Personality characteristics of adults with autism spectrum disorders or attention deficit hyperactivity disorder with and without substance use disorders.
We examined temperament and character profiles of 128 adults with autism spectrum disorder (ASD) or attention deficit and hyperactivity disorder (ADHD). Participants completed the abbreviated Temperament and Character Inventory. The ASD and ADHD groups showed distinct temperament profiles (ADHD: high novelty seeking, ASD: low reward dependence, high harm avoidance) and low character scores in both groups. We then stratified ASD and ADHD into current substance use disorder (SUD+), former (SUD;), or no history of Substance Use Disorder (SUD-). Novelty seeking and reward dependence were only significantly lower for ASD/SUD-, but normal for ASD/SUD; and ASD/SUD+ subgroups. Persistence scores were highest in both SUD; subgroups. We concluded that temperament profiles of ASD and ADHD patients differ significantly, and are similar to profiles reported in earlier studies, but appear to depend on the SUD status. Surprisingly, normal social orientation is found in ASD patients with former or current SUD. High persistence scores characterize patients who overcome SUD.


Mifepristone (RU 486) in Cushing's syndrome.
Mifepristone (RU 486) blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome. However, research in endogenous hypercortisolism has been hampered by the controversy related to the use of mifepristone for inducing abortion. Currently, new studies are planned to better define the role of RU 486 in Cushing's syndrome. This paper reviews the available evidence concerning the therapeutic effects and adverse events of RU 486 in Cushing's syndrome. Original articles and reviews were identified using a PubMed search strategy covering the time period until February 2007. Treatment of Cushing's syndrome with mifepristone has been reported in a total of 18 patients, with daily doses ranging from 5 to 30 mg/kg. Case reports indicate that the mifepristone-induced receptor blockade may lead to significant clinical improvement in patients with Cushing's syndrome in whom surgery and inhibitors of adrenal steroidogenesis fail to control hypercortisolism. Due to its rapid onset of action, mifepristone may be particularly useful in acute crises, e.g. in cortisol-induced psychosis. Side effects include adrenal insufficiency and, as a result of its antiprogestin action, endometrial hyperplasia in long-term treatment. Adrenal insufficiency can be assessed only by careful clinical evaluation, as the hormonal parameters are not reliable during receptor blockade, and is rapidly reversed by exogenous dexamethasone. Well-designed larger clinical trials are needed to better assess the value of this interesting drug in the treatment of Cushing's syndrome.


Cell Tracking in C. elegans with Cell Position Heatmap-Based Alignment and Pairwise Detection.
3D cell tracking in a living organism has a crucial role in live cell image analysis. Cell tracking in C. elegans has two difficulties. First, cell migration in a consecutive frame is large since they move their head during scanning. Second, cell detection is often inconsistent in consecutive frames due to touching cells and low-contrast images, and these inconsistent detections affect the tracking performance worse. In this paper, we propose a cell tracking method to address these issues, which has two main contributions. First, we introduce cell position heatmap-based non-rigid alignment with test-time fine-tuning, which can warp the detected points to near the positions at the next frame. Second, we propose a pairwise detection method, which uses the information of detection results at the previous frame for detecting cells at the current frame. The experimental results demonstrate the effectiveness of each module, and the proposed method achieved the best performance in comparison.


Contiguous phosphorylated and non-phosphorylated domains along axonal neurofilaments.
I have investigated the phosphorylation state of the medium molecular mass neurofilament protein (NF-M) along axonal neurofilaments. Cultured embryonic sensory neurons were treated with non-ionic detergent to cause the cytoskeletal polymers to splay apart from each other. Neurofilaments were visualized by double-label immunofluorescence microscopy and the proportion of their length that stained with various NF-M antibodies was determined using digital image analysis techniques. Monoclonal antibody RMO255, which binds to NF-M independently of phosphorylation state, stained an average of 98% of the neurofilament length. In contrast, monoclonal antibody RMO55, which binds specifically to a phosphorylated epitope on NF-M, stained some neurofilaments completely, some not at all, and some along part of their length. These partly stained neurofilaments exhibited single or multiple discrete segments of staining along their length separated by segments that were unstained. The average proportion of the neurofilament length that stained with this antibody was lowest proximally (12-22%, n=3) and increased along the axon to reach a maximum distally (58-87%, n=3). A converse pattern (77-87% proximally and 2-9% distally, n=3) was observed for neurons stained with monoclonal antibody FNP7, which binds to specifically to a non-phosphorylated epitope in both NF-M and the high molecular mass neurofilament protein, NF-H. Analysis of the staining of individual neurofilaments revealed a bimodal frequency distribution in which neurofilaments were more likely to be phosphorylated along either all or none of their length than along part of their length. These observations indicate that: (a) phosphorylated and non-phosphorylated neurofilaments can coexist side-by-side in these axons, (b) neurofilaments can be composed of single or multiple contiguous phosphorylated and non-phosphorylated epitope domains along their length, (c) the proportion of the neurofilament length that is phosphorylated at these epitopes increases along the axon in a proximal-to-distal manner, and (d) the pattern of phosphorylation is non-random, generating populations of phosphorylated and non-phosphorylated neurofilaments and discrete phosphorylated and non-phosphorylated domains along individual neurofilaments.


Th2 cells promote eosinophil-independent pathology in a murine model of allergic bronchopulmonary aspergillosis.
Repeated inhalation of airborne conidia derived from the fungus Aspergillus fumigatus (Af) can lead to a severe eosinophil-dominated inflammatory condition of the lung termed allergic bronchopulmonary aspergillosis (ABPA). ABPA affects about 5 million individuals worldwide and the mechanisms regulating lung pathology in ABPA are poorly understood. Here, we used a mouse model of ABPA to investigate the role of eosinophils and T cell-derived IL-4/IL-13 for induction of allergic lung inflammation. Selective deletion of IL-4/IL-13 in T cells blunted the Af-induced lung eosinophilia and further resulted in lower expression of STAT6-regulated chemokines and effector proteins such as Arginase 1, Relm-α, Relm-β, and Muc5a/c. Eosinophil-deficient ΔdblGata mice showed lower IL-4 expression in the lung and the number of Th2 cells in the lung parenchyma was reduced. However, expression of the goblet cell markers Clca1 and Muc5a/c, abundance of mucin-positive cells, as well as weight gain of lungs were comparable between Af-challenged ΔdblGata and WT mice. Based on these results, we conclude that T cell-derived IL-4/IL-13 is essential for Af-induced lung eosinophilia and inflammation while eosinophils may play a more subtle immunomodulatory role and should not simply be regarded as pro-inflammatory effector cells in ABPA.


Inhaled corticosteroids in COPD and onset of type 2 diabetes and osteoporosis: matched cohort study.
Some studies suggest an association between onset and/or poor control of type 2 diabetes mellitus and inhaled corticosteroid (ICS) therapy for chronic obstructive pulmonary disease (COPD), and also between increased fracture risk and ICS therapy; however, study results are contradictory and these associations remain tentative and incompletely characterized. This matched cohort study used two large UK databases (1983-2016) to study patients (≥ 40 years old) initiating ICS or long-acting bronchodilator (LABD) for COPD from 1990-2015 in three study cohorts designed to assess the relation between ICS treatment and (1) diabetes onset (N = 17,970), (2) diabetes progression (N = 804), and (3) osteoporosis onset (N = 19,898). Patients had ≥ 1-year baseline and ≥ 2-year outcome data. Matching was via combined direct matching and propensity scores. Conditional proportional hazards regression, adjusting for residual confounding after matching, was used to compare ICS vs. LABD and to model ICS exposures. Median follow-up was 3.7-5.6 years/treatment group. For patients prescribed ICS, compared with LABD, the risk of diabetes onset was significantly increased (adjusted hazard ratio 1.27; 95% CI, 1.07-1.50), with overall no increase in risk of diabetes progression (adjusted hazard ratio 1.04; 0.87-1.25) or osteoporosis onset (adjusted hazard ratio 1.13; 0.93-1.39). However, the risks of diabetes onset, diabetes progression, and osteoporosis onset were all significantly increased, with evident dose-response relationships for all three outcomes, at mean ICS exposures of 500 µg/day or greater (vs. < 250 µg/day, fluticasone propionate-equivalent). Long-term ICS therapy for COPD at mean daily exposure of ≥ 500 µg is associated with an increased risk of diabetes, diabetes progression, and osteoporosis.


Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment.
Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.


The role of the biomechanics analyst in swimming training and competition analysis.
Swimming analysts aid coaches and athletes in the decision-making by providing evidence-based recommendations. The aim of this narrative review was to report the best practices of swimming analysts that have been supporting high-performance athletes. It also aims to share how swimming analysts can translate applied research into practice. The role of the swimming analyst, as part of a holistic team supporting high-performance athletes, has been expanding and is needed to be distinguished from the job scope of a swimming researcher. As testing can be time-consuming, analysts must decide what to test and when to conduct the evaluation sessions. Swimming analysts engage in the modelling and forecast of the performance, that in short- and mid-term can help set races target-times, and in the long-term provide insights on talent and career development. Races can be analysed by manual, semi-automatic or fully automatic video analysis with single or multi-cameras set-ups. The qualitative and quantitative analyses of the swim strokes, start, turns, and finish are also part of the analyst job scope and associated with race performance goals. Land-based training is another task that can be assigned to analysts and aims to enhance the performance, prevent musculoskeletal injuries and monitor its risk factors.


