses, bind with high affinity and specificity to sites on the NaK-ATPase complex that face the outer surface of nearly all eukaryotic cells. Alternative receptors, if they exist, have not been defined. As might be expected, a broad range of biologic effects results from this basic interaction. The clinical therapeutic effects of digitalis include enhancement of myocardial contractility and changes in the properties of the cardiac conduction system; the latter, in turn, result from both direct and autonomically mediated effects [44]. Autonomic effects involve alterations in both parasympathetic and sympathetic activity, and these are attributable to both central and peripheral neural mechanisms [44]. As we have reviewed, there is compelling evidence that one mechanism leading to sustained positive inotropic effects of digitalis glycosides in heart muscle is partial inhibition of sodium transport. Earlier evidence [16, 17] is now supported by electrophysiologic studies [29, 30, 45, 46], intracellular ion-sensitive microelectrode methods [47, 48], and ion flux measurements using radioisotope tracers [14, 15, 49]. Inhibition of myocardial monovalent cation transport has been documented in intact glycoside-sensitive animal models at doses and plasma and myocardial levels causing a positive inotropic effect without overt toxicity [12]. However, these findings do not preclude other mechanisms that may be operative in addition to, or in some circumstances instead of, myocardial Na-K pump inhibition. In the context of much seemingly conflicting evidence [35, 36, 37, 50, 51], the hypothesis advanced by Akera and Brody is of interest [17]. These authors suggest that interaction of subtoxic digitalis concentrations with myocardial NaK-ATPase reduces maximum sodium transport capacity, resulting in an enhanced transient increase in [Na]i during the early phase of the cardiac cycle. Such an increase in subsarcolemmal [Na+] could cause increased Ca++ influx via Na+-Ca++ exchange, with a consequent positive inotropic effect. If the Na+ increase were cyclic and not cumulative, cell Na+ content could return to normal by the end of a cycle due to enhanced turnover of unblocked Na-K pump sites. This hypothesis suggests a mechanism by which Na-K pump inhibition could cause a positive inotropic effect without any measurable increase in steady-state [Na+]i or decrease in [K+]i.(ABSTRACT TRUNCATED AT 400 WORDS)


[The sauna in the treatment of children with atopic dermatitis].
Complex sauna therapy for children with atopic dermatitis gives positive clinical results and improves the condition of their autonomic nervous system. Marked clinical response but unsatisfied autonomic nervous system regulation necessitate long-term sauna treatment to cure this disease.


Histological Evidence of Diabetic Kidney Disease Precede Clinical Diagnosis.
In the absence of a histological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease (DKD). In the present retrospective study, we evaluated data from an Italian cohort of 42 deceased diabetic donors (mainly with type 2 diabetes). Using the kidney biopsies obtained at the time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes. All 42 donors presented with proteinuria in the normal range and an estimated glomerular filtration rate (eGFR) (chronic kidney disease [CKD]-EPI) >60 mL/min/1.73 m2. A kidney biopsy was available for 36 patients; of these, one was not interpretable and 32 showed histopathological lesions consistent with DKD and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven DKD that had been clinically undiagnosed, as none of the patient had significant proteinuria and eGFR <60 mL/min/1.73 m2. The data we present here support the need to implement routine kidney biopsies in normoalbuminuric diabetic subjects in the early stages of CKD. Such strategy may help to improve risk stratification in diabetic patients and guide therapeutic decisions during the early stages of the disease.


The existence of a highly ordered phase in fully hydrated dilauroylphosphatidylethanolamine.
Dilauroylphosphatidylethanolamine dispersion forms a crystalline phase at physiological pH and temperature and in the presence of excess water. This phenomenon was observed and studied by differential scanning calorimetry, scanning densitometry and X-ray diffraction. The crystalline phase is stable at pH 5.5-9.5 and below 40 degrees C. The crystalline phase formed at pH 5.5 and pH 9.5 index according to orthorhombic cells with a = 9.41, b = 8.15, c = 46.0 and a = 9.33, b = 8.05, c = 45.8 (A), respectively. Around 43 degrees C, the crystalline phase is transformed into a multilayer liquid crystal phase. Cooling from 44 degrees C results in the disappearance of the original transition at 43 degrees C and the appearance of a second transition at around 30 degrees C. Below 30 degrees C the lipid forms a gel phase. This gel phase is metastable at pH 5.5 and a crystalline phase may be recovered from it by dispersing or aging methods. Suspensions of dilauroylphosphatidylethanolamine show similar phase transition behaviour at pH 5.5 and pH 9.5, although the transitions are somewhat broader at the higher pH. The thermotropic phase behaviour of dilauroylphosphatidylethanolamine dispersions may be governed by changes in hydration.


A fast, reproducible, high-throughput variant calling workflow for population genomics.
The increasing availability of genomic resequencing datasets and high quality reference genomes across the tree of life present exciting opportunities for comparative population genomic studies. However, substantial challenges prevent the simple reuse of data across different studies and species, arising from variability in variant calling pipelines, data quality, and the need for computationally intensive reanalysis. Here, we present snpArcher, a flexible and highly efficient workflow designed for the analysis of genomic resequencing data in non-model organisms. snpArcher provides a standardized variant calling pipeline and includes modules for variant quality control, data visualization, variant filtering, and other downstream analysis. Implemented in Snakemake, snpArcher is user-friendly, reproducible, and designed to be compatible with HPC clusters and cloud environments. To demonstrate the flexibility of this pipeline, we applied snpArcher to 26 public resequencing datasets from non-mammalian vertebrates. These variant datasets are hosted publicly to enable future comparative population genomic analyses. With its extensibility and the availability of public datasets, snpArcher will contribute to a broader understanding of genetic variation across species by facilitating rapid use and reuse of large genomic datasets.


Acoustic resonances in straight micro channels: beyond the 1D-approximation.
Acoustic actuation can be used to perform several tasks in microfluidic systems. In this paper, we investigate an acoustic separator through micro-PIV analysis in stop-flow mode and numerical simulations, and a good agreement between the two is found. Moreover, we demonstrate that it is not sufficient only to characterize devices in flow-through mode, since in these systems much different resonant patterns can result in similarly looking band formations. Furthermore, we conclude that extended 1D approximations of the acoustic radiation force are inadvisable, and instead, a 2D model is preferred. The results presented here provide valuable insight into the nature and functionality of acoustic microdevices, and should be useful in the interpretation and understanding of the same.


Risk factors for treatment failure in patients with prosthetic joint infections.
A retrospective, observational cohort study was conducted to describe the incidence, clinical and microbiological findings and to evaluate risk factors for treatment failure associated with prosthetic joint infections (PJIs). We retrospectively reviewed the medical records of all patients undergoing total knee or total hip prosthesis implantation in our institution between 1994 and 2008. Our institution is a 1950-bed tertiary care university hospital and referral centre. A total of 93 patients with PJIs was identified although only 68 patients had undergone prosthesis implantation at our hospital. The overall infection rate was 0.63%. The most common organisms isolated were Gram positive (76.5%), including meticillin-resistant staphylococci. Two-stage arthroplasty was performed in 48 (51.6%) patients, and debridement and retention of the prosthesis in 34 (36.5%) patients. When 43 patients followed up for more than two years after treatment were included in treatment outcome analysis, the overall treatment failure rate was 41.8% (18/43). Staphylococcus aureus infection was the only clinical variable associated with treatment failure (odds ratio: 11.9; 95% confidence interval: 1.07e133.9; P = 0.044), after adjustment for the other variables. In conclusion, S. aureus was the most common pathogen isolated in patients with PJI, and an independent risk factor for treatment failure in patients with PJI.


The metabolism of 3,5-di-tert.-butyl-4-hydroxytoluene in the rat and in man.
1. The major metabolites of 3,5-di-tert.-butyl-4-hydroxytoluene (BHT) in the rat are 3,5-di-tert.-butyl-4-hydroxybenzoic acid (BHT-acid), both free (9% of the dose) and as a glucuronide (15%), and S-(3,5-di-tert.-butyl-4-hydroxybenzyl)-N-acetylcysteine. 2. The mercapturic acid does not appear to derive from the usually accepted enzyme mechanism, and may involve a non-enzymic reaction between BHT free radical and cysteine. 3. The ester glucuronide and mercapturic acid found in rat urine are also the major metabolites in rat bile and must be responsible for the enterohepatic circulation. 4. Free BHT-acid is the main component in rat faeces. 5. In man, BHT-acid, free and conjugated, is a minor component in urine, and the mercapturic acid is virtually absent. The bulk of the radioactivity is excreted as the ether-insoluble glucuronide of a metabolite in which the ring methyl group and one tert.-butyl methyl group are oxidized to carboxyl groups, and a methyl group on the other tert.-butyl group is also oxidized, probably to an aldehyde group. 6. These differences in metabolism by the rat and by man are sufficient to account for the difference in excretion by the two species.


