[Anatomy and physiology of the liver secretory apparatus].
Bile secretion by the liver is thoroughly reviewed on its histologic and functional aspects. Regarding biliary flux, it is quantified as dependent or independent from bile acids. The mechanisms of excretion of other compounds like organic anions, cholesterol and phospholipids, are described. Such aspects allow the classification of intrahepatic cholestasis, based on their mechanisms, which can encompass the following: 1) decreased bile acid synthesis; 2) qualitative changes of bile acids; 3) enzymatic changes of the canalicular membrane; 4) changes in the permeability of the canalicular membrane; 5) dysfunction of the contractile microfilaments of the hepatocyte.


The replication of type A influenza viruses in the infant rat: a marker for virus attenuation.
Twenty recombinant influenza virus strains bearing HSw1N1, H1N1 or H3N2 surface antigens, together with their respective wild-type or laboratory-propagated parent viruses, were inoculated into 2 day-old infant rats and their replication in the turbinates and lungs of these animals observed over a period of 5 days. In addition, the ability of each of the recombinant and parent viruses to enhance a subsequent infection of these infant rats by Haemophilus influenzae type b was determined. The results showed that both parent and recombinant viruses replicated less well in the lungs than in the turbinates of infant rats, but the titres in both tissues were generally lower for the recombinant strains. The capacity of the majority of the recombinant influenza viruses to promote bacterial infection of the infant rats, as determined by the incidence of H. influenzae bacteraemia and meningitis, was also markedly less than that of their parent viruses. A correlation between virulence for man and both the replication in infant rat turbinates and the ability to enhance H. influenzae infection, was established for the virus strains studied. The data are discussed in relationship to the value of the infant r-H influenzae system as a laboratory marker for the determination of the virulence of influenza virus strains.


Expression of pro- and antiapoptotic molecules of the Bcl-2 family in human islets postisolation.
Human islets are subjected to a number of stresses before and during their isolation that may influence their survival and engraftment after transplantation. Apoptosis is likely to be activated in response to these stresses. Apoptosis due to intrinsic stresses is regulated by pro- and antiapoptotic members of the Bcl-2 family. While the role of the Bcl-2 family in apoptosis of rodent islets is becoming increasingly understood, little is known about which of these molecules are expressed or required for apoptosis of human islets. This study investigated the expression of the Bcl-2 family of molecules in isolated human islets. RNA and protein lysates were extracted from human islets immediately postisolation. At the same time, standard quality control assays including viability staining and β-cell content were performed on each islet preparation. Microarrays, RT-PCR, and Western blotting were performed on islet RNA and protein. The prosurvival molecules Bcl-xl and Mcl-1, but not Bcl-2, were highly expressed. The multidomain proapoptotic effector molecule Bax was expressed at higher levels than Bak. Proapoptotic BH3-only molecules were expressed at low levels, with Bid being the most abundant. The proapoptotic molecules BNIP3, BNIP3L, and Beclin-1 were all highly expressed, indicating exposure of islets to oxygen and nutrient deprivation during isolation. Our data provide a comprehensive analysis of expression levels of pro- and antiapoptotic Bcl-2 family members in isolated human islets. Knowledge of which molecules are expressed will guide future research to understand the apoptotic pathways activated during isolation or after transplantation. This is crucial for the design of methods to achieve improved transplantation outcomes.


The value of fluorescence in situ hybridization for the detection of 11q in multiple myeloma.
A large number of chromosomal abnormalities have been detected in multiple myeloma (MM). The most frequent are chromosome 13q deletions and translocations affecting the immunoglobulin heavy chain gene (IGH). Recent studies using comparative genomic hybridization (CGH) have shown that gains of 11q represent one of the most frequent genomic changes in MM. However CGH is not generally used in routine clinical laboratories. In the present study, efficiency of fluorescent in situ analysis (FIS)H analysis in the detection of 11q abnormalities in MM patients was investigated. Cytogenetic and FISH studies with three different specific probes for the regions containing the genes BCL1 (11q13), ATM (11q22) and MLL (11q23) were simultaneously performed in 52 patients: 9 cases with 11q abnormalities detected by conventional cytogenetics and 43 cases without 11q abnormalities. FISH analysis identified 11q aberrations that were undetected by cytogenetics in 16 out the 43 cases (37%). Gains on 11q were present in 13 cases (30%) while rearrangements on 11q were observed in the remaining 3 cases. No losses were found. All 11q gains involved the three regions analyzed (BCL1, ATM and MLL genes) while only rearrangements of BCL1 were observed. In all control cases the 11q alterations were confirmed by FISH. A good overall correlation between CGH and FISH was observed. Nevertheless gains on BCL1, ATM and MLL genes were observed in 3 cases displaying a normal CGH. In summary, chromosomal abnormalities on 11q are frequent in MM. FISH studies demonstrate a high sensitivity at detecting this abnormality and should be used in the routine evaluation of MM.


Evaluation of a generic brief acculturation scale in a sample of male enlisted naval personnel.
This study examined the reliability and validity of the 3-item Generic Brief Acculturation Scale (GBAS). The GBAS was administered as a part of a larger Navy Health Behavior Survey of male enlisted personnel deployed on aircraft carriers. Analyses are reported here for the subsample for whom English was a second language (n = 529, 15% of original sample). Generic Brief Acculturation Scale reliability was assessed with internal consistency. Validity was assessed using t test and correlation. Results supported reliability and validity: Cronbach alpha was .81, mean GBAS scores for US-born participants were significantly higher than that for foreign born (P < .05), and GBAS scores were positively correlated with generation (r = 0.34). Additional research with civilian populations is needed, but these findings suggest that the GBAS could be useful either as a quick screen in clinical practice to determine when a translator may be needed or to guide decision making regarding health promotion programming.


Chromosome-scale genome assembly of the 'Munstead' cultivar of Lavandula angustifolia.
Lavandula angustifolia (English lavender) is commercially important not only as an ornamental species but also as a major source of fragrances. To better understand the genomic basis of chemical diversity in lavender, we sequenced, assembled, and annotated the 'Munstead' cultivar of L. angustifolia. A total of 80 Gb of Oxford Nanopore Technologies reads was used to assemble the 'Munstead' genome using the Canu genome assembler software. Following multiple rounds of error correction and scaffolding using Hi-C data, the final chromosome-scale assembly represents 795,075,733 bp across 25 chromosomes with an N50 scaffold length of 31,371,815 bp. Benchmarking Universal Single Copy Orthologs analysis revealed 98.0% complete orthologs, indicative of a high-quality assembly representative of genic space. Annotation of protein-coding sequences revealed 58,702 high-confidence genes encoding 88,528 gene models. Access to the 'Munstead' genome will permit comparative analyses within and among lavender accessions and provides a pivotal species for comparative analyses within Lamiaceae.


Associations Between Dietary Energy Density in Mothers and Growth of Breastfeeding Infants During the First 4 Months of Life.
Objectives: Despite the overwhelming impact of dietary energy density on the quality of the entire diet, no research has investigated dietary energy density among lactating mothers. Hence, the present study was undertaken to assess the influence of maternal dietary energy density during lactation on infant growth.Method: Three hundred healthy lactating mother-infant pairs were enrolled in the study. Detailed demographic information and dietary intake data were collected from the lactating mothers. Anthropometric features such as infant weight, height, and head circumference at birth and 2 and 4 months and mother's pregnancy and postpartum weight and height were derived from health center records. Data on physical activity were reported using the International Physical Activity Questionnaire.Results: After adjusting for confounding variables, infant weight, length, weight-for-height, and head circumference at birth, 2 months, and 4 months did not show significant differences among four dietary energy density categories (all p values > 0.01).Conclusions: Our study showed no association among quartiles of dietary energy density among lactating mothers and infant weight, length, weight-for-height, and head circumference growth by 2 and 4 months of age.


RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye.
Macroautophagy/autophagy is an intracellular stress survival and recycling system whereas phagocytosis internalizes material from the extracellular milieu; yet, both pathways utilize lysosomes for cargo degradation. Whereas autophagy occurs in all cells, phagocytosis is performed by cell types such as macrophages and the retinal pigment epithelial (RPE) cells of the eye where it is supported by the noncanonical autophagy process termed LC3-associated phagocytosis (LAP). Autophagy and LAP are distinct pathways that use many of the same mediators and must compete for cellular resources, suggesting that cells may regulate both processes under homeostatic and stress conditions. Our data reveal that RPE cells promote LAP through the expression of RUBCN/Rubicon (RUN domain and cysteine-rich domain containing Beclin 1-interacting protein) and suppress autophagy through the activation of EGFR (epidermal growth factor receptor). In the morning when photoreceptor outer segments (POS) phagocytosis and LAP are highest, RUBCN expression is increased. At the same time, outer segment phagocytosis activates the EGFR resulting in MTOR (mechanistic target of rapamycin [serine/threonine kinase]) stimulation, the accumulation of SQSTM1/p62, and the phosphorylation of BECN1 (Beclin 1, autophagy related) on an inhibitory residue thereby suppressing autophagy. Silencing Rubcn, preventing EGFR activity or directly inducing autophagy in RPE cells by starvation inhibits phagocytic degradation of POS. Thus, RPE cells regulate lysosomal pathways during the critical period of POS phagocytosis to support retinal homeostasis.


Simultaneous multiplane in vivo nonlinear microscopy using spectral encoding.
Conventional point-by-point imaging schemes for laser scanning microscopy limit acquisition speeds, particularly when imaging three-dimensional volumes. We report a novel approach that achieves parallelization of multiple fields of view through the use of spectral encoding. By focusing two or more beams of different wavelengths at different positions within a suitable tissue, fluorescence or second/third harmonic generation emissions from these regions can be uniquely separated. We demonstrate that this approach can allow simultaneous in vivo imaging of fluorescence in two planes within the living rodent cortex, and of second harmonic generation in fresh tissue.