Testicular oocytes in smallmouth bass in northeastern Minnesota in relation to varying levels of human activity.
Testicular oocytes (TOs) have been found in black bass (Micropterus spp.) from many locations in North America. The presence of TOs is often assumed to imply exposure to estrogenic endocrine disrupting compounds (EDCs); however, a definitive causal relationship has yet to be established, and TO prevalence is not consistently low in fish from areas lacking evident EDC sources. This might indicate any of a number of situations: 1) unknown or unidentified EDCs or EDC sources, 2) induction of TOs by other stressors, or 3) testicular oocytes occurring spontaneously during normal development. In the present study, we analyzed TO occurrence in smallmouth bass (Micropterus dolomieu) from 8 populations in northeastern Minnesota watersheds with differing degrees of human development and, hence, presumed likelihood of exposure to anthropogenic chemicals. Three watersheds were categorized as moderately developed, based on the presence of municipal wastewater discharges and higher human population density (4-81 per km2 ), and 5 watersheds were minimally developed, with very low human population density (0-1 per km2 ) and minimal built environment. Testicular tissues from mature fish were evaluated using a semiquantitative method that estimated TO density, normalized by cross-sectional area. Testicular oocyte prevalence and density among populations from moderately developed watersheds was higher than in populations from minimally developed watersheds. However, TO prevalence was unexpectedly high and variable (7-43%) in some populations from minimally developed watersheds, and only weak evidence was found for a relationship between TO density and watershed development, suggesting alternative or more complex explanations for TO presence in smallmouth bass from this region. Environ Toxicol Chem 2017;36:3424-3435. © 2017 SETAC.


Competing Mechanisms of Stress-Assisted Diffusivity and Stretch-Activated Currents in Cardiac Electromechanics.
We numerically investigate the role of mechanical stress in modifying the conductivity properties of cardiac tissue, and also assess the impact of these effects in the solutions generated by computational models for cardiac electromechanics. We follow the recent theoretical framework from Cherubini et al. (2017), proposed in the context of general reaction-diffusion-mechanics systems emerging from multiphysics continuum mechanics and finite elasticity. In the present study, the adapted models are compared against preliminary experimental data of pig right ventricle fluorescence optical mapping. These data contribute to the characterization of the observed inhomogeneity and anisotropy properties that result from mechanical deformation. Our novel approach simultaneously incorporates two mechanisms for mechano-electric feedback (MEF): stretch-activated currents (SAC) and stress-assisted diffusion (SAD); and we also identify their influence into the nonlinear spatiotemporal dynamics. It is found that (i) only specific combinations of the two MEF effects allow proper conduction velocity measurement; (ii) expected heterogeneities and anisotropies are obtained via the novel stress-assisted diffusion mechanisms; (iii) spiral wave meandering and drifting is highly mediated by the applied mechanical loading. We provide an analysis of the intrinsic structure of the nonlinear coupling mechanisms using computational tests conducted with finite element methods. In particular, we compare static and dynamic deformation regimes in the onset of cardiac arrhythmias and address other potential biomedical applications.


Identification of the visceral pain pathway activated by noxious colorectal distension in mice.
In patients with irritable bowel syndrome, visceral pain is evoked more readily following distension of the colorectum. However, the identity of extrinsic afferent nerve pathway that detects and transmits visceral pain from the colorectum to the spinal cord is unclear. In this study, we identified which extrinsic nerve pathway(s) underlies nociception from the colorectum to the spinal cord of rodents. Electromyogram recordings were made from the transverse oblique abdominal muscles in anesthetized wild type (C57BL/6) mice and acute noxious intraluminal distension stimuli (100-120 mmHg) were applied to the terminal 15 mm of colorectum to activate visceromotor responses (VMRs). Lesioning the lumbar colonic nerves in vivo had no detectable effect on the VMRs evoked by colorectal distension. Also, lesions applied to the right or left hypogastric nerves failed to reduce VMRs. However, lesions applied to both left and right branches of the rectal nerves abolished VMRs, regardless of whether the lumbar colonic or hypogastric nerves were severed. Electrical stimulation applied to either the lumbar colonic or hypogastric nerves in vivo, failed to elicit a VMR. In contrast, electrical stimulation (2-5 Hz, 0.4 ms, 60 V) applied to the rectum reliably elicited VMRs, which were abolished by selective lesioning of the rectal nerves. DiI retrograde labeling from the colorectum (injection sites 9-15 mm from the anus, measured in unstretched preparations) labeled sensory neurons primarily in dorsal root ganglia (DRG) of the lumbosacral region of the spinal cord (L6-S1). In contrast, injection of DiI into the mid to proximal colon (injection sites 30-75 mm from the anus, measured in unstretched preparations) labeled sensory neurons in DRG primarily of the lower thoracic level (T6-L2) of the spinal cord. The visceral pain pathway activated by acute noxious distension of the terminal 15 mm of mouse colorectum is transmitted predominantly, if not solely, through rectal/pelvic afferent nerve fibers to the spinal cord. The sensory neurons of this spinal afferent pathway lie primarily in the lumbosacral region of the spinal cord, between L6 and S1.


Impairment of pulmonary vascular reserve and right ventricular systolic reserve in pulmonary arterial hypertension.
Exercise capacity is impaired in pulmonary arterial hypertension (PAH). We hypothesized that cardiovascular reserve abnormalities would be associated with impaired hemodynamic response to pharmacological stress and worse outcome in PAH. Eighteen PAH patients (p) group 1 NYHA class II/III and ten controls underwent simultaneous right cardiac catheterization and intravascular ultrasound at rest and during low dose-dobutamine (10 mcg/kg/min) with trendelenburg (DST). We estimated cardiac output (CO), pulmonary vascular resistance (PVR) and capacitance (PC), and PA elastic modulus (EM). We concomitantly measured tricuspid annular plane systolic excursion (TAPSE), RV myocardial peak systolic velocity (Sm) and isovolumic myocardial acceleration (IVA) in PAH patients. Based on the rounded mean + 2 SD of the increase in mPAP in our healthy control group during DST (2.8 + 1.8 mm Hg), PAH p were divided into two groups according to mean PA pressure (mPAP) response during DST, 1: ΔmPAP > 5 mm Hg and 2: ΔmPAP ≤ 5 mm Hg. Cardiovascular reserve was estimated as the change (delta, Δ) during DST compared with rest, including ΔmPAP with respect to ΔCO (ΔmPAP/ΔCO). All patients were prospectively followed up for 2 years. PAH p showed significant lower heart rate and CO increase than controls during DST, with a significant mPAP and pulse PAP increase and higher ΔmPAP/ΔCO (p < 0.05). Neither hemodynamic, IVUS and echocardiographic data were different between both PAH groups at rest. In group 1, DST caused a higher ΔEM, ΔmPAP/ΔCO, ΔPVR, and ΔTAPSE than group 2, with a lower IVA increase and a negative ΔSV (p < 0.05). TAPSE correlated with mPAP and RVP (p < 0.05) and, IVA and Sm correlated with CO (p < 0.05). ΔEM correlated with ΔmPAP and ΔIVA with ΔCO (p < 0.05). There were two deaths/pulmonary transplantations in group 1 and one death in group 2 during the follow-up (p > 0.05). Pulmonary vascular reserve and RV systolic reserve are significantly impaired in patients with PAH. The lower recruitable cardiovascular reserve is significantly related to a worse hemodynamic response to DST and it could be associated with a poor clinical outcome.


Effect of alcohol consumption on food energy intake: a systematic review and meta-analysis.
The relationship between alcohol consumption and body weight is complex and inconclusive being potentially mediated by alcohol type, habitual consumption levels and sex differences. Heavy and regular alcohol consumption has been positively correlated with increasing body weight, although it is unclear whether this is due to alcohol consumption per se or to additional energy intake from food. This review explores the effects of alcohol consumption on food energy intake in healthy adults. CINAHL Plus, EMBASE, Medline and PsycINFO were searched through February 2018 for crossover and randomised controlled trials where an alcohol dose was compared with a non-alcohol condition. Study quality was assessed using the Effective Public Health Practice Project tool. A total of twenty-two studies involving 701 participants were included from the 18 427 papers retrieved. Studies consistently demonstrated no compensation for alcoholic beverage energy intake, with dietary energy intake not decreasing due to alcoholic beverage ingestion. Meta-analyses using the random-effects model were conducted on twelve studies and demonstrated that alcoholic beverage consumption significantly increased food energy intake and total energy intake compared with a non-alcoholic comparator by weighted mean differences of 343 (95 % CI 161, 525) and 1072 (95 % CI 820, 1323) kJ, respectively. Generalisability is limited to younger adults (18-37 years), and meta-analyses for some outcomes had substantial statistical heterogeneity or evidence of small-study effects. This review suggests that adults do not compensate appropriately for alcohol energy by eating less, and a relatively modest alcohol dose may lead to an increase in food consumption.


Spatial and temporal control of transgene expression through ultrasound-mediated induction of the heat shock protein 70B promoter in vivo.
Adenoviral vectors have been constructed that express the transgenes luciferase (Adeno-HSP-Luc) or Fas ligand (Adeno-HSP-FasL) under the control of the heat shock protein 70B (hsp70B) promoter. Cultures infected with Adeno-HSP-Luc transiently expressed high levels of luciferase after heat shock. When cultures infected with Adeno-HSP-FasL were maintained at 37 degrees C, no transgene expression was observed, but when cultures were exposed to heat stress, transgene expression resulted in apoptotic cell death. In vivo, transgene expression was induced by ultrasound-mediated heating of adenovirus-infected tissue. In mice or rats injected with the Adeno-HSP-Luc construct, high levels of localized expression of luciferase activity were observed in regions subjected to ultrasound-mediated irradiation. Adeno-HSP-FasL was administered systemically to mice via the tail vein to evaluate safety. Animals receiving Adeno-HSP-FasL in the absence of ultrasound treatment did not display liver toxicity, whereas animals receiving ultrasound treatment to induce the expression of Fas ligand from the hsp70B promoter had significant increases in serum levels of liver enzymes. These data demonstrate that combining the inducible hsp70B promoter with ultrasound induction allows safe local expression of cytotoxic genes with possible therapeutic utility.


