Reverse feedback induces position and orientation specific changes.
To investigate the mechanisms of perceptual learning, we recently introduced a paradigm in which incorrect, reverse feedback followed after some but not all vernier presentations. This feedback paradigm exerted a strong effect on performance that seemed to bias decisions rather than to yield perceptual learning. Here, we show that observers can develop independent decision biases for different stimulus orientations as well as for different visual field positions. Our results demonstrate that the effects of incorrect, reverse feedback are surprisingly specific.


Intense (18)F-FDG uptake in brown fat can be reduced pharmacologically.
Physiologic (18)F-FDG uptake in areas of supraclavicular fat in humans ("USA-Fat") has recently been recognized as (18)F-FDG uptake in apparent brown adipose tissue (BAT) using fused PET/CT technology. In this study, we evaluated (18)F-FDG uptake in BAT of rats to determine whether pharmacologic or physiologic interventions affect the uptake, knowing that BAT has a high density of adrenergic innervation. Seven- to 8-wk-old female Lewis rats receiving intravenous (18)F-FDG injections were examined under various conditions to evaluate (18)F-FDG biodistribution into interscapular BAT and major organs. In series 1, rats were given ketamine-based anesthesia or were exposed to cold (4 degrees C for 4 h) to determine whether these interventions increased (18)F-FDG uptake in BAT. In series 2, anesthetized rats (ketamine-based anesthesia) were given propranolol, reserpine, or diazepam intraperitoneally before (18)F-FDG injection to determine whether the drug reduced (18)F-FDG uptake in BAT. The control and treated groups in series 2 were also evaluated with (18)F-FDG PET/CT imaging. In series 1, anesthesia or exposure to cold increased (18)F-FDG uptake in BAT to levels 14-fold and 4.9-fold, respectively, greater than the control nonstimulated values. BAT uptake was high, comparable to that in the brain. In series 2, (18)F-FDG uptake in BAT was significantly decreased to less than 30% of the control level after propranolol or reserpine (P < 0.05). Diazepam did not significantly decrease (18)F-FDG uptake in BAT. (18)F-FDG PET/CT findings reflected these biodistribution data: The control and diazepam groups exhibited intense (18)F-FDG uptake in BAT, whereas the propranolol and reserpine groups showed only faint to mild (18)F-FDG uptake in BAT. Among several organs whose (18)F-FDG uptake was affected after predosing drugs, the heart exhibited considerable decreases in tracer uptake with propranolol or reserpine. This rodent study demonstrated that BAT can exhibit high (18)F-FDG uptake under stimulated conditions including exposure to cold and that propranolol or reserpine treatment can remarkably reduce the high (18)F-FDG uptake in BAT. The effect of these drugs on (18)F-FDG uptake in human BAT, as well as on tracer accumulation in other organs, should carefully be evaluated clinically to minimize the USA-Fat artifact.


Association of dietary inflammatory index with risk of gestational diabetes mellitus and preeclampsia: a systematic review and meta-analysis.
Findings from observational studies have suggested a possible association between dietary inflammatory index (DII) and risk of gestational diabetes mellitus (GDM) and preeclampsia (PE). However, the results of these studies were inconclusive. A systematic review and meta-analysis was carried out to illuminate this association. Systematic literature search was conducted in PubMed, Web of Science, Cochrane Library, EMBASE, Scopus and other databases from inception until January 2023. The qualities of included studies were assessed using the Newcastle-Ottawa scale. Nine studies (seven cohort, two case-control) were included in the meta-analysis, including 11 423 participants from five different countries. The meta-analysis indicated that a 1-unit increase in the DII score, representing pro-inflammatory diet, was associated with 13 % higher risk of GDM (OR = 1·13; 95 % CI 1·02, 1·25, I2 = 68·4 %, P = 0·004) and 24 % higher risk of PE (OR = 1·24; 95 % CI 1·14, 1·35, I2 = 52·0 %, P = 0·125). Subgroup analysis found that this association was evident among studies with Chinese populations (OR = 1·16; 95 % CI 1·06, 1·28) and studies with mid pregnancy (OR = 1·20; 95 % CI 1·07, 1·34). The findings indicate that pro-inflammatory diet can increase the risk of GDM and PE. Considering some limitations in this study, more studies are needed to verify this association.


Care fragmentation, quality, and costs among chronically ill patients.
To assess the relationship between care fragmentation and both quality and costs of care for commercially insured, chronically ill patients. We used claims data from 2004 to 2008 for 506,376 chronically ill, privately insured enrollees of a large commercial insurance company to construct measures of fragmentation. We included patients in the sample if they had chronic conditions in any of the following categories: cardiovascular disease, diabetes, asthma, arthritis, or migraine. We assigned each patient a fragmentation index based on the patterns of care of their primary care provider (PCP), with care patterns spread across a higher number of providers considered to be more fragmented. We used regression analysis to examine the relationship between fragmentation and both quality and cost outcomes. Patients of PCPs in the highest quartile of fragmentation had a higher chance of having a departure from clinical best practice (32.8%, vs 25.9% among patients of PCPs in the lowest quartile of fragmentation; P < .001). Similarly, patients of PCPs with high fragmentation had higher rates of preventable hospitalizations (9.1% in highest quartile vs 7.1% in lowest quartile; P < .001). High fragmentation was associated with $4542 higher healthcare spending ($10,396 in the highest quartile vs $5854 in the lowest quartile; P < .001). We found similar or larger effects on quality and costs among patients when we examined the most frequently occurring disease groups individually. Chronically ill patients whose primary care providers offer highly fragmented care more often experience lapses in care quality and incur greater healthcare costs.


Well-being improvement in a midsize employer: changes in well-being, productivity, health risk, and perceived employer support after implementation of a well-being improvement strategy.
To evaluate employee well-being change and associated change in productivity, health risk including biometrics, and workplace support over 2 years after implementation of a well-being improvement strategy. This was an employer case study evaluation of well-being, productivity (presenteeism, absenteeism, and job performance), health risk, and employer support across three employee assessment spanning 2 years. Employee well-being was compared with an independent sample of workers in the community. Well-being and job performance increased and presenteeism and health risk decreased significantly over the 2 years. Employee well-being started lower and increased to exceed community worker averages, approaching significance. Well-being improvement was associated with higher productivity across all measures. Increases in employer support for well-being were associated with improved well-being and productivity. This employer's well-being strategy, including a culture supporting well-being, was associated with improved health and productivity.


Prescription practices involving opioid analgesics among Americans with Medicaid, 2010.
Recent state-based studies have shown an increased risk of opioid overdose death in Medicaid populations. To explore one side of risk, this study examines indicators of potential opioid inappropriate use or prescribing among Medicaid enrollees. We examined claims from enrollees aged 18-64 years in the 2010 Truven Health MarketScan® Multi-State Medicaid database, which consisted of weighted and nationally representative data from 12 states. Pharmaceutical claims were used to identify enrollees (n=359,368) with opioid prescriptions. Indicators of potential inappropriate use or prescribing included overlapping opioid prescriptions, overlapping opioid and benzodiazepine prescriptions, long acting/extended release opioids for acute pain, and high daily doses. In 2010, Medicaid enrollees with opioid prescriptions obtained an average 6.3 opioid prescriptions, and 40% had at least one indicator of potential inappropriate use or prescribing. These indicators have been linked to opioid-related adverse health outcomes, and methods exist to detect and deter inappropriate use and prescribing of opioids.


Rh-Catalyzed Ortho C-H Alkynylation of Aromatic Aldehydes.
The Rh(III)-catalyzed ortho-alkynylation of benzaldehydes is enabled by the transient formation of an imine as a directing group. A broad scope of substrates was obtained under mild reaction conditions, granting access to mono- and dialkynylated products. The functionalization of readily available building blocks allowed the development of modular syntheses of dibenzopentalenes, isoquinolines, indoles, and indolines.


Molar gestations and hydropic abortions differentiated by p57 immunostaining.
Classification of molar gestations into complete and partial and their differentiation from hydropic abortions traditionally are accomplished by morphology alone. The process sometimes may be inaccurate or inconclusive. With the availability of p57 immunostaining it may be possible to objectively classify these lesions. We used p57 for the differential diagnosis of hydropic abortions and molar gestations and correlated the findings with the clinical outcome of patients in each category. First, 86 cases were originally classified by histomorphology into hydropic abortion (42) and molar gestations (23 complete and 21partial). Based on the pattern of p57 staining the cases were reclassified into 45 hydropic abortions, 15 partial moles and 26 complete moles (3 cases with previous diagnosis of complete mole based on morphology were reclassified as hydropic abortion). Clinical follow-ups ranged from 6-24 months and showed persistent trophoblastic disease in 8 cases (31%) of complete moles and 3 cases (20%) of partial moles (p = 0.47). No hydropic abortion cases demonstrated persistent trophoblastic disease. One patient with partial mole developed choriocarcinoma. This study confirms that p57 objectively distinguishes hydropic abortions from molar gestations (partial and complete moles). This differentiation is clinically relevant since patients with hydropic abortions do not need to be followed while patients with molar gestations do.


Core/shell structured hollow mesoporous nanocapsules: a potential platform for simultaneous cell imaging and anticancer drug delivery.
A potential platform for simultaneous anticancer drug delivery and MRI cell imaging has been demonstrated by uniform hollow inorganic core/shell structured multifunctional mesoporous nanocapsules, which are composed of functional inorganic (Fe(3)O(4), Au, etc.) nanocrystals as cores, a thin mesoporous silica shell, and a huge cavity in between. The synthetic strategy for the creation of huge cavities between functional core and mesoporous silica shell is based on a structural difference based selective etching method, by which solid silica middle layer of Fe(2)O(3)@SiO(2)@mSiO(2) (or Au@SiO(2)@mSiO(2)) composite nanostructures was selectively etched away while the mesoporous silica shell could be kept relatively intact. The excellent biocompatibility of obtained multifunctional nanocapsules (Fe(3)O(4)@mSiO(2)) was demonstrated by very low cytotoxicity against various cell lines, low hemolyticity against human blood red cells and no significant coagulation effect against blood plasma. The cancer cell uptake and intracellular location of the nanocapsules were observed by confocal laser scanning microscopy and bio-TEM. Importantly, the prepared multifunctional inorganic mesoporous nanocapsules show both high loading capacity (20%) and efficiency (up to 100%) for doxorubicin simultaneously because of the formation of the cavity, enhanced surface area/pore volume and the electrostatic interaction between DOX molecules and mesoporous silica surface. Besides, the capability of Fe(3)O(4)@mSiO(2) nanocapsules as contrast agents of MRI was demonstrated both in vitro and in vivo, indicating the simultaneous imaging and therapeutic multifunctionalities of the composite nanocapsules. Moreover, the concept of multifunctional inorganic nanocapsules was extended to design and prepare Gd-Si-DTPA grafted Au@mSiO(2) nanocapsules for nanomedical applications, further demonstrating the generality of this strategy for the preparation of various multifunctional mesoporous nanocapsules.


