Brief exposure to female odors "emboldens" male mice by reducing predator-induced behavioral and hormonal responses.
In rodents, where chemical signals play a particularly important role in determining intersexual interactions, various studies have shown that male behavior and physiology is sensitive to female odor cues. Here we examined the effects of brief (1 min) and more prolonged (60 min) preexposure to the odors of a novel estrous female on the behavioral and hormonal responses of sexually experienced and inexperienced male mice, Mus musculus, to subsequent predator (cat and weasel) odor exposure and potential predator risk. Brief, but not prolonged, preexposure to the odors of an estrous female decreased the aversion and avoidance responses of male mice to cat odor in a Y-maze preference test, with the extent of responses being affected by a males prior sexual experience. Similarly, brief, but not prolonged, preexposure to female odors markedly attenuated the analgesic responses elicited in male mice by weasel odor. Brief exposure to a novel estrous female by itself had no significant immediate effects on either corticosterone or testosterone levels in the males. However, brief, but not prolonged, preexposure to the odors of an estrous female attenuated the marked increase in corticosterone and decrease in testosterone that were induced in males by exposure to weasel odor. The decreases in aversive responses to, and effects of, predator odor exposure that are induced by brief exposure to a novel estrous female may reflect a greater risk taking and boldness in males that could directly facilitate access to an immediately, and possibly transiently, available novel sexually receptive female.


The Brugada syndrome.
The Brugada syndrome is an inherited cardiac disorder initially described in 1992 by Pedro and Josep Brugada, with variable electrocardiographic features characteristic of right bundle-branch block, persistent ST-segment elevation in the precordial leads (VI-V3) at rest and sudden cardiac death. The genetic abnormalities that cause Brugada syndrome have been linked to mutations in the ion channel gene SCN5A which encodes for the alpha-subunit of the cardiac sodium channel. A consensus conference report published in 2002 described the diagnostic criteria for the Brugada syndrome and described the three distinct types of Brugada syndrome. In 2005, a second consensus report was published which described the risk stratification and approaches to therapy. Two specific types of ST-segment elevation, coved and saddleback, are observed in the Brugada syndrome, the former of which is reported to relate to a higher incidence of ventricular tachycardial ventricular fibrillation (VTNF) and sudden cardiac death.The objective of this paper is to review the genetics and the molecular biology behind the Brugada syndrome, the diagnostic criteria, including clinical and electrocardiographic characteristics, and current management.


Identification of mouse genes with highly specific expression patterns in differentiated intestinal epithelium.
Few genes that regulate intestinal epithelium development, homeostasis, or function are known. We reasoned that potential candidate regulators of these processes could be identified based on their activation during intestinal epithelium development and their subsequent specific and restricted expression. Genes were identified by differential display and microarray analyses, further selected according to sequence and UniGene expression profiles, and analyzed by RNA in situ hybridization of mouse fetal and adult intestines and in intestinal polyp tissue. Five genes with unknown physiological function predominantly or exclusively expressed in the intestinal epithelium were identified. Their expression is activated at distinct times during intestinal development and maturation and is maintained in highly specific, spatially distinct patterns in the adult intestinal epithelium. Two of the genes were up-regulated in intestinal tumors, 1 was down-regulated, and 2 were apparently unaltered. Based on sequence and expression, the identified genes represent good candidates for regulators of intestinal epithelium integrity or function. Their expression patterns suggest a morphologically not obvious molecular regionalization of the intestinal epithelium along the crypt villus axis. This approach should be an efficient means to identify novel genes required for intestinal epithelium homeostasis and function.


[X-ray- and other medical imaging in Iceland 1993. Assessed and compared with earlier surveys.].
A country-wide survey of the use and utilization of medical imaging in Iceland was undertaken, by gathering of available information for the year 1993. The aim was primarily to assess the overall consumption of these services, with regard to radiation and the impact of other imaging modalities. Reference was made to earlier studies of the same kind adding a more specified break-down of information regarding age and sex as well as types of examination. The results are presented in tables and figures with accompanying text in English. The conclusions may be summed up as follows: 1: The average yearly increase in diagnostic imaging using ionizing radiation for the past 10 years was 1.7%, whereas the total average yearly increase of diagnostic imaging was 3.6%. This difference may be almost exclusively attributed to the increase in the use of ultrasound. 2: Although x-ray facilities are quite widely distributed, mainly due to geographic reasons, the main bulk of all examinations are made in a few specialised departments, and 92.8% of all examinations made are supervised by specialists in radiology, either directly or by consultation. 3: The overall number of examinations per 1000 population was 680, having increased from 555 in 1984. Comparable figures (1990) were 800 in the U.S. and 465 in the U.K.


