The rod pathway in the rabbit retina: a depolarizing bipolar and amacrine cell.
Anatomical and electrophysiological techniques were combined to study the morphology, synaptic connections, and response properties of two neurons in the rod pathway of the rabbit retina: the rod bipolar cell and the narrow-field, bistratified (NFB) amacrine cell. Rod bipolars receive synaptic input from rod cells in the outer plexiform layer (OPL), where their dendrites end as central elements in the invaginating synapse of rod spherules. Their main synaptic output in the inner plexiform layer (IPL) is onto NFB amacrine cells and at least one other type of amacrine, which in turn feeds a reciprocal synapse back onto the bipolar endings. Rod bipolars, or a variety of them, respond to diffuse, white light stimulation with a transient-sustained depolarization dominated by rods; with high-intensity flashes, they generate a secondary depolarization at off, which is homologous to the rod aftereffect of horizontal cells, although opposite in polarity. NFB amacrine cells receive synaptic input from rod bipolars, cone bipolars, and other types of amacrine cells; they are presynaptic to ganglion cell dendrites and communicate via gap junctions with other processes, whose parent neuron has not yet been identified. They respond to light with a triphasic potential, characterized by a depolarizing transient at on, followed by a sustained plateau phase, and finally by a hyperpolarizing transient at off. Threshold of their responses is the same as in the depolarizing rod bipolars and saturation is reached with nearly the same stimulus intensity in both neurons. Furthermore, NFB amacrine cells exhibit a depolarizing rod aftereffect at the termination of high-intensity flashes. Thus, this amacrine cell type is inserted in series along the rod pathway in the rabbit retina and modulates the transfer of scotopic signals from rod bipolars to ganglion cells.


Role of nonmigratory mottled ducks (Anas fulvigula) as sentinels for avian influenza surveillance.
The objective of this study was to evaluate the mottled duck (Anas fulvigula), a nonmigratory dabbling duck, as a sentinel species for avian influenza virus (AIV) surveillance. A total of 235 cloacal swabs from 147 live-captured and 88 hunter-harvested mottled ducks during summer (June-August 2007) and winter (November 2007 to January 2008), respectively, were collected along the upper Texas coast. Samples were screened for AIV using real-time reverse transcription polymerase chain reaction (rRT-PCR); all rRT-PCR-positive samples were processed for virus isolation. Three samples were positive for AIV by AIV-matrix rRT-PCR. One of these samples also was positive for H5 by rRT-PCR, and a low pathogenic H5N2 AIV was isolated. Although isolation of AIVs from mottled ducks during the winter has been reported previously, to the authors' knowledge, this is the first H5 isolate from mottled ducks. Interestingly, this isolation was made during the same season that other H5N2 viruses were obtained from migratory waterfowl on the Texas coast, which suggests AIV transmission among waterfowl on the wintering grounds and the potential role of mottled ducks as a naturally occurring sentinel species for AIV surveillance.


Optimists' and pessimists' self-reported mental and global health during the COVID-19 pandemic in Norway.
The COVID-19 pandemic represents a global health crisis. How well people cope with this situation depends on many factors, including one's personality, such as dispositional optimism. The aim of the study was to investigate: 1) optimists' and pessimists' concerns during lockdown, and mental and global health; 2) whether pessimists without known risk factors more often than optimists report being at risk for COVID-19. A snowball sampling strategy was used; 4,527 people, 18 years or older, participated in a survey on a variety of mental health conditions and COVID-19 worries. In addition, they completed the Life Orientation Test-Revised (LOT-R). Optimism was defined by LOT-R f ≥ 17. Fewer optimists than pessimists reported that they were worried about COVID-19, respectively 51.2% vs. 66.8%, p < .001. Among those reporting none of the known somatic risk factors, more pessimists than optimists (14.3% vs. 9.1%, p < .001) considered themselves at risk of a fatal outcome from COVID-19. Significantly fewer optimists reported that they had anxiety (5.1%), depression (3.4%), suicidal ideation (0.7%) and insomnia (19.3%) during the COVID-19 outbreak than pessimists (24.7% anxiety, 18.4% depression, 5.4% suicidal ideation, 39.8% insomnia, all p < .001). Optimists reported better global health than pessimists (87.2 vs. 84.6, p < .001). Optimists were generally less worried about the COVID-19 pandemic than pessimists and reported better mental and global health during lockdown. Pessimists more often than optimists reported being at risk for COVID-19 without reporting known risk factors.


Stereotactic ablative radiotherapy (SABR) for non-small cell lung cancer.
Stereotactic ablative radiotherapy (SABR), otherwise known as stereotactic body radiation therapy (SBRT), is an external beam treatment modality that offers the ability to deliver with high precision large doses of radiation over a limited number of fractions. SABR is currently a standard of care in the treatment of early-stage primary non-small cell lung cancers (NSCLCs) that are medically inoperable and for metastases in many anatomical locations. To date, local control and toxicity parameters with SABR for early-stage NSCLCs are comparable to those found in reports of experiences with surgical resection. It is increasingly apparent that some patients with borderline resectable lung primaries are also looking to SABR as a noninvasive means of therapy. However, randomized comparisons have not been completed to assess survival in operable patients. This review summarizes the advanced technology and radiation concepts that have helped clinicians optimize the use of stereotactic ablative therapies for lung cancer, with an emphasis on the rationale for future continued use of this advanced treatment modality.


Superfluid-helium-cooled rocket-borne far-infrared radiometer.
A far-infrared radiometer, cooled to 1.6 K by superfluid helium, has been flown in a Terrier-Sandhawk rocket. The instrument was designed to measure night-sky radiation in three wavelength passbands between 6 mm and 0.1 mm at altitudes between 120 km and 350 km. A failure in the rocket nose cone separation system prevented the measurement of this radiation, but the performance of the instrument during flight was generally satisfactory. Design features and operational characteristics of the cryogenic, optical, detection, and electronic systems are presented.


Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents.
Human exposures to environmental toxicants have been associated with etiology of many diseases including inflammation, cancer, and cardiovascular and neurodegenerative disorders. To counteract the detrimental effect of environmental insults, mammalian cells have evolved a hierarchy of sophisticated sensing and signaling mechanisms to turn on or off endogenous antioxidant responses accordingly. One of the major cellular antioxidant responses is the induction of antioxidative and carcinogen-detoxification enzymes through the cytoplasmic oxidative stress system (Nrf2-Keap1) activated by a variety of natural and synthetic chemopreventive agents. Under normal conditions, Keap1 anchors the Nrf2 transcription factor within the cytoplasm targeting it for ubiquitination and proteasomal degradation to maintain low levels of Nrf2 that mediate the constitutive expression of Nrf2 downstream genes. When cells are exposed to chemopreventive agents and oxidative stress, a signal involving phosphorylation and/or redox modification of critical cysteine residues in Keap1 inhibits the enzymatic activity of the Keap1-Cul3-Rbx1 E3 ubiquitin ligase complex, resulting in decreased Nrf2 ubiquitination and degradation. As a consequence, free Nrf2 translocates into the nucleus and in combination with other transcription factors (e.g., sMaf, ATF4, JunD, PMF-1) transactivates the antioxidant response elements (AREs)/electrophile response elements (EpREs) of many cytoprotective genes, as well as Nrf2 itself. Upon recovery of cellular redox homeostasis, Keap1 travels into the nucleus to dissociate Nrf2 from the ARE. Subsequently, the Nrf2-Keap1 complex is exported out of the nucleus by the nuclear export sequence (NES) in Keap1. Once in the cytoplasm, the Nrf2-Keap1 complex associates with the Cul3-Rbx1 core ubiquitin machinery, resulting in degradation of Nrf2 and termination of the Nrf2/ARE signaling pathway. The discovery of multiple nuclear localization signals (NLSs) and nuclear export signals (NESs) in Nrf2 also suggests that the nucleocytoplasm translocation of transcription factors is the consequence of a dynamic equilibrium of multivalent NLSs and NESs. On the other hand, Keap1 may provide an additional regulation of the quantity of Nrf2 both in basal and inducible conditions. This chapter summarizes the current body of knowledge regarding the molecular mechanisms through which ARE inducers (chemopreventive agents) regulate the coordinated transcriptional induction of genes encoding phase II and antioxidant enzymes as well as other defensive proteins, via the nuclear factor-erythroid 2 (NF-E2-p45)-related factor 2(Nrf2)/(ARE) signaling pathway.


Learning impairment in transgenic mice with central overexpression of corticotropin-releasing factor.
The present studies were designed to test the learning and memory capacities of transgenic mice with central overexpression of corticotropin-releasing factor in a forced alternation water T-maze task and in the Morris water maze. In T-maze testing, littermate control mice reached a criterion of 70% correct responses after five days of trials, while the performance of transgenic subjects was still random after the same training. In Morris maze testing, control subjects reached the submerged platform significantly faster (F(1.48) = 4.51, P < 0.05) after three days of trials, while the performance of transgenic mice was unimproved over the same period. The deficit in Morris maze performance in transgenic mice was reversed when the platform was visible above the surface of the water. Pre-test administration of the benzodiazepine anxiolytic, chlordiazepoxide (10 mg/kg), before acquisition training also produced a significant (F(4.40) = 16.61, P < 0.001) and persistent improvement in Morris maze performance in transgenic mice when compared to vehicle-treated transgenic litter mates. Finally, there was no evidence of hippocampal cell loss in transgenic brains. The results suggest that corticotropin-releasing factor-overexpressing mice exhibit a profound learning deficit without sensory or motor-related impairments, and that memory plasticity can be restored by anxiolytic pre-treatment. Thus, constitutive overabundance of brain corticotropin-releasing factor may produce hyperemotionality that interferes with learned behaviors. Stress-related disorders characterized by co-morbid deficits in learning/memory may benefit from pharmacological normalization of brain corticotropin-releasing factor systems.