Chronic widespread pain in spondyloarthritis.
The pain associated with spondyloarthritis (SpA) can be intense, persistent and disabling. It frequently has a multifactorial, simultaneously central and peripheral origin, and may be due to currently active inflammation, or joint damage and tissue destruction arising from a previous inflammatory condition. Inflammatory pain symptoms can be reduced by non-steroidal anti-inflammatory drugs, but many patients continue to experience moderate pain due to alterations in the mechanisms that regulate central pain, as in the case of the chronic widespread pain (CWP) that characterises fibromyalgia (FM). The importance of distinguishing SpA and FM is underlined by the fact that SpA is currently treated with costly drugs such as tumour necrosis factor (TNF) inhibitors, and direct costs are higher in patients with concomitant CWP or FM than in those with FM or SpA alone. Optimal treatment needs to take into account symptoms such as fatigue, mood, sleep, and the overall quality of life, and is based on the use of tricyclic antidepressants or selective serotonin reuptake inhibitors such as fluoxetine, rather than adjustments in the dose of anti-TNF agents or disease-modifying drugs.


Epigenetic dysregulation in salivary glands from patients with primary Sjögren's syndrome may be ascribed to infiltrating B cells.
Sjögren's syndrome (SS) is an autoimmune exocrinopathy characterized by an epithelium injury with dense lymphocytic infiltrates, mainly composed of activated T and B cells. Present at the interface of genetic and environmental risk factors, DNA methylation is suspected to play a key role in SS. To clarify this point, global DNA methylation was tested within salivary gland epithelial cells (SGEC), peripheral T cells and B cells from SS patients. Global DNA methylation was reduced in SGEC from SS patients, while no difference was observed in T and B cells. SGEC demethylation in SS patients was associated with a 7-fold decrease in DNA methyl transferase (DNMT) 1 and a 2-fold increase in Gadd45-alpha expression. The other DNA methylation/demethylation partners, tested by real time PCR (DNMT3a/b, PCNA, UHRF1, MBD2, and MBD4), were not different. Interestingly, SGEC demethylation may be attributed in part to the infiltrating B cells as suspected in patients treated with anti-CD20 antibodies to deplete B cells. Such hypothesis was confirmed using co-culture experiments with human salivary gland cells and B cells. Furthermore, B cell-mediated DNA demethylation could be ascribed to an alteration of the PKC delta/ERK/DNMT1 pathway. As a consequence, part of the SGEC dysfunction in SS may be linked to epigenetic modifications, thus opening new therapeutic perspectives in SS.


[The interprostatic "partial catheter" (urologic spiral) II].
The intraprostatic partial catheter or the so-called "Urological Spiral" (US) is a novel development which was first used and tested with suitable urological patients in May 1978. - The "Urological Spiral" which is made of coiled rust-proof steel and can be used for implantation purposes can give unimpaired spontaneous miction back to patients where an operative removal of the prostatic urethra occlusion (caused by prostate adenoma or prostate carcinoma) has not been feasible by the therapeutic methods known so far. With inlying US the physiological valve function of the urethra makes a spontaneous healing up of an ascending bladder infection possible caused by ascension. The patency of the prostatic urethra is optimally secured by the shape und the elastic construction of the US. Judging from the experiences gained so far there are no essential contra-indications and the complication rates are very low. Insertion and removal of the US can be carried out by common urological instruments as e.g. urethroscope and elastic foreign-body removing forceps. There is no danger for the patient. The inserting and the removing of the US take place under local anaesthesia of the bladder and cause no discomfort to the patient.- This treatise ist the first to report on the experiences of the regular use of the intraprostatic partial catheter (US) on a larger number of patients and it is the first to give a critical assessment. The present construction has been considerably improved compared to the first prototypes of 1978.(ABSTRACT TRUNCATED AT 250 WORDS)


Phosphorylation of cardiac troponin inhibitory subunit (troponin I) and tropomyosin-binding subunit (troponin T) by cardiac phospholipid-sensitive Ca2+-dependent protein kinase.
Cardiac phospholipid-sensitive Ca2+-dependent protein kinase phosphorylated cardiac troponin inhibitory subunit (troponin I) and tropomyosin-binding subunit (troponin T), present either as the free form or as the troponin-tropomyosin complex. Exhaustive phosphorylation of troponin I and of troponin T revealed that 1.7 and 2 mol of phosphate was incorporated/mol of the subunits respectively. Cyclic AMP-dependent protein kinase, though incorporating 0.8 mol of phosphate/mol of troponin I, was unable to phosphorylate troponin T. Phosphorylation of troponin I (apparent Km = 3.4 microM; Vmax. = 2.6 mumol/min per mg of enzyme) or troponin T (apparent Km = 0.3 microM; Vmax. = 0.5 mumol/min per mg of enzyme) by the Ca2+-dependent enzyme was inhibited by various agents, such as adriamycin, palmitoylcarnitine, trifluoperazine, melittin and N-(6-aminohexyl)-5-chloronaphthalene-1-sulphonamide (compound W-7). Ca2+ antagonists (such as verapamil), forskolin and ouabain were ineffective. These findings indicate that troponin I and troponin T were effective substrates for this species of Ca2+-dependent protein kinase, suggesting its potential regulatory role in the contractile activity of myofibrils modulated by troponin.


Signature of dislocations and stacking faults of face-centred cubic nanocrystals in coherent X-ray diffraction patterns: a numerical study.
Crystal defects induce strong distortions in diffraction patterns. A single defect alone can yield strong and fine features that are observed in high-resolution diffraction experiments such as coherent X-ray diffraction. The case of face-centred cubic nanocrystals is studied numerically and the signatures of typical defects close to Bragg positions are identified. Crystals of a few tens of nanometres are modelled with realistic atomic potentials and 'relaxed' after introduction of well defined defects such as pure screw or edge dislocations, or Frank or prismatic loops. Diffraction patterns calculated in the kinematic approximation reveal various signatures of the defects depending on the Miller indices. They are strongly modified by the dissociation of the dislocations. Selection rules on the Miller indices are provided, to observe the maximum effect of given crystal defects in the initial and relaxed configurations. The effect of several physical and geometrical parameters such as stacking fault energy, crystal shape and defect position are discussed. The method is illustrated on a complex structure resulting from the simulated nanoindentation of a gold nanocrystal.


Surface-histogram: a new shape descriptor for protein-protein docking.
Determining the structure of protein-protein complexes remains a difficult and lengthy process, either by NMR or by X-ray crystallography. Several computational methods based on docking have been developed to support and even serve as possible alternatives to these experimental methods. In this article, we introduce a new protein-protein docking algorithm, shDock, based on shape complementarity. We characterize the local geometry on each protein surface with a new shape descriptor, the surface-histogram. We measure the complementarity between two surface-histograms, one on each protein, using a modified Manhattan distance. When a match is found between two local protein surfaces, a model is generated for the protein complex, which is then scored by checking for collision between the two proteins. We have tested our algorithm on Version 3 of the ZDOCK protein-protein docking benchmark. We found that for 110 out of the 124 test cases of bound docking in the benchmark, our algorithm was able to generate a model in the top 3600 candidates for the protein complex within an root-mean-square deviation of 2.5 Å from its native structure. For unbound docking predictions, we found a model within 2.5 Å in the top 3600 models in 54 out of 124 test cases. A comparison with other shape-based docking algorithms demonstrates that our approach gives significantly improved performance for both bound and unbound docking test cases.