Biocuration in the structure-function linkage database: the anatomy of a superfamily.
With ever-increasing amounts of sequence data available in both the primary literature and sequence repositories, there is a bottleneck in annotating molecular function to a sequence. This article describes the biocuration process and methods used in the structure-function linkage database (SFLD) to help address some of the challenges. We discuss how the hierarchy within the SFLD allows us to infer detailed functional properties for functionally diverse enzyme superfamilies in which all members are homologous, conserve an aspect of their chemical function and have associated conserved structural features that enable the chemistry. Also presented is the Enzyme Structure-Function Ontology (ESFO), which has been designed to capture the relationships between enzyme sequence, structure and function that underlie the SFLD and is used to guide the biocuration processes within the SFLD. http://sfld.rbvi.ucsf.edu/.


Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture.
The amount of fibrotic material in dystrophic mouse muscles relates to contractile function, but not passive function. Collagen fibres in skeletal muscle are associated with increased passive muscle stiffness in fibrotic muscles. The alignment of collagen is independently associated with passive stiffness in dystrophic skeletal muscles. These outcomes demonstrate that collagen architecture rather than collagen content should be a target of anti-fibrotic therapies to treat muscle stiffness. Fibrosis is prominent in many skeletal muscle pathologies including dystrophies, neurological disorders, cachexia, chronic kidney disease, sarcopenia and metabolic disorders. Fibrosis in muscle is associated with decreased contractile forces and increased passive stiffness that limits joint mobility leading to contractures. However, the assumption that more fibrotic material is directly related to decreased function has not held true. Here we utilize novel measurement of extracellular matrix (ECM) and collagen architecture to relate ECM form to muscle function. We used mdx mice, a model for Duchenne muscular dystrophy that becomes fibrotic, and wildtype mice. In this model, extensor digitorum longus (EDL) muscle was significantly stiffer, but with similar total collagen, while the soleus muscle did not change stiffness, but increased collagen. The stiffness of the EDL was associated with increased collagen crosslinking as determined by collagen solubility. Measurement of ECM alignment using polarized light microscopy showed a robust relationship between stiffness and alignment for wildtype muscle that broke down in mdx muscles. Direct visualization of large collagen fibres with second harmonic generation imaging revealed their relative abundance in stiff muscles. Collagen fibre alignment was linked to stiffness across all muscles investigated and the most significant factor in a multiple linear regression-based model of muscle stiffness from ECM parameters. This work establishes novel characteristics of skeletal muscle ECM architecture and provides evidence for a mechanical function of collagen fibres in muscle. This finding suggests that anti-fibrotic strategies to enhance muscle function and excessive stiffness should target large collagen fibres and their alignment rather than total collagen.


Shaping a femtosecond pulse with a programmable thermo-optically driven phase modulator.
A femtosecond pulse shaping apparatus based on a thermo-optically driven spatial phase modulator is presented. The modulator cell is illuminated by a standard projector and is easily controllable with a computer. In principle the setup allows for two dimensional pulse shaping, however, all initial demonstrations reported here, such as feedback controlled dispersion compensation or pulse train generation, are performed in a one dimensional phase-only shaping geometry.


Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases.
Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) is a newly identified substrate for protein tyrosine phosphatase N3 (PTPN3), which belongs to the FERM-containing PTP subfamily comprising five members including PTPN3, N4, N13, N14, and N21. We solved the crystal structures of the PTPN3-Eps15 phosphopeptide complex and found that His812 of PTPN3 and Pro850 of Eps15 are responsible for the specific interaction between them. We defined the critical role of the additional residue Tyr676 of PTPN3, which is replaced by Ile939 in PTPN14, in recognition of tyrosine phosphorylated Eps15. The WPD loop necessary for catalysis is present in all members but not PTPN21. We identified that Glu instead of Asp in the WPE loop contributes to the catalytic incapability of PTPN21 due to an extended distance beyond protonation targeting a phosphotyrosine substrate. Together with in vivo validations, our results provide novel insights into the substrate specificity and plasticity of FERM-containing PTPs.


Preparation and Comparative Stability of a Kaolinite-Tetrabutylphosphonium Bromide Intercalation Compound for Heat and Solvent Treatments.
A kaolinite-tetrabutylphosphonium bromide (TBPBr) intercalation compound (Kaol-TBPBr) was prepared from kaolinite providing inorganic aluminosilicate layers and TBPBr as intercalated salts between the layers through the use of an intermediate, a kaolinite-dimethylsulfoxide (DMSO) intercalation compound (Kaol-DMSO). The experimental data through complementary techniques, including X-ray diffraction, Fourier transform infrared spectroscopy, solid-state 13C and 29Si nuclear magnetic resonance (NMR) spectroscopy with cross polarization and magic angle spinning, inductively coupled plasma emission spectrometry, and ion chromatography, indicate complete removal of DMSO and intercalation of TBPBr with an increase in the basal spacing from 1.12 nm (Kaol-DMSO) to 1.53 nm (Kaol-TBPBr). In contrast to a similar intercalation compound, a kaolinite-tetrabutylammonium bromide (TBABr) intercalation compound (Kaol-TBABr) with a basal spacing of 1.51 nm, Kaol-TBPBr displayed interesting features such as enhanced thermal stabilities as well as bold resistance against several solvents. Kaol-TBPBr withstood thermal decomposition of the organic species over 100 °C much better than Kaol-TBABr. When Kaol-TBPBr and Kaol-TBABr were refluxed in methanol, ethanol, acetone, or toluene for 1 day, Kaol-TBPBr preserved the expanded kaolinite layers, while the Kaol-TBABr structure completely collapsed due to the release of TBABr. Thus, with these particular and unique features of Kaol-TBPBr, organophosphonium salts appear to be promising guest species for intercalation chemistry of kaolinite.


Diversity, geographic distribution, and habitat-specific variations of microbiota in natural populations of the chicken mite, Dermanyssus gallinae.
Dermanyssus gallinae is considered to be the most economically significant ectoparasite to affect egg-laying poultry in Europe. This mite can also act as a vector for a number of pathogens. The array of bacteria associated with D. gallinae mites could provide insight into the biology and population dynamics of arthropods, but at the present time little information is available. To understand the intra- and interpopulation diversity of its associated microbiota, we analyzed the whole internal bacterial community of natural populations of D. gallinae originating from two types of poultry farm habitats (standard and free-range) in two regions of France (Brittany and the Rhone-Alpes). Total DNA was extracted from individual or pooled mites, and polymerase chain reaction temporal temperature gradient gel electrophoresis of 16S rRNA was then done to separate bacterial DNA fragments associated with the host arthropod. A large diversity of bacteria was detected, but principally firmicutes and gamma-Proteobacteria. Between-group analyses of temporal temperature gradient gel electrophoresis-banding patterns revealed that bacterial populations clustered into categories according to their geographic origin and the habitat specifics of the farms. Some degree of stability of bacterial populations was observed within a specific time scale. These results suggest that environmental factors either recent (e.g., poultry farming practices) or long-standing (e.g., geographic isolation) may affect the bacterial communities present in D. gallinae. Further knowledge of the microbiota associated with D. gallinae and its variation would indeed offer new perspectives for biological control methods to prevent the establishment, proliferation, and transmission of pathogenic bacteria.


Plasma exchange for Guillain-Barré syndrome.
Guillain-Barré syndrome is an acute symmetric, usually ascending and usually paralysing illness, due to inflammation of peripheral nerves. It is thought to be caused by autoimmune factors, such as antibodies. Plasma exchange removes antibodies and other potentially injurious factors from the blood stream. It involves connecting the patient's blood circulation to a machine which exchanges the plasma for a substitute solution, usually albumin. Several studies have evaluated plasma exchange for Guillain-Barré syndrome. To systematically review the evidence concerning the efficacy of plasma exchange for treating Guillain-Barré syndrome. Search of the Cochrane Neuromuscular Disease Trial Register for randomised trials concerning plasma exchange in Guillain-Barré syndrome, search of the bibliographies of identified papers and enquiry from the authors of the papers. Randomised and quasi-randomised trials of plasma exchange versus sham exchange or supportive treatment. Potentially relevant papers were scrutinised by two reviewers and the selection of eligible studies was agreed by them and a third reviewer. Data were extracted by one reviewer and checked by a second reviewer. Some missing data were obtained from the authors of studies. Six eligible trials concerning 649 patients were identified, all comparing plasma exchange versus supportive treatment alone. Primary outcome measures ~bullet~Time to recover walking with aid In the only two trials for which this measure was reported, the median time to recover this ability was faster in the plasma exchange than the control group. ~bullet~Time to onset of motor recovery in mildly affected patients In the one trial for which this measure was available, the time was significantly shortened in the plasma exchange group. Secondary outcome measures ~bullet~Improvement in disability grade at four weeks In five trials, there were significantly more patients who had improved by one disability grade or more in the plasma exchange group as compared to the control group. Patients treated with plasma exchange fared significantly better in the following secondary outcome measures: time to recover walking without aid, percentage of patients requiring artificial ventilation, duration of ventilation, full muscle strength recovery after one year, and severe sequelae after one year. There were less patients with infectious events and cardiac arrhythmias in the plasma exchange than the control group. Subgroup analyses Plasma exchange was beneficial in patients with mild, moderate and severe (needing ventilation) Guillain-Barré syndrome. It was beneficial in patients with a disease duration of seven or less days and also in those with disease lasting more than seven days. However, in the only trial that enrolled patients up to 30 days from disease onset, the benefit of plasma exchange in patients treated after seven days was less apparent. Type of treatment Single studies showed that two plasma exchanges were significantly superior to none for mild Guillain-Barré syndrome and four to two for moderate Guillain-Barré syndrome, but that six were not superior to four for severe Guillain-Barré syndrome requiring ventilation. One study suggested that continuous flow plasma exchange was significantly superior to intermittent flow. Another study found no significant difference between the two techniques. The same study found a significantly higher rate of adverse events with fresh frozen plasma as the replacement fluid than albumin. Plasma exchange compared with cerebrospinal fluid filtration A single trial comparing these two treatments did not show any difference in outcomes but was too small to demonstrate equivalence. Plasma exchange is the first and only treatment that has been proven to be superior to supportive treatment alone in Guillain-Barré syndrome. Consequently, plasma exchange should be regarded as the treatment against which new treatments, such as intravenous immunoglobulin, should be judged. In mild Guillain-Barré syndrome two sessions of plasma exchange are superior to none. In moderate Guillain-Barré syndrome four sessions are superior to two. In severe Guillain-Barré syndrome six sessions are no better than four. Continuous flow plasma exchange machines may be superior to intermittent flow machines and albumin to fresh frozen plasma as the exchange fluid. Plasma exchange is more beneficial when started within seven days after disease onset rather than later, but was still beneficial in patients treated up to 30 days after disease onset. The value of plasma exchange in children less than 12 years old is not known. There is insufficient evidence to determine whether cerebrospinal fluid filtration is equivalent to plasma exchange.