Empirical Sensitivity Analysis of Discretization Parameters for Fault Pattern Extraction From Multivariate Time Series Data.
It has been a challenge to find patterns in a time series of sensor data for fault detection in a system. Since it is usually not straightforward to discover meaningful features and rules directly from complex time series, data discretization has been popularly employed to reduce data size while preserving meaningful features from the original data, for which the choice of appropriate discretization parameters is crucial. We thus present a systematic discretization procedure of multivariate time series data that includes: 1) label definition in consideration of the estimated distribution functions of sensor signals and the trends of signal's short-term variation and 2) label specification to a set of time segments in order to describe the state of a given system for the time segment as a discretized state vector. Formal definitions of fault patterns and discretization problems are made to conduct empirical sensitivity analysis of discretization parameters in finding the most informative fault patterns. We then investigate the relationship between the parameters and the key characteristic indicators of sensor signals. The computational results with the ten real-world data sets provide a practical advice to select appropriate parameters.


Unbiased and locally efficient estimation of genetic effect on quantitative trait in the presence of population admixture.
Population admixture can be a confounding factor in genetic association studies. Family-based methods (Rabinowitz and Larid, 2000, Human Heredity 50, 211-223) have been proposed in both testing and estimation settings to adjust for this confounding, especially in case-only association studies. The family-based methods rely on conditioning on the observed parental genotypes or on the minimal sufficient statistic for the genetic model under the null hypothesis. In some cases, these methods do not capture all the available information due to the conditioning strategy being too stringent. General efficient methods to adjust for population admixture that use all the available information have been proposed (Rabinowitz, 2002, Journal of the American Statistical Association 92, 742-758). However these approaches may not be easy to implement in some situations. A previously developed easy-to-compute approach adjusts for admixture by adding supplemental covariates to linear models (Yang et al., 2000, Human Heredity 50, 227-233). Here is shown that this augmenting linear model with appropriate covariates strategy can be combined with the general efficient methods in Rabinowitz (2002) to provide computationally tractable and locally efficient adjustment. After deriving the optimal covariates, the adjusted analysis can be carried out using standard statistical software packages such as SAS or R. The proposed methods enjoy a local efficiency in a neighborhood of the true model. The simulation studies show that nontrivial efficiency gains can be obtained by using information not accessible to the methods that rely on conditioning on the minimal sufficient statistics. The approaches are illustrated through an analysis of the influence of apolipoprotein E (APOE) genotype on plasma low-density lipoprotein (LDL) concentration in children.


Effect of different types of plastic packaging films on the moisture and aflatoxin contents of pistachio nuts during storage.
Pistachio nut (Pistacia vera L.) is one of the popular tree nuts in the world. Proper selection of packaging materials is necessary to prevent absorption of moisture and aflatoxin formation which will influence the overall product quality and safety. This research is undertaken to study the effect of different type of flexible packaging films on the moisture and aflatoxin contents of whole pistachio nuts during storage at ambient temperature (22-28 °C) and relative humidity of 85-100%. Five types of plastic films tested were low density polyethylene (LDPE) which serves as the control, food-grade polyvinyl chloride (PVC), nylon (LDPE/PA), polyamide/polypropylene (PA/PP) and polyethylene terephthalate (PET). The moisture content and aflatoxin content of pistachio nuts were measured using oven drying method and HPLC, respectively. Sample were analysed at 0, 2, 4, 6, 8 and 10 months during the storage period. Results showed that there was an increase in moisture content with the increase in storage time of pistachio nuts. The increase in moisture content was associated with the aflatoxin level of pistachio nuts during storage time. All the packaging materials except LDPE delayed the moisture absorption and aflatoxin formation of the product. The most suitable packaging materials for maintaining the quality and safety of pistachio nuts is PET films followed by nylon, PA/PP and PVC. The shelf-life of pistachio can be extended from 2 months (Control) to 5 months when PET is used as the packaging material.


Prospective evaluation of Roux-en-Y gastric bypass as primary operation for medically complicated obesity.
To determine prospectively the results of Roux-en-Y gastric bypass (RYGB) used as the primary weight-reducing operation in patients with medically complicated ("morbid") obesity. The RYGB procedure combines the advantages of a restrictive physiology (pouch of 10 mL) and a "dumping physiology" for high-energy liquids without requiring an externally reinforced (banded) stoma. Between April 1987 and December 1998, a total of 191 consecutive patients with morbid obesity (median weight, 138 kg [range, 91-240 kg]; median body mass index, 49 kg/m2 [range, 36-74 kg/m2]), all of whom had directly weight-related morbidity, underwent RYGB and prospective follow-up. Hospital mortality was 0.5% (1/191), and hospital morbidity occurred in 10.5% (20/191). Good long-term weight loss was achieved, and patients adapted well to the required new eating habits. The mean +/- SD weight loss at 1 year after operation (113 patients) was 52 +/- 1 kg or 68% +/- 2% of initial excess body weight. By 3 years postoperatively (74 patients), weight loss was still 66% +/- 2% of excess body weight. Overall, 53 (72%) of 74 patients had achieved and maintained a weight loss of 50% or more of their preoperative excess body weight 3 years after the operation. In addition, only 1 (1%) of 98 patients had persistent postoperative vomiting 1 or more times per week. We believe that RYGB is a safe, effective procedure for most patients with morbid obesity and thus may be the current procedure of choice in patients requiring bariatrics++ surgery for morbid obesity.


Inflammatory Bowel Disease and Acute Coronary Syndromes: From Pathogenesis to the Fine Line Between Bleeding and Ischemic Risk.
Inflammatory bowel disease (IBD) is a pathological condition that first involves the gastrointestinal wall but can also trigger a systemic inflammatory state and thus extraintestinal manifestations. Systemic inflammation is probably secondary to the passage of bacterial products into the bloodstream because of altered intestinal permeability and the consequent release of proinflammatory mediators. Inflammation, through several diverse pathophysiological pathways, determines both a procoagulative state and systemic endothelial dysfunction, which are both deemed to be responsible for venous and arterial thromboembolic adverse events. The management of systemic thrombotic complications is particularly challenging in this category of patients, who also present a high bleeding risk; what is more, both bleeding and thrombotic risks peak during the active phases of the disease. The literature suggests that treating physicians have been, so far, more heavily influenced by concerns about bleeding than by the thrombotic risk. Despite the absence of data provided by large cohorts or randomized studies, the high risk of arterial and venous atherothrombosis in patients with IBD seems unquestionable. Moreover, several reports suggest that when arterial thromboembolism involves the coronary vessels, causing acute coronary syndromes, ischemic complications from antithrombotic drug undertreatment are frequent and severe. This review aims to shed light on the tricky balance between the ischemic and hemorrhagic risks of patients with IBD and to highlight how difficult it is for clinicians to define a tailored therapy based on a case-by-case, careful, and unprejudiced clinical evaluation.


A large diversity of organohalogen contaminants reach the meso- and bathypelagic organisms in the Bay of Biscay (northeast Atlantic).
Deep-sea ecosystems play a key role in the cycling and vertical transfer of matter and energy in oceans. Although the contamination of deep-sea demersal and benthic organisms by persistent organic pollutants has been proven, deep pelagic species have been far less studied. To fill these gaps, we studied the occurrence of a large variety of hydrophobic organic contaminants including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), legacy and alternative brominated flame retardants (BFRs) and per- and polyfluoroalkyl substances (PFASs) in crustaceans and fish species collected in the Bay of Biscay, northeast Atlantic. The results highlighted the global predominance of PCBs in fish, followed by OCPs, PFASs and PBDEs, with highly variable concentrations among species. Most of the chlorinated or brominated contaminants showed increasing concentrations with increasing δ15N values, while most PFASs showed inverse trends. The contaminant profiles and diagnostic ratios revealed species-specific metabolic capacities and peculiar contribution of highly-brominated BFRs.


Comparison of extrapyramidal features in 31 pathologically confirmed cases of diffuse Lewy body disease and 34 pathologically confirmed cases of Parkinson's disease.
To compare the extrapyramidal features of pathologically confirmed cases of diffuse Lewy body disease (DLBD) and Parkinson's disease (PD). The proportion of pathologically confirmed cases of DLBD diagnosed clinically as PD is as high as 88%. Few papers focus specifically on the extrapyramidal features of DLBD. Further characterization of these features might facilitate antemortem diagnosis, in particular, distinguishing DLBD from PD. Review of prospective and retrospective clinical data on a large series of pathologically diagnosed cases of DLBD (N = 31) and PD (N = 34) seen between 1984 and 1995 at Columbia-Presbyterian Medical Center or the University of Rochester. Those with DLBD had an older mean age of onset (67.9 years) than PD (62.0 years) (z = 6.5, p < 0.0001). Rest tremor was more common in PD (85.0%) than DLBD (55.0%) (chi 2 = 4.3, p = 0.038). Myoclonus was more common in DLBD (18.5%) than PD (0%) (Fisher's p = 0.021). There were no differences in rigidity, bradykinesia, dystonia, or gaze palsies. Clinical response to levodopa may have been more common in PD (100%) than DLBD (70.0%) (Fisher's p = 0.059). The occurrence of any one of four clinical features (myoclonus, absence of rest tremor, no response to levodopa, or no perceived need to treat with levodopa) was 10 times more likely in DLBD than PD (odds ratio = 10.29, 95% confidence interval = 2.58-41.11). We demonstrated that several clinical features distinguish DLBD from PD. These features, in combination with reported differences in cognitive and psychiatric manifestations, may be used for diagnostic purposes in distinguishing DLBD from PD in prospective longitudinal cohort studies of DLBD.