Oral rehydration solution for acute diarrhea prevents subsequent unscheduled follow-up visits.
Oral rehydration solutions (ORS) for the treatment of acute diarrhea remain an underutilized therapy in the United States, despite multiple clinical trials confirming their efficacy and safety. Economic barriers to their use have been identified. To determine whether providing ORS to patients at the time of their office visit for acute diarrhea can increase ORS utilization and reduce unscheduled follow-up visits. Randomized, controlled clinical trial. Seven health centers of a large health maintenance organization. Children (N = 479) 0 to 60 months of age with acute diarrhea (at least three watery or loose stools in the previous 24 hours for </=7 days). Prescription for 2 quarts of ORS filled for free at on-site pharmacy plus written instructions versus written instructions alone. Self-reported use of ORS; unscheduled follow-up visits in office, urgent care, and/or emergency department setting. Subjects in the intervention group were significantly more likely to use ORS after the initial office visit (85% vs 71%; RR: 1.19; 95% CI: 1.08-1.32). Of the standard treatment group subjects, 40 (17.3%) sought unscheduled follow-up care for diarrhea versus 27 (10.9%) of the intervention group subjects (RR: 0.63; 95% CI: 0.40-0.99). Subjects seeking unscheduled follow-up care tended to younger (15.7 vs 19.4 months old), have more stools (7.1 vs 6.2 stools), and more vomiting episodes (4.1 vs 3.0) in the 24 hours before initial evaluation than those not seeking unscheduled follow-up care. Multivariate analysis showed that randomization to the intervention group was associated with a 25% reduction in unscheduled follow-up visits for acute diarrhea. Providing ORS to families at the time of their office visit for acute diarrhea is associated with a significant increase in ORS use and substantially reduces the need for unscheduled follow-up visits. Health maintenance organizations should consider routine provision of ORS to children presenting with acute diarrhea.


Critical race theory as a tool for understanding poor engagement along the HIV care continuum among African American/Black and Hispanic persons living with HIV in the United States: a qualitative exploration.
African American/Black and Hispanic persons living with HIV (AABH-PLWH) in the U.S. evidence insufficient engagement in HIV care and low uptake of HIV antiretroviral therapy, leading to suboptimal clinical outcomes. The present qualitative study used critical race theory, and incorporated intersectionality theory, to understand AABH-PLWH's perspectives on the mechanisms by which structural racism; that is, the macro-level systems that reinforce inequities among racial/ethnic groups, influence health decisions and behaviors. Participants were adult AABH-PLWH in New York City who were not taking antiretroviral therapy nor well engaged in HIV care (N = 37). Participants were purposively sampled for maximum variation from a larger study, and engaged in semi-structured in-depth interviews that were audio-recorded and professionally transcribed verbatim. Data were analyzed using a systematic content analysis approach. We found AABH-PLWH experienced HIV care and medication decisions through a historical and cultural lens incorporating knowledge of past and present structural racism. This contextual knowledge included awareness of past maltreatment of people of color in medical research. Further, these understandings were linked to the history of HIV antiretroviral therapy itself, including awareness of the first HIV antiretroviral regimen; namely, AZT (zidovudine) mono-therapy, which was initially prescribed in unacceptably high doses, causing serious side effects, but with only modest efficacy. In this historical/cultural context, aspects of structural racism negatively influenced health care decisions and behavior in four main ways: 1) via the extent to which healthcare settings were experienced as overly institutionalized and, therefore, dehumanizing; 2) distrust of medical institutions and healthcare providers, which led AABH-PLWH to feel pressured to take HIV antiretroviral therapy when it was offered; 3) perceptions that patients are excluded from the health decision-making process; and 4) an over-emphasis on antiretroviral therapy compared to other non-HIV related priorities. We found that although participants were located at the intersection of multiple social categories (e.g., gender, social class, AABH race/ethnicity), race/ethnicity and social class were described as primary factors. Critical race theory proved useful in uncovering how macro-level structural racism affects individual-level health decisions and behaviors. HIV clinical settings can counter-balance the effects of structural racism by building "structural competency," and interventions fostering core self-determination needs including autonomy may prove culturally appropriate and beneficial for AABH-PLWH.


Isolation, characterization, and mapping of Tn5 insertions into the 140-megadalton invasion plasmid defective in the mouse Sereny test in Shigella flexneri 2a.
Using Shigella flexneri 2a YSH6000, we isolated 304 independent Tn5 insertion mutants in the 230-kilobase invasion plasmid, pMYSH6000. The site of each Tn5 insertion was assigned to 23 SalI fragments on the previously made SalI cleavage map of pMYSH6000. Among the 304 insertions, 150 were negative in expression of four phenotypes examined (mouse Sereny test [Ser], invasion into epithelial cells [Inv], Congo red binding [Pcr], and inhibition of bacterial growth [Igr] ): 12 were Ser- Inv+ Pcr+ Igr+, and 142 were positive in all four phenotypes. Tn5 insertions in the avirulent mutants were distributed in two separate SalI fragments, F and G, and in four contiguous SalI fragments, B, P, H, and D. Fragment G contains a novel class of determinant(s) which is required only for Ser+ but not for Inv+, Pcr+, and Igr+. Fragment F contains the previously characterized virF locus. B, P, H, and D each contained both virulent and avirulent Tn5 insertions. This indicates that more than two gene clusters exist within this region. Both are required for expression of all four virulence phenotypes.


Dysregulation of the neuregulin-1-ErbB network modulates endogenous oligodendrocyte differentiation and preservation after spinal cord injury.
Spinal cord injury (SCI) results in degeneration of oligodendrocytes that leads to demyelination and axonal dysfunction. Replacement of oligodendrocytes is impaired after SCI, owing to the improper endogenous differentiation and maturation of myelinating oligodendrocytes. Here, we report that SCI-induced dysregulation of neuregulin-1 (Nrg-1)-ErbB signaling may underlie the poor replacement of oligodendrocytes. Nrg-1 and its receptors, ErbB-2, ErbB-3, and ErbB-4, play essential roles in several aspects of oligodendrocyte development and physiology. In rats with SCI, we demonstrate that the Nrg-1 level is dramatically reduced at 1 day after injury, with no restoration at later time-points. Our characterisation shows that Nrg-1 is mainly expressed by neurons, axons and oligodendrocytes in the adult spinal cord, and the robust and lasting decrease in its level following SCI reflects the permanent loss of these cells. Neural precursor cells (NPCs) residing in the spinal cord ependyma express ErbB receptors, suggesting that they are responsive to Nrg-1 availability. In vitro, exogenous Nrg-1 enhanced the proliferation and differentiation of spinal NPCs into oligodendrocytes while reducing astrocyte differentiation. In rats with SCI, recombinant human Nrg-1β1 treatment resulted in a significant increase in the number of new oligodendrocytes and the preservation of existing ones after injury. Nrg-1β1 administration also enhanced axonal preservation and attenuated astrogliosis, tumor necrosis factor-α release and tissue degeneration after SCI. The positive effects of Nrg-1β1 treatment were reversed by inhibiting its receptors. Collectively, our data provide strong evidence to suggest an impact of Nrg-1-ErbB signaling on endogenous oligodendrocyte replacement and maintenance in the adult injured spinal cord, and its potential as a therapeutic target for SCI.


Robotic Ventral Hernia Repair and Endoscopic Component Separation: Outcomes.
Robot-assisted hernia repair, combined with endoscopic component separation, has reduced recurrence and complication rates and allowed immediate intervention in obese patients. We sought to study surgical outcomes in this high-risk group of patients in a community hospital. We conducted a retrospective chart review of ventral, incisional, and umbilical hernia repairs performed at a small community hospital by a single surgeon from March 2014 through November 2016, with statistical analysis of the surgical outcomes. Patients included were those who underwent hernia repair during the study period and had a body mass index (BMI) >30. Patients were followed up for a minimum of 6 months (range, 6-37). Forty-seven hernia repairs were performed, including 33 combined and 14 control cases. The demographics of each group were comparable when comparing sex, age, BMI, and ASA classification. Mean follow-up was 19.39 months in the study group and 28.64 months in the control group. There were no significant differences in total operative time, estimated blood loss, conversion rates, or hospital length of stay. Two complications occurred in each of the study and control groups, with no recurrences in the study group and 3 in the control group and no mortalities. Robotic laparoscopic repair of abdominal wall defects offers significant advantages, including easier primary defect closure. Our analyses showed that combining robot-assisted hernia repair with mesh and endoscopic component separation is an effective intervention in obese patients.


A Upf3b-mutant mouse model with behavioral and neurogenesis defects.
Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders.


Efficacy and safety of trastuzumab with or without a tyrosine kinase inhibitor for HER2-positive breast cancer: A systematic review and meta-analysis.
This study aimed to explore the efficacy and safety of trastuzumab plus tyrosine kinase inhibitors (TKIs) compared with those of trastuzumab monotherapy in patients with human epidermal growth factor receptor (HER2)-positive breast cancer. The PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for relevant articles from inception until September 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed based on disease status, TKI type, and hormone receptor status. Sixteen studies were included in the current analysis. Trastuzumab plus TKI significantly improved OS and PFS compared to trastuzumab monotherapy. In the neoadjuvant setting, trastuzumab plus TKI significantly increased the pathologic complete response (pCR) rate compared to trastuzumab monotherapy. Moreover, a higher objective response rate (ORR) was observed with trastuzumab plus TKI. Patients who received the combination therapy had a higher incidence of discontinuation, all-grade diarrhea, and grade ≥ 3 diarrhea. Trastuzumab plus TKI was better than trastuzumab monotherapy for treating different stages of HER2-positive breast cancer. The safety of trastuzumab plus TKI anti-HER2 therapy was controllable. The different efficacies of TKIs combined with trastuzumab may be related to the mechanism of action of the different TKIs, needing further investigations.


