Effects of anesthesia on lipopolysaccharide-induced changes in serum cytokines.
The pathophysiology of sepsis is incompletely understood, however alterations in systemic inflammation and serum cytokines are thought to play a central role. In the rat, ketamine, but not isoflurane, prevents hepatic injury from lipopolysaccharide (LPS). The effect of these anesthetics on the systemic inflammatory response and other organs remains to be fully elucidated. We hypothesized that ketamine, but not isoflurane, would blunt the cytokine response to LPS administration. Male rats received no anesthesia, intraperitoneal ketamine (70 mg/kg), or inhalational isoflurane. One hour later, LPS (20 mg/kg, intraperitoneal) or saline was given for 5 hours and rats were killed. Gastric fluid volumes were determined as an index of gastric emptying. Serum was collected and cytokines measured via a multiplexed suspension immunoassay. In nonanesthetized rats, LPS increased gastric luminal fluid accumulation and serum levels of proinflammatory cytokines when compared with saline controls. Anesthesia with either ketamine or isoflurane caused a significant reduction in LPS-induced changes in serum cytokines, although ketamine had a more dramatic reduction in tumor necrosis factor alpha levels than did isoflurane. Both anesthetics reduced the interleukin IL-6/IL-10 ratio in response to LPS when compared with LPS alone. Ketamine, but not isoflurane, prevented LPS-induced gastric luminal fluid accumulation. These data indicate that both ketamine and isoflurane diminish the systemic inflammatory response to LPS in the rat as measured by serum cytokines and a reduced IL-6/IL-10 ratio. However, only ketamine improves LPS-induced gastric dysfunction, perhaps secondary to its ability to reduce serum tumor necrosis factor alpha levels more effectively.


Guidelines for managing lesser prairie-chicken populations and their habitats.
Lesser prairie-chicken (Tympanuchus pallidicinctus) populations have declined by >90% since the 1800s. These declines have concerned both biologists and private conservation groups and led to a petition to list the lesser prairie-chicken as threatened under the Endangered Species Act. Most of the land in the current range of the lesser prairie-chicken is privately owned, and declines have been primarily attributed to anthropogenic factors. Conversion of native rangeland to cropland and excessive grazing have been implicated as leading causes in the species' decline. Periodic drought probably has exacerbated these problems. Little research on habitat requirements was conducted prior to 1970. Despite recent advances in the knowledge of lesser prairie-chicken ecology, no comprehensive guidelines for management of the species have been published. In these guidelines, we provide a synopsis of our current knowledge of lesser prairie-chicken habitat requirements and suggest management strategies to monitor, maintain, and enhance lesser prairie-chicken populations.


Spatial coherence in strongly scattering media.
We study the spatial coherence of an optical beam in a strongly scattering medium confined in a slab geometry. Using the radiative transfer equation, we study numerically the behavior of the transverse spatial coherence length in the different transport regimes. Transitions from the ballistic to the diffusive regimes are clearly identified.


Spectroscopic Evidence for Electronic Control of Heme Hydroxylation by IsdG.
Staphylococcus aureus IsdG catalyzes a unique trioxygenation of heme to staphylobilin, and the data presented in this article elucidate the mechanism of the novel chemical transformation. More specifically, the roles of the second-sphere Asn and Trp residues in the monooxygenation of ferric-peroxoheme have been clarified via spectroscopic characterization of the ferric-azidoheme analogue. Analysis of UV/vis absorption data quantified the strength of the hydrogen bond that exists between the Asn7 side chain and the azide moiety of ferric-azidoheme. X-band electron paramagnetic resonance data were acquired and analyzed, which revealed that this hydrogen bond weakens the π-donor strength of the azide, resulting in perturbations of the Fe 3d based orbitals. Finally, nuclear magnetic resonance characterization of 13C-enriched samples demonstrated that the Asn7···N3 hydrogen bond triggers partial porphyrin to iron electron transfer, resulting in spin density delocalization onto the heme meso carbons. These spectroscopic experiments were complemented by combined quantum mechanics/molecular mechanics computational modeling, which strongly suggested that the electronic structure changes observed for the N7A variant arose from loss of the Asn7···N3 hydrogen bond as opposed to a decrease in porphyrin ruffling. From these data a fascinating picture emerges where an Asn7···N3 hydrogen bond is communicated through four bonds, resulting in meso carbons with partial cationic radical character that are poised for hydroxylation. This chemistry is not observed in other heme proteins because Asn7 and Trp67 must work in concert to trigger the requisite electronic structure change.


RUVBL1-RUVBL2 AAA-ATPase: a versatile scaffold for multiple complexes and functions.
RUVBL1 and RUVBL2 are two highly conserved AAA+ ATPases that form a hetero-hexameric complex that participates in a wide range of unrelated cellular processes, including chromatin remodeling, Fanconi Anemia (FA), nonsense-mediated mRNA decay (NMD), and assembly and maturation of several large macromolecular complexes such as RNA polymerases, the box C/D small nucleolar ribonucleoprotein (snoRNP) and mTOR complexes. How the RUVBL1-RUVBL2 complex works in such a variety of processes, sometimes antagonistic, has been obscure for a long time. Recent cryo-electron microscopy (cryo-EM) studies have started to reveal how RUVBL1-RUVBL2 forms a scaffold for complex protein-protein interactions and how the structure and ATPase activity of RUVBL1-RUVBL2 can be affected and regulated by the interaction with clients.


Serum amyloid A protein levels as a possible aid in the diagnosis of acute appendicitis in children.
Hematological and biochemical tests, including white blood cell count (WBC), C-reactive protein (CRP) and other acute-phase reactants, have been used in the diagnosis of acute appendicitis. However, there is controversy among physicians about the value of this practice in children. The objective of our study was to evaluate serum amyloid A protein (SAA) levels in children with confirmed acute appendicitis and to compare the sensitivity and specificity of this marker of inflammation with those for WBC and CRP. A prospective cohort study of 60 children admitted with abdominal pain to rule out appendicitis was used in the study. Of these, 42 underwent surgery, while 18 children who had spontaneous amelioration within 24 h of admission were not operated on and served as controls. WBC and serum SAA and CRP levels were obtained preoperatively. Serum concentrations of the analytes were determined with particle-enhanced immunonephelometric methods. Patients with acute appendicitis had WBC, SAA and CRP levels higher than those of the control group (p<0.001). There was no appendicitis patient with a normal SAA value, while 21.4% of the patients had CRP values within the normal range. The performance of each test was measured by receiver-operating characteristic curves. Area under the curve (AUC) values were 0.849 for WBC, 0.868 for CRP and 0.964 for SAA. The sensitivity and specificity of these methods were 76% and 75% for WBC>10.0 x 10(9) /L, 62% and 94% for CRP>10 mg/L and 86% and 83% for SAA >45.0 mg/L, respectively. Circulating SAA levels have better discriminatory value than WBC or CRP in the assessment of acute appendicitis in children. Thus, this test appears to be of higher value than the current standards of care in the diagnosis of this condition.