Detecting in situ copepod diet diversity using molecular technique: development of a copepod/symbiotic ciliate-excluding eukaryote-inclusive PCR protocol.
Knowledge of in situ copepod diet diversity is crucial for accurately describing pelagic food web structure but is challenging to achieve due to lack of an easily applicable methodology. To enable analysis with whole copepod-derived DNAs, we developed a copepod-excluding 18S rDNA-based PCR protocol. Although it is effective in depressing amplification of copepod 18S rDNA, its applicability to detect diverse eukaryotes in both mono- and mixed-species has not been demonstrated. Besides, the protocol suffers from the problem that sequences from symbiotic ciliates are overrepresented in the retrieved 18S rDNA libraries. In this study, we designed a blocking primer to make a combined primer set (copepod/symbiotic ciliate-excluding eukaryote-common: CEEC) to depress PCR amplification of symbiotic ciliate sequences while maximizing the range of eukaryotes amplified. We firstly examined the specificity and efficacy of CEEC by PCR-amplifying DNAs from 16 copepod species, 37 representative organisms that are potential prey of copepods and a natural microplankton sample, and then evaluated the efficiency in reconstructing diet composition by detecting the food of both lab-reared and field-collected copepods. Our results showed that the CEEC primer set can successfully amplify 18S rDNA from a wide range of isolated species and mixed-species samples while depressing amplification of that from copepod and targeted symbiotic ciliate, indicating the universality of CEEC in specifically detecting prey of copepods. All the predetermined food offered to copepods in the laboratory were successfully retrieved, suggesting that the CEEC-based protocol can accurately reconstruct the diets of copepods without interference of copepods and their associated ciliates present in the DNA samples. Our initial application to analyzing the food composition of field-collected copepods uncovered diverse prey species, including those currently known, and those that are unsuspected, as copepod prey. While testing is required, this protocol provides a useful strategy for depicting in situ dietary composition of copepods.


Arrival and magnetization of carbonaceous chondrites in the asteroid belt before 4562 million years ago.
Meteorite magnetizations can provide rare insight into early Solar System evolution. Such data take on new importance with recognition of the isotopic dichotomy between non-carbonaceous and carbonaceous meteorites, representing distinct inner and outer disk reservoirs, and the likelihood that parent body asteroids were once separated by Jupiter and subsequently mixed. The arrival time of these parent bodies into the main asteroid belt, however, has heretofore been unknown. Herein, we show that weak CV (Vigarano type) and CM (Mighei type) carbonaceous chondrite remanent magnetizations indicate acquisition by the solar wind 4.2 to 4.8 million years after Ca-Al-rich inclusion (CAI) formation at heliocentric distances of ~2-4 AU. These data thus indicate that the CV and CM parent asteroids had arrived near, or within, the orbital range of the present-day asteroid belt from the outer disk isotopic reservoir within the first 5 million years of Solar System history.


Anaesthetic management of people with multiple sclerosis.
There is a lack of published guidelines on the management of patients with multiple sclerosis (MS) undergoing procedures that require anaesthesia and respective advice is largely based on retrospective studies or case reports. The aim of this paper is to provide recommendations for anaesthetists and neurologists for the management of patients with MS requiring anaesthesia. This review covers issues related to the anaesthetic management of patients with MS, with a focus on preoperative assessment, choice of anaesthetic techniques and agents, side-effects of drugs used during anaesthesia and their potential impact on the disease evolution, drug interactions that may occur, and the need to use monitoring devices. A systematic PubMed research was performed to retrieve relevant articles.


Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene transcription.
Elevation of glucose transport is an alteration common to most virally induced tumors. Rat fibroblasts transformed with wild-type or a temperature-sensitive Fujinami sarcoma virus (FSV) were studied in order to determine the mechanisms underlying the increased transport. Five- to tenfold increases in total cellular glucose transporter protein in response to transformation were accompanied by similar increases in transporter messenger RNA levels. This, in turn, was preceded by an absolute increase in the rate of glucose transporter gene transcription within 30 minutes after shift of the temperature-sensitive FSV-transformed cells to the permissive temperature. The transporter messenger RNA levels in transformed fibroblasts were higher than those found in proliferating cells maintained at the nonpermissive temperature. The activation of transporter gene transcription by transformation represents one of the earliest known effects of oncogenesis on the expression of a gene encoding a protein of well-defined function.


Posterior petrous face meningiomas presenting with Ménière's-like syndrome: a case series and review of the literature.
Ménière's disease is an inner ear disorder classically characterized by fluctuating hearing loss, tinnitus, and aural fullness accompanied by episodic vertigo. While the pathogenesis of Ménière's remains under debate, histopathological analyses implicate endolymphatic sac dysfunction with inner ear fluid homeostatic dysregulation. Little is known about whether external impingement of the endolymphatic sac by tumors may present with Ménière's-like symptoms. The authors present a case series of 7 patients with posterior fossa meningiomas that involved the endolymphatic sac and new onset of Ménière's-like symptoms and review the literature on this rare clinical entity. A retrospective review of patients undergoing resection of a posterior petrous meningioma was performed at the authors' institution. Inclusion criteria were age older than 18 years; patients presenting with Ménière's-like symptoms, including episodic vertigo, aural fullness, tinnitus, and/or hearing loss; and tumor location overlying the endolymphatic sac. There were 7 cases of posterior petrous face meningiomas involving the vestibular aperture presenting with Ménière's-like symptoms. Imaging and intraoperative examination confirmed no cranial nerve VIII compression or labyrinthine artery involvement accounting for audiovestibular symptoms. Of the 7 patients in the series, 6 experienced significant improvement or resolution of their vertigo, and all 7 had improvement or resolution of their tinnitus after resection. Of the 5 patients who had preoperative hearing loss, 2 experienced improvement or resolution of their ipsilateral preoperative hearing deficit, whereas the other 3 had unchanged hearing loss compared to preoperative evaluation. Petrous face meningiomas overlying the endolymphatic sac can present with a Ménière's syndrome. Early recognition and microsurgical excision of these tumors is critical for resolution of most symptoms and stabilization of hearing loss.


Phylogenetic analysis of the hemagglutinin genes of 12 H9N2 influenza viruses isolated from chickens in Iran from 2003 to 2005.
In the present study, the hemagglutinin genes from 12 influenza viruses of the H9N2 subtype were isolated from chicken flocks in different provinces of Iran from 2003 to 2005, amplified and sequenced. All of the 12 isolates showed similar sequences at the cleavage site, RSSF/GLF, bearing eight potential glycosylation sites and sharing the characteristic deduced amino acid residues alanine-190, glutamine-226, and glutamine-227 at the receptor-binding site. Ten out of these 12 isolates possessed leucine at position 226, which prevails in the sequences found in human H2 and H3 strains. Overall, the presence in these Iranian poultry H9N2 viruses of the sequence known to bind to human-type receptors and the presence of antibodies in the human population of Iran to H9N2 showed that it is possible for circulating H9N2 avian influenza viruses in Iran to infect humans. Hence, extensive surveillance of H9N2 in this country is highly recommended.


Cell wall-related bionumbers and bioestimates of Saccharomyces cerevisiae and Candida albicans.
Bionumbers and bioestimates are valuable tools in biological research. Here we focus on cell wall-related bionumbers and bioestimates of the budding yeast Saccharomyces cerevisiae and the polymorphic, pathogenic fungus Candida albicans. We discuss the linear relationship between cell size and cell ploidy, the correlation between cell size and specific growth rate, the effect of turgor pressure on cell size, and the reason why using fixed cells for measuring cellular dimensions can result in serious underestimation of in vivo values. We further consider the evidence that individual buds and hyphae grow linearly and that exponential growth of the population results from regular formation of new daughter cells and regular hyphal branching. Our calculations show that hyphal growth allows C. albicans to cover much larger distances per unit of time than the yeast mode of growth and that this is accompanied by strongly increased surface expansion rates. We therefore predict that the transcript levels of genes involved in wall formation increase during hyphal growth. Interestingly, wall proteins and polysaccharides seem barely, if at all, subject to turnover and replacement. A general lesson is how strongly most bionumbers and bioestimates depend on environmental conditions and genetic background, thus reemphasizing the importance of well-defined and carefully chosen culture conditions and experimental approaches. Finally, we propose that the numbers and estimates described here offer a solid starting point for similar studies of other cell compartments and other yeast species.


[Premorbid stage in the development of anxiety in children].
The peculiarities of premorbid stage in children, aged 5-15 years, with ICD-10 diagnosis of anxiety-phobic disorders have been studied. The patient's mental state has been described earlier (Savostyanova, 2001). Retrospective evaluation of the patient's state in premorbid allowed to detect the disturbances in personality formation, anxiety phobic reactions and autochthon phases, represented by continuum of subclinical disorders, from floating anxiety to the signs of vital anxiety. These traits are distinguished by instability and inconsistency as well as by mild expression, which did not reach a level of manifest disorders. Personality of the children, who develop anxiety phobic disorders, may be emotionally labile as well as rigid one inclining to negative effectiveness. Hereditable and environment factors influencing anxiety phobic disorders development were detected. The premorbid traits are concluded to reflect inherited anxiety diathesis, which determines the peculiarities of reaction to negative environment and results not only in personality development but also in the large spectrum of future anxiety phobic symptoms.


Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids.
Varieties of alkaloids are known to be produced by various organisms, including bacteria, fungi and plants, as secondary metabolites that exhibit useful bioactivities. However, understanding of how those metabolites are biosynthesized still remains limited, because most of these compounds are isolated from plants and at a trace level of production. In this review, we focus on recent efforts in identifying the genes responsible for the biosynthesis of those nitrogen-containing natural products and elucidating the mechanisms involved in the biosynthetic processes. The alkaloids discussed in this review are ditryptophenaline (dimeric diketopiperazine alkaloid), saframycin (tetrahydroisoquinoline alkaloid), strictosidine (monoterpene indole alkaloid), ergotamine (ergot alkaloid) and opiates (benzylisoquinoline and morphinan alkaloid). This review also discusses the engineered biosynthesis of these compounds, primarily through heterologous reconstitution of target biosynthetic pathways in suitable hosts, such as Escherichia coli, Saccharomyces cerevisiae and Aspergillus nidulans. Those heterologous biosynthetic systems can be used to confirm the functions of the isolated genes, economically scale up the production of the alkaloids for commercial distributions and engineer the biosynthetic pathways to produce valuable analogs of the alkaloids. In particular, extensive involvement of oxidation reactions catalyzed by oxidoreductases, such as cytochrome P450s, during the secondary metabolite biosynthesis is discussed in details.