[Interhemispheric functional relations during formation of temporary connections in humans].
In the course of formation of temporary connection between a nonverbal visual stimulus and an emotional word, interhemispheric functional relations are significantly changed. The conditioned stimulus elicits local activation mainly in the visual cortex of the left hemisphere, which results in reversion of interhemispheric relations during latency of cortical evoked response. In the "associative" area, the elaboration of the temporary connection does not affect latency and amplitude of the evoked response to the conditioned stimulus. Extinction of the temporary connection and, hence, recovery of the interhemispheric functional relations observed before its elaboration, proceeds slowly, and sets in after 100-150 presentations of the signal without reinforcement.


Homing pigeons only navigate in air with intact environmental odours: a test of the olfactory activation hypothesis with GPS data loggers.
A large body of evidence has shown that anosmic pigeons are impaired in their navigation. However, the role of odours in navigation is still subject to debate. While according to the olfactory navigation hypothesis homing pigeons possess a navigational map based on the distribution of environmental odours, the olfactory activation hypothesis proposes that odour perception is only needed to activate a navigational mechanism based on cues of another nature. Here we tested experimentally whether the perception of artificial odours is sufficient to allow pigeons to navigate, as expected from the olfactory activation hypothesis. We transported three groups of pigeons in air-tight containers to release sites 53 and 61 km from home in three different olfactory conditions. The Control group received natural environmental air; both the Pure Air and the Artificial Odour groups received pure air filtered through an active charcoal filter. Only the Artificial Odour group received additional puffs of artificial odours until release. We then released pigeons while recording their tracks with 1 Hz GPS data loggers. We also followed non-homing pigeons using an aerial data readout to a Cessna plane, allowing, for the first time, the tracking of non-homing homing pigeons. Within the first hour after release, the pigeons in both the Artificial Odour and the Pure Air group (receiving no environmental odours) showed impaired navigational performances at each release site. Our data provide evidence against an activation role of odours in navigation, and document that pigeons only navigate well when they perceive environmental odours.


Save the torn labrum in hips with borderline acetabular coverage.
Hip arthroscopy for labral tears improves short-term function, but reoperations occur in 5% to 47% of patients. The effect of borderline acetabular coverage on reoperation rate has been debated. Labral repair rather than débridement has been proposed to improve function, but the effect on reoperation rate is unclear. We determined whether (1) borderline compared to adequate acetabular coverage increased reoperations and (2) labral repair compared to débridement reduced reoperations. We retrospectively reviewed 106 patients (mean age, 39 years) who underwent hip arthroscopy for labral tears. Based on radiographs, we classified patients into those with borderline (n = 50) or adequate (n = 56) acetabular coverage. We further divided each group into those with labral débridement or repair: borderline acetabular coverage, n = 25 and 25, respectively; adequate acetabular coverage, n = 39 and 17, respectively. We assessed reoperations in borderline versus adequate acetabular coverage and labral débridement versus repair, modified Harris hip scores (mHHSs), and survival. Minimum followup was 12 months (mean, 33 months; range, 12-65 months). Twenty-three of 106 patients had reoperations. Reoperation rate was higher with borderline than with adequate acetabular coverage. Reoperation rate was lower with labral repair than with débridement. Survival to reoperation was similar in the four subgroups although there was a tendency for early reoperation in patients with borderline acetabular coverage with débridement. Improvement in mean mHHS was comparable in the four subgroups. We found borderline acetabular coverage increased reoperation rates. Labral repair reduced the likelihood of reoperation, especially in hips with borderline acetabular coverage. Hip arthroscopy for labral tears was associated with high reoperation rates in hips with borderline acetabular coverage. Level IV, prognostic study. See Instructions for Authors for a complete description of levels of evidence.


Electron-multiplying charge-coupled detector-based bioluminescence recording of single-cell Ca2+.
The construction and application of genetically encoded intracellular calcium concentration ([Ca2+]i) indicators has a checkered history. Excitement raised over the creation of new probes is often followed by disappointment when it is found that the initial demonstrations of [Ca2+]i sensing capability cannot be leveraged into real scientific advances. Recombinant apo-aequorin cloned from Aequorea victoria was the first Ca2+ sensitive protein genetically targeted to subcellular compartments. In the jellyfish, bioluminescence resonance energy transfer (BRET) between Ca2+ bound aequorin and green fluorescent protein (GFP) emits green light. Similarly, Ca2+ sensitive bioluminescent reporters undergoing BRET have been constructed between aequorin and GFP, and more recently with other fluorescent protein variants. These hybrid proteins display red-shifted spectrums and have higher light intensities and stability compared to aequorin alone. We report BRET measurement of single-cell [Ca2+]i based on the use of electron-multiplying charge-coupled-detector (EMCCD) imaging camera technology, mounted on either a bioluminescence or conventional microscope. Our results show for the first time how these new technologies make facile long-term monitoring of [Ca2+]i at the single-cell level, obviating the need for expensive, fragile, and sophisticated equipment based on image-photon-detectors (IPD) that were until now the only technical recourse to dynamic BRET experiments of this type.


Mobile phone technology and hospitalized patients: a cross-sectional surveillance study of bacterial colonization, and patient opinions and behaviours.
Healthcare workers' mobile phones provide a reservoir of bacteria known to cause nosocomial infections. UK National Health Service restrictions on the utilization of mobile phones within hospitals have been relaxed; however, utilization of these devices by inpatients and the risk of cross-contamination are currently unknown. Here, we examine demographics and characteristics of mobile phone utilization by inpatients and phone surface microbial contamination. One hundred and two out of 145 (70.3%) inpatients who completed a questionnaire detailing their opinions and utilization of mobile phones, also provided their mobile phones for bacteriological analysis and comparative bacteriological swabs from their nasal cavities; 92.4% of patients support utilization of mobile phones by inpatients; indeed, 24.5% of patients stated that mobile phones were vital to their inpatient stay. Patients in younger age categories were more likely to possess a mobile phone both inside and outside hospital (p <0.01) but there was no gender association. Eighty-six out of 102 (84.3%) patients' mobile phone swabs were positive for microbial contamination. Twelve (11.8%) phones grew bacteria known to cause nosocomial infection. Seven (6.9%) phones and 32 (31.4%) nasal swabs demonstrated Staphylococcus aureus contamination. MSSA/MRSA contamination of phones was associated with concomitant nasal colonization. Patient utilization of mobile phones in the clinical setting is popular and common; however, we recommend that patients are educated by clear guidelines and advice on inpatient mobile phone etiquette, power charging safety, regular cleaning of phones and hand hygiene, and advised not to share phones or related equipment with other inpatients in order to prevent transmission of bacteria.


Volume-regulated anion conductance in cultured rat cerebral astrocytes requires calmodulin activity.
We examined the calmodulin dependence of anion channel activation during hypo-osmotic swelling in rat cerebral astrocytes. Control cells bathed in iso-osmotic (290 mOsm) phosphate-buffered saline (PBS) and recorded using a patch electrode containing 140 mM KCl increased membrane conductance threefold over basal levels after 12 min in hypo-osmotic (200 mOsm) PBS. Cells injected with monoclonal anticalmodulin antibody demonstrated no increase in membrane conductance during a subsequent exposure to hypo-osmotic PBS. In contrast, cells iontophoretically injected with monoclonal antiglial fibrillary acidic protein antibody or with anticalmodulin antibody absorbed with an excess of free calmodulin demonstrated an increase in conductance during hypo-osmotic exposure similar to that of control cells. Conductance in iso-osmotic conditions was unchanged by antibody injection. Similar results were obtained when using patch electrode and bath solutions containing chloride as the only cell permeant ion, indicating a calmodulin-dependent anion current is activated with this degree of hypo-osmotic treatment. Western blots confirmed the specificity of the anticalmodulin and antiglial fibrillary acidic protein antibodies used in this study for proteins of 17 and 51 kD, respectively. In addition, in vitro studies demonstrated inhibition of the calmodulin-dependent activation of phosphodiesterase by the anticalmodulin antibody. Thus, binding of this antibody to calmodulin causes functional inhibition of calmodulin activity. No change in the intensity or cellular distribution of calmodulin immunostaining was observed during 30 min of hypo-osmotic exposure. However, increased immunostaining for activated calmodulin kinase IIalpha was observed after 10 min of hypo-osmotic exposure, suggesting initiation of calmodulin-dependent processes by cell swelling. The data indicate calmodulin activity is critical for activation of volume-regulated anion channels in rat cerebral astrocytes.