Structural stigma and its impact on healthcare for borderline personality disorder: a scoping review.
People with Borderline Personality Disorder (BPD) and their carers/families continue to experience structural stigma when accessing health services. Structural stigma involves societal-level conditions, cultural norms, and organizational policies that inhibit the opportunities, resources, and wellbeing of people living with attributes that are the object of stigma. BPD is a serious mental illness characterized by pervasive psychosocial dysfunction including, problems regulating emotions and suicidality. This scoping review aimed to identify, map, and explore the international literature on structural stigma associated with BPD and its impact on healthcare for consumers with BPD, their carers/families, and health practitioners. A comprehensive search of the literature encompassed MEDLINE, CINAHL, PsycINFO, Scopus, Cochrane Library, and JBI Evidence-Based databases (from inception to February 28th 2022). The search strategy also included grey literature searches and handsearching the references of included studies. Eligibility criteria included citations relevant to structural stigma associated with BPD and health and crisis care services. Quality appraisal of included citations were completed using the Mixed Methods Appraisal Tool 2018 version (MMAT v.18), the Joanna Briggs Institute (JBI) Checklist for Systematic Reviews and Research Syntheses Tool, and the AGREE II: advancing guideline development, reporting, and evaluation in health care tool. Thematic Analysis was used to inform data extraction, analysis, interpretation, and synthesis of the data. A total of 57 citations were included in the review comprising empirical peer-reviewed articles (n = 55), and reports (n = 2). Studies included quantitative, qualitative, mixed methods, and systematic review designs. Review findings identified several extant macro- and micro-level structural mechanisms, challenges, and barriers contributing to BPD-related stigma in health systems. These structural factors have a substantial impact on health service access and care for BPD. Key themes that emerged from the data comprised: structural stigma and the BPD diagnosis and BPD-related stigma surrounding health and crisis care services. Narrative synthesis of the findings provide evidence about the impact of structural stigma on healthcare for BPD. It is anticipated that results of this review will inform future research, policy, and practice to address BPD-related stigma in health systems, as well as approaches for improving the delivery of responsive health services and care for consumers with BPD and their carers/families. Open Science Framework ( https://osf.io/bhpg4 ).


Characteristics and epitope mapping of a cloned human autoantigen La.
The La (SS-B) polypeptide is a ribonucleoprotein against which high titer antinuclear antibodies (ANA) react in the human autoimmune disease primary Sjögren's syndrome. To identify the autoepitopes with which the ANA anti-La (anti-SS-B) reacts, we isolated a 1.4-kb cDNA clone for La from a lambda gt10 library made from a human Burkitt's cell line. This clone contained an open reading frame of 1065 bp, encoding a 40.1-kDa polypeptide that corresponded to the carboxyl-terminal end of the La protein. The predicted polypeptide sequence of the recombinant protein was highly charged and unrelated to any previously published sequence. We also compared this clone to a previously published cDNA sequence for La and demonstrated significant differences, particularly that the open reading frame in our cDNA continued for 926 additional bases 3' to a putative termination codon in the previously reported sequence. The recombinant La protein was expressed in Escherichia coli and tested for reactivity with 200 sera containing ANA of various specificities. Only the sera containing anti-La antibodies reacted with the cloned La. By expressing subclones of the La cDNA as fusion proteins with beta-galactosidase, we have localized at least one epitope for the binding of anti-La antibodies to the carboxyl-terminal 103 amino acids of the La protein. No anti-La binding could be demonstrated to the region of the La protein that had previously been predicted to contain an autoepitope for the binding of anti-La (SS-B) antibodies. Studies of cloned autoepitopes could provide important clues to the role ANA play in disease and lead to targeted intervention in the treatment of primary Sjögren's syndrome.


Explicit Diagnostic Criteria for Transient Ischemic Attacks Used in the Emergency Department Are Highly Sensitive and Specific.
Making a correct diagnosis of a transient ischemic attack (TIA) is prone to errors because numerous TIA mimics exist and there is a shortage of evidence-based diagnostic criteria for TIAs. In this study, we applied for the first time the recently proposed explicit diagnostic criteria for transient ischemic attacks (EDCT) to a group of patients presenting to the emergency department of a large German tertiary care hospital with a suspected TIA. The aim was to determine the sensitivity and specificity of the EDCT in its clinical application. A total of 128 patients consecutively presenting to the emergency department of the University Hospital of Lübeck, Germany, under the suspicion of a TIA were prospectively interviewed about their clinical symptoms at the time of presentation. The diagnosis resulting from applying the EDCT was compared to the diagnosis made independently by the senior physicians performing the usual diagnostic work-up ("gold standard"), allowing calculation of sensitivity and specificity of the EDCT. EDCT achieved a sensitivity of 96% and a specificity of 88%. When adding the additional criterion F ("the symptoms may not be better explained by another medical or mental disorder"), specificity significantly increased to 98%. The data show that the EDCT in its modified version as proposed by us are a highly useful tool for clinicians. They display a high sensitivity and specificity to accurately diagnose TIAs in patients referred to the emergency department with a suspected TIA.


Lecithin organogels used as bioactive compounds carriers. A microdomain properties investigation.
Organogels were obtained by adding small amounts of water to a solution of lecithin in organic solvents. Either isooctane or isopropyl palmitate and isopropyl myristate were used as the continuous organic phase of the gels. EPR spectroscopy using both DSA membrane-sensitive and lipophilic spin probes was applied to define the dynamic structure of the surfactant monolayer and the continuous oil phase of lecithin organogels. It was found that by increasing the water quantity, an increase of the polar head area per lecithin molecule was induced, and as a consequence the total interface expanded. It was found that the use of esters as organic solvents induced a decrease of the size of the dispersed structures. The interconnection of the aqueous microdomains and their dynamics were monitored by both static and time-resolved fluorescence quenching spectroscopy using Ru(bipy)32+ as fluorophore and Fe(CN)63- as quencher. It was found that the rates of inter- and/or intra-micellar exchange of water molecules were very slow because they appeared quite immobilized close to the lecithin polar heads. According to the results of the dynamic studies, appropriate organogels were formulated and used to incorporate model bioactive compounds with medicinal or cosmetic interest such as caffeine and theophylline. When these systems were tested for trans-membrane diffusion, they showed a 24 h permeation of 20% and 35%, respectively.


Probe-Dependent Negative Allosteric Modulators of the Long-Chain Free Fatty Acid Receptor FFA4.
High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein-coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues. To date, a single molecule, 4-methyl-N-9H-xanthen-9-yl-benzenesulfonamide (AH-7614), has been described as an FFA4 antagonist; however, its mechanism of antagonism remains unknown. We synthesized AH-7614 and a chemical derivative and demonstrated these to be negative allosteric modulators (NAMs) of FFA4. Although these NAMs did inhibit FFA4 signaling induced by a range of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many anticancer drugs suggests that a novel close chemical analog of AH-7614 devoid of FFA4 activity, 4-methyl-N-(9H-xanthen-9-yl)benzamide (TUG-1387), will also provide a useful control compound for future studies assessing FFA4 function. Using TUG-1387 alongside AH-7614, we show that endogenous activation of FFA4 expressed by murine C3H10T1/2 mesenchymal stem cells is required for induced differentiation of these cells toward a more mature, adipocyte-like phenotype.


The role of smoking status on the progression-free survival of non-small cell lung cancer patients harboring activating epidermal growth factor receptor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor versus platinum doublet chemotherapy: a meta-analysis of prospective randomized trials.
Univariate analyses from several randomized phase III trials seemed to suggest ever-smokers with advanced mutated epidermal growth factor receptor (EGFRm) non-small cell lung cancer (NSCLC) did not seem to benefit from EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment when compared with platinum-doublet chemotherapy as measured by progression-free survival (PFS). A literature-based meta-analysis of PFS outcomes as measured by log-transformed pooled hazard ratio (HR) was performed using a random-effect model. Pooled HRs for smoking status, age, gender, ethnicity, type of EGFR mutation, and EGFR TKI were obtained. Comparison of the pooled HR was performed by metaregression analysis. Among the 1,649 EGFRm NSCLC patients analyzed from 7 prospective randomized trials (WJTOG3405, NEJ002, EURTAC, OPTIMAL, LUX Lung-3, LUX Lung-6, and ENSURE), 83.7% were Asians, and 30.0% were ever-smokers. An equal percentage of ever-smokers received doublet chemotherapy (30.2%) or EGFR TKI (30.0%). The pooled HR for PFS was 0.29 (95% confidence interval [CI]: 0.21-0.39) for never-smokers and 0.54 (95% CI: 0.38-0.76) for ever-smokers (p < .007 by metaregression). The pooled PFS HR for exon 19 deletion was 0.25 (95% CI: 0.19-0.31) and 0.44 for exon 21 substitution (95% CI: 0.34-0.57) (p < .001 by metaregression analysis). The pooled PFS HR was 0.33 (95% CI: 0.24-0.46) for Asians and 0.48 for non-Asians (95% CI: 0.28-0.84) (p = .261 by metaregression analysis). EGFRm NSCLC patients derived significant PFS benefit from TKI over platinum-doublet chemotherapy as first-line treatment regardless of smoking status; however, PFS benefit is significantly better in never-smokers by metaregression analysis.


Menstrual and reproductive factors and risk of breast cancer in Asian-Americans.
We conducted a population-based case-control study of breast cancer among Chinese-, Japanese- and Filipino-American women in Los Angeles County Metropolitan Statistical Area (MSA), San Francisco-Oakland MSA and Oahu, Hawaii. One objective of the study was to quantify breast cancer risks in relation to menstrual and reproductive histories in migrant and US-born Asian-Americans and to establish whether the gradient of risk in Asian-Americans can be explained by these factors. Using a common study design and questionnaire in the three study areas, we successfully conducted in-person interviews with 597 Asian-American women diagnosed with incident, primary breast cancer during the period 1983-87 (70% of those eligible) and 966 population-based controls (75% of those eligible). Controls were matched to cases on age, ethnicity and area of residence. In the present analysis, which included 492 cases and 768 controls, we observed a statistically non-significant 4% reduction in risk of breast cancer with each year delay in onset of menstruation. Independent of age at menarche risk of breast cancer was lower (odds ratio; OR=0.77) among women with menstrual cycles greater than 29 days. Parous Asian-American women showed a significantly lower risk of breast cancer then nulliparous women (OR=0.54). An increasing number of livebirths and a decreasing age at first livebirth were both associated with a lower risk of breast cancer, although the effect of number of livebirths was no longer significant after adjustment for age at first livebirth. Women with a pregnancy (spontaneous or induced abortions) but no livebirth had a statistically non-significant increased risk (OR=1.84), but there was no evidence that one type of abortion was particularly harmful. A positive history of breastfeeding was associated with non-significantly lower risk of breast cancer (OR=.78). There are several notable differences in the menstrual and reproductive factors between Asian-Americans in this study and published data on US whites. US-born Asian Americans had an average age at menarche of 12.12 years-no older than has been found in comparable studies of US whites, but 1.4 years earlier than Asian women who migrated to the US. Asian-American women, particularly those born in the US and those who migrated before age 36, also had a later age at first birth and fewer livebirths than US whites. A slightly higher proportion of Asian-American women breastfed, compared with US whites. The duration of breastfeeding was similar in US-born Asians and US whites, but was longer in Asian migrants, especially those who migrated at a later age. Menstrual and reproductive factors in Asian-American women are consistent with their breast cancer rates being at least as high as in US whites, and they are. However, the effects of these menstrual and reproductive factors were small and the ORs for migration variables changed only slightly after adjustment for these menstrual and reproductive factors. These results suggest that the lower rates of breast cancer in Asians must be largely as a result of other environmental/lifestyle factors.