The effect of observational learning on students' performance, processes, and motivation in two creative domains.
Previous research has shown that observation can be effective for learning in various domains, for example, argumentative writing and mathematics. The question in this paper is whether observational learning can also be beneficial when learning to perform creative tasks in visual and verbal arts. We hypothesized that observation has a positive effect on performance, process, and motivation. We expected similarity in competence between the model and the observer to influence the effectiveness of observation. Sample. A total of 131 Dutch students (10(th) grade, 15 years old) participated. Two experiments were carried out (one for visual and one for verbal arts). Participants were randomly assigned to one of three conditions; two observational learning conditions and a control condition (learning by practising). The observational learning conditions differed in instructional focus (on the weaker or the more competent model of a pair to be observed). We found positive effects of observation on creative products, creative processes, and motivation in the visual domain. In the verbal domain, observation seemed to affect the creative process, but not the other variables. The model similarity hypothesis was not confirmed. Results suggest that observation may foster learning in creative domains, especially in the visual arts.


Epigenetic differences between male and female bovine blastocysts produced in vitro.
Epigenetic differences between male and female bovine blastocysts provide a plausible link between physiological and gene transcription differences observed between male and female embryos. The aim of this study was to examine sex-related epigenetic differences in bovine blastocysts produced in vitro. Oocytes were matured in vitro and inseminated with frozen-thawed sex-sorted (X or Y) and unsorted (control) bull sperm. Zygotes were cultured to blastocyst stage and were analyzed for embryo sexing, mtDNA content, telomere lengths, methylation analysis, and quantification of mRNA transcripts of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) HMT1 hnRNP methyltransferase-like 2 (Hmt1), and interleukin enhancer binding factor 3 (Ilf3). There was a difference (P < 0.05) in the mean mtDNA copy number between male (410,000 +/- 23,000) and female (360,000 +/- 21,000) blastocysts. Telomere length was shorter in male blastocysts (P < 0.01). The level of methylation in a sequence near a variable number of tandem repeats minisatellite region [variable number of tandem repeats (VNTR)] in males (39.8% +/- 4.8) was higher than in females (23.7% +/- 3.1) (P < 0.05); however, no differences were found in other regions analyzed. Moreover, transcription differences between sexes were observed for Dnmt3a, Dnmt3b, Hmt1, and Ilf3. These results provide evidence of epigenetic differences between male and female bovine in vitro produced embryos and suggest that before initiation of gonadal differentiation, epigenetic events may modulate the difference between speed of development, metabolism, and transcription observed during preimplantation development between male and female embryos.


Enhancement by flumazenil of dopamine release in the nucleus accumbens of rats repeatedly exposed to diazepam or imidazenil.
The effect of long-term treatment (three times daily for 3 weeks) with a behaviorally relevant dose of the benzodiazepine receptor partial agonist imidazenil (0.5 mg/kg, IP) on basal dopamine release in the nucleus accumbens of freely moving rats was compared with that of diazepam (3 mg/kg, IP), a benzodiazepine receptor full agonist. Challenge doses of imidazenil and diazepam decreased the extracellular dopamine concentration in the nucleus accumbens by approximately the same extent in animals repeatedly exposed to vehicle or to the respective drug. Moreover, the abrupt discontinuation of long-term treatment with diazepam or imidazenil failed to affect basal dopamine release in this brain area during the first 5 days of withdrawal. In contrast, administration of the benzodiazepine receptor antagonist flumazenil (4 mg/kg, IP) elicited a marked increase (95 or 60%) in dopamine release in the nucleus accumbens 6 h after withdrawal of diazepam or imidazenil, respectively. Flumazenil induced a similar but smaller effect (50% increase) 5 days after diazepam withdrawal but had no effect 5 days after discontinuation of imidazenil treatment. The results support an involvement of the mesoaccumbens dopaminergic neurons in the withdrawal syndrome precipitated by flumazenil and allow further differentiation of benzodiazepine receptor partial and full agonists with respect to dependence liability of dopaminergic neurons in the nucleus accumbens.


Validity of the Marshall Sitting Questionnaire in people with multiple sclerosis.
This study examines the validity of the Marshall Sitting Questionnaire (MSQ) in people with multiple sclerosis (MS) and presents a prediction model to improve the accuracy of the MSQ estimates. Participants (n = 63 [15M and 48F], age: 56.6 ± 7.3 years) wore an accelerometer on the hip for a 7-day period and completed the MSQ. Sedentary behaviour (SB) estimates were computed as min/day for both the MSQ and accelerometer. Associations between the two methods were examined using the Pearson correlation and agreement was assessed using a Bland-Altman plot. A linear prediction model was developed to improve the accuracy of the MSQ estimates using a selection of predictor variables routinely collected in MS research. There was a moderate correlation between MSQ and accelerometer SB estimates (r = 0.34, p < 0.01). The Bland-Altman plot indicated that the MSQ overestimated SB (mean bias: 80.54 min/day, 95% limits of agreement: -410.5 to 571.5 min/day). The prediction model improved the MSQ estimates by 39% and virtually eliminated measurement bias (mean bias:-0.21 min/day; 95% limits of agreement:-109.8 to 109.4 min/day). The results indicate preliminary evidence for the validity of the MSQ in people with MS, and support the application of an alternative prediction model to improve the accuracy of the MSQ estimates. Abbreviations: SB = sedentary behaviour; MS = multiple sclerosis; MSQ = Marshall Sitting Questionnaire; PA = physical activity; EDSS = Expanded Disability Status Scale; LPA = light physical activity; MVPA = moderate-to-vigorous physical activity; GLTEQ = Godin Leisure Time Exercise Questionnaire; PDDS = Patient-Determined Disease Steps; RMSE = root mean square error.


Mechanisms of decreased susceptibility to beta-defensins by Treponema denticola.
Treponema denticola, a periodontal pathogen, is relatively resistant to human beta-defensins, which are small cationic antimicrobial peptides produced by a number of cells, including the gingival epithelium. Using two independent methods, we previously demonstrated that T. denticola proteases are not responsible for decreased vulnerability to defensins. In this study, we confirmed that the major outer membrane protease, dentilisin, is not responsible for T. denticola insensitivity to defensins and examined several other possible mechanisms, including reduced binding to the bacterial surface and efflux pump activity. It has been suggested that some bacteria mask their surfaces with serum proteins. T. denticola grown in a serum-free medium did not exhibit increased susceptibility to human beta-defensin 2 and 3 (hbetaD-2 and hbetaD-3, respectively), suggesting that cloaking of the outer surface with host proteins is not involved in defensin resistance. Nonetheless, we demonstrated that T. denticola binds significantly less hbetaD-2 and -3 than susceptible organisms bind, suggesting that the unusual outer membrane composition of T. denticola may discourage cationic peptide binding. Efflux pumps have been shown to mediate resistance to antibiotics and cationic peptides in other bacteria, and their role in T. denticola's relative resistance to beta-defensins was investigated. Three inhibitors of bacterial ATP-binding cassette (ABC) efflux pumps had no effect on T. denticola's susceptibility to hbetaD-2 or -3. In contrast, a proton motive force inhibitor, carbonyl cyanide 3-chlorophenylhydrazone, increased the susceptibility of T. denticola to killing by hbetaD-3, demonstrating a potential role for efflux pumps (other than ABC pumps) in resistance to this peptide. Our data suggest that the combination of decreased defensin binding and efflux of any peptide which enters the cytoplasm may explain T. denticola's relative resistance to human beta-defensins.


[Changes in the cerebral serotonin and noradrenaline levels in the brains of white rats trained with emotionally different reinforcement].
The changes in the serotonin (5-OT) and noradrenaline (NA) content in the brain of rats taught on the emotionally-positive (food) and emotionally-negative (pain) reinforcement were compared. The process of animal learning was accompanied by increase in the biogenic amine level. But when the teaching was conducted on the emotionally-positive reinforcement there was a greater increase in the 5-OT and NA level than in the case of the emotionally negative reinforcement. The process of animal teaching on food reinforcement was accompanied by an elevation of 5-OT chiefly in the cerebral cortex which apparently reflected the active functioning of the 5-OT system. An intensification of the NA system occurred in teaching the animals in the defence situation. A conclusion was thus drawn that the character of the changes in the biogenic amine level in the brain during learning depended on the emotions experienced by the animal (the emotional reinforcement utilized).