Apparent accommodation in pseudophakic eyes after implantation of posterior chamber intraocular lenses: optical analysis.
The authors measured apparent accommodation in 39 pseudophakic eyes (31 patients) after implantation of posterior chamber intraocular lenses. The mean apparent accommodation was 2.01 +/- 0.95 D. The authors also measured each patient's pupillary diameter, anterior chamber depth, and corneal refractive power to calculate the factor that represents the depth of field. The authors found a significant correlation between apparent accommodation and depth of field. The correlation between apparent accommodation and calculated depth of field is statistically significant (r = 0.48, P less than 0.005).


Prediction of tyrosine sulfation sites in animal viruses.
Post-translational modification of proteins by tyrosine sulfation enhances the affinity of extracellular ligand-receptor interactions important in the immune response and other biological processes in animals. For example, sulfated tyrosines in polyomavirus and varicella-zoster virus may help modulate host cell recognition and facilitate viral attachment and entry. Using a Position-Specific-Scoring-Matrix with an accuracy of 96.43%, we analyzed the possibility of tyrosine sulfation in all 1517 animal viruses available in the Swiss-Prot database. From a total of 97,729 tyrosines, we predicted 5091 sulfated tyrosine sites from 1024 viruses. Our site predictions in hemagglutinin of influenza A, VP4 of rotavirus, and US28 of cytomegalovirus strongly suggest an important link between tyrosine sulfation and viral disease mechanisms. In each of these three viral proteins, we observed highly conserved amino acid sequences surrounding predicted sulfated tyrosine sites. Tyrosine sulfation appears to be much more common in animal viruses than is currently recognized.


Immediate implant placement in molar regions: risk factors for early failure.
To identify risk factors for early failure of immediately placed implants in molar regions associated with three bone regenerative techniques. Ninety-two patients (44 women and 48 men; mean age 50 years, 35 smokers and 57 non-smokers) in need of a single implant crown to replace a molar were included. After placing the implant, patients were randomized to one of three treatment groups for bone reconstruction of remaining periimplant defects: Autologous bone (AB) chips, Ossix membrane (OM) or a combination of AB chips and OM. The implant was submerged, and after 4 months of healing a re-entry surgery was made to connect a healing abutment. Implants with a dehiscence on ≥2 sites (mesial/distal/oral/buccal) together with ≥50% visible threads, were judged as failures. A series of simple logistic regression analyses were performed to identify risk factors for failure among the following independent variables: sex, jaw, smoking status, plaque, bleeding on probing, fistula, extraction reason, mean initial periimplant defect size, treatment group, implant length, buccal bone dehiscence (BBD), soft-tissue dehiscence and infection. The identified risk factors entered a multiple logistic regression analysis. Fifteen implants failed before abutment operation (13 explantations/two non-osseointegrated). Treatment group had no impact on failure. Risk factors for failure were: Smoking >10 cigarettes/day (odds ratio [OR]=9.29, confidence interval [CI]=1.21-71.16), BBD (OR=11.43, CI=1.34-97.74) and infection (OR=36.7, CI=2.75-489.31). Implants placed immediately after extraction of a molar were associated with a high risk for failure at abutment operation. There was no difference in failure rate between three bone reconstructive techniques.


Efficient degradation of imipramine by iron oxychloride-activated peroxymonosulfate process.
Synthesized iron oxychloride (FeOCl) was firstly applied to activate peroxymonosulfate (PMS) to degrade imipramine (IMI), a tricyclic antidepressant. Compared to some other Fe-based materials including zero valent iron, Fe2O3, Fe3O4 and ferric ions, FeOCl presented an impressive catalytic activity on PMS at near-neutral condition due to its unique structure containing abundant unsaturated iron atoms and oxo-bridged configuration. With an increase of FeOCl dose, PMS dose or initial pH in ranges of 0.02 - 0.5 g/L, 0.1 - 2.5 mM and 4.0 - 8.0, the degradation efficiency of IMI was effectively raised by 64.0%, 48.5% and 50.6%, respectively. The presence of either bicarbonate or chloride stimulated the removal of IMI. Moreover, 70.4% of IMI was degraded under the background of real water with 2 mM PMS. The possible reactive species were identified as sulfate and hydroxyl radicals. The formed hypochlorite through the reaction of PMS and the released chloride ions may also contribute to the degradation of IMI. Among the oxidants, sulfate radical was proven to be the dominate one in the system. Additionally, the FeOCl/PMS system can overall effectively degrade six other organic compounds including amitriptyline, desipramine, propranolol, nitrobenzene, methyl-paraben and ethyl-paraben, further suggesting the possible application of this system in treatment of vast aquatic micro-organic pollutants.