Same-strand overlapping genes in bacteria: compositional determinants of phase bias.
Same-strand overlapping genes may occur in frameshifts of one (phase 1) or two nucleotides (phase 2). In previous studies of bacterial genomes, long phase-1 overlaps were found to be more numerous than long phase-2 overlaps. This bias was explained by either genomic location or an unspecified selection advantage. Models that focused on the ability of the two genes to evolve independently did not predict this phase bias. Here, we propose that a purely compositional model explains the phase bias in a more parsimonious manner. Same-strand overlapping genes may arise through either a mutation at the termination codon of the upstream gene or a mutation at the initiation codon of the downstream gene. We hypothesized that given these two scenarios, the frequencies of initiation and termination codons in the two phases may determine the number for overlapping genes. We examined the frequencies of initiation- and termination-codons in the two phases, and found that termination codons do not significantly differ between the two phases, whereas initiation codons are more abundant in phase 1. We found that the primary factors explaining the phase inequality are the frequencies of amino acids whose codons may combine to form start codons in the two phases. We show that the frequencies of start codons in each of the two phases, and, hence, the potential for the creation of overlapping genes, are determined by a universal amino-acid frequency and species-specific codon usage, leading to a correlation between long phase-1 overlaps and genomic GC content. Our model explains the phase bias in same-strand overlapping genes by compositional factors without invoking selection. Therefore, it can be used as a null model of neutral evolution to test selection hypotheses concerning the evolution of overlapping genes.


Field, coil, and echo-time influence on sensitivity and reproducibility of brain proton MR spectroscopy.
Clinical MR imaging scanners now offer many choices of hardware configurations that were not available in the first 25 years of their existence. Our goal was to assess the influence of coil technology, magnetic field strength, and echo time (TE) on the sensitivity, reflected by the signal intensity-to-noise-ratio (SNR) and reproducibility of proton MR spectroscopy (1H-MR spectroscopy). The SNR, the intersubject reproducibility, and the intrasubject reproducibility of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) levels were compared at the common TEs of 30, 144, and 288 ms, by using 1H-MR spectroscopy in 6 volunteers at (1) 3T with a single-element quadrature (SEQ); (2) 1.5T with SEQ; and (3) 1.5T with a 12-channel phased-array (PA) head coil. In terms of sensitivity, the best SNR for all metabolites was obtained at the shortest TE (30 ms). It was comparable between the 3 and 1.5T with the PA, but approximately 35% better than the 1.5T with SEQ. This SNR difference declined <25% at TE of 144 ms and to equity among all imagers at TE of 288 ms. Reproducibility, reflected in the coefficient of variation (CV), was best for NAA at TE of 288 ms, 15%-50% better than at TE of 30 ms in either gray (GM) or white matter (WM). The CV for Cr was best, at TE of 288 ms for GM, but its WM results were independent of TE. Metabolite level reproducibility did not depend on coil technology or magnetic field strength. For the same coil type, the SNR of all major metabolites was approximately 35% better at 3T than at 1.5T. This advantage, however, was offset at 1.5T with a PA coil, making it a cost-effective upgrade for existing scanners. Surprisingly and counterintuitively, despite the lowest SNR, the best reproducibility was obtained at the longest TE (288 ms), regardless of field or coil.


Diverse roles of metformin during peri-implantation development: revisiting novel molecular mechanisms underlying clinical implications.
Metformin is not only a widely used oral antidiabetic drug, which acts as an insulin sensitizer and suppressor of hepatic gluconeogenesis, but it also exhibits antitumor properties. Besides, it has been utilized in the treatment of polycystic ovary syndrome (PCOS) for infertile women with glucose intolerance and as a component of combination therapy to reduce early (first trimester) pregnancy loss or spontaneous abortion (SAB). Based on recent studies demonstrating its beneficial effects on mothers and the fetus, metformin is even recommended for later stages of pregnancy. Probing into the mechanism of action revealed that it can activate a stress modulatory pathway, none other than the AMP-activated protein kinase (AMPK) via LKB 1. It is well accepted that AMPK signaling plays a crucial role during implantation by combating stress in multiple ways. Stress factors commonly encountered during pregnancy are malnutrition, diabetes, and hypoxia, which may result in SABs or other complications. For instance, the elevated levels of insulin, which are a typical characteristic of hyperinsulinemic, obese, or PCOS patients, can impair the development of the blastocyst and the preimplantation embryo. Further, a severe hypoxic environment prompts early and untimely differentiation of the embryonic cells leading to abnormal growth and development. Therefore, the modulation of stress-related pathways could be pivotal in ameliorating such stress responses during implantation. Here we hypothesize a putative noncanonical pathway underpinning the role of metformin in high-risk pregnancies to counteract stress by recreating an in vitro replica of human implantation, engaging embryonic stem cells, trophoblast stem cells, and endometrial stromal cells in a three-dimensional scaffold.


Evaluation of non-invasive continuous physiological monitoring devices for neonates in Nairobi, Kenya: a research protocol.
Continuous physiological monitoring devices are often not available for monitoring high-risk neonates in low-resource settings. Easy-to-use, non-invasive, multiparameter, continuous physiological monitoring devices could be instrumental in providing appropriate care and improving outcomes for high-risk neonates in these low-resource settings. The purpose of this prospective, observational, facility-based evaluation is to provide evidence to establish whether two existing non-invasive, multiparameter, continuous physiological monitoring devices developed by device developers, EarlySense and Sibel, can accurately and reliably measure vital signs in neonates (when compared with verified reference devices). We will also assess the feasibility, usability and acceptability of these devices for use in neonates in low-resource settings in Africa. Up to 500 neonates are enrolled in two phases: (1) a verification and accuracy evaluation phase at Aga Khan University-Nairobi and (2) a clinical feasibility evaluation phase at Pumwani Maternity Hospital in Nairobi, Kenya. Both quantitative and qualitative data are collected and analysed. Agreement between the investigational and reference devices is determined using a priori-defined accuracy thresholds. This trial was approved by the Aga Khan University Nairobi Research Ethics Committee and the Western Institutional Review Board. We plan to disseminate research results in peer-reviewed journals and international conferences. NCT03920761.


Comparative examinations of 99mTc-DMS preparations obtained by labelling dimercaptosuccinate kits with different formulations. I. Comparison of chemical and biological characteristics of Tc P-5 and TCK-12 kits.
The chemical and biological properties of two freeze-dried DMS kits for labelling with 99mTc (Tc P-5, manufactured by Boris Kidric Institute, Vinca, and TCK-12, by CIS, Saclay) were compared. A method for the determination of the radiochemical composition of the injection solution is proposed: ascending Whatman 31 paper chromatography in 50% aqueous methanol. The chromatographic results correspond to the biologic activity of the preparations. The biodynamics of both radiopharmaceuticals were determined at intervals in rats. Maximum renal concentrations were achieved at 3-4 hrs post injection (52% kidney and 3% liver uptake for Tc P-5; 59% kidney and 6-8% liver uptake for TCK-12). The bench-lifes of the injection solutions were compared by determining organ distribution after standing of the solutions for 0, 2 and 4 hrs. The Tc P-5 preparation was more stable, since the renal and hepatic concentrations were nearly constant. On the other hand, the hepatic concentration of TCK-12 was increasing during aging of the solution with a simultaneous decrease in renal concentration.


Novel Regulators of Retina Neovascularization: A Proteomics Approach.
The purpose of this study was to identify proteins that regulate vascular remodeling in an ROP mouse model. Pups were subjected to fluctuating oxygen levels and retinas sampled during vessel regression (PN12) or neovascularization (PN17) for comparative SWATH-MS proteomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We developed a human retinal endothelial cell (HREC) ROP correlate to validate the expression of retina neovascular-specific markers. A total of 5191 proteins were identified in OIR retinas with 498 significantly regulated in elevated oxygen and 345 after a return to normoxia. A total of 122 proteins were uniquely regulated during vessel regression and 69 during neovascularization (FC ≥ 1.5; p ≤ 0.05), with several validated by western blot analyses. Expressions of 56/69 neovascular-specific proteins were confirmed in hypoxic HRECs with 23 regulated in the same direction as OIR neovascular retinas. These proteins control angiogenesis-related processes including matrix remodeling, cell migration, adhesion, and proliferation. RNAi and transfection overexpression studies confirmed that VASP and ECH1, showing the highest levels in hypoxic HRECs, promoted human umbilical vein (HUVEC) and HREC cell proliferation, while SNX1 and CD109, showing the lowest levels, inhibited their proliferation. These proteins are potential biomarkers and exploitable intervention tools for vascular-related disorders. The proteomics data set generated has been deposited to the ProteomeXchange/iProX Consortium with the Identifier:PXD029208.