Surgical Outcomes and Quality Assessment of Trabeculectomy: Leveraging Electronic Health Records for Clinical Data Visualization.
PRéCIS:: This electronic medical record-based study demonstrates 1 approach to monitor clinical outcomes for individual physicians performing trabeculectomy. The purpose of this study was to develop an interactive data visualization platform for evaluating trabeculectomy outcomes and monitoring clinical care quality. This is a retrospective electronic health record study in a glaucoma division of an academic medical center. We included 633 patients who underwent trabeculectomy between July 2016 and December 2018. Data were collected for intraocular pressure (IOP), vision loss, number of follow-up visits, and return to the operating room within the initial 3 months. Regression analyses were used to assess factors associated with these study outcomes. Risk of IOP ≤5 mm Hg was assessed using survival analysis. An interactive data visualization platform was created. A total of 429 trabeculectomy and 204 combined surgeries were analyzed, with preoperative IOP of 21.9±9.4 and 19.4±6.9 mm Hg, respectively. Mean pressure declined by 53% and 41% (P=0.001) by 3 months. Risk of pressure ≤5 mm Hg was higher in white patients and those who underwent trabeculectomy alone. At 3 months, patients on average had 5 clinic visits; 5.5% required additional surgical procedures, and 18% experienced loss of at least 3 lines of best-recorded (not best-corrected) vision. Returning to the operating room was significantly associated with an increased number of clinic visits (coefficient=3.94) and higher odds of vision loss (odds ratio=11.12). Over the initial 3 months after trabeculectomy, additional surgeries are rare, while a significant proportion of patients lost vision, and this was strongly associated with a need to return to the operating room. Interactive electronic health record data visualization can be a useful tool for monitoring clinical outcomes.


Determination of prestenotic flow volume using an automated method based on colour Doppler imaging for evaluating orifice area by the continuity equation: validation in a pulsatile flow model.
To evaluate, in a pulsatile flow model simulating flow conditions in valvar stenoses, whether accurate determination of orifice area can be achieved by the continuity equation using automated determination of flow volumes based on spatiotemporal integration of digital colour Doppler flow velocities. A method for automated determination of flow volumes which takes into account the velocity distribution across a region of interest was examined using flow through a tube and various restrictive outlet orifices with areas ranging between 0.2 and 3.1 cm2. The sampling rectangle of the Doppler method was positioned proximal to the obstructions within the flow convergence zone for evaluating prestenotic flow volume. Stenotic jet velocities were recorded by continuous wave Doppler to obtain the integral under the velocity curve. Prestenotic flow volume was then divided by the velocity integral to calculate functional orifice area according to the continuity equation. The presence of parabolically shaped velocity profiles across the prestenotic region was demonstrated by the Doppler method. Excellent agreement was found between prestenotic flow volumes measured by the Doppler technique and actual values (r = 0.99, SEE = 1.35 ml, y = 0.99x-0.24). Use of the continuity equation led to a close correlation, with a systematic underestimation of geometric orifice sizes. Correction of Doppler data for flow contraction yielded an excellent agreement with actual orifice areas. The study validated the accuracy of a Doppler method for automated determination of flow volumes for quantifying orifice area by the continuity equation. Prestenotic flow volume and functional orifice area could be evaluated reliably in the presence of non-flat velocity profiles. Thus the method contributes to the non-invasive assessment of valvar stenoses.


Stably engineered nanobubbles and ultrasound - An effective platform for enhanced macromolecular delivery to representative cells of the retina.
Herein we showcase the potential of ultrasound-responsive nanobubbles in enhancing macromolecular permeation through layers of the retina, ultimately leading to significant and direct intracellular delivery; this being effectively demonstrated across three relevant and distinct retinal cell lines. Stably engineered nanobubbles of a highly homogenous and echogenic nature were fully characterised using dynamic light scattering, B-scan ultrasound and transmission electron microscopy (TEM). The nanobubbles appeared as spherical liposome-like structures under TEM, accompanied by an opaque luminal core and darkened corona around their periphery, with both features indicative of efficient gas entrapment and adsorption, respectively. A nanobubble +/- ultrasound sweeping study was conducted next, which determined the maximum tolerated dose for each cell line. Detection of underlying cellular stress was verified using the biomarker heat shock protein 70, measured before and after treatment with optimised ultrasound. Next, with safety to nanobubbles and optimised ultrasound demonstrated, each human or mouse-derived cell population was incubated with biotinylated rabbit-IgG in the presence and absence of ultrasound +/- nanobubbles. Intracellular delivery of antibody in each cell type was then quantified using Cy3-streptavidin. Nanobubbles and optimised ultrasound were found to be negligibly toxic across all cell lines tested. Macromolecular internalisation was achieved to significant, yet varying degrees in all three cell lines. The results of this study pave the way towards better understanding mechanisms underlying cellular responsiveness to ultrasound-triggered drug delivery in future ex vivo and in vivo models of the posterior eye.


Benchmarks for the energy demand of nutrient removal plants.
The energy demand of municipal wastewater treatment plants for nutrient removal equipped with primary clarifiers, activated sludge system, anaerobic sludge digestion, and CHP is evaluated theoretically, on the basis of COD balances. Operational experience from energy-efficient Austrian treatment plants confirms that the demand on external electrical energy can be kept as low as 5 to 10 kWh/(pe.a) depending on the N:COD ratio in the raw wastewater. A low N:COD ratio helps to keep not only the effluent nitrogen load low, but also the energy demand. Measures to minimise the energy demand at treatment plants and to reduce the nitrogen load are discussed.


Characterization of a class II pilin expression locus from Neisseria meningitidis: evidence for increased diversity among pilin genes in pathogenic Neisseria species.
Strains of Neisseria meningitidis elaborate one of two classes of pili. Meningococcal class I pili have many features in common with pili produced by N. gonorrhoeae, including the ability to bind monoclonal antibody SM1 and a common gene and protein structure consisting of conserved, semivariable, and hypervariable regions. Class II pili are SM1 nonreactive and display smaller subunit molecular weights than do gonococcal or meningococcal class I pili. In this study, we have determined the N-terminal amino acid sequence for class II pilin and isolated the expression locus encoding class II pilin from N. meningitidis FAM18. Meningococcal class II pilin displays features typical of type IV pili and shares extensive amino acid identity with the N-terminal conserved regions of other neisserial pilin proteins. However, the deduced class II pilin sequence displays several unique features compared with previously reported meningococcal class I and gonococcal pilin sequences. Class II pilin lacks several conserved peptide regions found within the semivariable and hypervariable regions of other neisserial pilins and displays a large deletion in a hypervariable region of the protein believed to be exposed on the pilus face in gonococcal pili. DNA sequence comparisons within all three regions of the coding sequence also suggest that the meningococcal class II pilin gene is the most dissimilar of the three types of neisserial pilE loci. Additionally, the class II locus fails to display flanking-sequence homology to class I and gonococcal genes and lacks a downstream Sma/Cla repeat sequence, a feature present in all other neisserial pilin genes examined to date. These data indicate meningococcal class II pili represent a structurally distinct class of pili and suggest that relationships among pilin genes in pathogenic Neisseria do not necessarily follow species boundaries.


Can change in prolonged walking be inferred from a short test of gait speed among older adults who are initially well-functioning?
The ability to walk for short and prolonged periods of time is often measured with separate walking tests. It is unclear whether decline in the 2-minute walk coincides with decline in a shorter 20-m walk among older adults. The aim of this study was to describe patterns of change in the 20-m walk and 2-minute walk over 8 years among a large cohort of older adults. Should change be similar between tests of walking ability, separate retesting of prolonged walking may need to be reconsidered. A longitudinal, observational cohort study was conducted. Data were from 1,893 older adults who were well-functioning (≥70 years of age). The 20-m walk and 2-minute walk were repeatedly measured over 8 years to measure change during short and prolonged periods of walking, respectively. Change was examined using a dual group-based trajectory model (dual model), and agreement between walking trajectories was quantified with a weighted kappa statistic. Three trajectory groups for the 20-m walk and 2-minute walk were identified. More than 86% of the participants were in similar trajectory groups for both tests from the dual model. There was high chance-corrected agreement (kappa=.84; 95% confidence interval=.82, .86) between the 20-m walk and 2-minute walk trajectory groups. One-third of the original Health, Aging and Body Composition (Health ABC) study cohort was excluded from analysis due to missing clinic visits, followed by being excluded for health reasons for performing the 2-minute walk, limiting generalizability to healthy older adults. Patterns of change in the 2-minute walk are similar to those in the 20-m walk. Thus, separate retesting of the 2-minute walk may need to be reconsidered to gauge change in prolonged walking.


Behavioural and psychiatric symptoms in people with dementia admitted to the acute hospital: prospective cohort study.
Dementia is common in older people admitted to acute hospitals. There are concerns about the quality of care they receive. Behavioural and psychiatric symptoms of dementia (BPSD) seem to be particularly challenging for hospital staff. AIMS To define the prevalence of BPSD and explore their clinical associations. Longitudinal cohort study of 230 people with dementia, aged over 70, admitted to hospital for acute medical illness, and assessed for BPSD at admission and every 4 (± 1) days until discharge. Other measures included length of stay, care quality indicators, adverse events and mortality. Participants were very impaired; 46% at Functional Assessment Staging Scale (FAST) stage 6d or above (doubly incontinent), 75% had BPSD, and 43% had some BPSD that were moderately/severely troubling to staff. Most common were aggression (57%), activity disturbance (44%), sleep disturbance (42%) and anxiety (35%). We found that BPSD are very common in older people admitted to an acute hospital. Patients and staff would benefit from more specialist psychiatric support.


Efficacy and Safety of Epirubicin Combined with Temozolomide for Treatment of Advanced Leiomyosarcoma.
Leiomyosarcoma (LMS) accounts for 24% of all soft tissue sarcomas (STSs) and this STS subtype has high metastatic potential. Previous studies indicated the best median progression-free survival (mPFS) time was 9.2 months and the best overall response rate (ORR) was 30.9%. We evaluated the efficacy and safety of epirubicin combined with temozolomide (EPI-TMZ) for treatment of advanced LMS. This was a retrospective review of the records of patients with advanced LMS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All patients initiated EPI-TMZ treatment between January 2018 and December 2020. We examined 15 patients who received EPI-TMZ for LMS. This was a first-line treatment in 6 patients, a second- or third-line treatment in 7 patients, and a fourth-line treatment in 2 patients. At the time of data cutoff (April 25, 2021), the median PFS was 10 months, 1 patient had clinical complete response (cCR), 7 had partial response (PR), and 7 had stable disease (SD). The overall response rate (ORR) was 53.3% (8/15) and the disease control rate (DCR) was 100.0% (15/15). The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. One patient had severe adverse effect (febrile neutropenia), but there were no treatment-related deaths. EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ provided better outcomes than reported in previous studies of other treatments for advanced LMS.