[Case of submucosal hematoma of the esophagus noticed postoperatively].
We experienced a case of submucosal hematoma of the esophagus noticed after cervical anterior spinal fusion (ASF) between C7 and T1 for ossification of posterior longitudinal ligament (OPLL). The patient was a 68-year-old man, and no abnormality was found in the preoperative examinations. Anesthesia was induced and maintained with remifentanil, propofol and vecuronium. Tracheal intubation was performed using fiberscope uneventfully, and gastric tube and esophageal stethoscope were inserted into the esophagus smoothly. The operation was completed in 7 hours and 10 minutes. When we removed the gastric tube and the esophageal stethoscope after the operation, no bloody secretion was noticed. The next day, the patient complained of melena, and gastrointestinal endoscopy showed a submucosal hematoma extending from the posterior wall of the cervico-thoracic border in the esophagus to the cardia. Submucosal hematoma of the esophagus is a rare complication. In this case, surgical procedure was suspected to have caused the hematoma, since the upper end of the hematoma corresponded to the surgical field.


The regulation of self-reactive B cells.
Self-reactive B cells are eliminated in a series of checkpoints that are triggered by antigen binding. Recent reports have shown that in addition to the processes of elimination at the immature B-cell stage, B-cell anergy and regulation of T-cell help, self-reactive cells are also controlled by follicular competition, Fas-mediated elimination by T cells and censoring in the germinal centres. Each checkpoint operates at a threshold that reflects the need to maintain immune diversity at the same time as suppressing autoimmune disease. Analysis of the motheaten mutation has given a direct demonstration of how such thresholds can be modulated by genetic effects.


Seed maturation regulators are related to the control of seed dormancy in wheat (Triticum aestivum L.).
In Arabidopsis, the regulation network of the seed maturation program controls the induction of seed dormancy. Wheat EST sequences showing homology with the master regulators of seed maturation, leafy cotyledon1 (LEC1), LEC2 and FUSCA3 (FUS3), were searched from databases and designated respectively as TaL1L (LEC1-LIKE), TaL2L (LEC2-LIKE), and TaFUS3. TaL1LA, TaL2LA and TaFUS3 mainly expressed in seeds or embryos, with the expression limited to the early stages of seed development. Results show that tissue-specific and developmental-stage-dependent expressions are similar to those of seed maturation regulators in Arabidopsis. In wheat cultivars, the expression level of TaL1LA is correlated significantly with the germination index (GI) of whole seeds at 40 days after pollination (DAP) (r = -0.83**). Expression levels of TaFUS3 and TaL2LA are significantly correlated respectively with GIs at 40 DAP and 50 DAP, except for dormant cultivars. No correlation was found between the expression level of TaVP1, orthologue of ABA insensitive3 (ABI3), and seed dormancy. Delay of germination1 (DOG1) was identified as a quantitative trait locus (QTL) for the regulation of seed dormancy in Arabidopsis. Its promoter has RY motif, which is a target sequence of LEC2. Significant correlation was found between the expression of TaDOG1 and seed dormancy except for dormant cultivars. These results indicate that TaL1LA, TaL2LA, and TaFUS3 are wheat orthologues of seed maturation regulators. The expressions of these genes affect the level of seed dormancy. Furthermore, the pathways, which involve seed maturation regulators and TaDOG1, are important for regulating seed dormancy in wheat.


A State-of-the-Art Review on the Use of Modafinil as A Performance-enhancing Drug in the Context of Military Operationality.
Modafinil is an eugeroic drug that has been examined to maintain or recover wakefulness, alertness, and cognitive performance when sleep deprived. In a nonmilitary context, the use of modafinil as a nootropic or smart drug, i.e., to improve cognitive performance without being sleep deprived, increases. Although cognitive performance is receiving more explicit attention in a military context, research into the impact of modafinil as a smart drug in function of operationality is lacking. Therefore, the current review aimed at presenting a current state-of-the-art and research agenda on modafinil as a smart drug. Beside the question whether modafinil has an effect or not on cognitive performance, we examined four research questions based on the knowledge on modafinil in sleep-deprived subjects: (1) Is there a difference between the effect of modafinil as a smart drug when administered in repeated doses versus one single dose?; (2) Is the effect of modafinil as a smart drug dose-dependent?; (3) Are there individual-related and/or task-related impact factors?; and (4) What are the reported mental and/or somatic side effects of modafinil as a smart drug? We conducted a systematic search of the literature in the databases PubMed, Web of Science, and Scopus, using the search terms "Modafinil" and "Cognitive enhance*" in combination with specific terms related to the research questions. The inclusion criteria were studies on healthy human subjects with quantifiable cognitive outcome based on cognitive tasks. We found no literature on the impact of a repeated intake of modafinil as a smart drug, although, in users, intake occurs on a regular basis. Moreover, although modafinil was initially said to comprise no risk for abuse, there are now indications that modafinil works on the same neurobiological mechanisms as other addictive stimulants. There is also no thorough research into a potential risk for overconfidence, whereas this risk was identified in sleep-deprived subjects. Furthermore, eventual enhancing effects were beneficial only in persons with an initial lower performance level and/or performing more difficult tasks and modafinil has an adverse effect when used under time pressure and may negatively impact physical performance. Finally, time-on-task may interact with the dose taken. The use of modafinil as a smart drug should be examined in function of different military profiles considering their individual performance level and the task characteristics in terms of cognitive demands, physical demands, and sleep availability. It is not yet clear to what extent an improvement in one component (e.g., cognitive performance) may negatively affect another component (e.g., physical performance). Moreover, potential risks for abuse and overconfidence in both regular and occasional intake should be thoroughly investigated to depict the trade-off between user benefits and unwanted side effects. We identified that there is a current risk to the field, as this trade-off has been deemed acceptable for sleep-deprived subjects (considering the risk of sleep deprivation to performance) but this reasoning cannot and should not be readily transposed to non-sleep-deprived individuals. We thus conclude against the use of modafinil as a cognitive enhancer in military contexts that do not involve sleep deprivation.