Screw- versus cement-retained implant restorations: current concepts.
The debate between screw- versus cement-retained implant prostheses has long been discussed but the best type of implant prosthesis remains controversial among practitioners. An understanding of their properties will help the clinician in selecting the ideal prosthesis for each clinical case while promoting final esthetic outcomes. With the evolving technology and knowledge, an update of the current trends is necessary. This article provides an overview of the different characteristics of screw- and cement-retained implant restorations, and how they may influence the esthetics, retrievability, retention, passivity, occlusion, accessibility, cost, and provisional restorations. Problems and complications frequently encountered are discussed and treatment solutions are proposed.


[The role of mitogen-activated protein kinases family in ischemic preconditioning of rat heart].
To investigate the cardioprotective effect of mitogen-activated protein kinases (MAPKs) of ischemic preconditioning (IPC) in rat heart. In the model of ischemia/reperfusion (I/R) of isolated perfused SD rat heart, the effect of IPC on I/R injury was observed. The activities of MAPK family members, ERKs, p38 and SAPK, and their relationship with IPC phenomenon were also observed. IPC significantly improved myocardial functions in heart subjected to I/R injury, and attenuated leakage of myocardial creatine kinase and depletion of ATP. IPC activated ERK and p38 kinase. Their activities were increaed by 73% (P < 0.01) and 69% (P < 0.01) respectively. However, IPC showed no effect on myocardial SAPK activity. Preparation with genistein (an inhibitor of tyrosine kinase) and PD098059 (an inhibitor of ERK) abolished IPC cardioprotection, while p38 kinase inhibitor SB202190 had no effect on IPC. ERKs, but not p38 and SAPK of MAPK, mediates the IPC cardioprotective effect.


Ultrafast Through-Space Electronic Energy Transfer in Molecular Dyads Built around Dynamic Spacer Units.
A pair of complementary molecular dyads have been synthesized around a 1,2-diaminocyclohexyl spacer that itself undergoes ring inversion. Despite these conformational exchange processes, the donor and acceptor occupy quite restricted spatial regions, and they are not interchangeable. The donor and acceptor pair comprise disparate boron dipyrromethene dyes selected to display favorable electronic energy transfer (EET). Steady-state emission spectroscopy confirms that through-space EET from donor to acceptor is almost quantitative, aided by the relatively short separations. Ultrafast time-resolved fluorescence spectroscopy has allowed determination of the rates of EET for both dyads. Surprisingly, in view of the close proximity of donor and acceptor (center-to-center separations less than 20 Å), the EET dynamics are well-accounted for in terms of the computed molecular conformations and conventional Förster theory. One dyad appears as a single family of conformations, but EET for the second dyad corresponds to dual-exponential kinetics. In this latter case, an intramolecular hydrogen bond helps stabilize an open geometry, wherein EET is relatively slow.


Increasing lay-people's intentions to initiate CPR in out of hospital cardiac arrest: Results of a mixed-methods 'before and after' pilot study of a behavioural text-message intervention (BICeP).
Prompt, effective cardio-pulmonary resuscitation (CPR) increases survival in out-of-hospital cardiac arrest. However, CPR is often not provided, even by people with training. Low confidence, perceptions of risks and high emotion can prevent initiation of CPR. Behaviour-change techniques may be helpful in increasing CPR rates. To pilot a text-message behavioural intervention designed to increase intentions to initiate CPR, explore participant responses and pilot methods for future randomised controlled trial of effectiveness. A 'before and after' pilot study plus qualitative interviews was undertaken. Participants were lay-people who had undertaken CPR training in previous 2 years.Participants were sent an intervention, comprising 35 text-messages containing 14 behaviour-change techniques, to their mobile phone over 4-6 weeks.Primary outcome: intentions to initiate CPR assessed in response to 4 different scenarios.Secondary outcomes: theory-based determinants of intention (attitudes, subjective norms, perceived behavioural control and self-efficacy) and self-rated competence. 20 participants (6 female, 14 male), aged 20-84 provided baseline data. 17 received the full suite of 35 text messages.15 provided follow-up data. Intentions to perform CPR in scenarios where CPR was indicated were high at baseline and increased (18.1 ± 3.2-19.5 ± 1.8/21) after the intervention, as did self-efficacy and self-rated competency. Self-efficacy, attitudes, perceived behavioural control and subjective norms were positively correlated with intentions. Qualitative data suggest the intervention was perceived as useful. Additional options for delivery format and pace were suggested. Pilot-testing suggests a text-message intervention delivered after CPR training is acceptable and may be helpful in increasing/maintaining intentions to perform CPR.


First East Asian record of the genus Alpagut (Hemiptera: Heteroptera: <br />Dipsocoridae), with description of a new species and a note on the metacoxal adhesive pad of Dipsocoridae.
The genus Alpagut Kıyak, 1995, is recorded from East Asia for the first time based on the description of A. masakazui sp. nov. from Japan. Habitus images and illustrations of diagnostic features, including genitalia structures, are provided. The loculus capsulae of A. masakazui sp. nov. is discussed. The presence of a metacoxal adhesive pad is reconfirmed in Dipsocoridae along with a discussion of its morphology.