Locoregionally advanced nasopharyngeal carcinoma: induction chemotherapy with cisplatin and 5-fluorouracil followed by radiotherapy and concurrent cisplatin: a phase II study.
Chemoradiotherapy is the current standard of care for locoregionally advanced nasopharyngeal carcinoma. The purpose of this study was to assess the feasibility and efficacy of induction chemotherapy (CHT) followed by concomitant chemoradiotherapy in this patient population. In this single-arm, phase II study, patients with locoregionally advanced nasopharyngeal carcinoma were treated with 3 cycles of induction CHT with cisplatin (100 mg/m(2) on day 1) and 5-fluorouracil (1,000 mg/m(2) continuous infusion on days 1-4) followed by 3 cycles of cisplatin (100 mg/m(2) on days 1, 22 and 43) and concurrent radiotherapy up to 70 Gy. The primary endpoint was objective response. Thirty-four patients were enrolled, and all completed both induction treatment and subsequent chemoradiotherapy. Objective response rates were 79.4% (95% CI 62.1-91.3) and 85.3% (95% CI 68.9-95.0) after induction CHT and chemoradiation, respectively. Treatment was well tolerated and toxicity was manageable. At a median follow-up of 29 months, 3-year overall survival and progression-free survival rates are 80.0% (95% CI 0.64-0.95) and 54.0% (95% CI 0.36-0.73), respectively. Induction CHT with cisplatin and 5-fluorouracil followed by concomitant chemoradiotherapy is a feasible and active regimen for patients with stage IIB-IVB nasopharyngeal carcinoma. This regimen resulted in excellent locoregional disease control and overall survival.


Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus.
Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017-2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.


Using Process Mining Techniques to Study Workflows in a Pre-operative Setting.
Information technologies have transformed healthcare delivery and promise to improve efficiency and quality of care. However, in-depth analysis of EHR-mediated workflows is challenging. Our goal was to apply process mining, in combination with observational techniques, to understand EHR-based workflows. We reviewed nearly 76,000 event logs from 15 providers and supporting staff, and 142 patients in a pre-operative setting and we inspected 3 weeks of interviews and video observations. We found that on average 44 minutes were spent per patient interacting with the EHR, 55% of the time of the patient visit was spent by personnel interacting with the EHR and for over 5% of the time personnel used or reviewed paper-based artifacts. We also discovered the handover-of-care network and compared frequency of interactions between personnel. This study suggests that applying process mining in combination with observational techniques has vast potential for informing Mayo Clinic in the forthcoming EHR conversion.


The mucosal response in the excluded limb after jejunoileal bypass for morbid obesity.
Twelve patients underwent a takedown of the jejunoileal bypass with restoration of normal continuity of the intestine. Specimens were obtained for biopsy from the excluded proximal jejunum and distal ileum as well as the distal in continuity jejunum. Hypertrophy of the mucosa was observed in the in continuity segment, as previously described. Villi of the bypassed jejunum displayed no evidence of hypertrophy or of atrophy and were identical in size to villous measurements prior to creation of the jejunoileal bypass. At the ultrastructural level, absorptive cells of bypassed jejunal segments exhibited normal morphologic characteristics. There was no indication of cellular immaturity above the level of the intestinal crypts. In contrast, villi of bypassed ileum, near the colonic anastomosis, demonstrated hypertrophy, presumably reflecting reflux of luminal material into this segment of bypassed intestine. The results of this investigation support the concept that significant morphologic alterations of the mucosa do not occur in totally bypassed segments of intestine after the jejunoileal bypass procedures with attainment of weight stabilization.


Osteoblasts increase proliferation and release of pro-angiogenic interleukin 8 by native human acute myelogenous leukemia blasts.
Interactions between acute myelogenous leukemia (AML) blasts and non-leukemic cells in the bone marrow seem to be important for both disease development and susceptibility to chemotherapy. Recent studies have focused on the endothelial cells, but other non-leukemic cells may also be involved. In the present study we investigated how osteoblasts affect native human AML blasts. AML cells were derived from a large group of consecutive patients. The AML blasts and osteoblastic sarcoma cell lines (Cal72, SJSA-1) were incubated together in different chambers separated by a semipermeable membrane. We investigated effects of co-culture on proliferation, apoptosis and cytokine release. The cross-talk between these two cell populations, achieved via release of soluble mediators, resulted in increased AML blast proliferation, including increased proliferation of clonogenic progenitors, but did not affect spontaneous in vitro apoptosis. Both interleukin (IL) 1-b and granulocyte-macrophage colony-stimulating factor were involved in this growth-enhancing cross-talk, and normal osteoblasts could also increase the AML blast proliferation. Furthermore, co-culture of AML blasts with osteoblastic sarcoma cells as well as normal osteoblasts increased the levels of the pro-angiogenic mediator IL8. Our in vitro results suggest that the release of soluble mediators by osteoblasts supports leukemic hematopoiesis through two major mechanisms: (i) direct enhancement of AML blast proliferation; and (ii) enhanced angiogenesis caused by increased IL8 levels.


Reward Responsiveness, Optimism, and Social and Mental Functioning in Children Aged 6-7: Protocol of a Cross-Sectional Pilot Study.
There is evidence that reward responsiveness and optimism are associated with mental and social functioning in adolescence and adulthood, but it is unknown if this is also the case for young children. Part of the reason for this gap in the literature is that the instruments that are used to assess reward responsiveness and optimism in adolescents and adults are usually not suitable for young children. Two behavioral tasks to assess reward learning, a questionnaire on reward responsiveness, and a questionnaire on optimism/pessimism will be tested on their feasibility and reliability in children aged 6-7. Depending on their feasibility and reliability, these instruments will also be used to investigate if reward responsiveness and optimism are associated with mental and social functioning in young children. For this cross-sectional pilot study, we adapted a number of tasks and questionnaires to the needs of 6-7-year-old children, by simplification of items, oral rather than written assessment, and reducing the number of conditions and items. We will approach teachers and, with their help, aim to include 70 children aged 6-7 to assess the feasibility and reliability of the tasks and questionnaires. Feasibility measures that will be reported are the proportion of children completing the task/questionnaire, the proportion of children that were able to explain the instructions in their own words to the researcher, and the proportion of children that correctly answered the control questions. The reliability of the scales will be assessed by computing Cronbach α and item-total score correlations and the reliability of the tasks by correlations between different consecutive blocks of trials. Ethics approval was obtained from the Ethics Committee of the Department of Pedagogy and Educational Sciences. Data collection was originally planned in March and April 2020, but has been postponed due to Corona virus regulations. We expect to collect the data in the first half of 2021. The findings will be disseminated in preprints and peer-reviewed publications. The development of feasible and reliable instruments for assessing reward responsiveness and optimism in young children is expected to benefit future research on underlying mechanisms of mental and social functioning in young children. If the instruments assessed in this study are usable with young children, it would be particularly interesting to include them in cohort studies because this would enable investigating not only concurrent associations, but also prospective associations between reward responsiveness and optimism early in life and mental and social functioning later in life. If, as we hypothesize, reward responsiveness and optimism are not only associated with (prospective) mental and social functioning in adults and adolescents but also in young children, this could provide a way of identifying vulnerable children already at an early stage. PRR1-10.2196/18902.


Harnessing intrinsic fluorescence for typing of secondary structures of DNA.
High-throughput investigation of structural diversity of nucleic acids is hampered by the lack of suitable label-free methods, combining fast and cheap experimental workflow with high information content. Here, we explore the use of intrinsic fluorescence emitted by nucleic acids for this scope. After a preliminary assessment of suitability of this phenomenon for tracking conformational changes of DNA, we examined steady-state emission spectra of an 89-membered set of oligonucleotides with reported conformation (G-quadruplexes (G4s), i-motifs, single- and double-strands) by means of multivariate analysis. Principal component analysis of emission spectra resulted in successful clustering of oligonucleotides into three corresponding conformational groups, without discrimination between single- and double-stranded structures. Linear discriminant analysis was exploited for the assessment of novel sequences, allowing the evaluation of their G4-forming propensity. Our method does not require any labeling agent or dye, avoiding the related bias, and can be utilized to screen novel sequences of interest in a high-throughput and cost-effective manner. In addition, we observed that left-handed (Z-) G4 structures were systematically more fluorescent than most other G4 structures, almost reaching the quantum yield of 5'-d[(G3T)3G3]-3' (G3T, the most fluorescent G4 structure reported to date).


Structural and functional, empirical and modeled connectivity in the cerebral cortex of the rat.
Connectomics data from animal models provide an invaluable opportunity to reveal the complex interplay between structure and function in the mammalian brain. In this work, we investigate the relationship between structural and functional connectivity in the rat brain cortex using a directed anatomical network generated from a carefully curated meta-analysis of published tracing data, along with resting-state functional MRI data obtained from a group of 14 anesthetized Wistar rats. We found a high correspondence between the strength of functional connections, measured as blood oxygen level dependent (BOLD) signal correlations between cortical regions, and the weight of the corresponding anatomical links in the connectome graph (maximum Spearman rank-order correlation ρ=0.48). At the network-level, regions belonging to the same functionally defined community tend to form more mutual weighted connections between each other compared to regions located in different communities. We further found that functional communities in resting-state networks are enriched in densely connected anatomical motifs. Importantly, these higher-order structural subgraphs cannot be explained by lower-order topological properties, suggesting that dense structural patterns support functional associations in the resting brain. Simulations of brain-wide resting-state activity based on neural mass models implemented on the empirical rat anatomical connectome demonstrated high correlation between the simulated and the measured functional connectivity (maximum Pearson correlation ρ=0.53), further suggesting that the topology of structural connections plays an important role in shaping functional cortical networks.