Semiconducting tin and lead iodide perovskites with organic cations: phase transitions, high mobilities, and near-infrared photoluminescent properties.
A broad organic-inorganic series of hybrid metal iodide perovskites with the general formulation AMI3, where A is the methylammonium (CH3NH3(+)) or formamidinium (HC(NH2)2(+)) cation and M is Sn (1 and 2) or Pb (3 and 4) are reported. The compounds have been prepared through a variety of synthetic approaches, and the nature of the resulting materials is discussed in terms of their thermal stability and optical and electronic properties. We find that the chemical and physical properties of these materials strongly depend on the preparation method. Single crystal X-ray diffraction analysis of 1-4 classifies the compounds in the perovskite structural family. Structural phase transitions were observed and investigated by temperature-dependent single crystal X-ray diffraction in the 100-400 K range. The charge transport properties of the materials are discussed in conjunction with diffuse reflectance studies in the mid-IR region that display characteristic absorption features. Temperature-dependent studies show a strong dependence of the resistivity as a function of the crystal structure. Optical absorption measurements indicate that 1-4 behave as direct-gap semiconductors with energy band gaps distributed in the range of 1.25-1.75 eV. The compounds exhibit an intense near-IR photoluminescence (PL) emission in the 700-1000 nm range (1.1-1.7 eV) at room temperature. We show that solid solutions between the Sn and Pb compounds are readily accessible throughout the composition range. The optical properties such as energy band gap, emission intensity, and wavelength can be readily controlled as we show for the isostructural series of solid solutions CH3NH3Sn(1-x)Pb(x)I3 (5). The charge transport type in these materials was characterized by Seebeck coefficient and Hall-effect measurements. The compounds behave as p- or n-type semiconductors depending on the preparation method. The samples with the lowest carrier concentration are prepared from solution and are n-type; p-type samples can be obtained through solid state reactions exposed in air in a controllable manner. In the case of Sn compounds, there is a facile tendency toward oxidation which causes the materials to be doped with Sn(4+) and thus behave as p-type semiconductors displaying metal-like conductivity. The compounds appear to possess very high estimated electron and hole mobilities that exceed 2000 cm(2)/(V s) and 300 cm(2)/(V s), respectively, as shown in the case of CH3NH3SnI3 (1). We also compare the properties of the title hybrid materials with those of the "all-inorganic" CsSnI3 and CsPbI3 prepared using identical synthetic methods.


delta-Opioid receptors stimulate ERK1/2 activity in NG108-15 hybrid cells by integrin-mediated transactivation of TrkA receptors.
This study demonstrates that activation of delta-opioid receptors (DORs) in neuroblastomaxglioma (NG108-15) hybrid cells by [D-Ala2, D-Leu5]enkephalin (DADLE) and etorphine significantly enhances cell adhesion to fibronectin-coated wells. This effect is blocked by both naloxone and integrin binding RGDT peptides. In addition, cell adhesion turned out to be a prerequisite for DOR-stimulated transactivation of Tropomyosin-related kinase A (TrkA) and extracellular signal-regulated kinases 1/2 (ERK1/2). Because inhibition of TrkA activation by AG879 completely blocked DOR- and integrin-mediated ERK1/2 signaling, the present results indicate that in NG108-15 cells DOR-stimulated ERK1/2 activation is mediated by integrin-induced transactivation of TrkA.


Residual tumor volume and patient survival following reoperation for recurrent glioblastoma.
Maximal safe tumor resection is part of the standard of care for patients with newly diagnosed glioblastoma. The role of reoperation in the care of patients with recurrent glioblastoma is less clear, and less than a quarter of patients undergo a second surgery. Previous studies have identified preoperative variables associated with the improved survival of patients following reoperation, and guidelines for the selection of patients for reoperation have been devised and validated. In this study, the authors analyzed the relative survival benefit of maximal safe tumor removal in a series of patients with recurrent glioblastoma who all underwent reoperation. In this longitudinal study, the clinical and radiological data of 97 consecutive patients who underwent reoperation for recurrent glioblastoma were prospectively collected. Multiple regression analyses and Kaplan-Meier plotting were performed to identify pre- and postoperative clinical and radiological variables associated with increased survival following reoperation. The median postoperative survival of all patients following reoperation was 12.4 months (95% confidence interval [CI] 9.0-15.6 months). Multiple Cox regression analysis revealed that patients with large (> 3 cm(3)) residual tumors following reoperation had significantly decreased survival relative to those with residual tumors that were small (> 0-3 cm(3); hazard ratio [HR] = 3.10, 95% CI 1.69-5.70; p < 0.001) or radiologically absent (0 cm(3); HR = 5.82, 95% CI 2.98-11.37; p < 0.001). Large residual tumors had faster rates of subsequent regrowth than small (odds ratio [OR] = 4.22, 95% CI 1.19-14.97; p = 0.026) or radiologically absent (OR = 11.00, 95% CI 2.79-43.43; p = 0.001) residual tumors, and a faster regrowth rate was significantly associated with decreased survival (HR = 4.01, 95% CI 2.26-7.14; p < 0.001). The overall survival of patients with recurrent glioblastoma who underwent reoperations increased with decreasing postoperative residual tumor volumes. For patients meeting prognostic criteria for reoperation, the surgical goal should be to minimize residual tumor volume to maximize overall survival. Clinical trial registration no.: NCT00060541 ( ClinicalTrials.gov ).


A Circuit for Gradient Climbing in C. elegans Chemotaxis.
Animals have a remarkable ability to track dynamic sensory information. For example, the nematode Caenorhabditis elegans can locate a diacetyl odor source across a 100,000-fold concentration range. Here, we relate neuronal properties, circuit implementation, and behavioral strategies underlying this robust navigation. Diacetyl responses in AWA olfactory neurons are concentration and history dependent; AWA integrates over time at low odor concentrations, but as concentrations rise, it desensitizes rapidly through a process requiring cilia transport. After desensitization, AWA retains sensitivity to small odor increases. The downstream AIA interneuron amplifies weak odor inputs and desensitizes further, resulting in a stereotyped response to odor increases over three orders of magnitude. The AWA-AIA circuit drives asymmetric behavioral responses to odor increases that facilitate gradient climbing. The adaptation-based circuit motif embodied by AWA and AIA shares computational properties with bacterial chemotaxis and the vertebrate retina, each providing a solution for maintaining sensitivity across a dynamic range.


On an Additive Semigraphoid Model for Statistical Networks With Application to Pathway Analysis.
We introduce a nonparametric method for estimating non-gaussian graphical models based on a new statistical relation called additive conditional independence, which is a three-way relation among random vectors that resembles the logical structure of conditional independence. Additive conditional independence allows us to use one-dimensional kernel regardless of the dimension of the graph, which not only avoids the curse of dimensionality but also simplifies computation. It also gives rise to a parallel structure to the gaussian graphical model that replaces the precision matrix by an additive precision operator. The estimators derived from additive conditional independence cover the recently introduced nonparanormal graphical model as a special case, but outperform it when the gaussian copula assumption is violated. We compare the new method with existing ones by simulations and in genetic pathway analysis.