Sex-specific and age-specific suicide mortality by method in 58 countries between 2000 and 2015.
To examine recent changes in sex-specific and age-specific suicide mortality by method across countries. Using mortality data from the WHO mortality database, we compared sex-specific, age-specific and country-specific suicide mortality by method between 2000 and 2015. We considered seven major suicide methods: poisoning by pesticides, all other poisoning, firearms and explosives, hanging, jumping from height, drowning and other methods. Changes in suicide mortality were quantified using negative binomial models among three age groups (15-44 years, 45-64 years, and 65 years and above) for males and females separately. Suicide mortality declined substantially for both sexes and all three age groups studied in 37 of the 58 included countries between 2000 and 2015. Males consistently had much higher suicide mortality rates than females in all 58 countries. Hanging was the most common suicide method in the majority of 58 countries. Sex-specific suicide mortality varied across 58 countries significantly for all three age groups. The spectrum of suicide method generally remained stable for 28 of 58 included countries; notable changes occurred in the other 30 countries, including especially Colombia, Finland and Trinidad and Tobago. Likely as a result of prevention efforts as well as sociodemographic changes, suicide mortality decreased substantially in 37 of the included 58 countries between 2000 and 2015. Further actions are needed to explore specific drivers of the recent changes (particularly for increases in eight countries), to understand substantial disparities in suicide rates across countries, and to develop interventions to reduce suicide rates globally.


Ankle bracing in running: the effect of a Push type medium ankle brace upon movements of the foot and ankle during the stance phase.
Functional ankle braces are designed to limit medio-lateral movements of the ankle without affecting ankle dorsiflexion or plantar flexion. As running forms a basic activity in sports, the current study investigated the influence of wearing a Push type medium ankle brace upon movements of the foot and ankle during the stance phase in running. The movements of the lower extremity of seven trained male long-distance runners were filmed frontally (250 s-1) and sagittally (50 s-1) while running at 4.5 +/- 0.1 m.s-1 over a Kistler force platform. The tested brace significantly reduced the range (total subtalar eversion 13.3 deg vs 18.1 deg, p < 0.05) and rate of subtalar eversion (maximal velocity -309 deg.s-1 vs -533 deg.s-1). Plantar and dorsiflexion were not affected. The vertical impact force peak was not altered. It was argued that, although this might not be the prime design feature of the tested ankle brace, this orthotic offers a strategy to influence the range and the rate of subtalar eversion. It may have the potential to prevent runners from overuse injuries associated with overpronation, but interaction between the passive support by the brace and the muscular stabilization of the ankle joint needs further investigation.


Is psychosexual therapy a reliable alternative to bupropion extended-release to promote the sexual function in infertile women? An RCT.
Various treatment methods are used to deal with sexual problems. This study was applied to answer the question of whether psychosexual therapy (PST) can be a reliable alternative to bupropion extended-release (BUP ER) to promote sexual function in infertile women. In this randomized clinical trial, 105 infertile women with sexual dysfunction were randomly allocated to three groups: PST, BUP ER, and a control group. The PST group participated in a total of eight 2-hr group sessions. In BUP ER group, 150 mg/day Bupropion ER was administered for eight weeks. The control group did not receive any interventions. The female sexual function index (FSFI) and a clinical interview were used to assess their sexual dysfunction. The mean pre-to-post treatment scores of FSFI and its subscales increased significantly in PST and BUP ER groups (except in the subscale of sexual pain) (p = 0.0001, p = 0.0001). The changes in the subjects were not significant in the control group. After adjusting for the baseline values, the results remained significant for the mean FSFI (p = 0.0001), and its subscales between the groups. Compared to the control group, a significant increase was observed in the mean FSFI (p = 0.0001, p = 0.002) and its subscales in the PST group and in the BUP ER group (except in the subscale of sexual pain). Comparison of two intervention methods showed that PST had the better effect on the sexual function improving (p = 0.0001) and its subscales (exempting the subscale of orgasm) than BUP ER. PST can be considered not only a reliable alternative to pharmacotherapy; it also produces better results in terms of improving sexual function in infertile women.


Three-dimensional movable metamaterial using electric split-ring resonators.
We have demonstrated a three-dimensional movable metamaterial (MM) with reconfigurable electric split-ring resonators (eSRR) at terahertz frequencies. This is accomplished by making planar arrays of eSRR with movable stress curved beams (eSRR-MSCBs) which are actuated out-of-plane by electrostatic force. Our results have demonstrated that the eSRR-MSCBs possess blueshifting capabilities and polarization dependent state at terahertz frequencies, while such adaptive MMs offer significant potential in realizing electromagnetic functionality with diversified applications, such as sensors, switches, and filters.


A genetic screen for the isolation and characterization of site-specific proteases.
Site-specific proteolysis is an important regulatory mechanism in basic cellular and viral processes. Using the protease of the HIV as a model, a genetic system has been developed for the isolation and characterization of site-specific proteases. The system utilizes the well defined bacteriophage lambda regulatory circuit where the viral repressor, cI, is specifically cleaved to initiate the lysogenic-to-lytic switch. The model system is rapid, highly specific, and demonstrates the ability to isolate and characterize enzymes of limited expression or activity. In addition, the system has a significant potential for the selection of clinically relevant mutant enzymes and in the development of anti-protease therapeutics.


Bandwidth-adaptable silicon photonic differentiator employing a slow light effect.
A photonic differentiator (DIFF) plays a crucial role in photonic circuits. Despite the fact that a DIFF having a terahertz bandwidth has been reported, the practical bandwidth is limited to being a bandpass response. In this Letter, we propose the concept of a bandwidth-adaptable DIFF, which exploits the slow light effect in a photonic crystal waveguide (PhCW) to overcome the inherent bandwidth limitation of current photonic DIFFs. We fabricated a PhCW Mach-Zehnder interferometer (PhCW-MZI) on the silicon-on-isolator material platform to validate our concept. Input Gaussian pulses with full width to half-maximums (FWHMs) ranging from 2.7 to 81.4 ps are accurately differentiated using our PhCW-MZI. Our all-passive scheme circumvents the bandwidth bottlenecks of previously reported photonic DIFFs and can greatly broaden the application area of photonic DIFFs.


Raman spectroscopy of fullerenes and fullerene-nanotube composites.
The discovery of fullerenes in 1985 opened a completely new field of materials research. Together with the single-wall carbon nanotubes (SWCNTs) discovered later, these curved carbon networks are a playground for pure as well as applied science. We present a review of Raman spectroscopy of fullerenes, SWCNTs and composite materials. Beginning with pristine C(60), we discuss intercalated C(60) compounds and polymerized C(60), as well as higher and endohedral fullerenes. Concerning SWCNTs, we show how the diameter distribution can be obtained from the Raman spectra and how doping modifies the spectra. Finally, the Raman response of C(60) encapsulated into SWCNTs (C(60) peapods) is discussed.


Liquid Extraction Surface Analysis Mass Spectrometry Method for Identifying the Presence and Severity of Nonalcoholic Fatty Liver Disease.
The early stages of nonalcoholic fatty liver disease (NAFLD) are characterized by the accumulation of fat in the liver (steatosis). This can lead to cell injury and inflammation resulting in nonalcoholic steatohepatitis (NASH). To determine whether lipid profiling of liver tissue can identify metabolic signatures associated with disease presence and severity, we explored liquid extraction surface analysis mass spectrometry (LESA-MS) as a novel sampling tool. Using LESA-MS, lipids were extracted directly from the surface of ultrathin slices of liver tissue prior to detection by high-resolution mass spectrometry (MS). An isotopically labeled internal standard mix was incorporated into the extraction solvent to attain semiquantitative data. Data mining and multivariate statistics were employed to evaluate the generated lipid profiles and abundances. With this approach, we were able to differentiate healthy and NAFLD liver in mouse and human tissue samples, finding several triacylglyceride (TAG) and free fatty acid (FFA) species to be significantly increased. Furthermore, LESA-MS was able to successfully differentiate between simple steatosis and more severe NASH, based on a set of short-chain TAGs and FFAs. We compared the data obtained by LESA-MS to that from liquid chromatography (LC)-MS and matrix-assisted laser desorption ionization MS. Advantages of LESA-MS include rapid analysis, minimal sample preparation, and high lipid coverage. Furthermore, since tissue slices are routinely used for diagnostics in clinical settings, LESA-MS is ideally placed to complement traditional histology. Overall LESA-MS is found to be a robust, fast, and discriminating approach for determining NAFLD presence and severity in clinical samples.


Ethical issues in healthcare reform: the experts and the public compared.
Those of us in the healthcare industry have done a good job in demonstrating the value of our services in relationship to other activities government might undertake. We have done less well in recognizing the demands of individuals to make decisions about their own lives and the healthcare benefits they want. We continue to believe we know best, even to the point that we distrust the public to make appropriate decisions on their own behalf. A major part of freedom is the opportunity to learn from mistakes. When professionals restrict our freedom to choose, we all lose important rights. As the various bills make their way through Congress, we should look beyond our healthcare blinders and see that the public will reject industry-driven plans with almost the same level of suspicion given to the government and business.


Evidence for mineralocorticoid receptor facilitation of glucocorticoid receptor-dependent regulation of hypothalamic-pituitary-adrenal axis activity.
These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.