The viability of a proposed psychoeducational neurodiversity approach in children services: The PANDA (the Portsmouth alliance's neuro-diversity approach).
People with Neurodevelopmental (ND) conditions are often unfairly stereotyped by society, without fully appreciating their strengths. As a result, their advantageous behaviours may be overlooked or ignored. Despite wide psychoeducation on ND in society there is a push from the scientific and ND community to move from a binary diagnostic system to an approach that encompasses the spectrum experienced by individuals. In view of this, we have developed the Portsmouth Alliance Neuro-Diversity Approach (PANDA), a coproduced method which helps facilitate understanding, communication and early support for individuals who may be Neuro-Diverse. 51 young people, their parents and attached professionals participated in the approach's feasibility to improve wellbeing and symptom management measured by quantitative and qualitative means. Results showed a significant improvement in the child's wellbeing, but not symptom management. Overall, this indicates the PANDA could facilitate a more holistic approach for referrals, information gathering, psychoeducation and cross-system relationship building to be used in conjunction with a traditional pathway. Though, this study is limited in scope, its main purpose is to inform future development of the approach. Additionally, more research investigating the specific narrative, and separate structure of the PANDA would be required to highlight the strengths and limitations of implementation.


Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1alpha in human melanoma cells.
Endothelin (ET) B receptor (ET(B)R), which is overexpressed in human cutaneous melanomas, promotes tumorigenesis upon activation by ET-1 or ET-3, thus representing a potential novel therapeutic target. Hypoxia-inducible factor-1alpha (HIF-1alpha) is the transcriptional factor that conveys signaling elicited by hypoxia and growth factor receptors. Here, we investigated the interplay between ET axis and hypoxia in primary and metastatic melanoma cell lines. We report that under normoxic conditions, ET(B)R activation by ET-1/ET-3 enhances vascular endothelial growth factor (VEGF) up-regulation, cyclooxygenase (COX)-1/COX-2 protein expression and COX-2 promoter activity, prostaglandin E(2) (PGE(2)) production, and do so to a greater extent under hypoxia. Moreover, COX-1/COX-2 inhibitors block ET-induced PGE(2) and VEGF secretion, matrix metalloproteinase (MMP) activation, and cell invasion, indicating that both enzymes function as downstream mediators of ET-induced invasive properties. The ET(B)R selective antagonist BQ788 or transfection with ET(B)R small interfering RNA (siRNA) block the ET-mediated effects. ETs also increase HIF-1alpha expression under both normoxic and hypoxic conditions and its silencing by siRNA desensitizes COX-2 transcriptional activity, PGE(2) and VEGF production, and MMP activation in response to ET-3, implicating, for the first time, HIF-1alpha/COX as downstream targets of ET(B)R signaling leading to invasiveness. In melanoma xenografts, specific ET(B)R antagonist suppresses tumor growth, neovascularization, and invasiveness-related factors. Collectively, these results identify a new mechanism whereby ET-1/ET-3/ET(B)R axis can promote and interact with the HIF-1alpha-dependent machinery to amplify the COX-mediated invasive behavior of melanoma. New therapeutic strategies using specific ET(B)R antagonist could provide an improved approach to the treatment of melanoma by inhibiting tumor growth and progression.


Net cadmium flux and accumulation reveal tissue-specific oxidative stress and detoxification in Populus × canescens.
To characterize the dynamics of Cd²⁺ flux in the rhizosphere and to study cadmium (Cd) plant-internal partitioning in roots, wood, bark and leaves in relation to energy metabolism, reactive oxygen species (ROS) formation and antioxidants, Populus × canescens plantlets were exposed to either 0 or 50 µM CdSO₄ for up to 20 days in the nutrient solution. A strong net Cd²⁺ influx in root apex was observed after Cd exposure for 24 h, even if net Cd²⁺ influx decreased gradually in roots. A large amount of Cd was accumulated in roots. Cd ions were uploaded via the xylem to leaves and further transported to the phloem where significant accumulation was detected. Cd accumulation led to decreased photosynthetic carbon assimilation but not to the depletion in soluble carbohydrates. Increased levels of ROS were present in all tissues, except the bark of Cd-exposed poplars. To combat Cd-induced superoxide and hydrogen peroxide, P. × canescens appeared to rely mainly on the formation of soluble phenolics as these compounds showed the highest accumulation in the bark and the lowest in wood. Other potential radical scavengers such as proline, sugar alcohols and antioxidant enzymes showed tissue- and exposure time-specific responses to Cd. These results indicate a complex pattern of internal Cd allocation in P. × canescens resulting in higher ROS stress in wood than in bark and intermediate responses in roots and leaves, probably because of differential capacities of these tissues for the production of protective phenolic compounds.


Burden of illness, quality of life, and healthcare utilization among patients with herpes zoster in South Korea: a prospective clinical-epidemiological study.
To assess the herpes zoster (HZ) disease burden, including the severity and duration of HZ-associated pain, its impact on quality of life (QoL), and healthcare resource utilization (HCRU) in a South Korean clinical setting. Patients aged ≥50 years were followed prospectively for ≤6 months. Based on the duration of their episode at enrollment, cases were classified as incident (<7 days) or prevalent (≥7 days). HZ pain and discomfort were measured with the HZ Severity of Illness (HZ-SOI) severity-by-duration composite score. One hundred fifty-one patients (69.5% prevalent cases) were enrolled. Prodrome pain was experienced by 68.2% of patients, of whom 95.1% experienced moderate-to-severe pain; post-herpetic neuralgia was experienced by 38.4%. Prevalent disease, higher acute pain, and older age were significant predictors of greater HZ-SOI, while use of antivirals was associated with decreased HZ-SOI. HZ-associated pain was associated with reduced QoL and affected all daily living activities (particularly mood, life enjoyment, general activities, and sleep), resulting in significant HCRU, including primary care doctor, specialist, or physiotherapist consultations, hospitalizations, and emergency department visits. Severe morbidity, impaired QoL, and significant HCRU are associated with HZ in South Korea, especially in older patients, supporting the need for early intervention and preventive strategies to reduce the HZ-associated disease burden.


Corneal biomechanical properties measured with the Ocular Response Analyser in a myopic population.
To explore the possible association between myopia and corneal biomechanical properties in a Caucasian population, and the correlations between the properties of right and left eyes. Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured using the Ocular Response Analyser (ORA) in both eyes of 95 normal adult subjects aged between 19 and 48 years. The spherical equivalent refractive errors of the participants ranged from 0.25 to -14.00 D. The mean CH and CRF values for the right and left eyes were recorded for each subject. CH and CRF data were compared between different refractive groups. CH was found to be slightly lower in high myopes (>-6.00 D, mean CH 10.0 ± 1.2 mmHg) in comparison to moderate myopes (>-3.00 to -6.00 D, 10.1 ± 1.4 mmHg) and emmetropes and low myopes (+0.25 to -2.75 D, 10.9 ± 1.5 mmHg). The decrease in CH with the degree of myopia was about 0.13 mmHg per D or roughly 1% per D (r(2) = 0.084, p < 0.001). Inter-subject variations were much greater than any systematic changes. CRF was not correlated with refractive error (r(2) = 0.001, p = 0.66). Although the refractive error was highly correlated between the two eyes (r(2) = 0.89, p < 0.001), CH and CRF showed a lower inter-ocular correlation (r(2) = 0.68, p < 0.001 and r(2) = 0.77, p < 0.001 respectively). These findings may indicate that the viscoelastic properties of the cornea are altered to a minor extent in myopia. However, in this normal population, any overall systematic changes in CH and CRF with refractive error were small in comparison with the considerable inter-subject scatter at any level of refraction.


Intake of Dietary Fruit, Vegetables, and Fiber and Risk of Colorectal Cancer According to Molecular Subtypes: A Pooled Analysis of 9 Studies.
Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF-wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (P trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.


Survey language preference as a predictor of meeting fruit and vegetable objectives among Hispanic adults in the United States, Behavioral Risk Factor Surveillance System, 2009.
Although Hispanics are a rapidly growing ethnic minority in the United States, the effect of acculturation on the proportion of Hispanics who meet national objectives for fruit and vegetable consumption has not been fully investigated. Our objective was to determine the extent to which ethnicity and acculturation (indicated by survey language preference) are associated with fruit and vegetable consumption among Hispanics in the United States. Fruit and vegetable consumption among adult respondents to the 2009 Behavioral Risk Factor Surveillance System was determined from data collected from the 31 states and 2 territories that offered the fruit and vegetable screener in Spanish and English (n = 287,997). Logistic regression analyses were used to determine whether ethnicity (Hispanic vs non-Hispanic white) and survey language preference (English vs Spanish) were related to meeting objectives of consuming fruit 2 or more times per day and vegetables 3 or more times per day. More Hispanics (37.6%) than non-Hispanic whites (32.0%) and more Spanish-speaking Hispanics (41.0%) than English-speaking Hispanics (34.7%) ate fruit 2 or more times per day. Conversely, more non-Hispanic whites (28.5%) than Hispanics (18.9%) and more English-speaking Hispanics (21.8%) than Spanish-speaking Hispanics (15.8%) ate vegetables 3 or more times per day. All associations remained significant after controlling for covariates. Our findings have implications regarding how brief screeners can be used to determine possible dietary disparities among the Hispanic population in the United States and to monitor population goals to eliminate racial and ethnic health disparities.