Promoting self-directed learning skills in residency: a case study in program development.
Self-directed learning (SDL) skills are essential for the formation and ongoing competence of today's physicians who work in the context of expanding scientific knowledge and changing health care systems. In 2007-2008, the authors developed a program to promote SDL in the Brown University Family Medicine Residency. Through an iterative process, the project team juggled learning theories (i.e., Knowles' SDL model, Collins' cognitive apprenticeship model, and Quirk's expertise development model) with curricular goals, instructional options, and local constraints to design a practical and theoretically robust intervention.The intervention that emerged from this process features a faculty physician serving as a learning coach who meets individually each month with all second-year residents to assist them in generating learning goals, reflecting on their learning experiences, and practicing evidence-based medicine (EBM) skills. An electronic portfolio serves as a documentation tool that supports reflection; residents record their goals and reflections in the portfolio, which also contains their formative assessments, procedure logs, and special projects. To address the hidden curriculum, the program designers took special care to avoid increasing faculty and resident workload and created a forum for discussion and group reflection. Program evaluation combines qualitative and quantitative methods, such as surveys of and interviews with residents and faculty, to assess changes in residents' SDL and EBM skills and in the program's educational culture. The authors use Kern and colleagues' six-step model for curriculum development to describe both the unfolding of this complex project and the choices that resulted in the current program design.


Variability in responses of retinal ganglion cells.
Changes in the maintained discharge of retinal ganglion cells have been modeled by addition of noise to a rate-setting signal, whereas the responses of cortical cells have been reported to indicate a nonlinear relationship between noise and signal. To determine whether this represents a difference between retinal cells and cortical cells, the variance of light-evoked responses of ganglion cells in the retinas of goldfish was compared with the magnitude of the responses. Variance increased for higher firing rates. These results are discussed in terms of mechanisms by which light-evoked signals might interact with the variability of maintained discharges.


Association of interleukin-6 gene polymorphisms and glaucoma: Systematic review and meta-analysis.
To conduct a systematic review and meta-analysis to explore the association between IL-6 gene polymorphisms (rs1800795 and rs1524107) and glaucoma. A comprehensive search was performed to select eligible studies regarding IL-6 polymorphisms and glaucoma. The effect sizes in the fixed-effects model were calculated using odds ratios (ORs) with 95% confidence intervals (CIs). Four eligible studies comprising 762 cases and 799 controls were selected for meta-analysis. Regarding the association between the IL-6 rs1800795 polymorphism and glaucoma, those who carried the G/G+G/C genotypes had a non-significant higher risk of glaucoma (OR = 1.29, 95% CI = 0.76-2.19) in the dominant model. However, no obvious association (OR = 0.97, 95% CI = 0.68-1.37) was found for the recessive model (G/G vs G/C+C/C). In the subgroup analysis stratified by ethnicity, no significant associations were observed in populations of Asian or European heritage. Significantly higher glaucoma risks of 15.9 and 99.0 were observed for the dominant (C/C+C/T vs T/T) and recessive (C/C vs C/T+T/T) models, respectively. No statistically significant glaucoma risks were observed for the rs1800795 except rs1524107 polymorphism of IL-6. Further studies with a larger sample size are required to validate the effects of IL-6 polymorphisms on glaucoma risk.


Effects of Spatial Frequencies on Word Identification by Fast and Slow Readers: Evidence from Eye Movements.
Recent research has shown that differences in the effectiveness of spatial frequencies for fast and slow skilled adult readers may be an important component of differences in reading ability in the skilled adult reading population (Jordan et al., 2016a). But the precise nature of this influence on lexical processing during reading remains to be fully determined. Accordingly, to gain more insight into the use of spatial frequencies by skilled adult readers with fast and slow reading abilities, the present study looked at effects of spatial frequencies on the processing of specific target words in sentences. These target words were of either high or low lexical frequency and each sentence was displayed as normal or filtered to contain only very low, low, medium, high, or very high spatial frequencies. Eye movement behavior for target words was closest to normal for each reading ability when text was shown in medium or higher spatial frequency displays, although reading occurred for all spatial frequencies. Moreover, typical word frequency effects (the processing advantage for words with higher lexical frequencies) were observed for each reading ability across a broad range of spatial frequencies, indicating that many different spatial frequencies provide access to lexical representations during textual reading for both fast and slow skilled adult readers. Crucially, however, target word fixations were fewer and shorter for fast readers than for slow readers for all display types, and this advantage for fast readers appeared to be similar for normal, medium, high, and very high spatial frequencies but larger for low and very low spatial frequencies. Therefore, although fast and slow skilled adult readers can both use a broad range of spatial frequencies when reading, fast readers make more effective use of these spatial frequencies, and especially those that are lower, when processing the identities of words.


Hydroxychloroquine against COVID-19: A critical appraisal of the existing evidence.
Hydroxychloroquine (HCQ) has sparked much interest in the therapeutics of the Coronavirus Disease 2019 (COVID-19) pandemic. Its antiviral properties have been studied for years; regarding the Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2), it has been shown that HCQ may act at multiple levels. These extend from the initial attachment of the virus to the respiratory epithelium to the inhibition of its replication by the alkalinisation of the phagolysosome's microenvironment and the post-translational modification of certain viral proteins. Preliminary clinical evidence from China and France showed significant virological and clinical benefit in HCQ-treated patients, while other studies, mostly including critically ill patients, did not show favorable results. In this review, we critically appraise the existing evidence on HCQ against SARS-CoV-2 with particular emphasis on its protective and therapeutic role. Safety concerns that are relevant to the short-term HCQ use are also discussed. In the context of the rapid evolution of the COVID-19 pandemic that strains the health care systems worldwide and considering limited population-wide testing rates in most of the vulnerable countries, early empiric short-term administration of HCQ in symptomatic individuals, may be a promising, safe and low-cost strategy.


Inhibition of endocannabinoid degradation rectifies motivational and dopaminergic deficits in the Q175 mouse model of Huntington's disease.
Prominent motor deficits (e.g., chorea) that typify Huntington's disease (HD) arise following a prolonged prodromal stage characterized by psychiatric disturbances. Apathy, a disorder of motivation characterized by diminished goal-directed behavior, is one of the earliest and most common psychiatric symptoms in HD, but the underlying neurobiology is unclear and treatment options are limited. Alterations in the endocannabinoid (eCB) and dopamine systems represent prominent pathophysiological markers in HD that-similar to motivational deficits-present early and decline across disease progression. Whether changes in dopamine and eCB systems are associated with specific behavioral impairments in HD and whether these deficits are amenable to viable treatments is unknown. Here, we show that dopaminergic encoding of effortful drive progressively declines with age in an HD mouse model, and is restored by elevating tissue levels of the eCB 2-arachidonoylglycerol (2-AG) through targeted inhibition of its enzymatic degradation. This work supports aberrant dopaminergic encoding of reward as a neurobiological correlate of apathy in HD, and indicates that cannabinoid receptor-based therapies may benefit neuropsychiatric care for HD.