No evidence that self-rated negative emotion boosts visual working memory precision.
Emotion is assumed to change how people process information by modulating attentional focus. Two recent studies (Spachtholz et al., 2014; Xie & Zhang, 2016) reported that self-reported negative emotion boosted the precision with which information was stored in visual working memory. Here we attempted and failed to replicate these findings across seven studies conducted in four countries. Emotion was induced by presenting emotional images (negative, neutral, and positive) before each trial of a visual working memory task (six experiments) or the images were combined with emotional music during a 3-min induction phase (one experiment) occurring prior to the memory task. In the visual working memory task, participants stored (emotionally neutral) continuously varying colored dots or oriented triangles. At test, the color or orientation of a probed item was reproduced. Although participants reported changes in their emotional state commensurate with the manipulations, six experiments showed substantial evidence against changes in visual working memory precision (and quantity) under negative (and positive) emotion in comparison with neutral, whereas one condition, in one study, showed increased precision under both negative and positive emotion compared with neutral. These results challenge the view that emotion modulates visual working memory quality and quantity. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Systematic evaluation of the Precision ID GlobalFiler™ NGS STR panel v2 using single-source samples of various quantity and quality and mixed DNA samples.
Massively parallel sequencing (MPS) techniques were developed approximately 15 years ago. Meanwhile, several MPS kits for forensic identification, phenotypic information, ancestry, and mitochondrial DNA analysis have been developed and their use has been established. Sequencing short tandem repeats (STRs) has certain advantages over the currently used length-based genotyping methods, which are based on PCR amplification followed by capillary electrophoresis (CE). MPS is more discriminative and includes the possibility of testing high numbers of targets (> 100), different types of markers [STRs and single nucleotide polymorphisms (SNPs)], as well as the use of smaller amplicons (< 300 bp). This study evaluated in 24 experimental runs the Precision ID GlobalFiler™ NGS STR panel v2 from ThermoFisher, which targets 31 autosomal STRs, amelogenin, and three Y-markers (one STR, SRY, and Yindel). Single-source samples were used in 18 experimental runs, for systematic evaluation. These included assessing library preparation benchmark conditions, limited DNA input, as well as testing repeatability, number of samples per run, and degraded DNA samples. Full profiles were consistently obtained from as little as 50 pg DNA input. Using the optional recovery PCR method improved outcomes for samples with low DNA input. Full profiles were also obtained from severely degraded DNA samples with degradation indices (DI) of > 60. In addition, six experimental runs were performed testing various two-person mixtures with mixture ratios ranging from 1:20 to 20:1. Major and minor contributors were distinguishable by their read counts (coverage), because less DNA input yielded lower read counts, analogous to the traditional CE technology, where less DNA produces lower peak heights. Mixture ratios of approximately 1:1 were indistinguishable, while a greater imbalance, i.e., higher mixture ratios, made the mixture more distinguishable between major and minor contributors. Based on this information, the highest success rate of correctly deconvoluted four-allelic loci was from mixtures with 1:3 ratios. At higher mixture ratios, the drop-out rate of the minor contributor increased, reducing the number of four-allelic loci.


The Tinnitus Retraining Therapy Counseling Protocol as Implemented in the Tinnitus Retraining Therapy Trial.
Purpose This clinical focus article is a companion to the work of Erdman et al. (2019), in which we described the rationale, development, and implementation of the standard-of-care protocol used in the Tinnitus Retraining Therapy Trial (TRTT), a multicenter, placebo-controlled, randomized, definitive efficacy trial of tinnitus retraining therapy (TRT). We now describe the historical background, development, and standardized implementation and delivery of the TRT counseling protocol (tinnitus counseling [TC]) used in the TRTT. TC is conjectured to be the key component in the TRT protocol for initiating the habituation process that reduces the response to the tinnitus signal and, ultimately, reduces its impact. In the TRTT, participants assigned to receive TC achieved > 30% reduction in the impact of tinnitus. Method and Results The design and implementation of standardized treatments in multisite randomized controlled trials presents many challenges for investigators. Here, subsequent to presenting the background, rationale, and the TRT protocol model, we describe the development, refinement, and training/certification for standardized delivery of TC in the TRTT. The primary challenges encountered while distilling and streamlining TC for standardized delivery across multiple clinicians and their replacements at six participating military treatment centers in the TRTT are considered, and the resulting counseling protocol is detailed. Conclusions The standardized and streamlined TC used in the TRTT was successful for treating debilitating tinnitus among persons with functionally adequate unaided hearing sensitivity. The structured TC protocol described here appears to be the main determinant of the significant and sizable TRT treatment effects measured in the TRTT, thus bolstering the merits of this standardized counseling approach as one model for the clinical implementation of TRT for the treatment of primary tinnitus.


Radial artery pseudoaneurysm: a simplified treatment method.
A radial artery pseudoaneurysm represents a rare, potentially catastrophic complication of arterial cannulation that has been reported after cardiac catheterization. Treatment options are limited to chemical, mechanical, and combined approaches to obliterate the radial artery pseudoaneurysm and tract. Manual compression protocols using the TR Band (Terumo Medical Corporation, Somerset, NJ) have been variable and anecdotal, without objective measurements of adequate compression, making this technique prone to failure. In this report, we present an efficient, safe, and noninvasive management protocol using a pulse oximeter and the TR Band for treatment of radial artery pseudoaneurysms that is cost-effective and efficient and ensures correction without occlusion of the radial artery.


[Factors related with the use of screening mammogram in middle age women in Puerto Rico].
Mammography for low-income women is an important intervention issue as it is still under utilized in these sectors. Despite evidence in favor of breast cancer screening with mammograms, research indicates that mammogram compliance among low-income females and women over 50 years of age has been slow. This article revolves around the factors that affect compliance with screening mammograms among low-income women ages 40 to 64 in Puerto Rico once they receive a referral from a physician. Although the multivariate analysis demonstrated that only age, work outside of the home and performing breast self-exams significantly increased the probability for middle-aged, low-income women in Puerto Rico to comply with referrals and have mammograms, this research illustrated that certain factors such as knowledge about the disease and screening practices, a satisfactory perception of the patient-physician relationship, and the performance of a clinical breast exam by a physician influence mammogram compliance.


Crystal Structure Determination of Nucleotide-sugar Binding Domain of Human UDP-glucuronosyltransferases 2B10.
UDP-glucuronosyltransferases (UGTs) play a crucial role in maintaining endobiotic homeostasis and metabolizing xenobiotic compounds, particularly clinical drugs. However, the detailed catalytic mechanism of UGTs has not been fully elucidated due to the limited availability of reliable protein structures. Determining the catalytic domain of human UGTs has proven to be a significant challenge, primarily due to the difficulty in purifying and crystallizing the full-length protein. This study focused on the human UGT2B10 C-terminal cofactor binding domain, aiming to provide structural insights into the fundamental catalytic mechanisms. In this study, the C-terminal sugar-donor binding domain of human UGT2B10 was purified and crystallized using the vapor-diffusion method. The resulting UGT2B10 CTD crystals displayed high-quality diffraction patterns, allowing for data collection at an impressive resolution of 1.53 Å using synchrotron radiation. Subsequently, the structure of the UGT2B10 CTD was determined using the molecule replacement method with a homologous structure. The crystals were monoclinic, belonging to the space C2 with unit-cell parameters a = 85.90 Å, b = 58.39 Å, c = 68.87 Å, α = γ = 90°, and β = 98.138°. The Matthews coefficient VM was determined to be 2.24 Å3 Da-1 (solvent content 46.43%) with two molecules in the asymmetric unit. The crystal structure of UGT2B10 CTD was solved at a high resolution of 1.53 Å, revealing a conserved cofactor binding pocket. This is the first study determining the C-terminal cofactor binding domain of human UGT2B10, which plays a key role in additive drug metabolism.


Change detection in complex auditory scenes is predicted by auditory memory, pitch perception, and years of musical training.
Our world is a sonically busy place and we use both acoustic information and experience-based knowledge to make sense of the sounds arriving at our ears. The knowledge we gain through experience has the potential to shape what sounds are prioritized in a complex scene. There are many examples of how visual expertise influences how we perceive objects in visual scenes, but few studies examine how auditory expertise is associated with attentional biases toward familiar real-world sounds in complex scenes. In the current study, we investigated whether musical expertise is associated with the ability to detect changes to real-world sounds in complex auditory scenes, and whether any such benefit is specific to musical instrument sounds. We also examined whether change detection is better for human-generated sounds in general or only communicative human sounds. We found that musicians had less change deafness overall. All listeners were better at detecting human communicative sounds compared to human non-communicative sounds, but this benefit was driven by speech sounds and sounds that were vocally generated. Musical listening skill, speech-in-noise, and executive function abilities were used to predict rates of change deafness. Auditory memory, musical training, fine-grained pitch processing, and an interaction between training and pitch processing accounted for 45.8% of the variance in change deafness. To better understand perceptual and cognitive expertise, it may be more important to measure various auditory skills and relate them to each other, as opposed to comparing experts to non-experts.


Piwi-interacting RNAs play a role in vitamin C-mediated effects on endothelial aging.
The underlying mechanisms that mediate the effects of vitamin C on endothelial cell aging are widely unknown. To investigate whether Piwi-interacting RNAs (piRNAs) are involved in this process, an endothelial aging model was induced in vitro using H2O2 in human umbilical vein endothelial cells (HUVECs) and then treated with vitamin C (VC). Untreated HUVECs without H2O2 exposure were used to serve as the negative control group. Cell cycle, cell viability, and aging-associated protein expression were assessed, and RNA sequencing was performed to reveal the piRNA profile. Functional and regulatory networks of the different piRNA target genes were predicted by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis. H2O2 induced G1 phase cell arrest, decreased cell viability, and upregulated the senescence marker p16 in HUVECs. We found that VC treatment inhibited G1 phase cell arrest, increased the number of cells in the S and G2/M phases, increased cell viability, and decreased p16 expression. The piRNA expression profiles revealed that a large proportion of piRNAs that were differentially expressed in H2O2-treated HUVECs were partly normalized by VC. Furthermore, a number of piRNAs associated with the response to VC in H2O2-treated HUVECs were linked with senescence and cell cycle-related pathways and networks. These results indicate that the ability of VC to attenuate H2O2-mediated endothelial cell senescence may be associated with changes in expression of piRNAs that are linked to the cell cycle.