Poly(N-acryloylglycine-acrylamide) Hydrogel Mimics the Cellular Microenvironment and Promotes Neurite Growth with Protection from Oxidative Stress.
In this work, the glycine-based acryloyl monomer is polymerized to obtain a neurogenic polymeric hydrogel for regenerative applications. The synthesized poly(N-acryloylglycine-acrylamide) [poly(NAG-b-A)] nanohydrogel exhibits high swelling (∼1500%) and is mechanically very stable, biocompatible, and proliferative in nature. The poly(NAG-b-A) nanohydrogel provides a stable 3D extracellular mimetic environment and promotes healthy neurite growth for primary cortical neurons by facilitating cellular adhesion, proliferation, actin filament stabilization, and neuronal differentiation. Furthermore, the protective role of the poly(NAG-b-A) hydrogel for the neurons in oxidative stress conditions is revealed and it is found that it is a clinically relevant material for neuronal regenerative applications, such as for promoting nerve regeneration via GSK3β inhibition. This hydrogel additionally plays an important role in modulating the biological microenvironment, either as an agonist and antagonist or as an antioxidant. Furthermore, it favors the physiological responses and eases the neurite growth efficiency. Additionally, we found out that the conversion of glycine-based acryloyl monomers into their corresponding polymer modulates the mechanical performance, mimics the cellular microenvironment, and accelerates the self-healing capability due to the responsive behavior towards reactive oxygen species (ROS). Thus, the p(NAG-b-A) hydrogel could be a potential candidate to induce neuronal regeneration since it provides a physical cue and significantly boosts neurite outgrowth and also maintains the microtubule integrity in neuronal cells.


Subcortical structures in amyotrophic lateral sclerosis.
The aim of this study was to assess the involvement of deep gray matter, hippocampal subfields, and ventricular changes in patients with amyotrophic lateral sclerosis (ALS). A total of 112 ALS patients and 60 healthy subjects participated. High-resolution T1-weighted images were acquired using a 3T MRI scanner. Thirty-nine patients underwent a follow-up scan. Volumetric and shape analyses of subcortical structures were performed, measures were correlated with clinical parameters, and longitudinal changes were assessed. At baseline, reduced hippocampal volumes (left: p = 0.007; right: p = 0.011) and larger inferior lateral ventricles (left: p = 0.013; right: p = 0.041) were found in patients compared to healthy controls. Longitudinal analyses demonstrated a significant decrease in volume of the right cornu ammonis 2/3 and 4/dentate gyrus and left presubiculum (p = 0.002, p = 0.045, p < 0.001), and a significant increase in the ventricular volume in the lateral (left: p < 0.001; right: p < 0.001), 3rd (p < 0.001) and 4th (p = 0.001) ventricles. Larger ventricles were associated with a lower ALSFRS-R score (p = 0.021). In conclusion, ALS patients show signs of neurodegeneration of subcortical structures and ventricular enlargement. Subcortical involvement is progressive and correlates with clinical parameters, highlighting its role in the neurodegenerative process in ALS.


Pediatric Motor Inflammatory Neuropathy: The Role of Antiphospholipid Antibodies.
We report the clinical case of a nine-year-old girl who presented with progressive motor neuropathy, revealed via the detection of a higher delay in F-wave recording using digitalized nerve conduction/electromyography. Since the lupus anticoagulant (LAC) positivity, detected using diluted Russell viper venom time (dRVVT), switched to persistent serological anticardiolipin immunoglobulin G (IgG) positivity, a possible non-thrombotic antiphospholipid antibody (aPL)-related clinical manifestation was suspected, and intravenous immunoglobulin treatment (IVIG) was started. The IVIG treatment was well tolerated and the complete resolution of motor impairment was obtained after the third IVIG infusion. Our findings suggest that it could be useful to check for antiphospholipid antibodies in children with a rapid onset of progressive neurological signs in order to provide the beneficial use of IVIG in the treatment of pediatric aPL neurological conditions.


[ACT/AA polymorphism could duplicate the APOE*epsilon4-associated Alzheimer's disease risk].
The association between the presence of the allele APOE*epsilon4 (apolipoprotein E) and sporadic Alzheimer disease (AD) has been long established. However, the possible influence of other genetic factors is still under debate. This study investigated the role of the a 1-antichymotrypsin (ACT) gene as a susceptibility factor for developing late-onset AD in the population of Navarra. The study group included 98 patients with late-onset AD and 188 control individuals 70-71 years of age. APOE*epsilon2,*epsilon3,*epsilon4 and ACT codon -17*A,*T polymorphisms were analyzed by PCR-RFLP. Statistical analyses were performed determining the chi-square test, using 2 x 2 contingency tables and logistic regression to calculate odds ratios. APOE*epsilon4 allele frequency was significantly higher in AD patients than in controls (odds ratio [OR] = 3.02; 95% confidence interval [CI], 1.59-5.73; p < 0.001 in heterozygous carriers, and OR = 9.40; 95% CI, 1.84-64.43; p = 0.001 in homozygous individuals). We found no significant differences in the distribution of ACT polymorphisms between AD cases and controls. However, APOE*epsilon4 carriers had a 2.5-fold increased risk of developing AD in the presence of the ACT/AA genotype (OR = 10.13; 95% CI, 1.98-97.81; p < 0.001). The risk difference, however, did not reach statistical significance (p = 0.271). APOE*epsilon4 heterozygous and homozygous carriers have a 3 and 9 times higher risk, respectively, of developing AD. We could not demonstrate an effect of ACT polymorphisms as a independent risk factor for this disease; however, the ACT/AA genotype seems to act as an additional susceptibility factor, duplicating the APOE*epsilon4-associated AD risk.


Association of lifetime blood pressure with adulthood exercise blood pressure response: the cardiovascular risk in young Finns study.
Elevated blood pressure (BP) in childhood has been associated with increased adulthood BP. However, BP and its change from childhood to adulthood and the risk of exaggerated adulthood exercise BP response are largely unknown. Therefore, we studied the association of childhood and adulthood BP with adulthood exercise BP response. This investigation consisted of 406 individuals participating in the ongoing Cardiovascular Risk in Young Finns Study (baseline in 1980, at age of 6-18 years; follow-up in adulthood in 27-29 years since baseline). In childhood BP was classified as elevated according to the tables from the International Child Blood Pressure References Establishment Consortium, while in adulthood BP was considered elevated if systolic BP was ≥120 mmHg or diastolic BP was ≥80 mmHg or if use of antihypertensive medications was self-reported. A maximal cardiopulmonary exercise test with BP measurements was performed by participants in 2008-2009, and exercise BP was considered exaggerated (EEBP) if peak systolic blood pressure exceeded 210 mmHg in men and 190 mmHg in women. Participants with consistently high BP from childhood to adulthood and individuals with normal childhood but high adulthood BP had an increased risk of EEBP response in adulthood (relative risk [95% confidence interval], 3.32 [2.05-5.40] and 3.03 [1.77-5.17], respectively) in comparison with individuals with normal BP both in childhood and adulthood. Interestingly, individuals with elevated BP in childhood but not in adulthood also had an increased risk of EEBP [relative risk [95% confidence interval], 2.17 [1.35-3.50]). These findings reinforce the importance of achieving and sustaining normal blood pressure from childhood through adulthood.