Surfactant and Plasticizer Segregation in Thin Poly(vinyl alcohol) Films.
The vertical depth distributions of individual additive components [cetyltrimethylammonium bromide (CTAB), deuterated pentaethylene glycol monododecyl ether (d25-C12E5), and deuterated glycerol (d-glycerol)] in PVA films have been isolated and explored by ion beam analysis techniques and neutron reflectometry. The additives display an unexpectedly rich variety of surface and interfacial behaviors in spin-cast films. In separate binary films with PVA, both d-glycerol and CTAB were evenly distributed, whereas d25-C12E5 showed clear evidence for surface and interfacial segregation. The behavior of each surfactant in PVA was reversed when the plasticizer (glycerol) was also incorporated into the films. With increasing plasticizer content, the surface activity of d25-C12E5 systematically decreased, but remarkably, when glycerol and CTAB were present in PVA, the surface and interfacial activities of CTAB increased dramatically in the presence of glycerol. Quantification of the surface excess by ion beam analysis revealed that, in many cases, the adsorbed quantity far exceeded what could reasonably be explained by a single layer, thus indicating a wetting transition of the small molecules at the surface or interface of the film. It appears that the surface and interfacial behaviors are partly driven by the relative surface energies of the components, but are also significantly augmented by the incompatibility of the components.


The interactions between the activatory guanine nucleotide binding protein and the catalytic subunit of adenylate cyclase in rat liver plasma membranes.
Three GTP-binding proteins of 50 kDa, 45 kDa and 28 kDa were identified by photoaffinity labelling with [gamma-32P]GTP-gamma-azidoanilide (A-GTP) in the rat liver plasma membrane. Pertussis toxin catalysed ADP-ribosylation of a single protein of 40 kDa. A-GTP had no effect on the basal labeling by pertussis toxin. After u.v. irradiation of the membrane in the presence of A-GTP, the GTP-dependent ADP-ribosylation by cholera toxin was increased, while the basal labelling was not affected. These results suggest that A-GTP interacts specifically with the activatory GTP-binding protein (Gs) and does not interact with the inhibitory GTP-binding protein (Gi). The effects of partial photoinactivation of Gs of the rat liver plasma membrane adenylate cyclase system by A-GTP were studied. U.v. irradiation in the presence of increasing concentrations of the analogue caused progressive decrease in the maximal extent of activation by guanosine 5'-[gamma-thio]triphosphate, but the Ka was not affected. The rate of activation of liver adenylate cyclase by guanosine 5'-[gamma-thio]triphosphate is temperature-dependent. The lag time increased from 0.5 min at 30 degrees C to 2.0-2.5 min at 15 degrees C in the presence of 10 microM-guanosine 5'-[gamma-thio]triphosphate. However, Ka remains unaffected by lowering the temperature. Photoinactivation by A-GTP or competitive inhibition by guanosine 5'-[beta-thio]diphosphate decreases the maximal extent of activation by guanosine 5'-[gamma-thio] triphosphate, but the lag time remains unaffected. The present results support the idea that Gs is tightly associated with the catalytic subunit under basal conditions. The present results also indicate that the transition of an inactive Gs to its active form is the rate-limiting step of the activation of adenylate cyclase by guanosine 5'-[gamma-thio]triphosphate in the intact rat liver plasma membranes.


Mutations from a family-shuffling-library reveal amino acid residues responsible for the thermostability of endoglucanase CelA from Clostridium thermocellum.
We constructed a library of chimeras from the major endoglucanase, CelA, of Clostridium thermocellum and a less stable endoglucanase CelB from Clostridium josui with multiple point mutations using low-fidelity family-shuffling method. Mutations that inactivated the enzyme were rapidly eliminated with high-throughput screening. The activities and thermostabilities of selected variants were evaluated, and four amino acid substitutions, K249R, P258S, S329N and E355G, were identified as having significant impact on the thermostability of CelA without affecting enzymatic activity. In the crystal structure of CelA, most of them are away from the activity cleft and are responsible for the stabilization of secondary structures.


Population genetics of Collisella subrugosa (Patellogastropoda: Acmaeidae): evidence of two scales of population structure.
Marine invertebrate populations usually show high levels of genetic variability that has frequently been associated with spatial and temporal environmental heterogeneity. One of the most heterogeneous marine environments is the intertidal zone, the habitat of Collisella subrugosa, the most widespread and abundant Brazilian limpet. C. subrugosa has planktonic larvae that can disperse over long distances, what can promote gene flow among shores, working against interpopulational differentiation. In this study we investigated the genetic variability and populational substructure of C. subrugosa through analysis of 24 allozyme loci in 14 samples (590 individuals) collected along 2,700 km of the Brazilian coast. The genetic variability was high ([Formula: see text] and [Formula: see text]), as expected for intertidal species. Genetic differentiation among samples was low (F (ST) = 0.03) what may reflect intensive gene flow associated with larval dispersal. However, we detected an isolation-by-distance pattern of population substructure in one sampled region. High levels of heterozygote deficiency were also observed for many loci in each sample. Alternative hypothesis are discussed, and the "breeding groups" is suggested to explain these pattern, indicating the main cause as environmental heterogeneity.


Developmental models for estimating ecological responses to environmental variability: structural, parametric, and experimental issues.
Developmental models that account for the metabolic effect of temperature variability on poikilotherms, such as degree-day models, have been widely used to study organism emergence, range and development, particularly in agricultural and vector-borne disease contexts. Though simple and easy to use, structural and parametric issues can influence the outputs of such models, often substantially. Because the underlying assumptions and limitations of these models have rarely been considered, this paper reviews the structural, parametric, and experimental issues that arise when using degree-day models, including the implications of particular structural or parametric choices, as well as assumptions that underlie commonly used models. Linear and non-linear developmental functions are compared, as are common methods used to incorporate temperature thresholds and calculate daily degree-days. Substantial differences in predicted emergence time arose when using linear versus non-linear developmental functions to model the emergence time in a model organism. The optimal method for calculating degree-days depends upon where key temperature threshold parameters fall relative to the daily minimum and maximum temperatures, as well as the shape of the daily temperature curve. No method is shown to be universally superior, though one commonly used method, the daily average method, consistently provides accurate results. The sensitivity of model projections to these methodological issues highlights the need to make structural and parametric selections based on a careful consideration of the specific biological response of the organism under study, and the specific temperature conditions of the geographic regions of interest. When degree-day model limitations are considered and model assumptions met, the models can be a powerful tool for studying temperature-dependent development.


Twisted amide electrophiles enable cyclic peptide sequencing.
There is an ever-increasing interest in synthetic methods that not only enable peptide macrocyclization, but also facilitate downstream application of the synthesized molecules. We have found that aziridine amides are stereoelectronically attenuated in a macrocyclic environment such that non-specific interactions with biological nucleophiles are reduced or even shut down. The electrophilic reactivity, revealed at high pH, enables peptide sequencing by mass spectrometry, which will further broaden the utility of aziridine amide-containing libraries of macrocycles.


Circannual changes in free thyroxine, prolactin, testes, and relative food intake in woodchucks, Marmota monax.
Woodchucks (n = 12-14/group) with circannual cycles entrained to northern versus southern hemisphere photoperiods were assessed monthly for 16 mo. Changes in serum total triiodothyronine (TT(3)), free thyroxine (T(4)), total thyroxine (TT(4)), and prolactin were determined in a subset of five animals per group. Metabolic hormone results were examined in relation to changes in body weight, food intake, and serum testosterone (n = 12-14/group). Seasonal changes in each parameter were similar in both groups as were nadir and peak TT(3) (162 +/- 6 and 392 +/- 12 ng/ml, respectively), free T(4) (19 +/- 2 and 86 +/- 7 ng/ml, repectively), TT(4) (3.2 +/- 0.2 and 8.0 +/- 0.5 ng/ml, respectively), and prolactin (0.6 +/- 0.1 and 14 +/- 2 ng/ml, respectively). In late winter and early spring, simultaneous increases in both free T(4) and prolactin were associated with 1) a large increase in food intake, 2) a decline in body weight to nadir values, 3) a corresponding negative energy balance, 4) a peak and decline in serum testosterone, and 5) a modest increase in TT(4) and large decline in serum TT(3). Low levels of free T(4) and prolactin were observed in summer when energy balance was very positive. The results demonstrate that, in woodchucks, serum T(4) and prolactin undergo seasonal changes during annual cycles entrained by photoperiod. The results suggest that changes in free T(4), acting as a calorigenic hormone, and changes in both T(4) and prolactin, potentially acting as lipolytic, antilipogenic, and/or orectic hormones, are likely involved in the mechanisms underlying the corresponding seasonal changes in food intake, fat metabolism, and energy balance in this species. Their potential roles in gonadal regression and recrudescence are less clear.