Retrospective on the early development of cryoelectron microscopy of macromolecules and a prospective on opportunities for the future.
Methods for preserving specimen hydration in protein crystals were pursued in the early 1970s as a prerequisite for protein crystallography using an electron microscope. Three laboratories approached this question from very different directions. One built a differentially pumped hydration chamber that could maintain the crystal in a liquid water environment, a second maintained hydration by rapidly freezing the protein crystal and examining it in a cold stage, and the third replaced the water of hydration by using glucose in the same way as one had previously used "negative stains". Each of these early efforts succeeded in preserving the structures of protein crystals at high resolution within the vacuum of the electron microscope, as demonstrated by electron diffraction patterns. The next breakthrough came in the early 1980s when a technique was devised to preserve noncrystalline specimens by freezing them within vitreous ice. Since then, with the development of high stability cold stages and transfer mechanisms compatible with many instrument platforms, and by using commercially provided low dose imaging techniques to avoiding radiation damage, there has been an explosion of applications. These now include single particles, helical filaments, 2-D arrays and even whole cells, where the most exciting recent applications involve cryoelectron tomography. These achievements and possibilities generate a new set of research opportunities associated with increasing the reliability and throughput with which specimens can be studied by cryoEM.


A powerful tool for genome analysis in maize: development and evaluation of the high density 600 k SNP genotyping array.
High density genotyping data are indispensable for genomic analyses of complex traits in animal and crop species. Maize is one of the most important crop plants worldwide, however a high density SNP genotyping array for analysis of its large and highly dynamic genome was not available so far. We developed a high density maize SNP array composed of 616,201 variants (SNPs and small indels). Initially, 57 M variants were discovered by sequencing 30 representative temperate maize lines and then stringently filtered for sequence quality scores and predicted conversion performance on the array resulting in the selection of 1.2 M polymorphic variants assayed on two screening arrays. To identify high-confidence variants, 285 DNA samples from a broad genetic diversity panel of worldwide maize lines including the samples used for sequencing, important founder lines for European maize breeding, hybrids, and proprietary samples with European, US, semi-tropical, and tropical origin were used for experimental validation. We selected 616 k variants according to their performance during validation, support of genotype calls through sequencing data, and physical distribution for further analysis and for the design of the commercially available Affymetrix® Axiom® Maize Genotyping Array. This array is composed of 609,442 SNPs and 6,759 indels. Among these are 116,224 variants in coding regions and 45,655 SNPs of the Illumina® MaizeSNP50 BeadChip for study comparison. In a subset of 45,974 variants, apart from the target SNP additional off-target variants are detected, which show only a minor bias towards intermediate allele frequencies. We performed principal coordinate and admixture analyses to determine the ability of the array to detect and resolve population structure and investigated the extent of LD within a worldwide validation panel. The high density Affymetrix® Axiom® Maize Genotyping Array is optimized for European and American temperate maize and was developed based on a diverse sample panel by applying stringent quality filter criteria to ensure its suitability for a broad range of applications. With 600 k variants it is the largest currently publically available genotyping array in crop species.


Cigarette smoking and risk of primary systemic vasculitis: a propensity score matching analysis.
Considering limited data about the association between smoking and primary systemic vasculitides (PSV), present study aims to investigate smoking habit in PSV patients compared to healthy subjects as well as to examine the effect of smoking on clinical characteristics, disease activity and disease outcome in PSV patients. We included 126 patients diagnosed with PSV and 210 age- and sex-matched healthy controls. Demographic and clinical information and smoking history of patients and healthy controls were obtained by direct interview and questionnaire. Individuals who had smoked at least 100 cigarettes in their lifetime before the first symptom of vasculitis were classified as smokers; those who had never smoked or smoked less than 100 cigarettes in their lifetime were categorized as never smokers. Disease activity was evaluated by Birmingham Vasculitis Activity Score (BVAS). Disease outcome was assessed by vasculitis damage index (VDI) and the number of patients with disease in remission. Propensity score matching analyses (PSM) for reducing the heterogeneity between studied groups and calculating the actual effect of smoking in PSV was performed. No significant differences were observed in clinical manifestations and disease outcome of patients including VDI and the patients with disease in remission between ever and never smokers. However, disease activity according to BVAS in ever smokers was significantly higher than never smokers (P=0.020). PSM resulted in 82 patients with PSV, and 164 matched healthy persons with similar baseline characteristics. By multivariate logistic regression and after adjustment for age, sex, marital status and educational status, ever smoking was not significantly associated with an increased risk of PSV compared with never smoking. Our study indicated a significant association between disease activity and smoking as well as a non-significant association between the clinical manifestations and disease outcome of PSV with smoking in Azeri population. Although further studies are needed to confirm these preliminary results, it seems that smoking may not be a significant risk factor for PSV.


Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a.
Casticin, a polymethoxyflavone, is reported to have anticancer activities. The aim of the present study was to examine the molecular mechanisms by which casticin induces apoptosis in ovarian cancer cells. The human ovarian cancer cell lines SKOV3 and A2780 were cultured in vitro. Various molecular techniques, including histone/DNA enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR), western blot analysis and gene transfection, were used to assess the expression of FOXO3a and forkhead box protein M1 (FoxM1) in casticin-treated ovarian cancer cell lines. Casticin-induced apoptotic cell death was accompanied by the activation of transcription factor FOXO3a, with a concomitant decrease in the expression levels of FoxM1 and its downstream target factors, namely survivin and polo-like kinase 1 (PLK1), and an increase in p27KIP1. A small inhibitory RNA (siRNA) knockout of FoxM1 potentiated casticin-induced apoptosis in ovarian cancer cells. Silencing FOXO3a expression using siRNA increased FoxM1 expression levels and clearly attenuated the induction of apoptosis by casticin treatment. These results show that casticin-induced apoptosis in ovarian cancer may be caused by the activation of FOXO3a, leading to FoxM1 inhibition.


Frankincense--therapeutic properties.
Recently, increasing interest in natural dietary and therapeutic preparations used as dietary supplements has been observed. One of them is frankincense. This traditional medicine of the East is believed to have anti-inflammatory, expectorant, antiseptic, and even anxiolytic and anti-neurotic effects. The present study aims to verify the reported therapeutic properties of Boswellia resin and describe its chemical composition based on available scientific studies. The main component of frankincense is oil (60%). It contains mono- (13%) and diterpenes (40%) as well as ethyl acetate (21.4%), octyl acetate (13.4%) and methylanisole (7.6%). The highest biological activity among terpenes is characteristic of 11-keto-ß-acetyl-beta-boswellic acid, acetyl-11-keto-ß-boswellic acid and acetyl-α-boswellic acid. Contemporary studies have shown that resin indeed has an analgesic, tranquilising and anti-bacterial effects. From the point of view of therapeutic properties, extracts from Boswellia serrata and Boswellia carterii are reported to be particularly useful. They reduce inflammatory conditions in the course of rheumatism by inhibiting leukocyte elastase and degrading glycosaminoglycans. Boswellia preparations inhibit 5-lipoxygenase and prevent the release of leukotrienes, thus having an anti-inflammatory effect in ulcerative colitis, irritable bowel syndrome, bronchitis and sinusitis. Inhalation and consumption of Boswellia olibanum reduces the risk of asthma. In addition, boswellic acids have an antiproliferative effect on tumours. They inhibit proliferation of tumour cells of the leukaemia and glioblastoma subset. They have an anti-tumour effect since they inhibit topoisomerase I and II-alpha and stimulate programmed cell death (apoptosis).


Selective and sensitive liquid chromatographic assay of amodiaquine and desethylamodiaquine in whole blood spotted on filter paper.
We have developed a sensitive, selective and reproducible reversed-phase HPLC method with ultraviolet detection (340 nm) for the simultaneous quantification of amodiaquine (AQ) and its major metabolite, desethylamodiaquine (AQm) in a small volume (200 microl) of whole blood spotted on filter paper. The method involves liquid-liquid extraction with diethyl ether followed by elution from a reversed-phase phenyl column with an acidic (pH 2.8) mobile phase (25 mM KH2PO4-methanol; 80:20% (v/v) +1% (v/v) triethylamine). Calibration curves in spiked whole blood were linear from 100-2500 ng/ml (r2 > or = 0.99) for AQ and 200-2500 ng/ml (r2 > or = 0.99) for AQm. The limit of detection was 5 ng for AQ and 10 ng for AQm. The relative recovery at 150 ng/ml of AQ (n = 6) was 84.0% and at 300 ng/ml of AQm the relative recovery was 74.3%. The intra-assay coefficients of variation at 150, 600 and 2250 ng/ml of AQ and 300, 600 and 2250 ng/ml of AQm were 7.7, 8.9 and 6.2% (AQ) and 10.1, 5.4 and 3.9% (AQm), respectively. The inter-assay coefficient of variation at 150, 600 and 2250 ng/ml of AQ and 300, 600 and 2250 ng/ml of AQm were 5.2, 8.1 and 6.9% (AQ) and 3.3, 2.3 and 4.6% (AQm). There was no interference from other commonly used antimalarial and antipyretic drugs (chloroquine, quinine, sulfadoxine, pyrimethamine, artesunate, acetaminophen and salicylate). The method is particularly suitable for pharmacokinetic studies in settings where facilities for storing blood/plasma samples are not available.


Effects of lateral hypothalamic lesions on food intake of rats during exposure to cold.
Lateral hypothalamic damage impaired both physiological and behavioral responses of rats during exposure to a 5 degree C environment. The brain-damaged animals usually did not conserve heat in the cold as well as control rats did, nor did they always increase their caloric intake to meet their energy needs. However, when given sucrose solution to drink instead of water, they did increase their ingestion of chow in response to cold exposure. It is likely that the elevated consumption of palatable fluid served to relieve dehydration and thereby removed its constraints on eating, thus permitting hyperphagia to occur. In contrast to these results, rats with large dopamine-depleting brain lesions, produced by intraventricular 6-hydroxydopamine treatments, always increased food intake when exposed to cold stress and demonstrated no apparent problems in peripheral vasoconstriction. Thus, it is unlikely that striatal dopamine depletions account for either the impaired feeding response or the inadequate heat conservation of rats with lateral hypothalamic lesions during cold stress.