Endogenous membrane tumor necrosis factor (TNF) is a potent amplifier of TNF receptor 1-mediated apoptosis.
The heat shock protein 90 (Hsp-90) inhibitor, geldanamycin, and the proteasome inhibitor, MG-132, both inhibited tumor necrosis factor receptor 1 (TNF-R1)- but not TRAIL-induced apoptosis in Kym-1 cells, suggesting that TNF-R1-induced cell death is dependent on NF-kappaB activation in this model. Triggering of TNF-R1 by agonistic antibodies led to cell-type specific induction of endogenous TNF and apoptosis, the latter of which was abrogated by neutralizing TNF specific antibodies. TNF-R1-stimulated cells expressed TNF mainly in a cell-associated form, suggesting that the endogenously produced TNF act in its membrane-bound form. Geldanamycin failed to inhibit apoptosis induction by a combination of agonistic TNF-R1- and TNF-R2-specific antibodies, indicating that both TNF receptors co-operate in TNF-R1-triggered apoptosis in Kym-1 cells. Thus, TNF-R1 stimulation can elicit a strong and rapid apoptotic response via induction of membrane TNF and subsequent cooperation of TNF-R1 and TNF-R2. Moreover, we give evidence that this mechanism circumvents the need of the prolonged presence of exogenous soluble TNF for TNF-R1-mediated apoptosis induction.


[Structural and metabolic status and functional properties of erythrocytes in schizophrenic patients].
Structural metabolic properties and functional state of blood erythrocytes have been studied in 118 patients with paranoid schizophrenia and 22 patients with residual schizophrenia. Control group comprised 103 normals. Thin layer chromatography, fluorescent probing Na+, K(+)-ATP-ase activity evaluation, scanning and transmission electron microscopy, laser difractometry and selectometry were used. A distinct increase of cholesterol and lysophosphatidylcholin, a decrease of phosphatidyl ethanolamine, higher organisation of both integral lipid biolayer and annular lipid fraction, structural modification of outer membrane layers, Na+, K(+)-ATP-ase activity decrease, disorganization of surface architectonics and ultrastructure of erythrocytes, decrease of their deformatability and aggretablity enhancement were found in erythrocyte membranes of the patients with paranoid schizophrenia who had not received psychopharmacocorrective therapy for 6 months before examination. The expression of the indices studied did not correlate with either the disease exacerbation or remission. A similar pattern of erythrocyte disturbances was detected in patients with paranoid and residual schizophrenia on long-term treatment with neuroleptics.


Current status and clinical presentations of invasive neonatal Group B streptococcal infections in Korea.
Group B streptococcus (GBS) is the most common cause of invasive neonatal infections in developed countries. The incidence of early-onset GBS disease in Korea is known to be much lower than that in other developed countries; however neonatal GBS disease has been frequently reported in recent years in Korea. This retrospective study sought to determine the current status and clinical presentation of neonatal GBS disease in Korea. From January 1996 through December 2005, GBS cases (n= 157) diagnosed in blood, cerebrospinal fluid, or other sterile body fluids among infants <3 months of age from 14 university hospitals in Korea were identified. Age of onset, diagnosis, underlying medical conditions, and outcomes were investigated by reviewing the medical records. A total of 157 cases were identified during the study period. Of the cases, 32 were early-onset disease (EOD) and 125 were late-onset disease (LOD). Twenty-six of the EOD cases had symptoms during the first 24 h after birth. One hundred of the 157 GBS cases were diagnosed as meningitis. The mortality rate of EOD was 20.7%. The case fatality rate of LOD was 7.2% and 25.2% of LOD cases had sequelae. GBS is becoming an important cause of invasive neonatal infections in Korea, with LOD being more common. It may not be currently necessary to adopt the prevention guidelines of perinatal GBS disease in Korea. However, studies of maternal GBS carriage rates and neonatal GBS disease will continue.


Intracellular modulation of NMDA receptor function by antipsychotic drugs.
The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.


Selected SALM (synaptic adhesion-like molecule) family proteins regulate synapse formation.
Synaptic cell adhesion molecules regulate various steps of synapse formation. Despite the great diversity of neuronal synapses, relatively few adhesion molecules with synaptogenic activity have been identified. Synaptic adhesion-like molecules (SALMs) are members of a family of cell adhesion molecules known to regulate neurite outgrowth and synapse maturation; however, the role of SALMs in synapse formation remains unknown. We found that expression of the SALM family proteins SALM3 and SALM5 in nonneural and neural cells induces both excitatory and inhibitory presynaptic differentiation in contacting axons. SALM3 and SALM5 proteins are enriched in synaptic fractions, and form strong (SALM3) or weak (SALM5) complexes with postsynaptic density-95 (PSD-95), an abundant postsynaptic scaffolding protein at excitatory synapses. Aggregation of SALM3, but not SALM5, on dendritic surfaces induces clustering of PSD-95. Knockdown of SALM5 reduces the number and function of excitatory and inhibitory synapses. These results suggest that selected SALM family proteins regulate synapse formation, and that SALM3 and SALM5 may promote synapse formation through distinct mechanisms.


Coronary arterial vessels in relation to sudden cardiac death: a review.
To review literature on the coronary vascular factors related to the syndrome of sudden cardiac death. DATA SOURCE/SYNTHESIS: Major published articles and case reports on the nature of sudden cardiac death were searched electronically (Medline, Internet) and through hand scanning. Comparison of the different studies with regard to common themes was undertaken and consensus opinions highlighted. The aetiology of sudden cardiac death is diverse. Many conditions, hitherto considered benign, including coronary arterial anomalies and muscle bridges have been shown to cause sudden cardiac death. Coronary atherosclerosis, hypoplastic coronary vessels, coronary artery dissections are the commoner causes. The role of coronary arterial thrombi is controversial. The protective role of exercise is seriously questioned by the many reports of sudden cardiac death in long distance runners. Cases of sudden cardiac death are increasingly being reported. As a minimum, autopsy worksheets for cases of sudden death should include atherosclerosis, congenital coronary anomalies, tunneling of coronary vessels and hyposplastic vessels in addition to valvular and myocardial disorders.


Expert Opinion on Biological Treatment of Chronic Rhinosinusitis with Nasal Polyps in the Gulf Region.
Chronic rhinosinusitis (CRS) is defined as the inflammation of nose and paranasal sinuses, affecting the patients' quality of life and productivity. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a principal clinical entity confirmed by the existence of chronic sinonasal inflammation and is characterized by anterior or posterior rhinorrhea, nasal congestion, hyposmia and/or facial pressure or facial pain. Several epidemiologic studies have revealed wide variations in the incidence of CRS among regions globally ranging from 4.6% to 12%. The Gulf countries are also witnessing an unprecedented burden of CRSwNP. According to the current clinical guidelines, glucocorticosteroids and antibiotics are the principal pharmacotherapeutic approaches. Endoscopic sinus surgery is recommended for those who have failed maximal pharmacotherapy. Recently, biologics are considered as an alternative best approach due to the complications associated with medical therapy and surgery. However, precise data on the clinical position of biologic agents in the management of CRSwNP in the Gulf region is not available. The present review article addresses the current diagnostic and management approaches for CRSwNP and also emphasizes the role of emerging biologics in the current treatment strategies for CRSwNP in the Gulf region. Further, a consensus protocol was convened to rationalize the guideline recommendations, strategize the best practices with biologics, and develop clinical practice guidelines for all primary-care specialists in the Gulf region. The consensus-based report will be a useful reference tool for primary-care physicians in primary-healthcare settings, regarding the appropriate time for the initiation of biological treatment in the Gulf region.


Differential distribution of the KCl cotransporter KCC2 in thalamic relay and reticular nuclei.
In the thalamus of the rat the reversal potential of GABA-induced anion currents is more negative in relay cells than in neurones of the reticular nucleus (nRt) due to different chloride extrusion mechanisms operating in these cells. The distribution of KCl cotransporter type 2 (KCC2), the major neuronal chloride transporter that may underlie this effect, is unknown in the thalamus. In this study the precise regional and ultrastructural localization of KCC2 was examined in the thalamus using immunocytochemical methods. The neuropil of all relay nuclei was found to display intense KCC2 immunostaining to varying degrees. In sharp contrast, the majority of the nRt was negative for KCC2. In the anterior and dorsal part of the nRt, however, KCC2 immunostaining was similar to relay nuclei and parvalbumin and calretinin were found to colocalize with KCC2. At the ultrastructural level, KCC2 immunoreactivity was mainly located in the extrasynaptic membranes of thick and thin dendrites and the somata of relay cells but was also found in close association with asymmetrical synapses formed by cortical afferents. Quantitative evaluation of KCC2 distribution at the electron microscopic level demonstrated that the density of KCC2 did not correlate with dendritic diameter or synaptic coverage but is 1.7 times higher on perisynaptic membrane surfaces than on extrasynaptic membranes. Our data demonstrate that the regional distribution of KCC2 is compatible with the difference in GABA-A reversal potential between relay and reticular nuclei. At the ultrastructural level, abundant extrasynaptic KCC2 expression will probably play a role in the regulation of extrasynaptic GABA-A receptor-mediated inhibition.