Video-assisted thoracic surgery in lung cancer resection: a meta-analysis and systematic review of controlled trials.
: This meta-analysis sought to determine whether video-assisted thoracic surgery (VATS) improves clinical and resource outcomes compared with thoracotomy (OPEN) in adults undergoing lobectomy for nonsmall cell lung cancer. : A comprehensive search was undertaken to identify all randomized (RCT) and nonrandomized (non-RCT) controlled trials comparing VATS with OPEN thoracotomy available up to April 2007. The primary outcome was survival. Secondary outcomes included any other reported clinical outcome and resource utilization. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences (SMD), and their 95% confidence intervals (95% CI) were analyzed as appropriate. : Baseline prognosis was more favorable for VATS (more females, smaller tumor size, less advanced stage, histology associated with peripheral location and with more indolent disease) than for OPEN in non-RCTs, but not RCT. Postoperative complications were significantly reduced in the VATS group compared with OPEN surgery when both RCT and non-RCT were considered in aggregate (OR 0.48, 95% CI 0.32-0.70). Although overall blood loss was significantly reduced with VATS compared with OPEN (-80 mL, 95% CI -110 to -50 mL), the incidence of excessive blood loss (generally defined as >500 mL) and incidence of re-exploration for bleeding was not significantly reduced. Pain measured via visual analog scales (10-point VAS) was significantly reduced by <1 point on day 1, by >2 points at 1 week, and by <1 point at week 2 to 4. Similarly, analgesia requirements were significantly reduced in the VATS group. Postoperative vital capacity was significantly improved (WMD 20, 95% CI 15-25), and at 1 year was significantly greater for VATS versus OPEN surgery (WMD 7, 95% CI 2-12). The incidence of patients reporting limited activity at 3 months was reduced (OR 0.04, 95% CI 0.00-0.82), and time to full activity was significantly reduced in the VATS versus OPEN surgery (WMD -1.5, 95% CI -2.1 to -0.9). Overall patient-reported physical function scores did not differ between groups at 3 years follow-up. Hospital length of stay was significantly reduced by 2.6 days despite increased 16 minutes of operating time for VATS versus OPEN. The incidence of cancer recurrence (local or distal) was not significantly different, but chemotherapy delays were significantly reduced for VATS versus OPEN (OR 0.15, 95% CI 0.06-0.38). The need for chemotherapy reduction was also decreased (OR 0.37, 95% CI 0.16-0.87), and the number of patients who did not receive at least 75% of their planned chemotherapy without delays were reduced (OR 0.41, 95% CI 0.18-0.93). The risk of death was not significantly reduced when RCTs were considered alone; however, when non-RCTs (n = 18) were included, the risk of death at 1 to 5 years was significantly reduced (OR 0.72, 95% CI 0.55-0.94; P = 0.02) for VATS versus OPEN. Stage-specific survival to 5 years was not significantly different between groups. : This meta-analysis suggests that there may be some short term, and possibly even long-term, advantages to performing lung resections with VATS techniques rather than through conventional thoracotomy. Overall, VATS for lobectomy may reduce acute and chronic pain, perioperative morbidity, and improve delivery of adjuvant therapies, without a decrease in stage specific long-term survival. However, the results are largely dependent on non-RCTs, and future adequately powered randomized trials with long-term follow-up are encouraged.


Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons.
Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, recent work has shown that BDNF also can induce rapid changes in synaptic efficacy. We have investigated the mechanism(s) of these synaptic effects on cultured embryonic hippocampal neurons. In the presence of the GABAA receptor antagonist, picrotoxin, the application of BDNF (100 ng/ml) for 1-5 min increased the amplitude of evoked synaptic currents by 48 +/- 9% in 10 of 15 pairs of neurons and increased the frequency of EPSC bursts to 205 +/- 20% of the control levels. There was no detectable effect of BDNF on various measures of electrical excitability, including the resting membrane potential, input resistance, action potential threshold, and action potential amplitude. In addition, BDNF did not change the postsynaptic currents induced by the exogenous application of glutamate. BDNF did increase the frequency of miniature EPSCs (mEPSCs) (268.0 +/- 46.8% of control frequency), however, without affecting the mEPSC amplitude. The effect of BDNF on mEPSC frequency was blocked by the tyrosine kinase inhibitor K252a and also by the removal of extracellular calcium ([Ca2+]o). Fura-2 recordings showed that BDNF elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was dependent on [Ca2+]o; it was blocked by K252a and by thapsigargin, but not by caffeine. The results demonstrate that BDNF enhances glutamatergic synaptic transmission at a presynaptic locus and that this effect is accompanied by a rise in [Ca2+]c that requires the release of Ca2+ from IP3-gated stores.


A pediatric case of hepatitis B virus subgenotype A2 in Japan.
Hepatitis B virus (HBV) has been classified into 10 major genotypes, and HBV genotypes C and B are found in the majority of Japanese patients. However, the prevalence of genotype A has been increasing in patients with chronic or acute hepatitis. Here we report a pediatric case of HBV subgenotype A2. A 2-year-old girl was referred to our hospital for liver damage caused by HBV infection. During the pregnancy, her father had developed acute sporadic hepatitis B. The child was born without any complications. She did not receive HBV vaccination at birth because her mother was negative for HBs antigen at the pre-delivery screening; however, her mother developed acute hepatitis B 2 months after delivery. At that time, HBs antigen was detected in the current patient. Phylogenetic full-length sequence analysis revealed HBV subgenotype A2. HBV sequencing was not performed for her parents; therefore, the intrafamilial transmission routes in these cases are unclear, although the authors speculate that, for the current patient, mother-to-child transmission may have occurred. This report illustrates the pitfalls of the selective vaccination strategy in Japan for preventing HBV infection. Universal vaccination to prevent HBV infection might be useful in Japan.


Purification of the bacteriocin bavaricin MN and characterization of its mode of action against Listeria monocytogenes Scott A cells and lipid vesicles.
Bavaricin MN was purified from Lactobacillus sake culture supernatant 135-fold with a final yield of 11%. Sequence analysis revealed bavaricin MN to be a 42-amino-acid peptide having a molecular weight of 4,769 and a calculated pI of 10.0. Computer analysis indicated that the C-terminal region may form an alpha-helical structure with an amphipathic nature deemed important in the interaction of bacteriocins with biological membranes. Bavaricin MN rapidly depleted the membrane potential (delta p) of energized Listeria monocytogenes cells in a concentration-dependent fashion. At a bavaricin MN concentration of 9.0 micrograms/ml, the delta p decreased by 85%. Both the electrical potential (delta psi) and Z delta pH components of the delta p were depleted, and this depletion was not dependent on a threshold level of proton motive force. In addition to studying the effect of bavaricin MN on the delta p of vegetative cells, bavaricin MN-induced carboxyfluorescein (CF) efflux from L. monocytogenes-derived lipid vesicles was also characterized. Bavaricin MN-induced CF leakage was also concentration dependent with an optimum of pH 6.0. The rate of CF efflux was 63% greater in lipid vesicles in which a delta psi was generated compared with that in lipid vesicles in the absence of a delta psi.


Impacts of diurnal temperature and larval density on aquatic development of Aedes aegypti.
The increasing range of Aedes aegypti, vector for Zika, dengue, chikungunya, and other viruses, has brought attention to the need to understand the population and transmission dynamics of this mosquito. It is well understood that environmental factors and breeding site characteristics play a role in organismal development and the potential to transmit pathogens. In this study, we observe the impact of larval density in combination with diurnal temperature on the time to pupation, emergence, and mortality of Aedes aegypti. Experiments were conducted at two diurnal temperature ranges based on 10 years of historical temperatures of Houston, Texas (21-32°C and 26.5-37.5°C). Experiments at constant temperatures (26.5°C, 32°C) were also conducted for comparison. At each temperature setting, five larval densities were observed (0.2, 1, 2, 4, 5 larvae per mL of water). Data collected shows significant differences in time to first pupation, time of first emergence, maximum rate of pupation, time of maximum rate of pupation, maximum rate of emergence, time of maximum rate of emergence, final average proportion of adult emergence, and average proportion of larval mortality. Further, data indicates a significant interactive effect between temperature fluctuation and larval density on these measures. Thus, wild population estimates should account for temperature fluctuations, larval density, and their interaction in low-volume containers.


Cost-effectiveness analysis of the introduction of rotavirus vaccine in Iran.
Although the mortality from diarrheal diseases has been decreasing dramatically in Iran, it still represents an important proportion of disease burden in children <5 years old. Rotavirus vaccines are among the most effective strategies against diarrheal diseases in specific epidemiological conditions. This study aimed to evaluate the cost-effectiveness of the introduction of rotavirus vaccine (3 doses of pentavalent RotaTeq (RV5)) in Iran, from the viewpoints of Iran's health system and society. The TRIVAC decision support model was used to calculate total incremental costs, life years (LYs) gained, and disability-adjusted life years (DALYs) averted due to the vaccination program. Necessary input data were collected from the most valid accessible sources as well as a systematic review and meta-analysis on epidemiological studies. We used WHO guidelines to estimate vaccination cost. An annual discount rate of 3% was considered for both health gain and costs. A deterministic sensitivity analysis was performed for testing the robustness of the models results. Our results indicated that total DALYs potentially lost due to rotavirus diarrhea within 10 years would be 138,161, of which 76,591 could be prevented by rotavirus vaccine. The total vaccination cost for 10 cohorts was estimated to be US$ 499.91 million. Also, US$ 470.61 million would be saved because of preventing outpatient visits and inpatient admissions (cost-saving from the society perspective). We estimated a cost per DALY averted of US$ 2868 for RV5 vaccination, which corresponds to a highly cost-effective strategy from the government perspective. In the sensitivity analysis, all scenarios tested were still cost-saving or highly cost-effective from the society perspective, except in the least favorable scenario and low vaccine efficacy and disease incidence scenario. Based on the findings, introduction of rotavirus vaccine is a highly cost-effective strategy from the government perspective. Introducing the vaccine to the national immunization program is an efficient use of available funds to reduce child mortality and morbidity in Iran.


Altered representation of expected value in the orbitofrontal cortex in mania.
Increased responsiveness to appetitive and reduced responsiveness to aversive anticipatory cues may be associated with dysfunction of the brain reward system in mania. Here we studied neural correlates of gain and loss expectation in mania using functional magnetic resonance imaging (fMRI). Fifteen manic patients and 26 matched healthy control individuals performed a monetary incentive delay task, during which subjects anticipated to win or lose a varying amount of money. Varying both magnitude and valence (win, loss) of anticipatory cues allowed us to isolate the effects of magnitude, valence and expected value (magnitude-by-valence interaction). Response times and total gain amount did not differ significantly between groups. FMRI data indicated that the ventral striatum responded according to cued incentive magnitude in both groups, and this effect did not significantly differ between groups. However, a significant group difference was observed for expected value representation in the left lateral orbitofrontal cortex (OFC; BA 11 and 47). In this region, patients showed increasing BOLD responses during expectation of increasing gain and decreasing responses during expectation of increasing loss, while healthy subjects tended to show the inverse effect. In seven patients retested after remission OFC responses adapted to the response pattern of healthy controls. The observed alterations are consistent with a state-related affective processing bias during the expectation of gains and losses which may contribute to clinical features of mania, such as the enhanced motivation for seeking rewards and the underestimation of risks and potential punishments.