Changes in Stepparents' Coparenting and Parenting Following Participation in a Community-Based Relationship Education Program.
Studies of coparents typically center on the relationship between parents who share a biological child; limited attention in research on community-based programs is given to the coparenting relationship within a stepfamily, even though clinicians note the challenges inherent in this relationship. We examined changes in coparenting agreement, parenting efficacy, and parental involvement for 96 stepparents following participation in a coparenting-focused community education program. A significant main effect of time was found for improvement in coparenting agreement, yet a significant time × gender interaction effect suggests that this is driven by improvements for stepmothers only. Parenting efficacy improved, regardless of gender, race, residence, or curriculum. A significant time × race interaction effect on change in parental involvement indicates increases in parental involvement for European American participants only. Finally, increases in coparenting agreement were associated with increases in parenting efficacy, and increases in parenting efficacy were associated with increases in parental involvement.


Confinement effects on the thermodynamics of protein folding: Monte Carlo simulations.
The effects of chaperonin-like cage-induced confinement on protein stability have been studied for molecules of varying sizes and topologies. Minimalist models based on Gō-like interactions are employed for the proteins, and density-of-states-based Monte Carlo simulations are performed to accurately characterize the thermodynamic transitions. This method permits efficient sampling of conformational space and yields precise estimates of free energy and entropic changes associated with protein folding. We find that confinement-driven stabilization is not only dependent on protein size and cage radius, but also on the specific topology. The choice of the confining potential is also shown to have an effect on the observed stabilization and the scaling behavior of the stabilization with respect to the cage size.


Characteristics and Outcomes of Cancer Patients With Venous Thromboembolic Events After Treatment With Immune Checkpoint Inhibitors.
This study aimed to describe the clinical characteristics and outcomes of patients with venous thromboembolism (VTE) after Immune checkpoint inhibitors (ICI), focusing on patients with gastrointestinal (GI) immune-related adverse events (irAE). In this retrospective, single-center study, we report the clinical outcomes of adult cancer patients who developed a VTE within 2 years of ICI initiation. Patients were excluded if alternate causes of VTE were present apart from malignancy and cancer therapy. The cohort was classified into those with GI-irAE, non-GI-irAE, and no irAE. A control group with ICI exposure without irAE and VTE was selected for comparative analysis. Of all ICI-treated patients, 1891 (17.2%) were diagnosed with VTE. In all, 501 (4.6%) had no etiology for VTE aside from malignancy and cancer therapy. Of these, 137 patients were included and classified as: 44 GI-irAE, 42 non-GI-irAE, and 51 no irAE. Chemotherapy within 6 months of ICI therapy was associated with increased VTE risk. There was no difference in the clinical course between those exposed to chemotherapy versus ICI therapy alone, time from ICI initiation to VTE, and VTE type, recurrence, or related hospitalization. While there was no difference in VTE-related mortality, the GI-irAE group was associated with lower all-cause mortality and superior overall survival. Combined ICI and chemotherapy use increased VTE risk. There is a similar disease course of VTE after ICI exposure, regardless of other irAEs. Co-existing GI-irAE with VTE is associated with superior overall survival. Prospective studies are needed to evaluate the relationship between ICI therapy and VTE and irAE impact on VTE outcomes.


The bioactive acidic serine- and aspartate-rich motif peptide.
The organic component of the bone matrix comprises 40% dry weight of bone. The organic component is mostly composed of type I collagen and small amounts of non-collagenous proteins (NCPs) (10-15% of the total bone protein content). The small integrin-binding ligand N-linked glycoprotein (SIBLING) family, a NCP, is considered to play a key role in bone mineralization. SIBLING family of proteins share common structural features and includes the arginine-glycine-aspartic acid (RGD) motif and acidic serine- and aspartic acid-rich motif (ASARM). Clinical manifestations of gene mutations and/or genetically modified mice indicate that SIBLINGs play diverse roles in bone and extraskeletal tissues. ASARM peptides might not be primary responsible for the functional diversity of SIBLINGs, but this motif is suggested to be a key domain of SIBLINGs. However, the exact function of ASARM peptides is poorly understood. In this article, we discuss the considerable progress made in understanding the role of ASARM as a bioactive peptide.


Single-Molecule Co-Immunoprecipitation Reveals Functional Inheritance of EGFRs in Extracellular Vesicles.
Cancer cells actively release extracellular vesicles (EVs) as important carriers of cellular information to tumor microenvironments. Although the composition and quantity of the proteins contained in EVs are characterized, it remains unknown how these proteins in EVs are related to those in the original cells at the functional level. With epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells as a model oncoprotein, it is studied how distinct types of EVs, microvesicles and exosomes, represent their original cells at the protein and protein-protein interaction (PPI) level. Using the recently developed single-molecule immunolabeling and co-immunoprecipitation schemes, the quantity and PPI strengths of EGFRs derived from EVs and the original lung adenocarcinoma cells are determined. It is found that the microvesicles exhibit higher correlations with the original cells than the exosomes in terms of the EGFR levels and their PPI patterns. In spite of these detailed differences between the microvesicles and exosomes, the EGFR PPI strengths measured for EVs generally show a tight correlation with those determined for the original cells. The results suggest that EGFRs contained in EVs closely reflect the cellular EGFR in terms of their downstream signaling capacity.