A mathematical model for comparison of bolus injection, continuous infusion, and liposomal delivery of doxorubicin to tumor cells.
Determining the optimal mode of delivery for doxorubicin is important given the wide use of the drug against many tumor types. The relative performances of bolus injection, continuous infusion, liposomal and thermoliposomal delivery are not yet definitely established from clinical trials. Here, a mathematical model is used to compare bolus injection, continuous infusion for various durations, liposomal and thermoliposomal delivery of doxorubicin. Effects of the relatively slow rate, and saturability, of doxorubicin uptake by cells are included. Peak concentrations attained in tumor cells are predicted and used as a measure of antitumor effectiveness. To measure toxicity, plasma area under the curve (AUC) and peak plasma concentrations of free doxorubicin are computed. For continuous infusion, the duration of infusion significantly affects predicted outcome. The optimal infusion duration increases with dose, and is in the range 1 to 3 hours at typical doses. The simulations suggest that continuous infusion for optimal durations is superior to the other protocols. Nonthermosensitive liposomes approach the efficacy of continuous infusion only if they release drug at optimal rates. Predictions for thermosensitive liposomes indicate a potential advantage at some doses, but only if hyperthermia is applied locally so that the blood is not significantly heated.


Enhanced sensitivity of pancreatic cells to cholecystokinin octapeptide in obstructive jaundice.
Exocrine function of the pancreas in obstructive jaundice was examined using dogs. Jaundice induced by choledochal ligation over 3 weeks showed pancreatic hypersecretion in response to cholecystokinin octapeptide (CCK-8) stimulation. To clarify the mechanism of pancreatic hypersecretion in obstructive jaundice, three experiments were undertaken. In a perfusion experiment performed on isolated pancreas, hypersecretion in obstructive jaundice was observed in response to CCK-8 stimulation. An incubation experiment showed an increase in secretion in response to CCK-8 stimulation in a dose-dependent manner, producing a greater increase in dogs with obstructive jaundice than in controls, despite the fact that basal secretion in both groups was the same. This would suggest that at least one of the mechanisms of pancreatic hypersecretion in obstructive jaundice may be related to the degree of sensitivity of acinar cells to CCK-8. In morphological observation of acinar cells by electron microscopy, the average number of zymogen granules and total granular area per unit of cytoplasm in both groups before and after stimulation with CCK-8 were compared. There was no difference between the groups before stimulation. Following stimulation, values for the control group decreased but appeared to increase in the jaundiced pancreas. These results strongly suggest that pancreatic acinar cells in obstructive jaundice may retain their secretory potential after stimulation for 60 min, though the potential in nonjaundiced pancreatic acinar cells may decrease after stimulation.


Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis.
Clear cell carcinoma of the ovary is thought to arise from endometriosis. In addition, retrograde menstruation of shed endometrium is considered the origin of endometriosis. However, little evidence supports cellular continuity from uterine endometrium to clear cell carcinoma through endometriosis at the genomic level. Here, we performed multiregional whole-exome sequencing to clarify clonal relationships among uterine endometrium, ovarian endometriosis and ovarian clear cell carcinoma in a 56-year-old patient. Many somatic mutations including cancer-associated gene mutations in ARID1A, ATM, CDH4, NRAS and PIK3CA were shared among epithelium samples from uterine endometrium, endometriotic lesions distant from and adjacent to the carcinoma, and the carcinoma. The mutant allele frequencies of shared mutations increased from uterine endometrium to distant endometriosis, adjacent endometriosis, and carcinoma. Although a splice site mutation of ARID1A was shared among the four epithelium samples, a frameshift insertion in ARID1A was shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events at PIK3CA and ATM, were identified only in adjacent endometriosis and carcinoma, suggesting that mutant allele-specific imbalance is another key factor driving malignant transformation. By reconstructing a clonal evolution tree based on the somatic mutations, we showed that the epithelium samples were derived from a single ancestral clone. Although the study was limited to a single patient, the results from this illustrative case could suggest the possibility that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.


Palestinian nurses' knowledge, attitudes, and practices regarding enteral nutrition: Cross-sectional study.
Enteral nutrition support plays a key role in minimizing malnutrition in critically-ill patients, and its provision is originally a nurse's responsibility. Thus, nurses need to have a sufficient knowledge and a positive attitude with regard to enteral nutrition. In Palestine, literature regarding nurses' knowledge, practices, and attitudes of enteral nutrition is rare. This study aimed to investigate Palestinian nurses' knowledge, practices, and attitudes regarding enteral nutrition. Interview based pre-tested questionnaire was used during data collection procedure. Cronbach Alpha was also used to determine the reliability of knowledge, attitude and practice questionnaire. Descriptive statistics, independent t-test, and ANOVA were performed. A total of 325 registered nurses were involved in the final analysis. The mean of the knowledge score is (9.6 ± 2.8) out of 20. It was confirmed that sociodemographic characteristics has no influence on nutrition knowledge score among nurses. The findings also reveal that certain aspects of enteral nutrition practices were consistent with the current guidelines such as flushing the tube and backrest elevation. On the other hand, certain practices showed inconsistency and differences with international guidelines such as checking gastric residual volume. Results also showed that nurses attitudes were positive towards enteral nutrition. It was found that nurses' have inadequate knowledge regarding enteral nutrition. The findings also showed that enteral nutrition practices among nurses were somewhat incongruent with best current evidence. However, it was noted that they have positive attitudes towards enteral nutrition. Promoting research utilization is highly needed as well as establishing evidence-based guidelines.


MOF-Based Photocatalytic Membrane for Water Purification: A Review.
Photocatalytic membranes can effectively integrate membrane separation and photocatalytic degradation processes to provide an eco-friendly solution for efficient water purification. It is of great significance to develop highly efficient photocatalytic membranes driven by visible light to ensure the long-term stability of membrane separation systems and the maximum utilization of solar energy. Metal-organic framework (MOF) is an emerging photocatalyst with a well-defined structure and tunable chemical properties, showing a broad application prospect in the construction of high-performance photocatalytic membranes. Herein, this work provides a comprehensive review of recent advancements in MOF-based photocatalytic membranes. Initially, this work outlines the main tailoring strategies that facilitate the enhancement of the photocatalytic activity of MOF-based photocatalysts. Next, this work introduces commonly used methods for fabricating MOF-based photocatalytic membranes. Subsequently, this work discusses the application and mechanisms of MOF-based photocatalytic membranes toward organic pollutant degradation, metal ion removal, and membrane fouling mitigation. Finally, challenges in developing MOF-based photocatalytic membranes and their practical applications are presented, while also pointing out future research directions toward overcoming these existing limitations.


The Photosensitivity Localized in a Vitiliginous Lesion Was Associated with the Intramuscular Injections of Synthetic Progesterone during an In Vitro Fertilization-embryo Transfer.
The cutaneous diseases associated with progesterone are autoimmune progesterone dermatitis, erythema multiforme-like eruption, drug-induced progesterone dermatitis and solar urticaria. Estrogen and progesterone are widely used in oral contraceptives and hormone replacement therapies, and they are rarely known to cause a photosensitive reaction. The mechanism of contraceptive-induced photosensitivity is uncertain. Estrogen, rather than progesterone, in the combined oral contraceptive pill has been most frequently implicated in the induction of photosensitivity. A 32-year-old woman presented with an erythematous patch with an itching sensation on the centrofacial area of a residual vitiligious lesion. She had a history of being previously treated with narrow band UVB for 1 year. Her skin lesions had mostly subsided, but some lesions continued. She underwent an in vitro fertilization-embryo transfer 3 months previously, and she then took synthetic progesterone for 3 weeks starting at the 4th week of pregnancy. She was in good health with neither a family history of photosensitivity nor a personal history of any other drug ingestion or topical agent such as sunscreen in association with the beginning of her lesions. Phototesting revealed her to be markedly photosensitive in the UVB and UVA ranges. The intradermal skin reactions to progesterone combined with irradiation with UVA or UVB were positive. We report here on an unusual case of photosensitivity that was localized in a vitiliginous lesion, and this was associated with the intramuscular injections of synthetic progesterone that she had received during an in vitro fertilization-embryo transfer.


Detection, isolation and characterization of multiple lectins from the haemolymph of the cockroach Blaberus discoidalis.
Three agglutinins (lectins), designated BDL1, BDL2 and BDL3, were identified in the haemolymph of the cockroach Blaberus discoidalis by erythrocyte cross-adsorption and sugar inhibition tests. With the use of (NH4)2SO4 fractionation, anion-exchange and affinity chromatography, BDL1 and BDL2 have been purified to homogeneity, and BDL3 has been partially purified to three bands on SDS/PAGE. BDL1 has a molecular-mass estimate of 390 kDa by gel filtration and approx. 158 kDa by SDS/PAGE under non-reducing conditions, further reduced to subunits of 36 kDa under reducing conditions. BDL2 has a molecular mass of approx. 140 kDa and is composed of subunits of 67 kDa which can be further reduced to identical subunits of 23 kDa. Isoelectric focusing in agarose gels revealed that BDL1 and BDL2 both focused as single bands at pH 6.0 and pH 5.2 respectively. The purified forms of BDL1 and BDL2 were stained by the periodic acid/Schiff's reagent showing that both lectins are glycoproteins. In addition, BDL1 was deglycosylated by endo-beta-N-acetylglucosaminidase H. Immunological tests showed that these three lectins are not structurally related. All three lectins bind galactose but have different specificities for binding other sugars and for a range of vertebrate erythrocytes. BDL1 is specifically inhibited by D-(+)-glucose, D-(+)-mannose and N-acetyl-D-mannosamine, but not by N-acetyl-D-glucosamine, and BDL2 is inhibited by N-acetyl-D-glucosamine, but not by D-(+)-glucose, D-(+)-mannose or N-acetyl-D-mannosamine. BDL3 is strongly inhibited by N-acetyl-D-galactosamine, but not by any of the other above-mentioned sugars. Erythrocyte specificities showed that BDL1 is more specific for rabbit than mouse erythrocytes, whereas BDL2 and BDL3 are more specific for mouse than rabbit erythrocytes. The haemagglutinating activities of both the serum and isolated lectins are Ca(2+)-dependent. Localization of BDL1 and BDL2 with fluorescein isothiocyanate-labelled antibodies showed that both lectins are associated with the granules and other areas of the cytoplasm of all blood cell types.