[Antioxidant properties of a series of extracts from medicinal plants].
Investigation of antioxidant properties of some plants was carried out. A group of plants affected human central nervous system was studied in detail. Efficiency of plants as antioxidants was tested by the influence of their extracts on the yield of photochemiluminescence of Gly-Trp solutions. Antioxidant properties were examined under conditions when their own absorption was minimized. Riboflavin as additional sensitizer was used in this experiment for superoxide generation. The antioxidant effect was evaluated with regard to single dose of plant extracts and their concentration in human organism. The effect decreases in the following consequence: Hypericum > Eleutherococcus > Rhodiola > Leonurus > Aralia > Valeriana > Echinopanax > Schizandra > Panax gin-seng.


Rotating suture technique combined with lid margin split and lower eyelid retractor disinsertion for epiblepharon.
Epiblepharon is an eyelid disease affecting 46-52.5% of Asian children. The Hotz procedure was commonly used for the treatment. However, the currently preferred technique is the rotating suture technique. This study aimed to report the recurrence rate and the complications of using the rotating suture technique combined with lid margin split and lower eyelid retractor (LER) disinsertion of epiblepharon. This was a retrospective study of the procedures performed between January 2017 and December 2020. This study included 64 eyelids of 37 patients who underwent the consecutive rotating suture technique, lid margin split, and LER disinsertion simultaneously for lower eyelid epiblepharon and were followed up for at least 6 months. The mean age of the patients who underwent surgery was 9.5 (5-28) years. The mean observation period was 8.3 (6-27) months. Recurrence was observed in one eyelid (1.6%). The complications included an ectopic eyelash on one eyelid (1.6%). LER disinsertion performed in this study had two advantages. First, the imbalance between the anterior and posterior lamellae was corrected. Disinserting the LER, the tarsal plate could be repositioned cranially, effectively addressing this imbalance. Second, LER disinsertion ensured direct exposure of the lower margin of the tarsal plate, facilitating the implementation of a reliable rotating suture. In conclusion, promising results were achieved by combining the rotating suture technique with LER disinsertion and lid margin splitting.


Thermomagnetic Convection of Ferrofluid in an Enclosure Channel with an Internal Magnetic Field.
Ferrofluid is a colloidal liquid in which magnetic nanoparticles such as Fe3O4 are dispersed in a nonconductive solution, and the average diameter of the nanoparticles is 10 nm. When a magnetic field is applied, the ferrofluid generates magnetization, which changes the physical properties of the fluid itself. In this study, characteristics of the thermomagnetic convection of ferrofluid (Fe3O4) by the permanent magnet in the enclosure channel were studied. To effectively mix the ferrofluid (Fe3O4) and disturb the boundary layer, the heat dissipation of the heat source depending on the strength of the magnetic field and the shape of the enclosure channel was numerically studied. In particular, four different enclosure channels were considered: Square, separated square, circle, and separated circle. The hot temperature was set at the center of the enclosure channel. The ferrofluid was affected by the permanent magnet in the center of the channel. The magnetic field strength in the region close to the permanent magnet was enhanced. The magnetophoretic (MAP) force increased with increasing magnetic field strength. The MAP force generated a vortex in the enclosure channel, disturbing the thermal boundary. The vortex occurs differently, depending on the shape of the enclosure channel and affects the thermomagnetic convection. The temperature and velocity fields for thermomagnetic convection were described and the convective heat flux was calculated and compared. Results show that when the magnetic field strength was 4000 kA/m and the shape of the enclosure channel was a circle, the maximum convective heat flux of 4.86 × 105 W/m2 was obtained.


V. Uterine fibroid embolization: management of complications.
Fortunately, the number of complications reported after uterine fibroid embolization (UFE) is extremely low. Angiographic mishap or drug reaction are probably more common than purely UFE-related complications. However, the possibility of infection or necrosis of the uterus, with their significant attendant morbidity, is a sobering reminder that embolotherapy can have a powerful impact on the target organ(s). Knowledge of the expected time course for symptom resolution and the often confusing imaging findings shortly after UFE are critical for avoiding unnecessary delay in surgical intervention or, perhaps more important, an inappropriate rush to surgery when antibiotics alone will suffice. Other complications include alteration of uterine physiology, which may disrupt sexual function, and menstrual irregularity and even premature menopause.


A fast fractal image coding based on kick-out and zero contrast conditions.
A fast algorithm for fractal image coding based on a single kick-out condition and the zero contrast prediction is proposed in this paper. The single kick-out condition can avoid a large number of range-domain block matches when finding the best matched domain block. An efficient method for zero contrast prediction is also proposed, which can determine whether the contrast factor for a domain block is zero or not, and compute the corresponding difference between the range block and the transformed domain block efficiently and exactly. The proposed algorithm can achieve the same reconstructed image quality as the exhaustive search, and can greatly reduce the required computation or runtime. In addition, this algorithm does not need any pre-processing step or additional memory for its implementation, and can combine with other fast fractal algorithms to further improve the speed. Experimental results show that the runtime is reduced by about 50% of that of the exhaustive search method. When combined with the DCT Inner Product algorithm, the required runtime for the algorithm can be further reduced by about 50%. The proposed algorithm was also compared to two other fast fractal algorithms. Experimental results also show that our algorithm achieves a better efficiency and requires a much smaller amount of memory for implementation.


Fragmented QRS frequency in patients with cardiac syndrome X.
Cardiac syndrome X (CSX) is characterised by typical exertional chest pain, a positive response to exercise testing, and a normal coronary angiography. The relationship of CSX with myocardial fibrosis and ischemia has been clearly demonstrated in previous studies. In addition, fragmented QRS (fQRS) has been reported in the literature as an indicator of myocardial fibrosis. The aim of this study was to investigate the frequency of fQRS in patients with CSX. This prospective case-control study included 37 patients (CSX group) with typical complaints of angina, ischemia on an exercise test, and normal coronary arteries as detected by angiography and 47 patients (control group) with normal coronary arteries. Echocardiographic examinations were performed according to the recommendations of the American Society of Echocardiography. Continuous variables were expressed as mean±standard deviation (SD), and the qualitative variables were expressed as a percentage or ratio. Data were compared statistically with Shapiro-Wilk test, Student's t-test, Mann-Whitney U, chi-square and Fisher exact test. There was no significant difference between the CRX and control groups with respect to basic characteristics such as age and sex. fQRS and the frequency of its presentation with stable angina pectoris at the clinic were significantly higher in the CSX group than in the control group (p values: 0.001 and <0.001, respectively). A close follow-up would be useful in CSX patients in whom fQRS is detected in an electrocardiogram (ECG) because of the association between fQRS and poor prognosis with respect to the prevention of late complications. We believe that the presence of fQRS in the ECG aids in the diagnosis of CSX in clinical practice and in the recognition of this group of patients.


Comparative in vitro study of the antimicrobial activities of different commercial antibiotic products for intravenous administration.
The antimicrobial resistance is a global problem, probably due to the indiscriminate and irrational use of antibiotics, prescriptions for incorrect medicines or incorrect determinations of dose, route and/or duration. Another consideration is the uncertainty of patients receiving antibiotics about whether the quality of a generic medicine is equal to, greater than or less than its equivalent brand-name drug. The antibiotics behaviors must be evaluated in vitro and in vivo in order to confirm their suitability for therapeutic use. The antimicrobial activities of Meropenem and Piperacillin/Tazobactam were studied by microbiological assays to determine their potencies (content), minimal inhibitory concentrations (MICs), critical concentrations and capacity to produce spontaneous drug-resistant mutants. With respect to potency (content) all the products fulfill USP requirements, so they should all be considered pharmaceutical equivalents. The MIC values of the samples evaluated (trade marks and generics) were the same for each strain tested, indicating that all products behaved similarly. The critical concentration values were very similar for all samples, and the ratios between the critical concentration of the standard and those of each sample were similar to the ratios of their specific antibiotic contents. Overall, therefore, the results showed no significant differences among samples. Finally, the production of spontaneous mutants did not differ significantly among the samples evaluated. All the samples are pharmaceutical equivalents and the products can be used in antimicrobial therapy.


The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities.
Research has suggested that individuals who engage in self-injurious behavior may have enhanced expressions of pain, which contradicts previous assertions of blunted pain sensitivity in this population. The purpose of this study was to measure expressions of pain among young children being evaluated for autism and other neurodevelopmental disabilities. The frequency of pain-related behaviors was assessed during everyday routines using the Non-Communicating Children's Pain Checklist (NCCPC-R) for 51 children. Significant group differences between children with and without self-injury were found for the NCCPC-R total scores. The frequency and severity of self-injury, aggression, and stereotypy were also highly correlated with the total scores on the NCCPC-R. These results continue to support that individuals with self-injury may have enhanced expressions of pain.


Posttraumatic stress symptoms in palliative care professionals seeking mindfulness training: Prevalence and vulnerability.
Vicarious exposure to trauma is ubiquitous in palliative medicine. Repeated exposure to trauma may contribute to compassion fatigue and posttraumatic stress disorder symptoms in medical and supportive care professionals such as physicians, nurses, and social workers. These symptoms may be intensified among medical and supportive care professionals who use avoidant or rigid coping strategies. This study aimed to provide an estimate of posttraumatic stress disorder symptoms in a sample of professionals who work in palliative care settings, and have already been enrolled in mindfulness-based communication training. Palliative care providers provided self-reported ratings of posttraumatic stress disorder symptoms, depression, and coping strategies using validated measures including the Acceptance and Action Questionnaire, Cognitive Fusion Questionnaire, and the Posttraumatic Stress Disorder Checklist-Civilian Version. A total of 21 professionals working with palliative care patients completed assessments prior to beginning mindfulness-based communication training. Posttraumatic stress disorder symptoms were prevalent in this sample of professionals; 42% indicated positive screens for significant posttraumatic stress disorder symptoms, and 33% indicated probable posttraumatic stress disorder diagnosis. Posttraumatic stress disorder symptoms may be common among professionals working in palliative medicine. Professionals prone to avoidant coping and those with more rigid negative thought processes may be at higher risk for posttraumatic stress disorder symptoms.