The N314D polymorphism of the GALT gene is not associated with congenital absence of the uterus and vagina.
The aetiology of anomalous embryonic and fetal development of the female reproductive tract, ranging from common uterine abnormalities to the somewhat rare congenital absence of the uterus and vagina (CAUV), is unknown. Some have proposed that abnormal galactose metabolism might cause CAUV. An association between CAUV and the N314D allele of the galactose-1-phosphate uridyl transferase (GALT) gene has been proposed as aetiological. We tested this hypothesis further by performing a case-control molecular study analysing 32 patients with CAUV for the presence of the N314D allele. These patients were compared with 138 normal controls. No association between CAUV and the N314D polymorphism was found (P = 0.32). It is unlikely that either maternal or fetal GALT enzyme activity could affect paramesonephric duct development, because neither galactosaemic subjects nor their children have an increased incidence of uterine anomalies.


Morphology, cytochemical staining, and ultrastructural characteristics of the blood cells of the giant lizard of El Hierro (Gallotia simonyi).
The object of this study was to examine the erythrocytes, leukocytes and thrombocytes of the giant lizard of El Hierro (Gallotia simonyi) by light and electron (TEM) microscopy, and cytochemical staining. Smears were prepared from blood from the ventral coccygeal vein of 10 healthy adult lizards (five males and five females) from the Giant Lizard of El Hierro Reproduction and Research Centre, Canary Islands, Spain. The cytochemical stains used were: benzidine peroxidase (BP), chloroacetate esterase (CAE), alpha-naphthyl acetate esterase (ANAE), acid phosphatase (AP), periodic acid-Schiff (PAS), toluidine blue (TB) and May-Grünwald-Giemsa (MGG). Electron microscopy was also performed on all samples. Heterophils had granules that were heterogeneous in both size and electron density, and stained with BP, PAS and ANAE. Eosinophil granules were homogeneously electron-dense and stained for AP, CAE and ANAE. Basophils had both highly and moderately electron-dense granules, and stained with TB and ANAE. Azurophil granules were of low electron-density and stained for AP, CAE and ANAE. Azurophil cytoplasm was vacuolated on TEM. The cytoplasm of lymphocytes contained many ribosomes and was positive for AP. Monocytes had a large nucleus and a vacuolated cytoplasm but did not stain by any of the cytochemical methods used. Thrombocytes had a relatively large nucleus but little cytoplasm; they did not stain cytochemically. The blood cells of the giant lizards of El Hierro differ from those of other members of the Order Squamata both morphologically and cytochemically. The variation in cytochemical responses in the blood of reptiles makes it necessary to study species individually if meaningful clinical decisions are to be made.


Peripheral NLCR4 inflammasome participates in the genesis of acute inflammatory pain.
Inflammatory hyperalgesia is a complex process that depends on the sensitization of primary nociceptive neurons triggered by proinflammatory mediators, such as interleukin 1β (IL-1β). Recently, the peripheral activation of caspase-1 (previously known as IL-1β-converting enzyme) was implicated in the induction of acute inflammatory pain by promoting the processing of IL-1β from its precursor form, pro-IL-1β. Caspase-1 activation in several systems requires the assembly of an intracellular molecular platform called an inflammasome. Inflammasomes consist of 1 nucleotide-binding oligomerization domain-like receptor (NLR), the adapter molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), and caspase-1. NLRP3 and NLRC4 inflammasomes are well described. However, the identity of the inflammasome that is involved in the peripheral activation of caspase-1 that accounts for acute inflammatory hyperalgesia has not been described. The present findings demonstrated that mice deficient in NLRC4 or ASC, but not in NLRP3, present reduced mechanical and thermal acute inflammatory hyperalgesia induced by carrageenan. The reduced hyperalgesia was accompanied by significant impairments in the levels of mature forms of IL-1β (p17) and caspase-1 (p20) compared to wild-type mice at the inflammatory site. Therefore, these results identified the inflammasome components NLRC4 and ASC as the molecular platform involved in the peripheral activation of caspase-1 and IL-1β maturation, which are responsible for the induction of acute inflammatory pain. In conclusion, our study provides new therapeutic targets for the control of acute inflammatory pain.


Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer.
Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers. SIGNIFICANCE: Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.