A century of Gestalt psychology in visual perception: I. Perceptual grouping and figure-ground organization.
In 1912, Max Wertheimer published his paper on phi motion, widely recognized as the start of Gestalt psychology. Because of its continued relevance in modern psychology, this centennial anniversary is an excellent opportunity to take stock of what Gestalt psychology has offered and how it has changed since its inception. We first introduce the key findings and ideas in the Berlin school of Gestalt psychology, and then briefly sketch its development, rise, and fall. Next, we discuss its empirical and conceptual problems, and indicate how they are addressed in contemporary research on perceptual grouping and figure-ground organization. In particular, we review the principles of grouping, both classical (e.g., proximity, similarity, common fate, good continuation, closure, symmetry, parallelism) and new (e.g., synchrony, common region, element and uniform connectedness), and their role in contour integration and completion. We then review classic and new image-based principles of figure-ground organization, how it is influenced by past experience and attention, and how it relates to shape and depth perception. After an integrated review of the neural mechanisms involved in contour grouping, border ownership, and figure-ground perception, we conclude by evaluating what modern vision science has offered compared to traditional Gestalt psychology, whether we can speak of a Gestalt revival, and where the remaining limitations and challenges lie. A better integration of this research tradition with the rest of vision science requires further progress regarding the conceptual and theoretical foundations of the Gestalt approach, which is the focus of a second review article.


Effects of environmental stress on mRNA expression levels of seven genes related to oxidative stress and growth in Atlantic salmon Salmo salar L. of farmed, hybrid and wild origin.
Ten generations of domestication selection has caused farmed Atlantic salmon Salmo salar L. to deviate from wild salmon in a range of traits. Each year hundreds of thousands of farmed salmon escape into the wild. Thus, interbreeding between farmed escapees and wild conspecifics represents a significant threat to the genetic integrity of wild salmon populations. In a previous study we demonstrated how domestication has inadvertently selected for reduced responsiveness to stress in farmed salmon. To complement that study, we have evaluated the expression of seven stress-related genes in head kidney of salmon of farmed, hybrid and wild origin exposed to environmentally induced stress. In general, the crowding stressor used to induce environmental stress did not have a strong impact on mRNA expression levels of the seven genes, except for insulin-like growth factor-1 (IGF-1) that was downregulated in the stress treatment relative to the control treatment. mRNA expression levels of glutathione reductase (GR), Cu/Zn superoxide dismutase (Cu/Zn SOD), Mn superoxide dismutase (Mn SOD), glutathione peroxidase (GP) and IGF-1 were affected by genetic origin, thus expressed significantly different between the salmon of farmed, hybrid or wild origin. A positive relationship was detected between body size of wild salmon and mRNA expression level of the IGF-1 gene, in both environments. No such relationship was observed for the hybrid or farmed salmon. Farmed salmon in this study displayed significantly elevated mRNA levels of the IGF-1 gene relative to the wild salmon, in both treatments, while hybrids displayed a non additive pattern of inheritance. As IGF-1 mRNA levels are positively correlated to growth rate, the observed positive relationship between body size and IGF-1 mRNA levels detected in the wild but neither in the farmed nor the hybrid salmon, could indicate that growth selection has increased IGF-1 levels in farmed salmon to the extent that they may not be limiting growth rate.


In Vitro and In Vivo Evaluation of the Toxic Effects of Dodecylguanidine Hydrochloride.
The toxicity profiles of the widely used guanidine-based chemicals have not been fully elucidated. Herein, we evaluated the in vitro and in vivo toxicity of eight guanidine-based chemicals, focusing on inhalation toxicity. Among the eight chemicals, dodecylguanidine hydrochloride (DGH) was found to be the most cytotoxic (IC50: 0.39 μg/mL), as determined by the water soluble tetrazolium salts (WST) assay. An acute inhalation study for DGH was conducted using Sprague-Dawley rats at 8.6 ± 0.41, 21.3 ± 0.83, 68.0 ± 3.46 mg/m3 for low, middle, and high exposure groups, respectively. The levels of lactate dehydrogenase, polymorphonuclear leukocytes, and cytokines (MIP-2, TGF-β1, IL-1β, TNF-α, and IL-6) in the bronchoalveolar lavage fluid increased in a concentration-dependent manner. Histopathological examination revealed acute inflammation with necrosis in the nasal cavity and inflammation around terminal bronchioles and alveolar ducts in the lungs after DGH inhalation. The LC50 of DGH in rats after exposure for 4 h was estimated to be >68 mg/m3. Results from the inhalation studies showed that DGH was more toxic in male rats than in female rats. Overall, DGH was found to be the most cytotoxic chemical among guanidine-based chemicals. Exposure to aerosols of DGH could induce harmful pulmonary effects on human health.


A Computational Role for Top-Down Modulation from Frontal Cortex in Infancy.
Recent findings have shown that full-term infants engage in top-down sensory prediction, and these predictions are impaired as a result of premature birth. Here, we use an associative learning model to uncover the neuroanatomical origins and computational nature of this top-down signal. Infants were exposed to a probabilistic audiovisual association. We find that both groups (full term, preterm) have a comparable stimulus-related response in sensory and frontal lobes and track prediction error in their frontal lobes. However, preterm infants differ from their full-term peers in weaker tracking of prediction error in sensory regions. We infer that top-down signals from the frontal lobe to the sensory regions carry information about prediction error. Using computational learning models and comparing neuroimaging results from full-term and preterm infants, we have uncovered the computational content of top-down signals in young infants when they are engaged in a probabilistic associative learning.


A randomized study of the effects of a home diabetes education program.
Home health nurses provided individualized instruction in diabetes self-care within the home environment of 393 diabetic individuals. Each subject was randomly assigned to either the intervention (those receiving home teaching) or control (those not receiving home teaching) group. At 6 mo postenrollment, intervention subjects showed significantly greater self-care knowledge and skills than control subjects, although the actual differences between the two groups in terms of self-care skills were probably too small to have any practical meaning. The primary objective of the study, which was the reduction of the number of preventable diabetes-related hospitalizations (ketoacidosis, ketotic coma, nonketotic coma, insulin reaction, and diabetes out of control), was not achieved; no differences between the groups were noted after 12 mo of follow-up. Similarly, length of hospital stay, foot problems, emergency room and physician visits, and sick days were roughly equivalent in both groups during the follow-up year. These results suggest that, in the absence of concurrent changes in the health-care delivery system and strategies for influencing attitudes toward self-care, education alone is ineffective.


The fundamental basis of inflammatory bowel disease.
Two broad hypotheses have arisen regarding the fundamental nature of the pathogenesis of inflammatory bowel diseases (IBDs, which include ulcerative colitis and Crohn disease). The first contends that primary dysregulation of the mucosal immune system leads to excessive immunologic responses to normal microflora. The second suggests that changes in the composition of gut microflora and/or deranged epithelial barrier function elicits pathologic responses from the normal mucosal immune system. Here we examine these hypotheses and conclude that IBD is indeed characterized by an abnormal mucosal immune response but that microbial factors and epithelial cell abnormalities can facilitate this response.