Creating and sustaining a culture of assessment.
Accreditation standards require that colleges and schools of pharmacy establish and conduct ongoing assessment of their programs. A case study of the University of Kentucky College of Pharmacy's experience developing and implementing an assessment program is described. A historical perspective of the School, implementation of an office of education, and steps taken to establish a college culture of assessment are discussed. Successful aspects of the program, including student course/instructor evaluations and curriculum committee review of individual courses, are outlined. Finally, roadblocks encountered while establishing the assessment program and lessons learned that may benefit other schools currently in the process of developing an assessment program are discussed.


Expanding Stereoelectronic Limits of endo-tet Cyclizations: Synthesis of Benz[b]azepines from Donor-Acceptor Cyclopropanes.
The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in n-endo-tet cyclizations, where the usual backside approach of a nucleophile to the breaking bond is impossible for the rings containing less than eight atoms. Herein, we expand the limits of endo-tet cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-endo-tet process. Substrates containing a N-alkyl-N-arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[b]azepin-2-ones in high yields. The reaction proceeds with the inversion of the configuration at the electrophilic carbon. In this process, a formally six-membered transition state yields a seven-membered ring as the pre-existing cycle is merged into the forming ring. The stereochemistry of the products can be controlled by the reaction time and by the nature of Lewis acid, opening access to both diastereomers by tuning of the reaction conditions.


Effect of dexamethasone on IL-2 and IL-3 production by mononuclear cells in neonates and adults.
The effect of dexamethasone on interleukin 2 (IL-2) and interleukin 3 (IL-3) production by mononuclear cells in preterm and term infants and adults was evaluated. The capacity of mononuclear cells to produce these cytokines, in preterm infants with bronchopulmonary dysplasia (BPD) and treated with dexamethasone, was compared with that before treatment. Twenty six preterm and 36 term neonates and 24 healthy adults were included in the study. Mononuclear cells isolated from neonatal cord blood (CBMC) and adult peripheral blood (PBMC) were stimulated with phytohaemagglutinin (PHA) in the absence or presence of dexamethasone at concentrations between 10(-8)M and 10(-5)M. IL-2 and IL-3 activities in the supernatant fluids were tested using bioassays. The in vivo effect of the drug on the production of these cytokines by PBMC in 10 preterms was determined before and 24 hours after dexamethasone administration (0.5 mg/kg/day). The production of both cytokines was inhibited in a dose dependent manner. A difference in the sensitivity of mononuclear cells to the inhibitory effect of the drug was found between neonatal cord blood cells and adult PBMC, the former being more sensitive. PBMC from preterm infants treated with dexamethasone for BPD produced significantly less IL-2 and IL-3 as early as 24 hours after the initiation of the treatment (43% and 31%; P < 0.05, respectively). It is concluded that mononuclear cells from preterm and term neonates are more sensitive to the inhibitory effect of dexamethasone on IL-2 and IL-3 production.


Dihydrotanshinone, a Natural Diterpenoid, Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor.
Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1β, IL-6, TNF-α, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and/or counteracting the BRB dysfunctions elicited by HG conditions.


Hyperhomocysteinemia and B-vitamin status after discontinuation of oral anticoagulation therapy in patients with a history of venous thromboembolism.
Although hyperhomocysteinemia is an established risk factor for venous thromboembolism there is no consensus for routine determination of circulating homocysteine in the UK, either at the beginning or end of oral anticoagulation therapy. The purpose of this study was to evaluate the prevalence of hyperhomocysteinemia and its relationship to folate and vitamin B12 status in subjects with venous thromboembolism 4 weeks after discontinuation of warfarin therapy. In 78 consecutively recruited patients, plasma homocysteine was significantly higher (p < 0.001) and red cell folate significantly lower (p = 0.03) than in controls. Plasma vitamin B12 was similar in both groups. Strikingly, 38.5% of patients had hyperhomocysteinemia (> 15 micromol/l). Retrospective analysis revealed a significant positive association between plasma total homocysteine and duration of warfarin therapy (p < 0.001) but a negative, though non-significant (p = 0.06), trend with warfarin dose. The results do not suggest any direct interaction between warfarin and plasma homocysteine but raise the possibility of reduced intake of a common food source of folate and vitamin K. One possibility is the shortage of green-leafy vegetables since patients are often advised to limit their intake of this major source of vitamin K. On the basis of this study we suggest that homocysteine screening should be carried out at the time that patients begin warfarin therapy.


Resveratrol regulates the expression of LXR-alpha in human macrophages.
The naturally occurring polyphenol resveratrol has been associated with the beneficial effects of red wine consumption on cardiovascular disease and shown to inhibit atherosclerosis in animal models. To determine if resveratrol affects the expression of genes that control lipid homeostasis in human macrophages, we measured expression changes in the LXR-alpha pathway, crucial to cholesterol efflux, and in genes that mediate lipoprotein uptake. Resveratrol treatment of THP-1 macrophages induced LXR-alpha at mRNA and protein levels. Increased recruitment of RNA polymerase II to the LXR-alpha promoter suggested that up-regulation was at least partly mediated by transcriptional mechanisms. Resveratrol also induced LXR-alpha in human monocyte-derived macrophages together with elevated ABCA1 and ABCG1 mRNA levels. Moreover, resveratrol repressed the expression of the lipid uptake genes LPL and SR-AII. The ability of resveratrol to modulate expression of the genes involved in lipid uptake and efflux suggests that polyphenols can potentially limit cholesterol accumulation in human macrophages.


Unfolding the complexation and extraction of Am3+ and Eu3+ using N-heterocyclic aromatic diphosphonic acids: a combined experimental and DFT study.
Phosphonate based ligands are well known for the extraction of 'f' block elements. Three N,O-donor N-heterocyclic aromatic diphosphonate ligands were evaluated in the present work for the extraction/separation studies of Am3+ and Eu3+. Complexation studies in aqueous medium using luminescence titration indicated the formation of anionic complexes in the case of Eu3+. Two phase liquid-liquid extraction studies were, therefore, carried out by employing Aliquat-336 as the liquid anion exchanger. The results indicated the formation of a species with a metal-ligand stoichiometry of 1 : 3 in the case of pyridine-2,6-diphosphonic acid (PyPOH). In the case of 2,2'-bipyridine-6,6'-diphosphonic acid (BipyPOH), however, a 1 : 2 complex was extracted and 1,10-phenanthroline-2,9-diphosphonic acid (PhenPOH) extracts the Am3+ and Eu3+ ions by forming both 1 : 2 and 1 : 3 complexes. Formation of these kinds of anionic complexes was further confirmed using electrospray ionization mass spectrometry (ESI-MS). DFT calculations predicted the structure of the anionic complexes. The non-selectivity of these kinds of ligands between Am3+ and Eu3+ was attributed to the presence of unfavorable covalent interactions in the metal-ligand bonds.


Oxytocin and Stress: Neural Mechanisms, Stress-Related Disorders, and Therapeutic Approaches.
Clinical reports show that oxytocin (OT) is related to stress-related disorders such as depression, anxiety disorder, and post-traumatic stress disorder. Two key structures in the brain should be paid special attention with regard to stress regulation, namely, the hypothalamus and the hippocampus. The former is the region for central command for most, if not all, of the major endocrine systems, and the latter takes a key position in the regulation of mood and anxiety. There are extensive neural projections between the two structures, and both are functionally intertwined. The hypothalamus projects OTergic neurons to the hippocampus, and the latter possesses high levels of OT receptors. The hippocampus also regulates the secretion of glucocorticoids, a major group of stress hormones. Excessive levels of glucocorticoids in chronic stress cause atrophy of the hippocampus, whereas OT has been shown to protect hippocampal neurons from the toxic effects of glucocorticoids. In this article, we discuss how neural and endocrine mechanisms interplay in stress regulation, with an emphasis on the role of OT, as well as its therapeutic potential in the treatment of stress-related disorders.


Evaluation of the root and canal morphology of mandibular first permanent molars in a sample of Pakistani population by cone-beam computed tomography.
To evaluate the root canal morphology of permanent mandibular first molars using Cone Beam Computed Tomography. The retrospective study was done at Aga Khan University Hospital, Karachi, and comprised medical records of patients who visited the dental clinics from December 2016 to March 2017. Mandibular first permanent molars were evaluated on Cone Beam Computed Tomography images. Frequency distribution of Vertucci's classification was determined, and so was the association between Vertucci's classifications and gender. SPSS 20 was used for data analysis. A total of 142 mandibular first permanent molars were evaluated on 78 Cone Beam Computed Tomography images. The most common Vertucci's classification was Type IV for mesial root 86(60.56%) and Type I for distal root 63(44%). There was no difference in the two genders for root canal morphology (p>0.05). Type IV Vertucci's were prevalent in the mesial root and Type I were common in the distal root of permanent mandibular first molars.


The Brief Core Schema Scales (BCSS): psychometric properties and associations with paranoia and grandiosity in non-clinical and psychosis samples.
Traditional instruments that measure self-esteem may not relate directly to the schema construct as outlined in recent cognitive models. The Brief Core Schema Scales (BCSS) aim to provide a theoretically coherent self-report assessment of schemata concerning self and others in psychosis. The scales assess four dimensions of self and other evaluation: negative-self, positive-self, negative-other, positive-other. We analysed the psychometric properties of the BCSS using a sample of 754 students recruited by email and 252 people with psychosis recruited as part of a trial of cognitive therapy. We report the internal consistency, stability and the factor structure of the scale, and the association of the BCSS with measures of self-esteem and with symptoms of paranoia and grandiosity. The BCSS have good psychometric properties and have more independence from mood than the Rosenberg Self-Esteem Schedule. People with chronic psychosis reported extreme negative evaluations of both self and others on these scales, but their levels of self-esteem and positive evaluations of self and others were similar to the student sample. Extreme negative evaluations of self and others appear to be characteristic of the appraisals of people with chronic psychosis, and are associated with symptoms of grandiosity and paranoia in the non-clinical population. The BCSS may provide a more useful measure of schemata about self and others than traditional measures of self-esteem.