Divergent mitochondrial respiratory chains in phototrophic relatives of apicomplexan parasites.
Four respiratory complexes and ATP-synthase represent central functional units in mitochondria. In some mitochondria and derived anaerobic organelles, a few or all of these respiratory complexes have been lost during evolution. We show that the respiratory chain of Chromera velia, a phototrophic relative of parasitic apicomplexans, lacks complexes I and III, making it a uniquely reduced aerobic mitochondrion. In Chromera, putative lactate:cytochrome c oxidoreductases are predicted to transfer electrons from lactate to cytochrome c, rendering complex III unnecessary. The mitochondrial genome of Chromera has the smallest known protein-coding capacity of all mitochondria, encoding just cox1 and cox3 on heterogeneous linear molecules. In contrast, another photosynthetic relative of apicomplexans, Vitrella brassicaformis, retains the same set of genes as apicomplexans and dinoflagellates (cox1, cox3, and cob).


Publication trends in the journal of cardiothoracic and vascular anesthesia: a 10-year analysis.
Good quality clinical research in anesthesiology is now performed all over the world. The aim of this article was to present and analyze the scientific contributions published in the Journal of Cardiothoracic and Vascular Anesthesia and to give a structured view focused on the countries where these studies were performed. Bibliometric analysis. Teaching hospital. None. The authors analyzed the geographic distribution of the authors publishing in cardiac anesthesia. Data were obtained from the Scopus database. All works belonging to document-type articles, reviews, letters, and editorials published over a 10-year period (2000-2009) in the Journal of Cardiothoracic and Vascular Anesthesia (JCVA) were tracked. For each article, the country of origin of the corresponding author was retrieved. JCVA published 1,816 articles from 45 different countries. The United States accounted for 43.8% of the total, followed by India (8.3%), Germany (5.5%), United Kingdom (4.7%), and Italy (4.4%). JCVA has a widespread influence and receives contributions from all over the world. More and more biomedical research is conducted outside North America and Europe, with India leading the group of "rest of the world" countries. The recent development of Asian countries clearly challenges North America and European countries that can no longer ignore the scientific contribution from these parts of the world. With this in mind, some journals such as JCVA are giving voice to these prolific countries, which represents a fundamental forum for these newcomers to the field of cardiac anesthesia.


Assays for the identification and prioritization of drug candidates for spinal muscular atrophy.
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder resulting in degeneration of α-motor neurons of the anterior horn and proximal muscle weakness. It is the leading cause of genetic mortality in children younger than 2 years. It affects ∼1 in 11,000 live births. In 95% of cases, SMA is caused by homozygous deletion of the SMN1 gene. In addition, all patients possess at least one copy of an almost identical gene called SMN2. A single point mutation in exon 7 of the SMN2 gene results in the production of low levels of full-length survival of motor neuron (SMN) protein at amounts insufficient to compensate for the loss of the SMN1 gene. Although no drug treatments are available for SMA, a number of drug discovery and development programs are ongoing, with several currently in clinical trials. This review describes the assays used to identify candidate drugs for SMA that modulate SMN2 gene expression by various means. Specifically, it discusses the use of high-throughput screening to identify candidate molecules from primary screens, as well as the technical aspects of a number of widely used secondary assays to assess SMN messenger ribonucleic acid (mRNA) and protein expression, localization, and function. Finally, it describes the process of iterative drug optimization utilized during preclinical SMA drug development to identify clinical candidates for testing in human clinical trials.


Recognition of time-compressed high- and low-predictability sentences by normal subjects.
Recall accuracy for time-compressed real sentences varying in contextual redundancy was documented on 12 normal-hearing young adults. Ss were required to identify the final word (key word) of uncompressed and 60% time-compressed high-predictability (HP) and low-predictability (LP) sentences of the SPIN test sentences. Time compression was more detrimental for the perception of LP sentences than for HP items, suggesting that especially under conditions of temporal stress normal Ss rely upon the linguistic and semantic information contained within real sentences.


Traveling wave solutions of a nerve conduction equation.
We consider a pair of differential equations whose solutions exhibit the qualitative properties of nerve conduction, yet which are simple enough to be solved exactly and explicitly. The equations are of the FitzHugh-Nagumo type, with a piecewise linear nonlinearity, and they contain two parameters. All the pulse and periodic solutions, and their propagation speeds, are found for these equations, and the stability of the solutions is analyzed. For certain parameter values, there are two different pulse-shaped waves with different propagation speeds. The slower pulse is shown to be unstable and the faster one to be stable, confirming conjectures which have been made before for other nerve conduction equations. Two periodic waves, representing trains of propagated impulses, are also found for each period greater than some minimum which depends on the parameters. The slower train is unstable and the faster one is usually stable, although in some cases both are unstable.


CO2 Hydrogenation Catalyzed by Iridium Complexes with a Proton-Responsive Ligand.
The catalytic cycle for the production of formic acid by CO2 hydrogenation and the reverse reaction have received renewed attention because they are viewed as offering a viable scheme for hydrogen storage and release. In this Forum Article, CO2 hydrogenation catalyzed by iridium complexes bearing sophisticated N^N-bidentate ligands is reported. We describe how a ligand containing hydroxy groups as proton-responsive substituents enhances the catalytic performance by an electronic effect of the oxyanions and a pendent-base effect through secondary coordination sphere interactions. In particular, [(Cp*IrCl)2(TH2BPM)]Cl2 (Cp* = pentamethylcyclopentadienyl; TH2BPM = 4,4',6,6'-tetrahydroxy-2,2'-bipyrimidine) enormously promotes the catalytic hydrogenation of CO2 in basic water by these synergistic effects under atmospheric pressure and at room temperature. Additionally, newly designed complexes with azole-type ligands were applied to CO2 hydrogenation. The catalytic efficiencies of the azole-type complexes were much higher than that of the unsubstituted bipyridine complex [Cp*Ir(bpy)(OH2)]SO4. Furthermore, the introduction of one or more hydroxy groups into ligands such as 2-pyrazolyl-6-hydroxypyridine, 2-pyrazolyl-4,6-dihydroxypyrimidine, and 4-pyrazolyl-2,6-dihydroxypyrimidine enhanced the catalytic activity. It is clear that the incorporation of additional electron-donating functionalities into proton-responsive azole-type ligands is effective for promoting further enhanced hydrogenation of CO2.


Bilateral Occlusion Reduces the Ocular Deviation in Intermittent Exotropia.
The most common form of strabismus, intermittent exotropia, is thought to become manifest when the drive to fuse is overcome by excessive divergent muscle tone. This principle is tested by examining the alignment of the eyes in the absence of vision. We compare the ocular deviation in patients with intermittent exotropia under conditions of monocular versus binocular occlusion. This prospective study of a patient cohort referred to our laboratory enrolled 18 patients with typical findings of well-controlled intermittent exotropia. Eye positions were recorded with video eye trackers while patients looked at a fixation spot at a distance of 57 cm. One eye was occluded, and the resulting ocular deviation was measured. Both eyes were then occluded, and the ocular deviation was re-measured. The majority of patients (11/18) had a smaller deviation when both eyes were covered. Occlusion of one eye resulted in a mean exotropia of 13.5° ± 4.7°. Occlusion of both eyes reduced the mean exotropia to 6.0° ± 6.5° (paired t-test, P < 0.001), corresponding to a 56% reduction in the ocular deviation. This reduction persisted during prolonged bilateral occlusion but reversed as soon as vision was restored. Bilateral occlusion reveals a fixation-free state of alignment that is different from orthotropia and usually less than the exotropia that occurs spontaneously during binocular viewing. This finding demonstrates that the deviation angle in patients with intermittent exotropia is actively mediated by visual feedback, which the fixating eye is capable of providing alone.


The effect of denervated muscle and Schwann cells on axon collateral sprouting.
The effects of denervated muscle and Schwann cells on collateral sprouting from peripheral nerve were studied in the peroneal and tibial nerves of 48 Sprague-Dawley rats. Three groups were prepared. In group MSW (muscle-Schwann cell-window), the peroneal nerves were transected 3 mm below the sciatic bifurcation. The proximal stumps were sealed in a blocked tube to prevent regeneration and the distal stumps were implanted into denervated muscle cells that were wrapped around the ipsilateral tibial nerve, which had a window of perineurium resected. Schwann cells from the ipsilateral sural nerve were implanted into the muscle. Group MS (muscle-Schwann cell) was similar to group MSW, except that the tibial nerve perineurium was kept intact. In group MW (muscle-window), the muscle was prepared without Schwann cells and the tibial nerve perineurium was windowed. S-100 immunostain was used to identify the Schwann cells surviving 1 week after transplantation. After 16 weeks of regeneration, horseradish peroxidase tracer was used to label motor neurons and sensory neurons reinnervating the peroneal nerve. Myelinated axons of the reinnervated peroneal nerves were quantified with the Bioquant OS/2 computer system (R&M Biometrics, Nashville, TN). A mean of 169 motor neurons in group MSW, 64 in group MW, and 26 in group MS reinnervated the peroneal nerve. In the dorsal root ganglion, the mean number of labeled sensory neurons was 1,283 in group MSW, 947 in group MS, and 615 in group MW. The mean number of myelinated axons in the reinnervated peroneal nerve was 1,659 in group MSW, 359 in group MS, and 348 in group MW. Reinnervated anterolateral compartment muscles in group MSW were significantly heavier than those in group MS or MW. This study demonstrates that the transplantation of denervated muscle and Schwann cells promotes motor and sensory nerve collateral sprouting through a perineurial window.


Modulation of NMDA-induced currents by mu-opioid receptor agonist DAGO in acutely isolated rat spinal dorsal horn neurons.
The whole-cell patch-clamp technique was used to examine effects of mu-opioid receptor agonist Tyr-D-Ala-Gly-Me-Phe-Gly-ol-enkephalin (DAGO) on N-methyl-D-aspartate (NMDA)-induced currents in freshly enzymatically and/or mechanically dissociated rat spinal dorsal horn neurons (laminae I-III). Here we report that the responses of dorsal horn neurons to NMDA were modulated by DAGO in a complex manner. When applied simultaneously with, or prior to NMDA, DAGO (10-100 nM) initially suppressed the response to NMDA in 52% of examined cells. Following removal of DAGO, the NMDA responses were potentiated in 71% of the cells. The enhancing effect of DAGO was rapid in onset and lasted up to 50 min after removal of the peptide. Both the initial depressant and the late enhancing effect were reversed by naloxone. These results are consistent with the possibility that DAGO might directly modulate the NMDA receptor-ion channel complex and that this action may contribute to the regulation of the strength of excitatory amino acid-mediated primary afferent neurotransmission, including nociception.