The treatment of black stain associated with of iron metabolism disorders with lactoferrin: a litterature search and two case studies.
Among the various pathologies of the oral cavity, the formation of "unsightly black spots" on the surface of the tooth, universally known as Black Stain (BS) has recently been acquiring more interest. Usually BS is typically found in individuals in prepubertal age, even though it has been identified in adults associated with microbial exchange and / or with iron metabolism disorders. Microbial exchange concerns the possible exchange of bacteria between family members which can take place directly, through effusions, or indirectly, through brushes, cutlery or glasses. For this reason, it is recommended that toothbrushes of family members not be left damp and in contact with each other. The bathroom, being a warm-humid environment, is in fact an optimal habitat for microbial proliferation. Of specific importance in BS is the accumulation of iron in tissues and secretions which, together with chromogenic bacteria, are the primary cause of this pathology. In fact, among the metabolic products synthesized by bacteria in the oral cavity, hydrogen sulfide is of considerable interest, since upon reacting with iron available in saliva, in pathological conditions (iron metabolism disorders), it forms black precipitates consisting of ferric sulfide. These precipitates bind to the surface of the teeth, tending to form a stria that usually follows the contour of the gingiva, with an unsightly and variable chromatic intensity. In physiological situations, iron homeostasis is defined as the state of equilibrium between iron present in tissues and in secretions and that which is present in the circulation. Instead, in pathological conditions, defined as iron metabolism disorders, there is an accumulation of iron in tissues and secretions and a lack of it in the circulation. It is also important to remember that subjects affected by BS are more protected from carious processes than healthy subjects, probably due to a significant predominance of chromogenic bacteria compared to those responsible for caries. It should also be remembered that in young subjects BS tends to regress with pubertal development and the transition to adult life. In any case, using common professional hygiene procedures, it is possible to remove BS as well as plaque and tartar deposits. In particular, with ultrasonic scalers, polishing pastes and powders carried by air and water jets, the surfaces of the teeth can be restored to their natural healthy state. All the techniques for removing the precipitates, are not enough however, to fix and permanently eradicate their appearance, as these precipitates last only for short periods and recur very frequently. Due to the frequent recurrences, new oral microbiota control therapies are emerging; among these the use of lactoferrin (Lf) in the dental field and particularly in the treatment of BS appears to be very promising. Taken togheter, here the effect of Lf in subjects affected by BS has been investigated.


Analysis of hepatofugal flow in portal venous system using ultrasonic Doppler duplex system.
Blood flow directions of the portal trunk, splenic vein, and superior mesenteric vein were studied using an ultrasonic Doppler duplex system in 146 healthy adults, 132 patients with liver cirrhosis, 76 with hepatocellular carcinoma, 32 with idiopathic portal hypertension, 134 with chronic hepatitis, 18 with acute hepatitis, and 142 with other diseases. Spontaneous hepatofugal flow in one or more of the three vessels examined was detected in 14 patients. Spontaneous hepatofugal flow in the portal trunk was detected in three patients with liver cirrhosis. In two of these three patients, the hepatofugal flow in the portal trunk disappeared after medication. This is interesting, since hepatofugal flow may, in fact, be more common than we suspected in patients who, because of the severity of their disease, are not able to undergo invasive examination. Postoperative hepatofugal flow in the portal system was detected in 20 of 71 cases: 15/17 patients after interposition mesocaval shunting, 2/17 after distal splenorenal shunting, 2/31 after splenectomy, and 1/6 after splenic artery occlusion with steel coils. In more than half the cases of interposition mesocaval shunting (9/17 patients), blood flow in the portal trunk was hepatofugal. However, hepatopetal blood flow in the portal trunk was maintained in most cases of distal splenorenal shunting (13/17), showing the merits of this technique as a selective portosystemic shunt operation.


Restriction enzyme analysis of lactose and bacteriocin plasmids from Streptococcus lactis subsp. diacetylactis WM4 and cloning of BclI fragments coding for bacteriocin production.
The 131.1-kilobase (kb) bacteriocin production (Bac) plasmid pNP2 and the 63.6-kb lactose metabolism (Lac) plasmid pCS26, from Streptococcus lactis subsp. diacetylactis WM4, as well as pWN8, a 116.7-kb recombinant plasmid from a Lac+ transconjugant, were analyzed with restriction enzymes to determine the origin of pWN8. Plasmid pWN8 conferred a Lac+ Bac- phenotype, contained DNA derived from pCS26 and pNP2, and, like pNP2, exhibited self-transmissibility (Tra+). In cloning attempts, Bac+ transformant S. lactis KSH1 was isolated. The recombinant plasmid, pKSH1, contained three BclI fragments from pNP2. Bac- transformants which individually contained each of the three fragments were also identified. Comparison of restriction maps of pKSH1 and pNP2 revealed an 18.4-kb region common to both plasmids, involving two of the three BclI fragments. S. lactis KSH1 also exhibited greater inhibitory activity against the indicator strain S. diacetylactis 18-16 than did a strain containing the 131.1-kb Bac plasmid.


Single-pass albumin dialysis in a child aged six months with phenobarbital poisoning.
A girl aged six months was hospitalized because of resistant seizures and was discharged with phenobarbital and carbamazepine therapy. She was admitted to a state hospital with symptoms of inability to waken and difficulty in breathing. It was learned that phenobarbital had been used incorrectly and the patient was sent to our pediatric intensive care unit because of severe phenobarbital overdose. The decision was taken for hemodialysis. Single-pass albumin dialysis was planned because phenobarbital can bind to high levels of plasma protein. The process was undertaken with 1% albumin-containing dialysate, which was prepared manually. After 6 hours of dialysis, the phenobarbital blood level measured 62 mcg/mL (>140 mcg/mL on admission) and the patient's clinical findings were markedly regressed. There are no case reports about phenobarbital overdose treated with single-pass albumin dialysis in the literature. We conclude that single-pass albumin dialysis may be a useful treatment, especially with intoxications of drugs that bind protein at high levels.


Perturbation of maize phenylpropanoid metabolism by an AvrE family type III effector from Pantoea stewartii.
AvrE family type III effector proteins share the ability to suppress host defenses, induce disease-associated cell death, and promote bacterial growth. However, despite widespread contributions to numerous bacterial diseases in agriculturally important plants, the mode of action of these effectors remains largely unknown. WtsE is an AvrE family member required for the ability of Pantoea stewartii ssp. stewartii (Pnss) to proliferate efficiently and cause wilt and leaf blight symptoms in maize (Zea mays) plants. Notably, when WtsE is delivered by a heterologous system into the leaf cells of susceptible maize seedlings, it alone produces water-soaked disease symptoms reminiscent of those produced by Pnss. Thus, WtsE is a pathogenicity and virulence factor in maize, and an Escherichia coli heterologous delivery system can be used to study the activity of WtsE in isolation from other factors produced by Pnss. Transcriptional profiling of maize revealed the effects of WtsE, including induction of genes involved in secondary metabolism and suppression of genes involved in photosynthesis. Targeted metabolite quantification revealed that WtsE perturbs maize metabolism, including the induction of coumaroyl tyramine. The ability of mutant WtsE derivatives to elicit transcriptional and metabolic changes in susceptible maize seedlings correlated with their ability to promote disease. Furthermore, chemical inhibitors that block metabolic flux into the phenylpropanoid pathways targeted by WtsE also disrupted the pathogenicity and virulence activity of WtsE. While numerous metabolites produced downstream of the shikimate pathway are known to promote plant defense, our results indicate that misregulated induction of phenylpropanoid metabolism also can be used to promote pathogen virulence.


Do antiarthritic drugs decrease the risk for cognitive decline? An analysis based on data from the MRC treatment trial of hypertension in older adults.
We ascertained nonsteroidal anti-inflammatory drug (NSAID) use in 2,651 participants in the UK MRC treatment trial of hypertension in older adults and measured change in cognitive function over the subsequent 54 months. There was a significant, although modest, association between change in the Paired Associate Learning Test score over time and NSAID use, which was modified by age. NSAID users showed less decline, with younger subjects seeming to benefit more than older. We found no relationship between NSAID use and time taken to complete the Trail Making Test and also no relationship between anti-indigestion drug use and either cognitive outcome. These analyses highlight the need for larger studies with prospective classification of NSAID use and adequate control of confounding, including exposure to other medications. A randomized controlled trial of NSAIDs, in those known to be at risk of cognitive decline or dementia, may be indicated in the future.


PCR typing of genetic determinants for metallo-beta-lactamases and integrases carried by gram-negative bacteria isolated in Japan, with focus on the class 3 integron.
From January 2001 to December 2002, 587 strains of gram-negative bacterial isolates demonstrating resistance to ceftazidime and a combination of sulbactam and cefoperazone were subjected to a disk diffusion screening test using sodium mercaptoacetic acid; 431 strains (73.4%) appeared to produce metallo-beta-lactamase (MBL). Of these 431 strains, 357 were found by PCR to carry genes for IMP-1 type MBL (bla(IMP-1)), while only 7 and 67 strains carried the IMP-2 gene (bla(IMP-2)) and the VIM-2 gene (bla(VIM-2)), respectively. Neither VIM-1 nor SPM-1 type MBL genes were found among the strains tested. Of 431 strains, 427 carried the intI1 gene, and 4 strains carrying both the intI1 and intI3 genes were reidentified as Pseudomonas putida harboring bla(IMP-1). Of these four P. putida strains, three strains and one strain, respectively, were separately isolated from two hospitals located in the same prefecture, and the three strains showed very similar pulsed-field gel electrophoresis patterns. Of 357 bla(IMP-1) carriers, 116, 53, 51, 47, and 30 strains were identified as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, P. putida/fluorescens, Serratia marcescens, and Acinetobacter baumannii, respectively. Four strains carrying bla(IMP-2) were reidentified as P. putida. Sixty-three P. aeruginosa strains and four P. putida strains carried bla(VIM-2). Of 427 intI1-positive strains, 180, 53, 51, 47, and 35 were identified as P. aeruginosa, A. xylosoxidans, P. putida/fluorescens, S. marcescens, and A. baumannii, respectively. In the present study, it was confirmed that strains carrying bla(IMP-1) with a class 1 integron are the most prevalent type in Japan, although several intI3 carriers have also been identified sporadically in this country.