The Spanish ser/estar distinction in bilingual children's reasoning about human psychological characteristics.
Children's reasoning about the stability of human psychological characteristics was investigated in relation to the obligatory distinction between the Spanish verb forms ser and estar (which convey different information about the stability of characteristics) and the corresponding English form to be. Participants (85 bilingual children, ages 6 to 10 years) were interviewed to determine (a) whether the ser/estar distinction is relevant to reasoning about the stability of human characteristics and (b) whether beliefs about the stability of psychological characteristics relate to differences in the use of ser and estar to describe and explain social events. Children treated ser and to be as more likely than estar to convey the stability of psychological characteristics. Children who tended to endorse stable views of psychological characteristics were especially likely to use the ser form in their descriptions and explanations.


Pharmacology of GPR55 in yeast and identification of GSK494581A as a mixed-activity glycine transporter subtype 1 inhibitor and GPR55 agonist.
GPR55 is a G protein-coupled receptor activated by L-α-lysophosphatidylinositol and suggested to have roles in pain signaling, bone morphogenesis, and possibly in vascular endothelial cells. It has affinity for certain cannabinoids (molecules that interact with the cannabinoid CB(1) and CB(2) receptors), but investigation of its functional role in cell-based systems and in tissue has been limited by a lack of selective pharmacological tools. Here, we present our characterization of GPR55 in the yeast Saccharomyces cerevisiae and in human embryonic kidney (HEK293) cells. We describe GSK494581A (1-{2-fluoro-4-[1-(methyloxy)ethyl]phenyl}-4-{[4'-fluoro-4-(methylsulfonyl)-2-biphenylyl]carbonyl}piperazine), a selective small-molecule ligand of GPR55 identified through diversity screening. GSK494581A is one of a series of benzoylpiperazines originally identified and patented as inhibitors of the glycine transporter subtype 1 (GlyT1). The structure-activity relationship between GPR55 and GlyT1 is divergent across this series. The most GPR55-selective example is GSK575594A (3-fluoro-4-(4-{[4'-fluoro-4-(methylsulfonyl)-2-biphenylyl]carbonyl}-1-piperazinyl)aniline), which is approximately 60-fold selective for GPR55 (pEC(50) = 6.8) over GlyT1 (pIC(50) = 5.0). Several exemplars with activity at GPR55 and GlyT1 have been profiled at a broad range of other molecular targets and are inactive at cannabinoid receptors and all other targets tested. The benzoylpiperazine agonists activate human GPR55 but not rodent GPR55, suggesting that the relatively low level of sequence identity between these orthologs (75%) translates to important functional differences in the ligand-binding site.


Role of Inositol-1,4,5-Trisphosphate Receptor in the Regulation of Calcium Transients in Neonatal Rat Ventricular Myocytes.
This study determined the regulatory effect of inositol 1,4,5-trisphosphate receptors (IP3Rs) on the basal Ca2+ transients in cardiomyocytes. In cultured neonatal rat ventricular myocytes (NRVMs) at different densities, we used confocal microscopy to assess the effect of IP3Rs on the endogenous spontaneous Ca2+ oscillations through specific activation of IP3Rs with myo-IP3 hexakis (butyryloxymethyl) ester (IP3BM), a membrane permeable IP3, and interference of IP3R expression with shRNA. We found that NRVMs at the monolayer state displayed coordinated Ca2+ transients with less rate, shorter duration, and higher amplitude compared to single NRVMs. In addition, monolayer NRVMs exhibited 4 or 10 times more increased Ca2+ transients in response to phenylephrine, an α-adrenergic receptor agonist, or IP3BM than single NRVMs did, while the transient pattern remained unaltered, suggesting that the sensitivity of intracellular Ca2+ response to IP3R activation is different between single and monolayer NRVMs. However, interference of IP3R expression with shRNA reduced the frequency and amplitude of the spontaneous Ca2+ fluctuates similarly in both densities of NRVMs, resembling the effects of ryanodine receptor inhibition by ryanodine or tetracaine. Our findings suggest that IP3Rs are involved, in part, in the regulation of native Ca2+ transients, in profiles of their initiation and Ca2+ release extent, in developing cardiomyocytes. In addition, caution should be paid in evaluating the behavior of Ca2+ signaling in primary cultured cardiomyocytes at different densities.


Stimulating creativity in the classroom: examining the impact of sense of place on students' creativity and the mediating effect of classmate relationships.
Although previous studies have found a close relationship between sense of place and creativity, few studies have been conducted considering the micro-environment of the classroom. The mediating role of classmate relationships in the association between students' sense of place and creativity remains unclear. This study explores classmate relationships as a mediating factor in the relationship between sense of place and creativity. Therefore, we considered a sample of 1555 Chinese high-school students and used a paper-based questionnaire survey. Data analysis was performed using SPSS 24.0, PROCESS 3.2 plugin, and AMOS. Sense of place in the micro-environment of the classroom has a significant positive predictive effect on creativity. Sense of place also has a significant positive predictive effect on peer relationships. The mediation analysis reveals that peer relationships play a mediating role in the relationship between the sense of place and creativity. This study revealed the associations between sense of place, classmate relationships, and creativity. Creativity is better expressed in students with a strong sense of place in the classroom. Moreover, a student's sense of place can enhance their creativity by influencing their peer relationships. These findings enrich the research in educational psychology within the classroom, providing new insights for fostering creativity.


Time-dependent aggravation or attenuation of lipopolysaccharide-induced gastric injury by nitric oxide synthase inhibition.
This study was conducted to test the hypothesis that nonselective nitric oxide synthase (NOS) inhibitors have different effects on lipopolysaccharide (LPS)-induced gastric injury depending upon whether they are given concurrently with LPS or after LPS at a time point that inducible NOS is up-regulated. Female Sprague-Dawley rats received intraperitoneal (IP) LPS (20 mg/kg) for 3 h. Western immunoblot was used to determine iNOS, eNOS, and nNOS immunoreactivity after 3 h. In an additional set of experiments, we assessed the time dependent effects of nitric oxide synthase inhibition by giving rats LPS (20 mg/kg, IP) concurrently with Nitro-l-arginine methyl ester (l-NAME; 2-5 mg/kg, SC) or l-N(G)-(1-iminoethyl) lysine (l-NIL; 10 mg/kg, IP) for 5 h or LPS and delayed administration of l-NAME or l-NIL 3 h following LPS injection in identical doses. For these NOS inhibition experiments microscopic and macroscopic injury was assessed by a blinded observer using previously published scoring systems. Injury studies were conducted by exposing the stomach to 3 ml of 5 mM acidified taurocholate for 5 minutes in an anesthetized prep. A 3-h treatment with LPS (20 mg/kg IP) significantly increased iNOS protein immunoreactivity (Western immunoblot) but not eNOS or nNOS. N(G)-l-NAME (2-5 mg/kg SC) dose dependently aggravated macroscopic (computerized planimetry) and morphological gastric injury caused by the intraluminal bile irritant 5 mm acidified taurocholate for 10 min when given concurrently with LPS, an effect reversed by l- but not D-arginine (300 mg/kg). In contrast, delayed administration of l-NAME (3 h after LPS) dose dependently attenuated the ability of LPS to exacerbate gastric injury from bile. Both concurrent and delayed administration of the selective iNOS inhibitor, l-NIL (10 mg/kg IP) attenuated the effects of LPS. These data indicate that during endotoxemia, the stomach is rendered more susceptible to damage from luminal irritants such as bile, a frequent occurrence in septic patients with a gastrointestinal ileus. In this setting, iNOS has a pathologic role while the constitutive NOS isoforms play gastroprotective roles.


Association between Nfr2, HO-1, NF-kB Expression, Plasma ADMA, and Oxidative Stress in Metabolic Syndrome.
Endothelial dysfunction is one of the major factors in the pathogenesis of metabolic syndrome (MetS), and its molecular mechanisms are not completely understood. The present study aimed to examine the connection between nuclear factor2-related factor2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), heme oxygenase 1 (HO-1), and plasma asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) in people with MetS. Participants in the study were as follows: with MetS (n = 30) and without MetS (Control) (n = 14). Expression of Nrf2, NF-kB, and HO-1 was measured in peripheral blood mononuclear cells (PBMCs). Plasma ADMA was determined using the ELISA technique and MDA via the thiobarbituric acid method. Our study showed that mRNA of NF-kB, Nrf2, and HO-1 levels in PBMCs in the MetS group were significantly higher than in the controls by 53%, 130%, and 185% (p < 0.05), respectively. Similarly, elevated levels of MDA (by 78%, p < 0.001) and ADMA (by 18.7%, p < 0.001) were established in the MetS group. Our findings show the importance of transcription factor Nrf2, playing an integral role in the protection of the endothelium, and of NF-κB, a transcription factor mediating the inflammatory response in MetS. Knowledge of complex cellular-molecular mechanisms would allow the use of biomarkers such as Nrf2, NF-kB, HO-1, and ADMA for the assessment of endothelial dysfunction in clinical practice.