Safer sex and condom use: a convenience sample of Aboriginal young people in New South Wales.
This paper examines condom use in a sample of Aboriginal young people in New South Wales (NSW) aged 16-30 years. Cross-sectional data were collected using hand-held computer devices from 293 Aboriginal people attending two Aboriginal events in NSW. Almost two-thirds of respondents reported having had a casual sex partner in the previous 6 months. Of these, 39.2% reported always using a condom with casual partners. Having always used a condom with casual partners varied among respondents, and was more likely among younger respondents (adjusted odds ratio (AOR): 2.7, 95% confidence interval (CI): 1.2-6.1) and less likely among those who used illicit drugs (AOR: 0.2, 95% CI: 0.1-0.7). In comparison to published studies of other Australians, casual sex appears to be more common among this sample of Aboriginal young people; however, the proportion who report having always used condoms with casual partners is very similar. This suggests that although casual sex is more common, Aboriginal young people do not engage in risky behaviour any more often than other young Australians. Further work should be conducted with those who do not always use condoms, such as those who are older and who use illicit drugs, particularly with regards to how abstinence from drug use supports protective behaviours such as condom use among this population of Aboriginal young people.


RNA silencing: Recent developments on miRNAs.
MicroRNAs (miRNAs) are small non-protein-coding transcripts that regulate gene expression post-transcriptionally by pairing with target messenger RNAs (mRNAs). It is predicted that humans express thousands of miRNAs and, although only a few hundred have been identified, there is already mounting evidence suggesting that they play an important role in several different developmental processes. It is therefore not surprising that miRNAs have been found to be deregulated in many diseases. The discovery of miRNAs has uncovered a natural form of controlling RNA transcription and translation, which could provide new avenues for diagnosis, prognostic, and therapeutic applications. This review summarizes some of the key recently published patents and relevant research advances on miRNA target identification, strategies to modulate their activity and the potential applications in human diseases such as cancer and viral infections, as well as methods and techniques for purification, detection and quantification of miRNAs.


The neurologic presentation of vasculitic and rheumatologic syndromes. A review.
Most rheumatologic and vasculitic syndromes can affect the central nervous system (CNS). In the vast majority of cases, however, the systemic disease is present at the time of first CNS manifestations. Certain of these diseases, including SLE, PSS, Behçet syndrome, cryoglobulinemia and lymphomatoid granulomatoses can present with CNS findings in the absence of any peripheral evidence of the underlying process. The CNS presentations of these and the other rheumatologic and vasculitic syndromes which may affect the CNS are discussed. Isolated CNS vasculitis may be due to granulomatous angiitis of the nervous system (GANS) or delayed contralateral hemiplegia following HZO. These are distinct clinical entities which can be differentiated by clinical and angiographic findings. The former is often severe and diffuse in nature, whereas the latter is usually milder and more focal. There are few if any peripheral findings in either syndrome. The cause of GANS is unknown, but the hemiplegia following HZO is clearly due to a virus-induced vasculitis spread from the overlying Gasserian nucleus; the history of preceding herpes zoster ophthalmicus strongly suggests the diagnosis. The collected evidence suggests that an aggressive evaluation, including meningeal biopsy, and early therapy with steroids (and perhaps cytotoxic agents) can alter the prognosis in GANS. It is not clear that hemiplegia following HZO requires treatment. GANS and HZO-associated CNS damage should be considered in the differential diagnosis of isolated CNS dysfunction in the absence of history, signs, or laboratory abnormalities suggestive of systemic disease.


Energy intake and nutrition counseling in cystic fibrosis.
Historically, it has been thought that the patient with cystic fibrosis (CF) has a voracious appetite. It is now becoming apparent that many patients do not have caloric intakes which meet their full energy requirements. Our study of CF patient, utilizing, a five-day written record of food consumptions and direct observation, supports this finding and points out the need for further nutritional counseling in providing optimal care for these patients. The cause of increased nutrient requirements and considerations for individualization of counseling are briefly discussed.


Skin Barrier and Autoimmunity-Mechanisms and Novel Therapeutic Approaches for Autoimmune Blistering Diseases of the Skin.
One of the most important functions of the skin besides regulating internal body temperature includes formation of the barrier between the organism and the external environment, hence protecting against pathogen invasion, chemical and physical assaults and unregulated loss of water and solutes. Disruption of the protective barrier is observed clinically in blisters and erosions of the skin that form in autoimmune blistering diseases where the body produces autoantibodies against structural proteins of the epidermis or the epidermal-dermal junction. Although there is no cure for autoimmune skin blistering diseases, immune suppressive therapies currently available offer opportunities for disease management. In cases where no treatment is sought, these disorders can lead to life threatening complications and current research efforts have focused on developing therapies that target autoantibodies which contribute to disease symptoms. This review will outline the involvement of the skin barrier in main skin-specific autoimmune blistering diseases by describing the mechanisms underpinning skin autoimmunity and review current progress in development of novel therapeutic approaches targeting the underlying causes of autoimmune skin blistering diseases.


Fluctuating, Lorentz-force-like coupling of Langevin equations and heat flux rectification.
In a description of physical systems with Langevin equations, interacting degrees of freedom are usually coupled through symmetric parameter matrices. This coupling symmetry is a consequence of time-reversal symmetry of the involved conservative forces. If coupling parameters fluctuate randomly, the resulting noise is called multiplicative. For example, mechanical oscillators can be coupled through a fluctuating, symmetric matrix of spring "constants." Such systems exhibit well-studied instabilities. In this article, we study the complementary case of antisymmetric, time-reversal symmetry-breaking coupling that can be realized with Lorentz forces or various gyrators. We consider the case in which these antisymmetric couplings fluctuate. This type of multiplicative noise does not lead to instabilities in the stationary state but renormalizes the effective nonequilibrium friction. Fluctuating Lorentz-force-like couplings also allow one to control and rectify heat transfer. A noteworthy property of this mechanism of producing asymmetric heat flux is that the controlling couplings do not exchange energy with the system.


The use of marginal donors for liver transplantation. A retrospective study of 365 liver donors.
A total of 365 donor hepatectomies performed between May 1985 and March 1990 were reviewed and analyzed retrospectively to identify risk factors associated with poor graft function and to study the outcome of grafts retrieved from "marginal" donors. The donor mean age was 27.1 years (8-69 years). Mean ICU donor stay was 2.7 days (range 0 to 18 days), and the mean ischemic time was 8.6 hr (range 3 to 22 hr). The pancreas was retrieved in 39 donors. Donor's weight above 100 kg was the only variable found to be associated with both significantly increased 3-month graft loss (P less than 0.01) and early hepatocellular damage--AST or ALT greater than 2000 U/ml, 1st day posttransplant (P less than 0.02). Prolonged stay in the ICU (greater than 3 days), although associated with a significantly increased rate of hepatocellular damage (P less than 0.05), did not affect early graft survival. A systolic blood pressure less than 90 mmHg despite the use of high-dose dopamine (greater than 15 micrograms/mg/min), but not each of these variables itself, was also associated with a significantly increase rate of hepatocellular damage (P less than 0.001). All other variables, including age greater than 50, ischemic time greater than 12 hr, combined liver-pancreas procurement, and liver function test abnormalities, did not affect the outcome. We conclude that extending our limits to accept donors of the higher age group and those who have moderately abnormal liver function tests or a prolonged ischemic time will not jeopardize our results. It is suggested to perform liver biopsy in overweight donors during the retrieval to prevent using grafts with severe fatty infiltration. It is hypothesized that hormonal changes, starvation, and increased risk to develop infection might jeopardize the outcome of grafts from donors with a prolonged ICU stay. Although 70% of the early hepatocellular injuries are reversible, the remaining 30% result in graft failure.


Contamination of Fresh Produce with Antibiotic-Resistant Bacteria and Associated Risks to Human Health: A Scoping Review.
Fresh produce, when consumed raw, can be a source of exposure to antimicrobial residues, antimicrobial-resistant bacteria (ARB) and antimicrobial resistance genes (ARGs) of clinical importance. This review aims to determine: (1) the presence and abundance of antimicrobial residues, ARB and ARGs in fresh agricultural products sold in retail markets and consumed raw; (2) associated health risks in humans; and (3) pathways through which fresh produce becomes contaminated with ARB/ARGs. We searched the Ovid Medline, Web of Science and Hinari databases as well as grey literature, and identified 40 articles for inclusion. All studies investigated the occurrence of multidrug-resistant bacteria, and ten studies focused on ARGs in fresh produce, while none investigated antimicrobial residues. The most commonly observed ARB were E. coli (42.5%) followed by Klebsiella spp. (22.5%), and Salmonella spp. (20%), mainly detected on lettuce. Twenty-five articles mentioned health risks from consuming fresh produce but none quantified the risk. About half of the articles stated produce contamination occurred during pre- and post-harvest processes. Our review indicates that good agricultural and manufacturing practices, behavioural change communication and awareness-raising programs are required for all stakeholders along the food production and consumption supply chain to prevent ARB/ARG exposure through produce.


Variation in Lyman-alpha fine structure components for Cl XVII during a tokamak plasma shot.
In this Brief Report we study the measured and modeled Lyman-alpha intensity ratios for hydrogenlike Cl XVII in a deuterium base plasma in the Joint European Torus tokamak and examine the agreement between experiment and theory for a particular plasma shot. A collisional-radiative model is used to calculate the values of the intensity ratios using measured plasma parameters for comparison with line-of-sight values. When variations in the electron parameters during the discharge are taken into account, the variations in the modeled values are seen to follow the experimental data. The difference between the values of observed and modeled intensity ratios is discussed.