Relation of increased leptin concentrations to history of myocardial infarction and stroke in the United States population.
Leptin, an adipose tissue-derived hormone, has been linked to cardiovascular outcomes; however, data are limited in the United States population, especially women. To assess the association between leptin concentrations and history of myocardial infarction (MI) and stroke independently of traditional cardiovascular risk factors, we analyzed data from 6,239 subjects (mean age 47 years; 3,336 women) with measurements of serum leptin and full assessment of cardiovascular risk factors from the National Health and Nutrition Examination Survey (NHANES) III. Logistic regression was used to estimate the cross-sectional association of leptin concentrations (highest quartile versus lowest quartile) and history of MI, stroke, and the composite end point of MI or stroke (MI/stroke). Gender-specific models of leptin were adjusted for age, race, dyslipidemia, hypertension, diabetes, smoking, and obesity status. There were 212 men with MI/stroke (5.4%), 154 with MI (4.1%), and 82 with stroke (1.7%). There were 135 women with MI/stroke (2.6%), 74 with MI (1.5%), and 78 with stroke (1.4%). In multivariate analysis, high leptin level was significantly and independently associated with MI/stroke in men (odds ratio [OR] 2.41, 95% confidence interval [CI] 1.20 to 4.93) and women (OR 4.26, 95% CI 1.75 to 10.73); with MI in men (OR 3.16, 95% CI 1.40 to 7.37) and women (OR 3.96, 95% CI 1.29 to 12.72), and with stroke in women (OR 3.20, 95% CI 1.04 to 10.54) but not in men (OR 1.37, 95% CI 0.38 to 3.88). In conclusion, in the United States population, increased leptin concentrations are significantly associated with MI/stroke in men and women independently of traditional cardiovascular risk factors and obesity status.


Acute renal vein thrombosis, oral contraceptive use, and hyperhomocysteinemia.
Oral contraceptive use and hyperhomocysteinemia are considered to be relatively weak risk factors for venous thromboembolism. We report a case of acute renal vein thrombosis, a rare and aggressive form of thromboembolism, that occurred in a 21-year-old woman taking oral contraceptives, who was subsequently found to have marked hyperhomocysteinemia. This case suggests that the oral contraceptive and hyperhomocysteinemia may interact in a synergistic manner in the pathogenesis of thrombosis. In oral contraceptive users who develop venous thrombosis in the absence of other risk factors, clinicians should consider investigations for an underlying prothrombotic biochemical disorder.


Metabolic syndrome prediction using non-invasive and dietary parameters based on a support vector machine.
Metabolic syndrome (MetS) is a widely used index for finding people at risk for chronic diseases, including cardiovascular disease and diabetes. Early detection of MetS is especially important in prevention programs. Relying on previous studies that suggest machine learning methods as a valuable approach for diagnosing MetS, this study aimed to develop MetS prediction models based on support vector machine (SVM) algorithms, applying non-invasive and low-cost (NI&LC), and also dietary parameters. This population-based research was conducted on a large dataset of 4596 participants within the framework of the Shahedieh cohort study. An Extremely Randomized Trees Classifier was used to select the most effective features among NI&LC and dietary data. The prediction models were developed based on SVM algorithms, and their performance was assessed by accuracy, sensitivity, specificity, positive prediction value, negative prediction value, f1-score, and receiver operating characteristic curve. MetS was diagnosed in 14% of men and 22% of women. Among NI&LC features, waist circumference, body mass index, waist-to-height ratio, waist-to-hip ratio, systolic blood pressure, and diastolic blood pressure were the most predictive variables. By using NI&LC features, models with 78.4% and 63.5% accuracy and 81.2% and 75.3% sensitivity were yielded for men and women, respectively. By incorporating NI&LC and dietary features, the accuracy of the model in women improved by 3.7%. SVM algorithms had promising potential for early detection of MetS relying on NI&LC parameters. These models can be used in prevention programs, clinical practice, and personal applications.


Routine use of clinical exome-based next-generation sequencing for evaluation of patients with thrombotic microangiopathies.
Next-generation sequencing is increasingly used for clinical evaluation of patients presenting with thrombotic microangiopathies because it allows for simultaneous interrogation of multiple complement and coagulation pathway genes known to be associated with disease. However, the diagnostic yield is undefined in routine clinical practice. Historic studies relied on case-control cohorts, did not apply current guidelines for variant pathogenicity assessment, and used targeted gene enrichment combined with next-generation sequencing. A clinically enhanced exome, targeting ~54 Mb, was sequenced for 73 patients. Variant analysis and interpretation were performed on genes with biological relevance in thrombotic microangiopathy (C3,CD46, CFB, CFH, CFI, DGKE, and THBD). CFHR3-CFHR1 deletion status was also assessed using multiplex ligation-dependent probe amplification. Variants were classified using American College of Medical Genetics and Genomics guidelines. We identified 5 unique novel and 14 unique rare variants in 25% (18/73) of patients, including a total of 5 pathogenic, 4 likely pathogenic, and 15 variants of uncertain clinical significance. Nine patients had homozygous deletions in CFHR3-CFHR1. The diagnostic yield, defined as the presence of a pathogenic variant, likely pathogenic variant or homozygous deletion of CFHR3-CFHR1, was 25% for all patients tested. Variants of uncertain clinical significance were identified in 21% (15/73) of patients.These results illustrate the expected diagnositic yield in the setting of thrombotic microangiopathies through the application of standardized variant interpretation, and highlight the utility of such an approach. Sequencing a clinically enhanced exome to enable targeted, disease-specific variant analysis is a viable approach. The moderate rate of variants of uncertain clinical significance highlights the paucity of data surrounding the variants in our cohort and illustrates the need for expanded variant curation resources to aid in thrombotic microangiopathy-related disease variant classification.


Prenatal Exposure to Fever and Infections and Academic Performance: A Multilevel Analysis.
Prenatal exposure to fever and infections has been linked to various neurodevelopmental disorders, but it is not yet known whether more subtle effects on neurodevelopment may exist as well. Therefore, we aimed to investigate whether these early-life exposures were associated with academic performance in childhood and early adolescence. Children and mothers who were enrolled in the Danish National Birth Cohort during 1996-2002 were included in this study. Information on fever and infections common in pregnancy was prospectively collected in 2 pregnancy interviews and linked with assessments of academic performance from the 2010-2013 Danish National Tests. Hierarchical multilevel linear regression of 216,350 assessments made in 71,850 children born to 67,528 mothers revealed no differences in academic performance among the children according to prenatal exposure to fever (odds ratio (OR) = 1.01, 95% confidence interval (CI): 1.00, 1.03), any infection (OR = 1.00, 95% CI: 0.99, 1.01), genitourinary infection (OR = 1.01, 95% CI: 0.99, 1.02), prolonged cough (OR = 1.00, 95% CI: 0.99, 1.02), or diarrhea (OR = 0.99, 95% CI: 0.97, 1.00). The findings were supported in different types of academic assessments, with different timings of exposure, and in sibling comparisons. This large population-based study suggested that prenatal exposure to fever and common infections does not affect the child's basic school performance.


Age at First Childbirth and Hypertension in Postmenopausal Women.
Whether age at first childbirth has an effect on hypertension incidence is unclear. The objectives of this study were to examine the relationship between age at first childbirth and hypertension and to examine whether degree of obesity, measured as body mass index, mediates age at first childbirth-related hypertension in postmenopausal women. This study analyzed 4779 postmenopausal women data from the Korea National Health and Nutrition Examination Survey 2010 to 2012. Logistic regression analyses were used to investigate relationship between age at first childbirth and hypertension. Mediation analysis was performed to examine the contribution of body mass index to age at first childbirth-related hypertension. Mean of participants' age at first childbirth and current age were 23.8 and 63.4 years, respectively. The prevalence of hypertension was 51.1%. Age at first childbirth was significantly associated with the prevalence of hypertension (odds ratio, 0.963; 95% confidence interval, 0.930-0.998; P=0.036). Women with age at first childbirth ≤19 years had significantly higher risk of hypertension (odds ratio, 1.61; 95% confidence interval, 1.17-2.23; P=0.004) compared with those >19 years. Multivariable-adjusted prevalence of hypertension was significantly lower in women who delivered the first infant at 20 to 24 (45.5%), 25 to 29 (46.1%), and ≥30 (39.9%) years compared with those at ≤19 years (58.4%). Body mass index completely mediated age at first childbirth-hypertension relationship (indirect effect: odds ratio, 0.992; 95% confidence interval, 0.987-0.998; P=0.008). Age at first childbirth was significantly associated with hypertension in postmenopausal women. Body mass index mediated the effects of age at first childbirth on hypertension.