Development of a Nanostructured RNA/DNA Assembly as an Adjuvant Targeting Toll-Like Receptor 7/8.
Adjuvants are essential for efficiently inducing an antigen-specific immune response in vaccine therapy. Single-stranded RNA (ssRNA) containing guanosine- and uridine-rich sequences is recognized by Toll-like receptor (TLR)7 and/or TLR8 and induces strong immune responses; thus, the application of ssRNA as an adjuvant is desirable. The development of a ssRNA-based adjuvant, however, requires the efficient delivery of ssRNA into the endosomes of antigen-presenting cells, where the TLRs exist. To achieve this, we developed a nanostructured RNA/DNA assembly using DNA nanotechnology, which can be efficiently recognized by antigen-presenting cells. The nanostructured RNA/DNA assembly, named tetrapodRD3, was designed using a 40-mer phosphorothioate-stabilized RNA and three 40-mer phosphodiester DNAs. TetrapodRD3 was more stable than ssRNA under serum conditions. The secreted alkaline phosphatase assay using HEK-Blue hTLR cells showed that tetrapodRD3 triggered human TLR8-specific responses. Fluorescently labeled tetrapodRD3 was efficiently taken up by murine dendritic DC2.4 cells and induced a high level of tumor necrosis factor-α release from the cells. Antigen presentation by the major histocompatibility complex class I on bone marrow-derived dendritic cells was significantly increased by the addition of an antigen along with tetrapodRD3. These results indicate that tetrapodRD3 constructed using DNA nanotechnology can be a useful adjuvant targeting human TLR8.


Genetic polymorphisms of MTHFR and aberrant promoter hypermethylation of the RASSF1A gene in bladder cancer risk in a Chinese population.
Epidemiological studies have shown that folate deficiency increases the risk of cancer by affecting DNA repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. In this study, it was hypothesized that MTHFR (C677T and A1298C) polymorphisms would be associated with bladder cancer and also with hypermethylation of the promoter of the Ras association domain family 1A (RASSF1A) gene. This hospital-based, case-control study of 312 bladder cancer patients and 325 cancer-free controls found that individuals carrying the MTHFR 677TT genotype had a 2.00-fold increased risk of bladder cancer compared with those carrying the 677CC genotype. None of the MTHFR A1298C polymorphisms alone were associated with bladder cancer, but the combined haplotype 677TT/1298AA was associated with a 2.27-fold increased risk compared with haplotype 677CC/1298AA. There was no association between MTHFR gene variants and methylation status of the RASSF1A gene in the 45 bladder cancer patients in whom this was studied. It is concluded that the MTHFR 677TT genotype and the TTAA haplotype may increase the risk of bladder cancer.


Suppression of ASKβ (AtSK32), a Clade III Arabidopsis GSK3, Leads to the Pollen Defect during Late Pollen Development.
Arabidopsis Shaggy-like protein kinases (ASKs) are Arabidopsis thaliana homologs of glycogen synthase kinase 3/SHAGGY-like kinases (GSK3/SGG), which are comprised of 10 genes with diverse functions. To dissect the function of ASKβ (AtSK32), ASKβ antisense transgenic plants were generated, revealing the effects of ASKβ down-regulation in Arabidopsis. Suppression of ASKβ expression specifically interfered with pollen development and fertility without altering the plants' vegetative phenotypes, which differed from the phenotypes reported for Arabidopsis plants defective in other ASK members. The strength of these phenotypes showed an inverse correlation with the expression levels of ASKβ and its co-expressed genes. In the aborted pollen of ASKβ antisense plants, loss of nuclei and shrunken cytoplasm began to appear at the bicellular stage of microgametogenesis. The in silico analysis of promoter and the expression characteristics implicate ASKβ is associated with the expression of genes known to be involved in sperm cell differentiation. We speculate that ASKβ indirectly affects the transcription of its co-expressed genes through the phosphorylation of its target proteins during late pollen development.


A possible role of prolactin in preventing heartburn during pregnancy.
Although heartburn, thought to indicate reflux of gastric contents into the oesophagus, occurs frequently in pregnant women during the last trimester, its aetiology is not clear. Prolactin blood concentrations rise progressively during pregnancy and heartburn is known to disappear spontaneously during the last weeks of pregnancy. In view of this and other factors, motility studies and estimation of serum prolactin levels were carried out on 20 pregnant Black women. Results show that patients with prolactin levels over 3,000 microunits/ml had significantly higher mean barrier presures (sphincter pressure-gastric pressure) than the patients with hormone levels of less than 3,000 microunits/ml (P less than 0,02). No direct correlation could, however, be demonstrated between barrier pressures and prolactin levels (r = 0,3494). It is concluded that further studies would seem to be indicated on an animal model to establish the importance of prolactin in the regulation of the lower oesophageal sphincter tone.