Is there a role for neck dissection in T1 oral tongue squamous cell carcinoma? The UCLA experience.
We sought to examine prognostic and therapeutic implications, including cost-effectiveness, of elective neck dissection in the management of patients with clinically-determined T1N0 oral tongue carcinoma. A retrospective review of patients with cT1N0 oral tongue squamous cell carcinoma who underwent surgical extirpation of primary tumor, with or without elective neck dissection, at UCLA Medical Center from 1990 to 2009 was performed. Cox proportional hazards regression was used to assess effects of variables on time to first loco-regional recurrence. A healthcare costs analysis of elective neck dissection was performed by querying the SEER-Medicare linked database. Of the 123 patients identified with cT1N0 squamous cell carcinoma of the oral tongue, 88 underwent elective neck dissection at the time of tumor resection while 35 did not. For all patients, disease-free survival at 3, 5, and 10 years was 93%, 82%, and 79%. Of the 88 patients undergoing elective neck dissection, 20 (23%) demonstrated occult metastatic disease. Male gender, tumor size, perineural invasion, and occult metastatic disease were individually associated with higher rates of loco-regional recurrence. There was no significant difference in loco-regional recurrence between those who underwent elective neck dissection and those who did not (HR=0.76, p=0.52). On cost analysis, neck dissection was not associated with any significant difference in Medicare payments. The high rate of occult metastasis (23%) following elective neck dissection, which did not confer additional healthcare costs, leads to the recommendation of elective neck dissection in patients with cT1N0 oral tongue squamous cell carcinoma.


Transcript specificity in yeast pre-mRNA splicing revealed by mutations in core spliceosomal components.
Appropriate expression of most eukaryotic genes requires the removal of introns from their pre-messenger RNAs (pre-mRNAs), a process catalyzed by the spliceosome. In higher eukaryotes a large family of auxiliary factors known as SR proteins can improve the splicing efficiency of transcripts containing suboptimal splice sites by interacting with distinct sequences present in those pre-mRNAs. The yeast Saccharomyces cerevisiae lacks functional equivalents of most of these factors; thus, it has been unclear whether the spliceosome could effectively distinguish among transcripts. To address this question, we have used a microarray-based approach to examine the effects of mutations in 18 highly conserved core components of the spliceosomal machinery. The kinetic profiles reveal clear differences in the splicing defects of particular pre-mRNA substrates. Most notably, the behaviors of ribosomal protein gene transcripts are generally distinct from other intron-containing transcripts in response to several spliceosomal mutations. However, dramatically different behaviors can be seen for some pairs of transcripts encoding ribosomal protein gene paralogs, suggesting that the spliceosome can readily distinguish between otherwise highly similar pre-mRNAs. The ability of the spliceosome to distinguish among its different substrates may therefore offer an important opportunity for yeast to regulate gene expression in a transcript-dependent fashion. Given the high level of conservation of core spliceosomal components across eukaryotes, we expect that these results will significantly impact our understanding of how regulated splicing is controlled in higher eukaryotes as well.


Temporal evolution of beta bursts in the parkinsonian cortical and basal ganglia network.
Beta frequency oscillations (15 to 35 Hz) in cortical and basal ganglia circuits become abnormally synchronized in Parkinson's disease (PD). How excessive beta oscillations emerge in these circuits is unclear. We addressed this issue by defining the firing properties of basal ganglia neurons around the emergence of cortical beta bursts (β bursts), transient (50 to 350 ms) increases in the beta amplitude of cortical signals. In PD patients, the phase locking of background spiking activity in the subthalamic nucleus (STN) to frontal electroencephalograms preceded the onset and followed the temporal profile of cortical β bursts, with conditions of synchronization consistent within and across bursts. Neuronal ensemble recordings in multiple basal ganglia structures of parkinsonian rats revealed that these dynamics were recapitulated in STN, but also in external globus pallidus and striatum. The onset of consistent phase-locking conditions was preceded by abrupt phase slips between cortical and basal ganglia ensemble signals. Single-unit recordings demonstrated that ensemble-level properties of synchronization were not underlain by changes in firing rate but, rather, by the timing of action potentials in relation to cortical oscillation phase. Notably, the preferred angle of phase-locked action potential firing in each basal ganglia structure was shifted during burst initiation, then maintained stable phase relations during the burst. Subthalamic, pallidal, and striatal neurons engaged and disengaged with cortical β bursts to different extents and timings. The temporal evolution of cortical and basal ganglia synchronization is cell type-selective, which could be key for the generation/ maintenance of excessive beta oscillations in parkinsonism.


Predictive Modeling of Hamstring Strain Injuries in Elite Australian Footballers.
Three of the most commonly identified hamstring strain injury (HSI) risk factors are age, previous HSI, and low levels of eccentric hamstring strength. However, no study has investigated the ability of these risk factors to predict the incidence of HSI in elite Australian footballers. Accordingly, the purpose of this prospective cohort study was to investigate the predictive ability of HSI risk factors using machine learning techniques. Eccentric hamstring strength, demographic and injury history data were collected at the start of preseason for 186 and 176 elite Australian footballers in 2013 and 2015, respectively. Any prospectively occurring HSI were reported to the research team. Using various machine learning techniques, predictive models were built for 2013 and 2015 within-year HSI prediction and between-year HSI prediction (2013 to 2015). The calculated probabilities of HSI were compared with the injury outcomes and area under the curve (AUC) was determined and used to assess the predictive performance of each model. The minimum, maximum, and median AUC values for the 2013 models were 0.26, 0.91, and 0.58, respectively. For the 2015 models, the minimum, maximum and median AUC values were, correspondingly, 0.24, 0.92, and 0.57. For the between-year predictive models the minimum, maximum, and median AUC values were 0.37, 0.73, and 0.52, respectively. Although some iterations of the models achieved near perfect prediction, the large ranges in AUC highlight the fragility of the data. The 2013 models performed slightly better than the 2015 models. The predictive performance of between-year HSI models was poor however. In conclusion, risk factor data cannot be used to identify athletes at an increased risk of HSI with any consistency.