Retinoic acid and erythropoietin maintain alveolar development in mice treated with an angiogenesis inhibitor.
Bronchopulmonary dysplasia in premature infants is characterized by inhibited alveolarization and vasculogenesis. Our goal was to generate a mouse model of inhibited alveolarization by the administration of an inhibitor of angiogenesis. We then examined the effects of retinoic acid (RA) and erythropoietin (EPO) on alveolar development in this model. Three-day-old mice were injected with a single dose of SU1498 (30 mg/kg, subcutaneously) and either concomitant RA (2 mg/kg, intraperitoneally) or EPO (2,000 IU/kg, subcutaneously) for 10 consecutive days, then harvested on Day 21. Morphometric and electron microscopic analysis, and platelet endothelial cell adhesion molecule (PECAM) immunostaining of endothelial cells, were performed on the lung tissue. In vitro assays were also performed to characterize the effects of RA on endothelial cell growth. Alveolar development was attenuated in the SU1498-treated mice, and electron microscopy demonstrated dilated and dysmorphic capillaries in alveolar walls comparable to previous findings in lungs of infants with bronchopulmonary dysplasia. RA or EPO maintained mean alveolar volume, alveolar surface area, and endothelial cell volume density in the SU1498-treated animals. RA also increased the proliferation of human fetal lung capillary endothelial precursor cells in vitro. These results suggest that the maintenance or growth of the endothelial cell population of the distal lung plays a major role in postnatal alveolar development.


Does anodal cerebellar tDCS boost transfer of after-effects from throwing to pointing during prism adaptation?
Prism Adaptation (PA) is a useful method to study the mechanisms of sensorimotor adaptation. After-effects following adaptation to the prismatic deviation constitute the probe that adaptive mechanisms occurred, and current evidence suggests an involvement of the cerebellum at this level. Whether after-effects are transferable to another task is of great interest both for understanding the nature of sensorimotor transformations and for clinical purposes. However, the processes of transfer and their underlying neural substrates remain poorly understood. Transfer from throwing to pointing is known to occur only in individuals who had previously reached a good level of expertise in throwing (e.g., dart players), not in novices. The aim of this study was to ascertain whether anodal stimulation of the cerebellum could boost after-effects transfer from throwing to pointing in novice participants. Healthy participants received anodal or sham transcranial direction current stimulation (tDCS) of the right cerebellum during a PA procedure involving a throwing task and were tested for transfer on a pointing task. Terminal errors and kinematic parameters were in the dependent variables for statistical analyses. Results showed that active stimulation had no significant beneficial effects on error reduction or throwing after-effects. Moreover, the overall magnitude of transfer to pointing did not change. Interestingly, we found a significant effect of the stimulation on the longitudinal evolution of pointing errors and on pointing kinematic parameters during transfer assessment. These results provide new insights on the implication of the cerebellum in transfer and on the possibility to use anodal tDCS to enhance cerebellar contribution during PA in further investigations. From a network approach, we suggest that cerebellum is part of a more complex circuitry responsible for the development of transfer which is likely embracing the primary motor cortex due to its role in motor memories consolidation. This paves the way for further work entailing multiple-sites stimulation to explore the role of M1-cerebellum dynamic interplay in transfer.


The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis.
S100A4, belonging to a large multifunctional S100 protein family, is a Ca2+-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there is limited information concerning S100A4 presence and function. In this study, we analyzed the expression of S100A4 and the effect of the S100A4 transcriptional inhibitor niclosamide in murine activated primary microglia. We found that S100A4 was strongly up-regulated in reactive microglia and that niclosamide prevented NADPH oxidase 2, mTOR (mammalian target of rapamycin), and NF-κB (nuclear factor-kappa B) increase, cytoskeletal rearrangements, migration, and phagocytosis. Furthermore, we found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis. Finally, we demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants. These results ascribe S100A4 as a marker of microglial reactivity, suggesting the contribution of S100A4-regulated pathways to neuroinflammation, and identify niclosamide as a possible drug in the control and attenuation of reactive phenotypes of microglia, thus opening the way to further investigation for a new application in neurodegenerative conditions.


Digitally balanced detection for optical tomography.
Analog balanced Photodetection has found extensive usage for sensing of a weak absorption signal buried in laser intensity noise. This paper proposes schemes for compact, affordable, and flexible digital implementation of the already established analog balanced detection, as part of a multichannel digital tomography system. Variants of digitally balanced detection (DBD) schemes, suitable for weak signals on a largely varying background or weakly varying envelopes of high frequency carrier waves, are introduced analytically and elaborated in terms of algorithmic and hardware flow. The DBD algorithms are implemented on a low-cost general purpose reconfigurable hardware (field-programmable gate array), utilizing less than half of its resources. The performance of the DBD schemes compare favorably with their analog counterpart: A common mode rejection ratio of 50 dB was observed over a bandwidth of 300 kHz, limited mainly by the host digital hardware. The close relationship between the DBD outputs and those of known analog balancing circuits is discussed in principle and shown experimentally in the example case of propane gas detection.


PCR assessment of HSV-1 corneal infection in animals treated with rose bengal and lissamine green B.
In vivo, the ophthalmic dye rose bengal displays profound antiviral effects against herpes simplex virus (HSV)-1, thus limiting its utility in diagnosis of epithelial keratitis when used before viral culture is performed. In contrast, lissamine green B does not possess significant antiviral activity in vivo. To determine whether polymerase chain reaction (PCR) could successfully detect HSV-1 DNA in ocular samples that have been exposed to ophthalmic dyes, animal models were used to observe the presence of infectious HSV-1 and viral DNA in eyes treated with rose bengal or lissamine green B. Animals were bilaterally infected with HSV-1 strain H129, and at daily intervals up to 16 days post infection (dpi) rose bengal or lissamine green B was instilled in the left eyes. The right eyes were not treated with dyes. Swabs of the dye-treated and untreated eyes were assayed by PCR for viral infectivity by culture and the presence of DNA specific for a fragment of the HSV-1 DNA polymerase gene. A statistically equivalent number of samples from lissamine green B-treated and untreated eyes were positive by both viral culture and PCR. In contrast, rose bengal significantly decreased the infectious virus present in ocular secretions. A total of 44% and 78% of the rose bengal-treated and untreated eye samples, respectively, were positive by culture from 1 through 16 dpi. PCR was more sensitive than culture for detection of HSV-1 in rose bengal-treated eyes, in that 74% of rose bengal-treated samples were positive by PCR compared with 44% that were positive by culture during the 16-day period studied. It was also noted that both rose bengal and lissamine green B treatments slightly prolonged the period during which viral DNA was detectable in ocular secretions by PCR, possibly because the singlet oxygen produced by these photoreactive dyes compromised ocular cellular, humoral, and nonspecific immune factors allowing viral DNA to persist for slightly longer periods. PCR can successfully detect HSV-1 DNA in ocular samples that are culture negative and contain rose bengal or lissamine green B. Visualization of ocular epithelial defects with lissamine green B does not interfere with detection of infectious virus or HSV-1 DNA.


Daclatasvir combined with peginterferon alfa-2a and ribavirin in Japanese patients infected with hepatitis C genotype 1.
New direct-acting antiviral agents are currently being developed to treat chronic HCV. The efficacy and safety of daclatasvir combined with peginterferon alfa-2a (alfa-2a) and ribavirin were assessed in a randomized, double-blind Phase IIa study of Japanese patients with chronic HCV genotype-1 infection. Japanese patients who were treatment-naive (n=25) or prior null (n=12) or partial (n=5) responders received once-daily daclatasvir 10 mg or 60 mg or placebo in combination with alfa-2a and ribavirin. Daclatasvir recipients with a protocol-defined response (HCV RNA<15 IU/ml at week 4 and undetectable at week 12) were treated for 24 weeks; placebo recipients and patients without a protocol-defined response were treated for 48 weeks. Sustained virological response at 24 weeks post-treatment (SVR24) was achieved by 89% and 100% of treatment-naive patients receiving daclatasvir 10 mg and 60 mg, respectively, versus 75% in placebo recipients. Virological failure was more frequent in prior non-responder patients, with 50% and 78% achieving SVR24 in daclatasvir 10 mg and 60 mg groups, respectively. Adverse events occurred with similar frequency among treatment groups and were consistent with the adverse event profile of alfa-2a/ribavirin alone. The most commonly reported adverse events included pyrexia, alopecia, anaemia, lymphopenia, neutropenia, pruritus and diarrhoea. Three patients discontinued treatment due to anaemia. Daclatasvir combined with alfa-2a/ribavirin in treatment-naive patients showed greater efficacy than alfa-2a/ribavirin alone and was generally well tolerated. The 60-mg dose of daclatasvir achieved the highest rates of SVR24 in both treatment-naive and non-responder populations and will be evaluated in a Phase III clinical trial.