Enhancing Braden pressure ulcer risk assessment in acutely ill adult veterans.
This study sought to determine if a parsimonious pressure ulcer (PU) predictive model could be identified specific to acute care to enhance the current PU risk assessment tool (Braden Scale) utilized within veteran facilities. Factors investigated include: diagnosis of gangrene, anemia, diabetes, malnutrition, osteomyelitis, pneumonia/pneumonitis, septicemia, candidiasis, bacterial skin infection, device/implant/graft complications, urinary tract infection, paralysis, senility, respiratory failure, acute renal failure, cerebrovascular accident, or congestive heart failure during hospitalization; patient's age, race, smoking status, history of previous PU, surgery, hours in surgery; length of hospitalization, and intensive care unit days. Retrospective chart review and logistic regression analyses were used to examine Braden scores and other risk factors in 213 acutely ill veterans in North Florida with (n = 100) and without (n = 113) incident PU from January-July 2008. Findings indicate four medical factors (malnutrition, pneumonia/pneumonitis, candidiasis, and surgery) have stronger predictive value (sensitivity 83%, specificity 72%, area under receiver operating characteristic [ROC] curve 0.82) for predicting PUs in acutely ill veterans than Braden Scale total scores alone (sensitivity 65%, specificity 70%, area under ROC curve 0.70). In addition, accounting for four medical factors plus two Braden subscores (activity and friction) demonstrates better overall model performance (sensitivity 80%, specificity 76%, area under ROC curve 0.88).


Immune complexes in progressive systemic sclerosis (scleroderma).
Serum immune complexes were measured in 92 patients with progressive systemic sclerosis, and elevated levels were found as follows: Raji cell assay 72% (59% after pronase treatment of Raji cell), agarose gel electrophoresis 52%, and C1q binding 24%. Forty-three (47%) had abnormal results on two or more of these tests, but only 17 (18%) had normal results by all three assays. Computer-assisted analysis of immune complex results and extensive clinical and laboratory data compiled on these patients revealed that the patients with abnormal Raji cell assays more often had diffuse scleroderma, tendon friction rubs, and positive serum antinuclear antibody tests than did patients with negative results on Raji cell assays. Individuals with immune complexes detected by C1q binding had evidence of pulmonary involvement and positive serum rheumatoid factor more frequently than did patients whose C1q tests were negative.


Practical approaches to effective family intervention after brain injury.
Rehabilitation professionals have become increasingly aware that traumatic brain injury has a long-term adverse impact on family members as well as on survivors. Family members often have a critical supporting role in the recovery process, and researchers have identified a relationship between caregiver well-being and survivor outcome. Drawing from the fields of family therapy, cognitive-behavioral therapy, and individual psychotherapy, this article provides information to help clinicians effectively serve families. First, historically important and widely cited publications are reviewed and their implications for practice are discussed. Recommendations for developing successful therapeutic alliances are provided along with a rationale for their importance. Descriptions of common challenges and issues faced by families are presented along with corresponding therapeutic goals. Intervention principles and strategies, selectively chosen to help family members achieve therapeutic goals, are discussed. The article concludes with a presentation of ideas to help practitioners and systems of care more effectively help family members adjust and live fulfilling lives.


Severe convulsant hypomagnesaemia and short bowel syndrome.
Hypomagnesaemia as a primary cause of a generalized seizure is uncommon. A 60-year-old woman with Crohn's disease, who had had recent small bowel surgery and a total colectomy 10 years previously, was admitted complaining of severe nausea, vomiting, fatigue and thirst. Despite oral magnesium therapy she had a generalized seizure due to severe hypomagnesaemia of 0.09 mmol/l (normal range 0.65 to 1.05 mmol/l). Her serum calcium was 1.91 mmol/l (2.03 to 2.63 mmol/l). Hypomagnesaemia can cause generalized convulsions but is usually associated with hypocalcaemia. This patient had an almost normal serum calcium level, and therefore hypomagnesaemia would seem to have been the direct cause of her seizure. Long-term intravenous magnesium was necessary to prevent further seizures.


Reliability and validity of the Glittre-ADL test to assess the functional status of patients with interstitial lung disease.
The study objective was to investigated the reliability and validity of the ADL-Glittre test (TGlittre) to assess the functional status of patients with interstitial lung disease (ILD). Twenty-one individuals with ILD participated (age: 63 ± 11 years; DLCO: 51.0 ± 12.6%predicted), evaluated with body plethysmography, Saint George Respiratory Questionnaire, modified Medical Research Council dyspnea scale, six-minute walk test (6MWT) and monitoring of physical activity of daily living. Two TGlittre were performed, with an interval of 30 minutes between them. The TGlittre demonstrated high test-retest reliability, with an intraclass correlation coefficient of 0.90 (95%CI: 0.75-0.96; p < 0.001). Nineteen patients (90.5%) performed better on the second test (mean difference between TGlittre 1 and 2: -0.57 ± 0.96 minute; p = 0.001), with a learning effect of 11.6%. The time in TGlittre correlated with 6MWT (r = -0.70; p = 0.002) and with the total energy expenditure in physical activity of daily living (r = -0.52; p = 0.02). In %predicted, TGlittre and 6MWT also correlated (r = -0.50; p = 0.04). Correlations were observed between TGlittre and pulmonary function variables (r = -0.47 to -0.57; p = 0.01 to p = 0.04). There was no difference in the physiological response between TGlittre 1 and 2, and between TGlittre and 6MWT (p > 0.05). In conclusion, the TGlittre is reliable and valid for assessing functional status of patients with ILD.