Tracer studies on an aerated lagoon.
The city of Palmerston North, New Zealand, has two aerated lagoons as its secondary treatment facility. Interest about treatment efficiency led to an investigation into the hydraulics in the second lagoon to determine if further optimisation was viable. A tracer study using rhodamine WT was undertaken to ascertain the stimulus response output. Samples were also taken at 24 points within the lagoon to determine the tracer concentration profile throughout the lagoon. The mean residence time was determined to be 39.9 h compared with a theoretical residence time of 55.4 h. Peak concentration of the tracer at the outlet occurred at 0.44 of the mean residence time. The results of the tracer study pointed to 28% of volume being dead space. A subsequent sludge survey indicated that 26% of the design volume of the lagoon was filled with sludge. While the curved geometry of the lagoon did not appear to impact the hydraulics the fact that the first aerator is confined in a relatively smaller area will have locally boosted the mixing energy input in this inlet zone. From interpretation of the tracer response and the tracer distribution profiles it appears that the aerators are mixing the influent into the bulk flow effectively in the front end of the lagoon and that there was no evidence of any substantive short-circuiting path of concentrated tracer around to the outlet. The tracer distribution profiles gave direct insight as to how the tracer was being transported within the pond and should be used more often when conducting tracer studies. Comparison with the literature indicated that the lagoon's hydraulic efficiency was on par with a baffled pond system and it would be expected that addition of several baffles to the lagoon would provide minimal further improvement.


Functional integration of a metabolic network model and expression data without arbitrary thresholding.
Flux balance analysis (FBA) has been used extensively to analyze genome-scale, constraint-based models of metabolism in a variety of organisms. The predictive accuracy of such models has recently been improved through the integration of high-throughput expression profiles of metabolic genes and proteins. However, extensions of FBA often require that such data be discretized a priori into sets of genes or proteins that are either 'on' or 'off'. This procedure requires selecting relatively subjective expression thresholds, often requiring several iterations and refinements to capture the expression dynamics and retain model functionality. We present a method for mapping expression data from a set of environmental, genetic or temporal conditions onto a metabolic network model without the need for arbitrary expression thresholds. Metabolic Adjustment by Differential Expression (MADE) uses the statistical significance of changes in gene or protein expression to create a functional metabolic model that most accurately recapitulates the expression dynamics. MADE was used to generate a series of models that reflect the metabolic adjustments seen in the transition from fermentative- to glycerol-based respiration in Saccharomyces cerevisiae. The calculated gene states match 98.7% of possible changes in expression, and the resulting models capture functional characteristics of the metabolic shift. MADE is implemented in Matlab and requires a mixed-integer linear program solver. Source code is freely available at http://www.bme.virginia.edu/csbl/downloads/.


Lactose intolerance in irritable bowel syndrome patients with diarrhoea: the roles of anxiety, activation of the innate mucosal immune system and visceral sensitivity.
Irritable bowel syndrome patients with diarrhoea (IBS-D) often report intolerance to milk; however, the mechanism underlying these symptoms is unknown. To assess the role of psychological factors, immune activation and visceral sensitivity on the development of lactose intolerance (LI) in IBS-D patients. Fifty-five IBS-D patients and 18 healthy controls (HCs) with lactase deficiency underwent a 20-g lactose hydrogen breath test (LHBT). Patients were categorised as lactose malabsorption (LM; malabsorption only) or LI [malabsorption plus increase in total symptom score (TSS). Measurements included (i) psychological status; (ii) enteric biopsies with quantification of mast cells (MCs), T-lymphocytes and enterochromaffin cells; (iii) serum cytokines; (iv) rectal sensitivity before and after lactose ingestion. LI was more prevalent in IBS-D patients than HCs [25/55 (46%) vs. 3/18 (17%), P = 0.029]. IBS-D patients with LI had (i) higher levels of anxiety than those with LM (P = 0.017) or HCs (P = 0.006); (ii) increased mucosal MCs compared with LM (P = 0.006) and HCs (P < 0.001); (iii) raised serum TNF-α compared with LM (P = 0.034) and HCs (P < 0.001) and (iv) increased rectal sensitivity after lactose ingestion compared with LM (P < 0.001) or HCs (P < 0.001). Severity of abdominal symptoms after lactose ingestion was associated with the increase in visceral sensitivity after lactose intake (r = 0.629, P < 0.001), MCs (r = 0.650, P < 0.001) and anxiety (r = 0.519, P < 0.001). IBS-D patients with lactose intolerence are characterised by anxiety, mucosal immune activation and increased visceral sensitivity after lactose ingestion. The presence of these biomarkers may indicate an IBS phenotype that responds to dietary therapy and/or mast cell stabilisers.


Randomized controlled trial of video self-modeling following speech restructuring treatment for stuttering.
In this study, the authors investigated the efficacy of video self-modeling (VSM) following speech restructuring treatment to improve the maintenance of treatment effects. The design was an open-plan, parallel-group, randomized controlled trial. Participants were 89 adults and adolescents who undertook intensive speech restructuring treatment. Post treatment, participants were randomly assigned to 2 trial arms: standard maintenance and standard maintenance plus VSM. Participants in the latter arm viewed stutter-free videos of themselves each day for 1 month. The addition of VSM did not improve speech outcomes, as measured by percent syllables stuttered, at either 1 or 6 months postrandomization. However, at the latter assessment, self-rating of worst stuttering severity by the VSM group was 10% better than that of the control group, and satisfaction with speech fluency was 20% better. Quality of life was also better for the VSM group, which was mildly to moderately impaired compared with moderate impairment in the control group. VSM intervention after treatment was associated with improvements in self-reported outcomes. The clinical implications of this finding are discussed.


The origin of ocular microtremor in man.
A novel technique for the study of human eye movements was used to investigate the frequency components of ocular drift and microtremor in both eyes simultaneously. The tangential components of horizontal eye accelerations were recorded in seven healthy subjects using light-weight accelerometers mounted on scleral contact lenses during smooth pursuit movements, vestibulo-ocular reflexes and eccentric gaze with and without fixation. Spectral peaks were observed at low (up to 25 Hz) and high (60-90 Hz) frequencies. A multivariate analysis based on partial coherence analysis was used to correct for head movement. After correction, the signals were found to be coherent between the eyes over both low- and high-frequency ranges, irrespective of task, convergence or fixation. It is concluded that the frequency content of ocular drift and microtremor reflects the patterning of low-level drives to the extra-ocular muscle motor units.


Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy.
Whether to continue oral anticoagulant therapy beyond 6 months after an "unprovoked" venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants. In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5-7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule. We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%-11.3%). Men had a 13.7% (95% CI 10.8%-17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer > or = 250 microg/L while taking warfarin; body mass index > or = 30 kg/m(2); or age > or = 65 years. These women had an annual risk of 1.6% (95% CI 0.3%-4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%-17.3%). Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men.