Evaluation of the Surgical Margin Threshold for Avoiding Recurrence after Partial Nephrectomy in Patients with Renal Cell Carcinoma.
An adequate minimal surgical margin for partial nephrectomy (PN) has not yet been conclusively established. Therefore, we aimed to compare PN recurrence rates according to surgical margin status and to establish an adequate minimal surgical margin. We retrospectively studied patients with clinically localized renal cell carcinoma who underwent PN between 2005 and 2014. Surgical margin width (SMW) was assessed for all surgical tissues and divided into three groups: SMW <1 mm, SMW ≥1 mm, and positive surgical margin (PSM). The data were analyzed using the Kaplan-Meier method with log-rank tests and multivariate Cox regression models. Of 748 patients (median age, 55 years; interquartile range, 46-64 years; 220 female), 704 (94.2%) and 44 (5.8%) patients had negative and PSMs, respectively. Recurrence-free survival was significantly lower in patients with PSMs (p<0.001) and was not significantly different between SMW ≥1 mm and <1 mm groups (p=0.604). PSM was a significant predictor of recurrence (hazard ratio: 8.03, 95% confidence interval: 2.74-23.56, p<0.001), in contrast to SMW <1 mm (p=0.680). A PSM after PN significantly increases the risk of recurrence. We discovered that even a submillimeter safety surgical margin may be enough to prevent recurrence. To maximize normal renal parenchyma preservation and to avoid cancer recurrence in renal parenchymal tumor patients, PN may be a safe treatment, except for those with a PSM in the final pathology.


Scheduling algorithms for data-protection based on security-classification constraints to data-dissemination.
Communication networks have played a vital role in changing people's life. However, the rapid advancement in digital technologies has presented many drawbacks of the current inter-networking technology. Data leakages severely threaten information privacy and security and can jeopardize individual and public life. This research investigates the creation of a private network model that can decrease the number of data leakages. A two-router private network model is designed. This model uses two routers to manage the classification level of the transmitting network packets. In addition, various algorithmic techniques are proposed. These techniques solve a scheduling problem. This problem is to schedule packets through routers under a security classification level constraint. This constraint is the non-permission of the transmission of two packets that belongs to the same security classification level. These techniques are the dispatching rule and grouping method. The studied problem is an NP-hard. Eight algorithms are proposed to minimize the total transmission time. A comparison between the proposed algorithms and those in the literature is discussed to show the performance of the proposed scheme through experimentation. Four classes of instances are generated. For these classes, the experimental results show that the best-proposed algorithm is the best-classification groups' algorithm in 89.1% of cases and an average gap of 0.001. In addition, a benchmark of instances is used based on a real dataset. This real dataset shows that the best-proposed algorithm is the best-classification groups' algorithm in 88.6% of cases and an average gap of less than 0.001.


A 62-Year-Old Man with Acute Alcohol Withdrawal and Stress-Induced Cardiomyopathy.
BACKGROUND Stress-induced cardiomyopathy is also known as takotsubo cardiomyopathy, broken heart syndrome, and left ventricular apical ballooning syndrome. Patients may present with chest pain and electrocardiogram (EKG) changes, but without coronary artery occlusion, and a reduced ejection fraction that may undergo spontaneous reversal if the patient receives appropriate hemodynamic support. This is a case report of stress-induced cardiomyopathy associated with alcohol withdrawal in a 62-year-old man. CASE REPORT We present the case of 62-year-old man who came to the emergency room on account of nausea and vomiting after a reduction in the daily intake of alcohol. He had no chest pain or shortness of breath but had new T wave inversions in anterolateral leads on EKG, elevated troponin, and apical wall hypokinesis with ejection fraction 40% on echocardiography. He subsequently developed active symptoms of alcohol withdrawal and was managed with intravenous Lorazepam and chlordiazepoxide. With the improvement in his mental state over the next couple of days, he had a coronary angiogram which showed no coronary disease. He was diagnosed with stress-induced cardiomyopathy or takotsubo cardiomyopathy due to alcohol withdrawal. CONCLUSIONS This report describes a case of takotsubo cardiomyopathy, or stress-induced cardiomyopathy, that was believed to be associated with acute alcohol withdrawal, with spontaneous improvement in the reduced left ventricular ejection fraction following medical support.


Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies.
To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE). We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15). Eight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked. WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.


The Switch from Low-Pressure Sodium to Light Emitting Diodes Does Not Affect Bat Activity at Street Lights.
We used a before-after-control-impact paired design to examine the effects of a switch from low-pressure sodium (LPS) to light emitting diode (LED) street lights on bat activity at twelve sites across southern England. LED lights produce broad spectrum 'white' light compared to LPS street lights that emit narrow spectrum, orange light. These spectral differences could influence the abundance of insects at street lights and thereby the activity of the bats that prey on them. Most of the bats flying around the LPS lights were aerial-hawking species, and the species composition of bats remained the same after the switch-over to LED. We found that the switch-over from LPS to LED street lights did not affect the activity (number of bat passes), or the proportion of passes containing feeding buzzes, of those bat species typically found in close proximity to street lights in suburban environments in Britain. This is encouraging from a conservation perspective as many existing street lights are being, or have been, switched to LED before the ecological consequences have been assessed. However, lighting of all spectra studied to date generally has a negative impact on several slow-flying bat species, and LED lights are rarely frequented by these 'light-intolerant' bat species.


Vaccine preventable diseases and vaccination coverage in Aboriginal and Torres Strait Islander people, Australia 2006-2010.
This report outlines the major positive impacts of vaccines on the health of Aboriginal and Torres Strait Islander people from 2007 to 2010, as well as highlighting areas that require further attention. Hepatitis A disease is now less common in Aboriginal and Torres Strait Islander children than in their non-Indigenous counterparts. Hepatitis A vaccination for Aboriginal and Torres Strait Islander children was introduced in 2005 in the high incidence jurisdictions of the Northern Territory, Queensland, South Australia and Western Australia. In 2002–2005, there were 20 hospitalisations for hepatitis A in Aboriginal and Torres Strait Islander children aged<5 years--over 100 times more common than in other children--compared to none in 2006/07–2009/10. With respect to invasive pneumococcal disease (IPD), there has been a reduction of 87% in notifications of IPD caused by serotypes contained in 7-valent pneumococcal conjugate vaccine (7vPCV) since the introduction of the childhood 7vPCV program among Aboriginal and Torres Strait Islander children. However, due to a lower proportion of IPD caused by 7vPCV types prior to vaccine introduction, the decline in total IPD notifications has been less marked in Aboriginal and Torres Strait Islander children than in other children. Higher valency vaccines (10vPCV and 13vPCV) which replaced 7vPCV from 2011 are likely to result in a greater impact on IPD and potentially also non-invasive disease, although disease caused by non-vaccine serotypes appears likely to be an ongoing problem. Among Aboriginal and Torres Strait Islander people aged ≥50 years, there have been recent increases in IPD, which appear related to low vaccination coverage and highlight the need for improved coverage in this high-risk target group. Since routine meningococcal C vaccination for infants and the high-school catch-up program were implemented in 2003, there has been a significant decrease in cases caused by serogroup C. However, the predominant serogroup responsible for disease remains serogroup B, and Aboriginal and Torres Strait Islander children have significantly higher incidence of serogroup B disease than other children. A vaccine against meningococcus type B has now been licensed in Australia. The decline in severe rotavirus disease after vaccine introduction in 2007 was less marked in Aboriginal and Torres Strait Islander children than in other children. By far the highest hospitalisation rates continue to occur among Aboriginal and Torres Strait Islander children in the Northern Territory. Consideration of the role of age cut-offs and 2-dose versus 3-dose schedules may be necessary. Genotype surveillance is critically important to allow detection of any possible emergence of genotypes for which there is lower vaccine-derived immunity. Although Haemophilus influenzae type b disease rates have decreased significantly since the introduction of vaccines in 1993, the plateauing of rates in Aboriginal and Torres Strait Islander children, and increasing disparity with other children, are concerning. While it is possible that higher disease rates in young infants could be associated with the later age of protection from the newer 4-dose schedule, it is also possible that higher vaccine immunogenicity will result in reduced carriage. Close monitoring is important to detect any re-emergence of Hib disease as soon as possible. Pandemic and seasonal influenza and pneumonia are other diseases with comparatively higher rates in Aboriginal and Torres Strait Islander people. For Aboriginal and Torres Strait Islander people aged≥50 years, it is unclear whether or not there has been a decline in influenza hospitalisations since the start of the National Indigenous Pneumococcal and Influenza Immunisation Program in 1999, but hospitalisation rates are still higher in Aboriginal and Torres Strait Islander people. Achieving high coverage in those aged≥15 years should now be a priority. A prolonged mumps outbreak occurred in 2007/2008 predominantly affecting Aboriginal and Torres Strait Islander adolescents and young adults in north-western Australia. A potential contributor to this mumps outbreak was greater waning of immunity after receipt of the first dose of mumps-containing vaccine at 9, rather than 12, months of age in the Northern Territory in the 1980s and 1990s. However, outbreaks in Australia and overseas have subsided without additional boosters being routinely implemented. Pertussis epidemics continue to occur in Australia and affect both Aboriginal and Torres Strait Islander and other people. Parents are now encouraged to have their infant's first vaccination given at 6 weeks of age, instead of the usual 2 months, and this is being successfully implemented for Aboriginal and Torres Strait Islander and other infants. Timely provision of the 4- and 6-month doses remains very important. High coverage for standard vaccines, poor timeliness of vaccination and lower coverage for 'Indigenous only' vaccines are continuing features of vaccination programs for Aboriginal and Torres Strait Islander people. There have been some improvements in vaccination timeliness in recent years for all children, but disparities remain between Aboriginal and Torres Strait Islander and other children. Poor timeliness reduces the potential benefits of vaccination, most importantly for pneumococcal, Hib and rotavirus vaccines in infants. The age cut-offs for rotavirus vaccines present a particular challenge for timely vaccination, limiting the capacity for catching up on late vaccination and resulting in lower overall coverage. This is more pronounced for the 3-dose than for the 2-dose rotavirus schedule. Coverage for vaccines recommended only for Aboriginal and Torres Strait Islander children continues to remain substantially lower than that for universal vaccines. This underlines the importance of immunisation providers establishing the Indigenous status of their clients, so that additional vaccines are offered as appropriate. The absence of any coverage data for Aboriginal and Torres Strait Islander adolescents, or for adults since 2004/2005, is a substantial obstacle to implementing and improving programs in these age groups.