Complex emergencies in Indonesia.
Recently, Indonesia has experienced six major provincial, civil, armed conflicts. Underlying causes include the transmigration policy, sectarian disputes, the Asian economic crisis, fall of authoritarian rule, and a backlash against civil and military abuses. The public health impact involves the displacement nationwide of > 1.2 million persons. Violence in the Malukus, Timor, and Kalimantan has sparked the greatest population movements such that five provinces in Indonesia each now harbor > 100,000 internally displaced persons. With a background of government instability, hyperinflation, macroeconomic collapse, and elusive political solutions, these civil armed conflicts are ripe for persistence as complex emergencies. Indonesia has made substantial progress in domestic disaster management with the establishment of central administrative authority, strategic planning, and training programs. Nevertheless, the Indonesian experience reveals recurrent issues in international humanitarian health assistance. Clinical care remains complicated by absences of treatment protocols, inappropriate drug use, high procedural complication rates, and variable referral practices. Epidemiological surveillance remains complicated by unsettled clinical case definitions, non-standardized case management of diseases with epidemic potential, variable outbreak management protocols, and inadequate epidemiological analytic capacity. International donor support has been semi-selective, insufficient, and late. The militia murders of three UN staff in West Timor prompted the withdrawal of UN international staff from West Timor for nearly a year to date. Re-establishing rules of engagement for humanitarian health workers must address security, public health, and clinical threats.


Ethnic differences in antenatal care use in a large multi-ethnic urban population in the Netherlands.
to determine differences in antenatal care use between the native population and different ethnic minority groups in the Netherlands. the Generation R Study is a multi-ethnic population-based prospective cohort study. seven midwife practices participating in the Generation R Study conducted in the city of Rotterdam. in total 2093 pregnant women with a Dutch, Moroccan, Turkish, Cape Verdean, Antillean, Surinamese-Creole and Surinamese-Hindustani background were included in this study. to assess adequate antenatal care use, we constructed an index, including two indicators; gestational age at first visit and total number of antenatal care visits. Logistic regression analysis was used to assess differences in adequate antenatal care use between different ethnic groups and a Dutch reference group, taking into account differences in maternal age, gravidity and parity. overall, the percentages of women making adequate use are higher in nulliparae than in multiparae, except in Dutch women where no differences are present. Except for the Surinamese-Hindustani, all women from ethnic minority groups make less adequate use as compared to the native Dutch women, especially because of late entry in antenatal care. When taking into account potential explanatory factors such as maternal age, gravidity and parity, differences remain significant, except for Cape-Verdian women. Dutch-Antillean, Moroccan and Surinamese-Creole women exhibit most inadequate use of antenatal care. this study shows that there are ethnic differences in the frequency of adequate use of antenatal care, which cannot be attributed to differences in maternal age, gravidity and parity. Future research is necessary to investigate whether these differences can be explained by socio-economic and cultural factors. clinicians should inform primiparous women, and especially those from ethnic minority groups, on the importance of timely antenatal care entry.


Academia's Big Five: a normative taxonomy for the epistemic responsibilities of universities.
This paper proposes a normative taxonomy by which universities can express the extent to which they meet five core epistemic responsibilities. Epistemic responsibilities are responsibilities that have to do with the attainment of knowledge and understanding. The core epistemic responsibilities, which we call the Big Five, are to (1) foster research integrity, (2) teach for intellectual virtue, (3) address the big questions of life, (4) give humanistic inquiry and education a proper place, and (5) serve society. The paper characterizes the Big Five in some detail and explains why they are core epistemic responsibilities of universities. The paper concludes by describing the steps that should be taken in order to test, amend, and implement the taxonomy.


Plant oils thymol and eugenol affect cattle and swine waste emissions differently.
Wastes generated from the production of cattle and swine in confined facilities create the potential for surface and groundwater pollution, emission of greenhouse gases, transmission of pathogens to food and water sources, and odor. It is our hypothesis that something which inhibits microbial fermentation in livestock wastes will be beneficial to solving some of the environmental problems. Our work has concentrated on the use of antimicrobial plant oils, thymol, thyme oil, carvacrol, eugenol and clove oil. Anaerobic one-litre flasks with a working volume of 0.5 L cattle or swine manure were used to evaluate the effect of thymol and eugenol on production of fermentation gas, short-chain volatile fatty acids, lactate, and bacterial populations. Either oil at 0.2% in both wastes essentially stopped all production of gas and volatile fatty acids, and eliminated all fecal coliform bacteria. In cattle but not swine waste, thymol prevented the accumulation of lactate. However, eugenol stimulated lactate formation in cattle and swine wastes. Thus, eugenol may offer a distinct advantage over thymol, because lactate accumulation in the wastes causes the pH to drop more rapidly, further inhibiting microbial activity and nutrient emissions. We conclude that plant oils may offer solutions to controlling various environmental problems associated with livestock wastes, assuming that they are cost-effective.


Protective role for club cell secretory protein-16 (CC16) in the development of COPD.
Club cell secretory protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (WT) and CC16(-/-)mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16(-/-) mice had greater CS-induced emphysema, airway remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NF-κB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-κB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.


Selenium oxyanion bioconcentration in natural freshwater periphyton.
Selenium (Se) enrichment has been demonstrated to vary by several orders of magnitude among species of planktonic algae. This is a substantial source of uncertainty when modelling Se biodynamics in aquatic systems. In addition, Se bioconcentration data are largely lacking for periphytic species of algae, and for multi-species periphyton biofilms, adding to the challenge of modelling Se transfer in periphyton-based food webs. To better predict Se dynamics in periphyton dominated, freshwater ecosystems, the goal of this study was to assess the relative influence of periphyton community composition on the uptake of waterborne Se oxyanions. Naturally grown freshwater periphyton communities, sampled from five different water bodies, were exposed to environmentally relevant concentrations of selenite [Se(IV)] or selenate [Se(VI)] (nominal concentrations of 5 and 25 μg Se L-1) under similar, controlled laboratory conditions for a period of 8 days. Unique periphyton assemblages were derived from the five different field sites, as confirmed by light microscopy and targeted DNA sequencing of the plastid 23S rRNA gene in algae. Selenium accumulation demonstrated a maximum of 23.6-fold difference for Se(IV) enrichment and 2.1-fold difference for Se(VI) enrichment across the periphyton/biofilm assemblages tested. The assemblage from one field site demonstrated both high accumulation of Se(IV) and iron, and was subjected to additional experimentation to elucidate the mechanism(s) of Se accumulation. Selenite accumulation (at nominal concentrations of 5 and 25 μg Se L-1 and mean pH of 7.5 across all treatment replicates) was assessed in both unaltered and heat-killed periphyton, and in periphyton from the same site grown without light to exclude phototrophic organisms. Following an exposure length of 8 days, all periphyton treatments showed similar levels of Se accumulation, indicating that much of the apparent uptake of Se(IV) was due to non-biological processes (i.e., surface adsorption). The results of this study will help reduce uncertainty in the prediction of Se dynamics and food-chain transfer in freshwater environments. Further exploration of the ecological consequences of extracellular adsorption of Se(IV) to periphyton, rather than intracellular absorption, is recommended to further refine predictions related to Se biodynamics in freshwater food webs.


Prospect of immunotherapy combined with anti-angiogenic agents in patients with advanced non-small cell lung cancer.
In the latest years, some drugs have been approved by European Medicines Agency (EMA) and/or the US Food and Drug Administration (FDA) for the treatment of patients with advanced non-small cell lung cancer (NSCLC), particularly for the treatment of those who have no targeted gene mutations or who have progressed on previously targeted therapy or platinum-containing dual-agent chemotherapy. In general, these drugs fall into two categories: anti-angiogenic agents and immune checkpoint inhibitors (ICIs). Anti-angiogenic agents currently approved by the FDA and/or EMA for advanced NSCLC treatment include bevacizumab, nintedanib, and ramucirumab. Anlotinib has been approved in advanced NSCLC by Chinese Food and Drug Administration (CFDA). These anti-angiogenic agents can induce anti-angiogenesis by targeting vascular endothelial growth factor (VEGF)/VEGF2 or inhibiting multiple small molecules involved in angiogenic and proliferative pathways such as platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs). Although these drugs show significant therapeutic efficacy, most patients inevitably experience disease progression resulting in death. ICIs approved by the FDA and/or EMA for advanced NSCLC treatment include nivolumab, pembrolizumab, and atezolizumab. These ICIs can significantly improve efficacy compared with standard chemotherapy by targeting programmed cell death protein 1 (PD-1) receptor or PD-2 receptor with longer response duration and acceptable toxicity. However, the response rate of ICIs is suboptimal, and only a few patients ultimately benefit from immunotherapy. So current efforts have focused on exploring new potential combinatorial strategies with synergistic antitumor activity. Here, we summarized the theoretical basis, current clinical data, and potential future perspective of immunotherapy combined with anti-angiogenic agents for advanced NSCLC.


Muscarinic blockade inhibits gastric emptying of mixed-nutrient meal: effects of weight and gender.
We compared the vagal contribution to gastric emptying in lean and obese subjects by monitoring gastric emptying of a meal during muscarinic blockade. Lean (n = 6) and obese subjects (n = 6) underwent two treatments: 1) saline infusion and 2) atropine infusion [0.4 mg/m2 bolus, 0.4 mg. (m2)-1. h-1] for 2 h, initiated 30 min before ingestion of a 600-kcal breakfast (64% carbohydrate, 23% fat, 13% protein) composed of orange juice (labeled with Indium-111), egg sandwich (labeled with Technetium-99m), cereal, milk, and banana. Anterior and posterior images were taken every 90 s for 90 min using a dual-headed camera. Atropine significantly delayed emptying of both solid (P < 0.007) and liquid (P < 0.002). Obese subjects exhibited a greater delay in liquid emptying during muscarinic blockade compared with lean subjects (P < 0.02). Female subjects exhibited a slower rate of gastric emptying and were less sensitive to atropine. These data suggest that obese subjects exhibit altered gastric cholinergic activity compared with lean subjects and that gender differences in gastric emptying rate may be due to differences in autonomic tone.