Characterization of a novel third member of the human cytomegalovirus glycoprotein H-glycoprotein L complex.
A prerequisite for understanding the molecular function of the human cytomegalovirus (HCMV) gH (UL75)-gL (UL115) complex is a detailed knowledge of the structure of this complex in its functional form, as it is present in mature virions. The gH protein is known to be a component of a 240-kDa envelope complex designated as gCIII (D. R. Gretch, B. Kari, L. Rasmussen, R. C. Gehrz, and M. F. Stinski, J. Virol. 62:875-881, 1988). However, the exact composition of the gCIII complex remains unknown. In this report, we attempted reconstitution of the gCIII complex by coexpression of gH and gL in the baculovirus expression system. Formation of recombinant gH-gL complexes of approximately 115 kDa was demonstrated; however, no higher-molecular-mass (approximately 240-kDa) recombinant gH-gL complexes were detected, suggesting that the presence of gH and gL alone is not sufficient for reconstitution of the gCIII complex. To identify other mammalian and/or HCMV factors which may be necessary for gCIII formation, immunoprecipitates of gH and gL from HCMV-infected fibroblasts and purified HCMV virions were examined. This analysis did reveal a number of coprecipitating proteins which associate either transiently or integrally with gH and gL. One coprecipitating protein of 145 kDa was shown to be an integral component of gCIII, along with gH and gL. Characterization of the 145-kDa protein demonstrates that it is structurally and antigenically unrelated to gH and gL and that it appears to be virally encoded. Together, these data indicate that the 145-kDa protein is a third novel component of the mature HCMV gH-gL complex.


Selective downregulation of N-methyl-D-aspartate receptor (NMDAR) rather than non-NMDAR subunits in ipsilateral cerebral hemispheres in rats with middle cerebral artery occlusion.
Ischemic brain damage is believed to involve the drastic increase in extracellular glutamate levels after reperfusion and subsequent overactivation of both N-methyl-D-aspartate (NMDA) receptor (NMDAR) and non-NMDAR channels for delayed neuronal cell death mediated by Ca2+ overload. In this study, we evaluated expression profiles of mRNA and corresponding proteins for different subunits of NMDAR and non-NMDAR in brains of rats with transient middle cerebral artery occlusion (MCAO). Cellular vitality was markedly reduced in proportion to increasing durations of MCAO for 1 to 8 h when determined 1 day after reperfusion. Within 7 days after reperfusion, MCAO for 2 h led to a gradual decrease in the neuronal marker microtubules-associated protein-2 (MAP2) level in the ipsilateral cerebral hemisphere, in addition to inducing a transient increase in the microglial marker CD11b expression without affecting the astroglial marker protein levels. MCAO for 2 h significantly decreased the expression of both mRNA and corresponding proteins for NR1, NR2A and NR2B subunits of NMDAR, but not for non-NMDAR subunits, in the ipsilateral hemisphere. These results suggest that NMDAR may be preferentially down-regulated in response to ischemic signal inputs amongst three different subtypes of ionotropic glutamate receptors in rats with MCAO.


KLF5 regulates the integrity and oncogenicity of intestinal stem cells.
The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5(+) crypt-base columnar cells, but core mechanisms and their contributions to intestinal cancer are not fully defined. In this study, we examined a hypothesized role for KLF5, a zinc-finger transcription factor that is critical to maintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in the mouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. In mice, inducible deletion of Klf5 in Lgr5(+) stem cells suppressed their proliferation and survival in a manner associated with nuclear localization of β-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of β-catenin in Lgr5(+) stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/β-catenin pathway is the most frequently altered pathway in human colorectal cancer, our results argue that KLF5 acts as a fundamental core regulator of intestinal oncogenesis at the stem-cell level, and they suggest KLF5 targeting as a rational strategy to eradicate stem-like cells in colorectal cancer.


Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants.
Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.


The temporal characteristics of motion processing in hMT/V5+: combining fMRI and neuronavigated TMS.
Functional imaging has demonstrated the specific involvement of the human middle-temporal complex (hMT/V5+) during processing of moving stimuli. Some studies applied transcranial magnetic stimulation (TMS) to investigate the causal relevance of hMT/V5+ for motion perception. Although the studies used similar visual stimuli and TMS parameters, the critical time point of functionally relevant hMT/V5+ activity differed by 100 ms and more. The present study aimed to elucidate further the temporal characteristics of motion processing in hMT/V5+ by investigating all critical time windows currently debated in the literature. In contrast to previous studies, we used TMS neuronavigation based on individual fMRI results of five participants to target hMT/V5+, applying single-pulse TMS at 24 different time windows (-50 till +200 ms relative to stimulus onset). We revealed that TMS significantly impaired motion perception when applied over hMT/V5+ at 40 to 30 ms before as well as 130 to 150 ms after onset of the moving stimuli. While the late effective time window conforms to results from previous experiments, we did not find evidence for an early time window around 0 ms that has been reported in other studies. Our neuronavigation approach enabled us to quantify the interindividual variance in the exact location of hMT/V5+ and the respective TMS target position on the skull of the participants. Considering that shifting the TMS coil position only by a few millimeters can already lead to a complete loss of TMS effects, our study clearly demonstrates the utility of neuronavigated TMS when investigating specific neuronal effects as in the case of motion processing.


Skeleton of diacodexis, oldest known artiodactyl.
A nearly complete skeleton of early Eocene Diacodexis, the oldest known member of the mammalian order Artiodactyla, is described. Its slender, elongate limb elements indicate that Diacodexis was highly cursorial and closer in postcranial adaptations to tragulids and other primitive ruminants than to living or extinct nonruminant artiodactyls. Its skeletal specializations call into question the widespread notion that Diacodexis was the ancestor of all later artiodactyls.


Effects of laparoscopic adjustable gastric banding on sleep and metabolism: a 12-month follow-up study.
Obstructive sleep apnea is commonly associated with metabolic changes and obesity, and changes in body weight by either medical or surgical approaches have been considered to affect the severity of sleep apnea and appetite-controlling hormones. This prospective study evaluated the effect of weight loss induced by laparoscopic adjustable gastric banding (LAGB) surgery on respiratory disturbance during sleep, oxygen saturation levels, sleep architecture, and leptin and ghrelin levels. Participants were patients at a university-based medical center surgical weight loss program. All participants with a body mass index > 30 kg/m(2) undergoing LAGB surgery for weight reduction were offered the opportunity to participate in the study. Procedures included overnight polysomnography followed by fasting hormone levels at baseline and 12 months postoperatively. Thirty subjects (10 men, 20 women) of mean age 44.0 ± 12.5 years were recruited. At 12 months postoperatively, mean excess weight loss was 44.4% ± 14%. The apnea-hypopnea index decreased from 34.2 ± 35 to 19.0 ± 21.7 events per hour (P < 0.0001), while leptin levels decreased from 24.5 ± 17.42 pg/mL to 11.6 ± 10.6 pg/mL (P = 0.02). Ghrelin levels did not change substantially. Nadir oxygen saturation levels increased from 81% to 84% at 12 months (P = 0.03). Mean oxygen saturation improved and was positively correlated with ghrelin levels at both time points (r = 0.39, P = 0.07, and r = 0.60, P = 0.01). LAGB surgery was associated with 44.4% excess weight loss at 12 months, accompanied by a 33.7% improvement in apnea-hypopnea index as well as a reduction in leptin levels by 31.7% in this group. An association between ghrelin and mean oxygen saturation was seen and deserves further investigation.