Repetition risk for adolescent self-poisoning: a multiple event survival analysis.
To examine risk factors associated with re-presentation (event rates) following an initial episode of hospital treated self-poisoning. A longitudinal cohort study using the Hunter Area Toxicology Service (HATS) database of all presentations to hospital of self-poisoned patients aged 10-19 in Newcastle and Lake Macquarie Regions of New South Wales from January 1991 to December 1995. The study factors were: age, gender, employment status, 'substance abuse' and psychiatric diagnosis at index (first documented episode during the study time-period) admission. The main outcome measure was re-presentations per unit time. Time-event analysis (multivariate) was used to compare re-presentation rates per person-year exposure to the study factors. There were 450 patients who presented on a total of 551 occasions. The median and modal age at initial presentation was 17. Three hundred and nine (69%) were female and 141 (31%) were male. The probability (95% CI) of a patient re-presenting within one year of an index admission with self poisoning was 0.09 (0.07-0.12) and within 5 years was 0.16 (0.12-0.21). The adjusted rate ratios for episodes of re-presentation were: any 'substance abuse (ever)' 3.87 (2.08-7.21), 'alcohol abuse' 2.32 (1.15-4.68),'benzodiazepine abuse' 4.89 (1.63-14.62), schizophrenia and other psychotic disorders (DSM-IV) 2.85 (1.2-6.79), and any personality disorder (DSM-IV) 2.68 (1.73-4.16). Interventions to decrease recurrence rates for adolescent self poisoning should be directed towards substance (particularly alcohol or benzodiazepine) abuse, non-affective psychoses and personality disorder.


How Fermentation Affects the Antioxidant Properties of Cereals and Legumes.
The major role of antioxidant compounds in preserving food shelf life, as well as providing health promoting benefits, combined with the increasing concern towards synthetic antioxidants, has led the scientific community to focus on natural antioxidants present in food matrices or resulting from microbial metabolism during fermentation. This review aims at providing a comprehensive overview of the effect of fermentation on the antioxidant compounds of vegetables, with emphasis on cereals- and legumes- derived foods. Polyphenols are the main natural antioxidants in food. However, they are often bound to cell wall, glycosylated, or in polymeric forms, which affect their bioaccessibility, yet several metabolic activities are involved in their release or conversion in more active forms. In some cases, the antioxidant properties in vitro, were also confirmed during in vivo studies. Similarly, bioactive peptides resulted from bacterial and fungal proteolysis, were also found to have ex vivo protective effect against oxidation. Fermentation also influenced the bioaccessibility of other compounds, such as vitamins and exopolysaccharides, enabling a further improvement of antioxidant activity in vitro and in vivo. The ability of fermentation to improve food antioxidant properties strictly relies on the metabolic activities of the starter used, and to further demonstrate its potential, more in vivo studies should be carried out.


Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease.
The aim of this study was to investigate changes in protein profiles during the early phase of dopaminergic neuronal death using two-dimensional gel electrophoresis in conjunction with mass spectrometry. Several protein spots were identified whose expression was significantly altered following treatment of MN9D dopaminergic neuronal cells with 6-hydroxydopamine (6-OHDA). In particular, we detected oxidative modification of thioredoxin-dependent peroxidases (peroxiredoxins; PRX) in treated MN9D cells. Oxidative modification of PRX induced by 6-OHDA was blocked in the presence of N-acetylcysteine, suggesting that reactive oxygen species (ROS) generated by 6-OHDA induce oxidation of PRX. These findings were confirmed in primary cultures of mesencephalic neurons and in rat brain injected stereotaxically. Overexpression of PRX1 in MN9D cells (MN9D/PRX1) exerted neuroprotective effects against death induced by 6-OHDA through scavenging of ROS. Consequently, generation of both superoxide anion and hydrogen peroxide following 6-OHDA treatment was decreased in MN9D/PRX1. Furthermore, overexpression of PRX1 protected cells against 6-OHDA-induced activation of p38 MAPK and subsequent activation of caspase-3. In contrast, 6-OHDA-induced apoptotic death signals were enhanced by RNA interference-targeted reduction of PRX1 in MN9D cells. Taken together, our data suggest that the redox state of PRX may be intimately involved in 6-OHDA-induced dopaminergic neuronal cell death and also provide a molecular mechanism by which PRX1 exerts a protective role in experimental models of Parkinson disease.


ALKemy to enhance chimeric antigen receptor T cell immunotherapy for neuroblastoma.
Chimeric antigen receptor (CAR) T cell immunotherapy in solid cancer is severely limited by the absence of ideal targets. In this issue of Cancer Cell, Bergaggio et al. find that anaplastic lymphoma kinase (ALK) inhibitors can enhance the function of ALK-specific CAR T cells against neuroblastoma by increasing target density in cancer cells.


Solid-phase synthesis for the identification of high-affinity bivalent lectin ligands.
The development of carbohydrate-based therapeutics has been frustrated by the low affinities that characterize protein-carbohydrate complexation. Because of the oligomeric nature of most lectins, the use of multivalency may offer a successful strategy for the creation of high-affinity ligands. The solid-phase evaluation of libraries of peptide-linked multivalent ligands facilitates rapid examination of a large fraction of linker structure space. If such solid-phase assays are to replicate solution binding behavior, the potential for intermolecular bivalent binding on bead surfaces must be eliminated. Here we report the solid-phase synthesis and analysis of peptide-linked, spatially segregated mono- and bivalent ligands for the legume lectin concanavalin A. Bead shaving protocols were used for the creation of beads displaying spatially segregated binding sequences on the surface of Tentagel resins. The same ligands were also synthesized on PEGA resin to determine the effect of ligand presentation on solid-phase binding. While we set out to determine the lower limit of assay sensitivity, the unexpected observation that intermolecular bivalent ligand binding is enhanced for bivalent ligands relative to monovalent ligands allowed direct observation of the level of surface blocking required to prevent intermolecular bivalent ligand binding. For a protein with binding sites separated by 65 A, approximately 99.9% of Tentagel(1) surface sites and 99.99% of the total sites on a PEGA bead must be blocked to prevent intermolecular bivalent binding. We also report agglutination and calorimetric solution-phase binding studies of mono- and bivalent peptide-linked ligands.


Massive modulation of brain areas after mechanical pain stimulation: a time-resolved FMRI study.
To date, relatively little is known about the spatiotemporal aspects of whole-brain blood oxygenation level-dependent (BOLD) responses to brief nociceptive stimuli. It is known that the majority of brain areas show a stimulus-locked response, whereas only some are characterized by a canonical hemodynamic response function. Here, we investigated the time course of brain activations in response to mechanical pain stimulation applied to participants' hands while they were undergoing functional magnetic resonance imaging (fMRI) scanning. To avoid any assumption about the shape of BOLD response, we used an unsupervised data-driven method to group voxels sharing a time course similar to the BOLD response to the stimulus and found that whole-brain BOLD responses to painful mechanical stimuli elicit massive activation of stimulus-locked brain areas. This pattern of activations can be segregated into 5 clusters, each with a typical temporal profile. In conclusion, we show that an extensive activity of multiple networks is engaged at different time latencies after presentation of a noxious stimulus. These findings aim to motivate research on a controversial topic, such as the temporal profile of BOLD responses, the variability of these response profiles, and the interaction between the stimulus-related BOLD response and ongoing fluctuations in large-scale brain networks.


Association of Second-Trimester Cervical Length With Prolonged Pregnancy.
To estimate whether there is an association between second-trimester cervical length and prolonged pregnancy (defined as delivery at or beyond 41 weeks of gestation). This is a cohort study of nulliparous women with a singleton pregnancy who underwent routine cervical length measurement between 18 and 24 weeks of gestation. Women were divided into quartiles by cervical length and the association with prolonged pregnancy was evaluated in bivariable and multivariable analyses. A planned secondary analysis included only women who achieved at least 39 weeks of gestation. During the study period, a total of 9,165 women met inclusion criteria, of whom 1,481 (16.2%) had a prolonged pregnancy. Women in increasing cervical length quartiles were more likely to experience a prolonged pregnancy (12.9%, 15.8%, 17.1%, 18.6%, P<.001). This association remained significant when controlling for possible confounding variables. An analysis confined to women who achieved at least 39 weeks of gestation was consistent with the overall analysis. Increasing second-trimester cervical length is associated with an increased likelihood of having a prolonged pregnancy in nulliparous women. II.


Acetabular stress fractures in military endurance athletes and recruits: incidence and MRI and scintigraphic findings.
To evaluate the incidence and the MRI and scintigraphic appearance of acetabular stress (fatigue) fractures in military endurance athletes and recruits. One hundred and seventy-eight active duty military endurance trainees with a history of activity-related hip pain were evaluated by both MRI and bone scan over a 2-year period. Patients in the study ranged in age from 17 to 45 years. They had hip pain related to activity and had plain radiographs of the hip and pelvis that were interpreted as normal or equivocal. The study was originally designed to evaluate the MRI and scintigraphic appearance of femoral neck stress fractures. Patients had scintigraphy and a limited MRI examination (coronal imaging only) within 48 h of the bone scan. Twelve patients demonstrated imaging findings compatible with acetabular stress fractures. Stress fractures are common in endurance athletes and in military populations; however, stress fracture of the acetabulum is uncommon. Twelve of 178 patients (6.7%) in our study had imaging findings consistent with acetabular stress fractures. Two patterns were identified. Seven of the 12 (58%) patients had acetabular roof stress fractures. In this group, two cases of bilateral acetabular roof stress fractures were identified, one with a synchronous tensile sided femoral neck stress fracture. The remaining five of 12 (42%) patients had anterior column stress fractures, rarely occurring in isolation, and almost always occurring with inferior pubic ramus stress fracture (4 of 5, or 80%). One case of bilateral anterior column stress fractures was identified without additional sites of injury. Stress fractures are commonplace in military populations, especially endurance trainees. Acetabular stress fractures are rare and therefore unrecognized, but do occur and may be a cause for activity-related hip pain in a small percentage of military endurance athletes and recruits.