Biosynthesis of ZnO Nanoparticles by a New Pichia kudriavzevii Yeast Strain and Evaluation of Their Antimicrobial and Antioxidant Activities.
The potential ability of a new yeast strain, Pichia kudriavzevii, in the synthesis of zinc oxide nanoparticles (ZnO-NPs) through a green method was explored in this study. The effect of reaction time (12, 24 and 36 h) on the structure of the resulting ZnO nanoparticles was investigated. From the XRD and TEM results, the ZnO-NPs with a hexagonal wurtzite structure and a particle crystal size of ~10-61 nm was formed at different reaction times. Combing XRD, TEM, and PL results, it was revealed that the sample prepared at intermediate duration (24 h) has the most favorable nanosized structure with the lowest defect concentration. The biomedical properties of ZnO-NPs as free radical scavenging activity, cytotoxicity and antibacterial agents were characterized. Biosynthesized ZnO-NPs showed strong DPPH free radical scavenging and a dose dependent toxicity with non-toxic effects on Vero cells for concentrations below 190 µg/mL. Desirable bactericidal activity was shown by the ZnO-NPs on Gram-positive bacteria (Bacillus subtilis, Staphylococcus epidermidis and Staphylococcus aurous) and Gram-negative bacteria (Escherichia coli and Serratia marcescens). A maximum inhibition zone of ~19 mm was observed for Staphylococcus epidermidis at a concentration of 100 µg/mL for sample prepared at 24 h. The results from this study reveal that ZnO-NPs possesses potential for many medical and industrial applications.


[Great discoveries: from the painstaking efforts of researchers to the contribution of accidental findings and the dissemination of study results].
This article takes its cue from the original work of sir Alexander Fleming on penicillin, published in the first issue of Recenti Progressi in Medicina in 1946 and reproduced here on the occasion of the approaching 70-year anniversary of the journal. The path that brought Fleming to the discovery of penicillin, one of the major milestones in the history of clinical pharmacology, provides insight for a range of considerations: the painstaking efforts of researchers, the contribution from accidental findings, and the dissemination of study results. Although the discovery of penicillin has changed the course of medicine, the benefits deriving from such an important advance are most likely to be offset by the overprescription of antibiotics, which is the leading cause of antimicrobial resistance and one of the most serious public health problems of our time.


Multiscale in-vitro analysis of photo-activated riboflavin incorporated in an experimental universal adhesive.
To investigate the effect of blue light photoactivated riboflavin modified universal adhesives on dentin collagen biodegradation resistance, dentin apparent elastic modulus, and resin-dentin bond strength with interfacial morphology. Dentin slabs were treated with 0.1% riboflavin-5-phosphate modified (powder added slowly while shaking and then sonicated to enhance the dispersion process) Universal Adhesive Scotch Bond and Zipbond™ along with control (non-modified) and experimental adhesives, photoactivated with blue light for 20s. Hydroxyproline (HYP) release was assessed after 1-week storage. Elastic-modulus testing was evaluated using universal testing machine at 24 h. Resin-dentin interfacial morphology was assessed with scanning electron-microscope, after 6-month storage. 0.1% rhodamine dye was added into each adhesive and analyzed using CLSM. Detection of free amino groups was carried out using ninhydrin and considered directly proportional to optical absorbance. Collagen molecular confirmation was determined using spectropolarimeter to evaluate and assess CD spectra. For molecular docking studies with riboflavin (PDB ID file), the binding pocket was selected with larger SiteScore and DScore using Schrodinger PB software. After curing, Raman shifts in Amide regions were obtained at 8 μm levels. Data were analyzed using Two-way analysis of variance (ANOVA, p ≤ 0.05) and Tukey-Kramer multiple comparison post hoc tests. At baseline, bond strength reduced significantly (p ≤ 0.05) in control specimens. However, at 6 months' storage, UVA Zipbond™ had significantly higher μTBS. Resin was able to diffuse through the porous demineralized dentin creating adequate hybrid layers in both 0.1%RF modified adhesives in CLSM images. In riboflavin groups, hybrid layer and resin tags were more pronounced. The circular dichroism spectrum showed negative peaks for riboflavin adhesive specimens. Best fitted poses adopted by riboflavin compound are docked with MMP-2 and -9 proteases. Amide bands and CH2 peaks followed the trend of being lowest for control UA Scotch bond adhesive specimens and increasing in Amides, proline, and CH2 intensities in 0.1%RF modified adhesive specimens. All 0.1%RF application groups showed statistically significant (p < 0.05) less levels of HYP released compared to controls. Dentin Eappr of riboflavin application was significantly (p < 0.05) more as compared to control groups. Blue light photoactivated 0.1% riboflavin modified adhesives improved the biochemical and biomechanical properties of demineralized dentin as well as the long-term resin-dentin interfacial integrity and bond strength of universal adhesive to dentin.


Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures.
Neuromyelitis optica (NMO, Devic disease) is a severely disabling autoimmune disorder of the CNS, which was considered a subtype of multiple sclerosis (MS) for many decades. Recently, however, highly specific serum autoantibodies (termed NMO-IgG or AQP4-Ab) have been discovered in a subset (60-80%) of patients with NMO. These antibodies were subsequently shown to be directly involved in the pathogenesis of the condition. AQP4-Ab positive NMO is now considered an immunopathogenetically distinct disease in its own right. However, to date little is known about the cerebrospinal fluid (CSF) in AQP4-Ab positive NMO. To describe systematically the CSF profile of AQP4-Ab positive patients with NMO or its formes frustes, longitudinally extensive myelitis and optic neuritis. Cytological and protein biochemical results from 211 lumbar punctures in 89 AQP4-Ab positive patients of mostly Caucasian origin with neuromyelitis optica spectrum disorders (NMOSD) were analysed retrospectively. CSF-restricted oligoclonal IgG bands, a hallmark of MS, were absent in most patients. If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, transient, and, importantly, restricted to acute relapses. CSF pleocytosis was present in around 50% of samples, was mainly mild (median, 19 cells/μl; range 6-380), and frequently included neutrophils, eosinophils, activated lymphocytes, and/or plasma cells. Albumin CSF/serum ratios, total protein and CSF L-lactate levels correlated significantly with disease activity as well as with the length of the spinal cord lesions in patients with acute myelitis. CSF findings differed significantly between patients with acute myelitis and patients with acute optic neuritis at the time of LP. Pleocytosis and blood CSF barrier dysfunction were also present during remission in some patients, possibly indicating sustained subclinical disease activity. AQP4-Ab positive NMOSD is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and NMOSD and add to our understanding of the immunopathogenesis of this devastating condition.


Effects of i.v. push administration on β-lactam pharmacodynamics.
The effects of i.v. push administration on the pharmacodynamic exposures of meropenem, cefepime, and aztreonam were evaluated. Pharmacokinetic and pharmacodynamic analyses were conducted using previously published pharmacokinetic data for meropenem, cefepime, and aztreonam. The probability of target attainment (PTA) was assessed using Monte Carlo simulations for 30-minute and 5-minute infusions of approved dosing regimens and alternative dosing schemes often used in clinical practice, including 500 mg every 6 hours and 1 g every 8 hours for meropenem, 1 g every 6 hours and 2 g every 8 hours for cefepime, and 2 g every 8 hours for aztreonam. For each regimen examined, means and standard deviations for the percentage of the dosing interval that the free drug concentration remained above the minimum inhibitory concentration (MIC) were calculated and reported. No or only minor differences were noted between 30-minute and 5-minute infusions. The largest differences were observed at an MIC of 4 mg/L for meropenem and an MIC of 16 mg/L for aztreonam. At an MIC of 4 mg/L, meropenem 500 mg every 6 hours as a 30-minute infusion had an 8% greater PTA compared with the 5-minute infusion. At an MIC of 16 mg/L, a 30-minute infusion of aztreonam 2 g every 8 hours had a 12% greater PTA compared with the 5-minute infusion. Simulations of meropenem, cefepime, and aztreonam by i.v. push over 5 minutes indicated that there would be minimal or no effect on pharmacodynamic exposures compared with the effect when administered by 30-minute infusions.


Phytochrome A and B Negatively Regulate Salt Stress Tolerance of Nicotiana tobacum via ABA-Jasmonic Acid Synergistic Cross-Talk.
Light signaling and phytohormones play important roles in plant growth, development, and biotic and abiotic stress responses. However, the roles of phytochromes and cross-talk between these two signaling pathways in response to salt stress in tobacco plants remain underexplored. Here, we explored the defense response in phytochrome-defective mutants under salt stress. We monitored the physiological and molecular changes of these mutants under salt stress conditions. The results showed that phytochrome A (phyA), phytochrome B (phyB) and phyAphyB (phyAB) mutants exhibited improved salt stress tolerance compared with wild-type (WT) plants. The mutant plants had a lower electrolyte leakage (EL) and malondialdehyde (MDA) concentration than WT plants, and the effect was clearly synergistic in the phyAB double mutant plants. Furthermore, the data showed that the transcript levels of defense-associated genes and the activities of some antioxidant enzymes in the mutant plants were much higher than those in WT plants. Additionally, the results indicated that phytochrome signaling strongly modulates the expression of endogenous abscisic acid (ABA) and jasmonic acid (JA) of Nicotiana tobacum in response to salt stress. To illustrate further the relationship between phytochrome and phytohormone, we measured the expression of defense genes and phytochrome. The results displayed that salt stress and application of methyl jasmonate (MeJA) or ABA up-regulated the transcript levels of salt response-associated genes and inhibited the expression of NtphyA and NtphyB. Foliar application of inhibitors of ABA and JA further confirmed that JA co-operated with ABA in phytochrome-mediated salt stress tolerance.


[Photoactivated derivatives of peptide and protein ligands in the studies of neuroreceptors].
The application of photoactivatable derivatives for studies of different types of neuroreceptors belonging to two superfamilies, G-protein dependent receptors and ligand-gated ionic channels, is discussed. Studies of the structure of voltage-gated and ion-gated channels with the use of specific photoactivatable derivatives of neurotoxins are also described. Possibilities and prospects for the application of photoactivatable ligands in studies of the spatial structure of neuroreceptors are reviewed.