Propranolol use in the prevention and treatment of posttraumatic stress disorder in military veterans: forgetting therapy revisited.
The alarming number of military service members returning from combat suffering from posttraumatic stress disorder (PTSD) has stimulated research into the treatment and prevention of PTSD, using pharmacological agents including the beta-adrenergic blocker propranolol. Propranolol use has been examined in three phases of memory, including acquisition, formation, and encoding; emotional response and consolidation; and retrieval and reconsolidation. Early research focused on acquisition and consolidation with encouraging but inconsistent results, with more recent research directed towards memory reconsolidation, and dissociation of emotion and fear from memories. Ethical opposition to this research and therapy came from the President's Council on Bioethics, who argued in Beyond Therapy (2003) that this type of therapy disrupts sense of self, and from a target article and ensuing discussion in theAmerican Journal of Bioethics in 2007. These arguments preceded research on the effects of propranolol on reconsolidation, which impacts the ethical discussion. If propranolol use in dissociation of emotion and fear from memory is effective in individuals with PTSD, much of the argument against propranolol use is moot. Veterans who cannot function in society due to PTSD have essentially already lost their sense of self. The ethical issue is not how treatment may affect them, but whether withholding research and treatment that may alleviate the condition is justifiable.


Prophylactic cranial irradiation in small-cell lung cancer: findings from a North Central Cancer Treatment Group Pooled Analysis.
This pooled analysis evaluated the outcomes of prophylactic cranial irradiation (PCI) in 739 small-cell lung cancer (SCLC patients with stable disease (SD) or better following chemotherapy ± thoracic radiation therapy (TRT) to examine the potential advantage of PCI in a wider spectrum of patients than generally participate in PCI trials. Three hundred eighteen patients with extensive SCLC (ESCLC) and 421 patients with limited SCLC (LSCLC) participated in four phase II or III trials. Four hundred fifty-nine patients received PCI (30 Gy/15 or 25 Gy/10) and 280 did not. Survival and adverse events (AEs) were compared. PCI patients survived significantly longer than non-PCI patients {hazard ratio [HR] = 0.61 [95% confidence interval (CI): 0.52-0.72]; P < 0.0001}. The 1- and 3-year survival rates were 56% and 18% for PCI patients versus 32% and 5% for non-PCI patients. PCI was still significant after adjusting for age, performance status, gender, stage, complete response, and number of metastatic sites (HR = 0.82, P = 0.04). PCI patients had significantly more grade 3+ AEs (64%) compared with non-PCI patients (50%) (P = 0.0004). AEs associated with PCI included alopecia and lethargy. Dose fractionation could be compared only for LSCLC patients and 25 Gy/10 was associated with significantly better survival compared with 30 Gy/15 (HR = 0.67, P = 0.018). PCI was associated with a significant survival benefit for both ESCLC and LSCLC patients who had SD or a better response to chemotherapy ± TRT. Dose fractionation appears important. PCI was associated with an increase in overall and specific grade 3+ AE rates.


gamma-Tocopheryl quinone induces apoptosis in cancer cells via caspase-9 activation and cytochrome c release.
Recently, it was suggested the potential role of gamma-tocopheryl quinone (gamma-TQ), an oxidative metabolite of gamma-tocopherol, as a powerful chemotherapeutic agent, since it was shown that this molecule exerts powerful cytotoxic effects, induces apoptosis and escapes drug resistance in human acute lymphoblastic leukemia and promyelocytic leukemia cells. We have studied the apoptogenic potential of gamma-TQ in cultured human leukemia HL-60 and colon adenocarcinoma WiDr cells, and in murine thymoma cells growing in vivo in ascites form. The cells were treated with gamma-TQ and apoptosis was evaluated morphologically by acridine-orange staining and cytofluorimetrically by Annexin V binding assay. gamma-TQ-induced apoptosis in a dose- and time-dependent manner in all the cell types tested, although HL-60 and thymoma cells were much more sensitive than WiDr cells. In HL-60 cells apoptosis was mediated by the activation of the caspase-3 cascade. In particular, we observed a time- and dose-dependent increase in the activities of the upstream caspase-9 and caspase-8 and of the downstream caspase-3. The activation of caspase-9 preceded that of caspase-8 and its specific inhibition completely prevented apoptosis. These findings and data showing the precocious release of cytochrome c from mitochondria, a decrease in Bcl-2, and a change in mitochondrial transmembrane potential (Delta psi(m)), all suggest that the intrinsic mitochondrial pathway is primarily involved in the development of gamma-TQ-induced apoptosis. The late activation of caspase-8 and data showing the partial cleavage of pro-apoptotic protein BID suggest that the initial activation of caspase-9 may be potentiated by a feedback amplification loop involving the caspase-8/BID pathway.


Additive Manufacturing of Biomaterials, Tissues, and Organs.
The introduction of additive manufacturing (AM), often referred to as three-dimensional (3D) printing, has initiated what some believe to be a manufacturing revolution, and has expedited the development of the field of biofabrication. Moreover, recent advances in AM have facilitated further development of patient-specific healthcare solutions. Customization of many healthcare products and services, such as implants, drug delivery devices, medical instruments, prosthetics, and in vitro models, would have been extremely challenging-if not impossible-without AM technologies. The current special issue of the Annals of Biomedical Engineering presents the latest trends in application of AM techniques to healthcare-related areas of research. As a prelude to this special issue, we review here the most important areas of biomedical research and clinical practice that have benefited from recent developments in additive manufacturing techniques. This editorial, therefore, aims to sketch the research landscape within which the other contributions of the special issue can be better understood and positioned. In what follows, we briefly review the application of additive manufacturing techniques in studies addressing biomaterials, (re)generation of tissues and organs, disease models, drug delivery systems, implants, medical instruments, prosthetics, orthotics, and AM objects used for medical visualization and communication.


Competitive enzyme-linked immunosorbent assay for the determination of the phenylurea herbicide chlortoluron in water and biological fluids.
A competitive ELISA method suitable for the monitoring of the herbicide chlortoluron [N-(3-chloro-4-methylphenyl)-N'-dimethylurea] in different types of water and biological fluids was developed. The production of the immunogen utilized in this work was achieved by covalently coupling bovine thryroglobulin with the synthesized hapten (N'-3-chloro-4-methylphenyl-N-carboxypropyl urea) using the N-hydroxysuccinimide active ester method. The chlortoluron antibody, raised in sheep after immunization with the immunogen, showed no cross-reactivity with a large range of pesticides, although some cross-reactivity was displayed with various phenylurea herbicides (i.e., chlorbromuron, isoproturon and metoxuron). The limit of detection of the chlortoluron ELISA method was 0.015 microgram l-1, well below the legal European limit for individual pesticides in drinking water (the EC maximum admissible concentration, 0.1 microgram l-1). In addition, reproducible and quantitative recovery of chlortoluron from water, obtained from various sources, and biological fluids was possible without any sample preparation. The ELISA technique for chlortoluron developed and described here proved to be rapid, sensitive and specific, fulfilling the needs of present legislation relating to the use and levels of pesticides in the environment.


Intrusive memories and voluntary memory of a trauma film: Differential effects of a cognitive interference task after encoding.
Methods to reduce intrusive memories (e.g., of traumatic events) should ideally spare voluntary memory for the same event (e.g., to report on the event in court). Single-trace memory accounts assume that interfering with a trace should impact both its involuntary and voluntary expressions, whereas separate-trace accounts assume these two can dissociate, allowing for selective interference. This possibility was investigated in 3 experiments. Nonclinical participants viewed a trauma film followed by an interference task (Tetris game-play after reminder cues). Next, memory for the film was assessed with various measures. The interference task reduced the number of intrusive memories (diary-based, Experiments 1 and 2), but spared performance on well-matched measures of voluntary retrieval-free recall (Experiment 1) and recognition (Experiments 1 and 2)-challenging single-trace accounts. The interference task did not affect other measures of involuntary retrieval-perceptual priming (Experiment 1) or attentional bias (Experiment 2). However, the interference task did reduce the number of intrusive memories in a laboratory-based vigilance-intrusion task (Experiments 2 and 3), irrespective of concurrent working memory load during intrusion retrieval (Experiment 3). Collectively, results reveal a robust dissociation between intrusive and voluntary memories, having ruled out key methodological differences between how these two memory expressions are assessed, namely cue overlap (Experiment 1), attentional capture (Experiment 2), and retrieval load (Experiment 3). We argue that the inability of these retrieval factors to explain the selective interference is more compatible with separate-trace than single-trace accounts. Further theoretical developments are needed to account for this clinically important distinction between intrusive memories and their voluntary counterpart. (PsycINFO Database Record (c) 2019 APA, all rights reserved).