Normative data and percentile curves for long-term athlete development in swimming.
To provide normative data and establish percentile curves for long-course (50 m pool length) swimming events and to compare progression of race times longitudinally for the various swimming strokes and race distances. Descriptive approach with longitudinal tracking of performance data. A total of 2,884,783 race results were collected from which 169,194 annual best times from early junior to elite age were extracted. To account for drop-outs during adolescence, only swimmers still competing at age of peak performance (21-26 years) were included and analyzed retrospectively. Percentiles were established with z-scores around the median and the Lambda-Mu-Sigma (LMS) method applied to account for potential skewness. A two-way analysis of variance (ANOVA) with repeated measure and between-subject factor was applied to compare race times across the various events and age groups. Percentile curves were established based on longitudinal tracking of race times specific to sex, swimming stroke, and race distance. Comparing performance progression, race times of freestyle sprint events showed an early plateau with no further significant improvement (p > 0.05) after late junior age (15-17 years). However, the longer the race distance, the later the race times plateaued (p < 0.05). Female swimmers generally showed an earlier performance plateau than males. Backstroke and freestyle showed an earlier performance plateau compared to the other swimming strokes (p < 0.05). Performance progression varied between sex, swimming strokes, and race distances. Percentile curves based on longitudinal tracking may allow an objective assessment of swimming performance, help discover individual potentials, and facilitate realistic goal setting for talent development.


Kidney-targeted transplantation of mesenchymal stem cells by ultrasound-targeted microbubble destruction promotes kidney repair in diabetic nephropathy rats.
We test the hypothesis that ultrasound-targeted microbubble destruction (UTMD) technique increases the renoprotective effect of kidney-targeted transplantation of bone-marrow-derived mesenchymal stem cells (BM-MSCs) in diabetic nephropathy (DN) rats. Diabetes was induced by streptozotocin injection (60 mg/Kg, intraperitoneally) in Sprague-Dawley rats. MSCs were administered alone or in combination with UTMD to DN rats at 4 weeks after diabetes onset. Random blood glucose concentrations were measured at 1, 2, 4, and 8 weeks, and plasma insulin levels, urinary albumin excretion rate (UAER) values, the structures of pancreas and kidney, the expressions of TGF- β 1, synaptopodin, and IL-10 were assessed at 8 weeks after MSCs transplantation. MSCs transplantation decreased blood glucose concentrations and attenuated pancreatic islets/ β cells damage. The permeability of renal interstitial capillaries and VCAM-1 expression increased after UTMD, which enhanced homing and retention of MSCs to kidneys. MSCs transplantation together with UTMD prevented renal damage and decreased UAER values by inhibiting TGF- β 1 expression and upregulating synaptopodin and IL-10 expression. We conclude that MSCs transplantation reverts hyperglycemia; UTMD technique noninvasively increases the homing of MSCs to kidneys and promotes renal repair in DN rats. This noninvasive cell delivery method may be feasible and efficient as a novel approach for personal MSCs therapy to diabetic nephropathy.


Management of the multiple phases of heparin-induced thrombocytopenia.
The clinical course of heparin-induced thrombocytopenia (HIT) may be separated into five sequential phases: 1. suspected HIT, 2. acute HIT, 3. subacute HIT A, 4. subacute HIT B, and 5. remote HIT. Each phase confronts the clinician with a unique set of management questions. In this review, the phases of HIT are defined and key management questions associated with each phase are discussed. Among patients with Suspected HIT, I use the 4Ts score to determine which patients have a sufficiently high probability of HIT to justify discontinuation of heparin and initiation of a non-heparin parenteral anticoagulant. An algorithm for selecting an appropriate non-heparin anticoagulant based on the patient's clinical stability, renal and hepatic function, drug availability, and physician comfort is provided. In patients with Acute HIT, I generally avoid prophylactic platelet transfusion and inferior vena cava filter insertion because of a potential increased risk of thrombosis. I perform 4-limb screening compression ultrasonography. In patients with symptomatic thromboembolism or asymptomatic proximal deep-vein thrombosis, I treat with anticoagulation for three months. In patients without thrombosis, I discontinue anticoagulation upon platelet count recovery. I do not transition patients to an oral anticoagulant until platelet count recovery (i. e. Subacute HIT A). I increasingly choose direct oral anticoagulants over vitamin K antagonists in this setting because of their greater convenience and safety. In Subacute HIT B and Remote HIT, I use heparin for cardiovascular surgery, whereas I use bivalirudin in patients with Acute HIT and Subacute HIT A in whom surgery cannot be delayed.


Circulating non-coding RNAs as biomarkers of beta cell death in diabetes.
Death of pancreatic islet beta cells is a common feature of type 1 and 2 diabetes and often follows islet cell transplantation. Measurement of blood glucose is currently the only blunt instrument available to diagnose diabetes mellitus, and we lack tools to quantify islet cell loss or protection thereof. A class of RNA molecules (called microRNAs/miRNAs/miRs) that regulate endogenous gene expression via mRNA cleavage or translational arrest have been identified to be critical for birth, maintenance and regeneration of pancreatic beta cells. Recent demonstration that microRNAs can potentially be utilised as biomarkers due to their serum stability, has triggered increasing interest in understanding their role as regulators or biomarkers of disease. This review aims to delve into the potential of miRNA biomarkers, and whether miRNA profiles are indicators or effector of disease pathology. Furthermore, an outline for identifying and confirming islet-specific miRNA biomarkers is discussed.


Thermodynamic Aspects in Non-Ideal Metal Membranes for Hydrogen Purification.
In this paper, an overview on thermodynamic aspects related to hydrogen-metal systems in non-ideal conditions is provided, aiming at systematically merging and analyzing information achieved from several different studies present in the open literature. In particular, the relationships among inner morphology, dissolved hydrogen and internal stresses are discussed in detail, putting in evidence the conformation complexity and the various types of dislocations induced by the presence of H-atoms in the lattice. Specifically, it is highlighted that the octahedral sites are preferentially occupied in the FCC metals (such as palladium), whereas tetrahedral sites are more energetically favored in BCC-structured ones (such as vanadium). These characteristics are shown to lead to a different macroscopic behavior of the two classes of metals, especially in terms of solubility and mechanical failure due to the consequent induced stresses. Furthermore, starting from the expression of the chemical potential generally presented in the literature, a new convenient expression of the activity of the H-atoms dissolved into the metal lattice as a function of the H-concentration is achieved. Such an activity expression is then used in the dissolution equilibrium relationship, which is shown to be the overall result of two different phenomena: (i) dissociative adsorption of molecular hydrogen onto the surface; and (ii) atomic hydrogen dissolution from the surface to the metal bulk. In this way, the obtained expression for equilibrium allows a method to calculate the equilibrium composition in non-ideal conditions (high pressure), which are of interest for real industrial applications.


Alpha 1-adrenergic blockade increases coronary blood flow during coronary hypoperfusion.
Coronary hypoperfusion was elicited in alpha-chloralose-anesthetized open-chest dogs by reducing left coronary perfusion pressure to 50 mmHg. Left coronary blood flow, as well as left ventricular oxygen extraction, oxygen consumption, and contractile force were measured. The reduction in perfusion pressure caused significant reductions in coronary flow, oxygen consumption, and peak reactive hyperemic flow. During hypoperfusion in 11 dogs, intracoronary infusion of the specific alpha 1-adrenergic antagonist prazosin (0.1 mg/min) increased coronary flow and oxygen consumption by 22 and 16%, respectively. Peak increases were observed after 6-8 min of prazosin infusion (0.6-0.8 mg prazosin), and both increases were statistically significant (P less than 0.05). In seven additional dogs, beta-adrenergic blockade with propranolol (1.0 mg ic) did not significantly affect the actions of prazosin. In five additional dogs, the specific alpha 2-adrenergic antagonist yohimbine (1.3 mg ic) in the presence of propranolol (1.0 mg ic) did not affect coronary flow or oxygen consumption during coronary hypoperfusion. Those results suggest that an alpha 1- but not an alpha 2-adrenergic constrictor tone was operative in the left coronary circulation under the conditions of these experiments.


Characteristics and causes of the inadequate corpus luteum.
An inadequate luteal phase occurs in domestic ruminants in several physiological situations (e.g. puberty, post partum), and also following the induction of ovulation in anoestrous ewes with GnRH treatment. The induced corpora lutea (CL) initially developed, but then regressed rapidly after Day 4, unless the animals had been primed with progesterone before GnRH therapy or hysterectomized. Significant increases in prostaglandin F-2 alpha metabolite (PGFM) secretion and coincident peaks of oxytocin and PGFM occurred around the time of premature regression. Endometrial oxytocin receptors were also detectable at this time in ewes which had abnormal luteal phases, but not in ewes which had been progesterone primed and thus had normal luteal phases. This suggests that the presence or otherwise of the oxytocin receptor during the early luteal phase may be crucial in determining whether the CL has a short or normal lifespan. These results show that an inadequate luteal phase is often caused by the premature induction of luteolysis and the presence of the endometrial oxytocin receptor in necessary for this occurrence. This receptor in turn is controlled by the steroid environment to which the uterus has previously been exposed.


Specific thermal ablation of tumor cells using single-walled carbon nanotubes targeted by covalently-coupled monoclonal antibodies.
CD22 is broadly expressed on human B cell lymphomas. Monoclonal anti-CD22 antibodies alone, or coupled to toxins, have been used to selectively target these tumors both in SCID mice with xenografted human lymphoma cell lines and in patients with B cell lymphomas. Single-walled carbon nanotubes (CNTs) attached to antibodies or peptides represent another approach to targeting cancer cells. CNTs convert absorbed near-infrared (NIR) light to heat, which can thermally ablate cells that have bound the CNTs. We have previously demonstrated that monoclonal antibodies (MAbs) noncovalently coupled to CNTs can specifically target and kill cells in vitro. Here, we describe the preparation of conjugates in which the MAbs are covalently conjugated to the CNTs. The specificity of both the binding and NIR-mediated killing of the tumor cells by the MAb-CNTs is demonstrated by using CD22+CD25- Daudi cells, CD22-CD25+ phytohemagglutinin-activated normal human peripheral blood mononuclear cells, and CNTs covalently modified with either anti-CD22 or anti-CD25. We further demonstrate that the stability and specificity of the MAb-CNT conjugates are preserved following incubation in either sodium dodecyl sulfate or mouse serum, indicating that they should be stable for in vivo use.