Staphylococcus argenteus from rabbits in Thailand.
Staphylococcus argenteus, a novel species of the genus Staphylococcus or a member of the S. aureus complex, is closely related to S. aureus and is usually misidentified. In this study, the presence of S. argenteus in isolated S. aureus was investigated in 67 rabbits with abscess lesions during 2014-2016. Among 19 S. aureus complex isolates, three were confirmed to be S. argenteus by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, nonribosomal peptide synthetase gene amplification, and multilocus sequence type. All S. aureus complex isolates, including the S. aureus isolates, were examined for their antimicrobial resistance phenotype by disk diffusion and for their resistance genotype by PCR assays. Among the S. argenteus isolates, one was susceptible to all antimicrobial drugs and the other two were resistant to penicillin and doxycycline. In contrast, most S. aureus isolates were resistant to penicillin (37.5%), and gentamicin (12.5%). Moreover, S. aureus isolates harbored the blaZ, mecA, aacA-aphD, and mrs(A) as well as mutations of gyrA and grlA, but S. argenteus isolates carried solely the blaZ. S. argenteus isolates were investigated for enterotoxin (sea-sed) and virulence genes by PCR. One isolate carried sea, sec, and sed, whereas the other two isolates carried only sea or sed. No isolate carried seb and see. All three S. argenteus isolates carried hla, hlb, and clfA, followed by pvl, whereas coa, spa (IgG-binding region), and spa (x region) were not detected in the three isolates. This paper presents the first identification of S. argenteus from rabbits in Thailand. S. argenteus might be pathogenic because the isolates carried virulence genes. Moreover, antimicrobial resistance was observed. Investigations of this new bacterial species should be conducted in other animal species as well as in humans.


Auditory-Motor Mapping Training in a More Verbal Child with Autism.
We tested the effect of Auditory-Motor Mapping Training (AMMT), a novel, intonation-based treatment for spoken language originally developed for minimally verbal (MV) children with autism, on a more-verbal child with autism. We compared this child's performance after 25 therapy sessions with that of: (1) a child matched on age, autism severity, and expressive language level who received 25 sessions of a non-intonation-based control treatment Speech Repetition Therapy (SRT); and (2) a matched pair of MV children (one of whom received AMMT; the other, SRT). We found a significant Time × Treatment effect in favor of AMMT for number of Syllables Correct and Consonants Correct per stimulus for both pairs of children, as well as a significant Time × Treatment effect in favor of AMMT for number of Vowels Correct per stimulus for the more-verbal pair. Magnitudes of the difference in post-treatment performance between AMMT and SRT, adjusted for Baseline differences, were: (a) larger for the more-verbal pair than for the MV pair; and (b) associated with very large effect sizes (Cohen's d > 1.3) in the more-verbal pair. Results hold promise for the efficacy of AMMT for improving spoken language production in more-verbal children with autism as well as their MV peers and suggest hypotheses about brain function that are testable in both correlational and causal behavioral-imaging studies.


Low incidence of severe respiratory syncytial virus infections in lung transplant recipients despite the absence of specific therapy.
Respiratory syncytial virus (RSV) infections in lung transplant recipients (LTRs) have been associated with significant morbidity and mortality. Immunoglobulins, ribavirin, and palivizumab are suggested treatments for both pre-emptive and therapeutic purposes. However, in the absence of randomized, placebo-controlled trials, efficacy is controversial and there is toxicity as well as cost concerns. We retrospectively reviewed cases of lower respiratory tract RSV infections in adult LTRs. Diagnosis was based on clinical history, combined with a positive polymerase chain reaction (PCR) and/or viral cultures of bronchoalveolar lavage (BAL) specimens. Ten symptomatic patients were identified (7 men and 3 women, age range 28 to 64 years). All were hospitalized for community-acquired respiratory tract infections. Two patients had a concomitant acute Grade A3 graft rejection, and 1 patient had a concomitant bacterial pneumonia. Eight patients did not receive a specific anti-RSV treatment because of clinical stability and/or improvement at the time of RSV diagnosis. Only 2 patients (1 with Grade A3 allograft rejection and 1 requiring mechanical ventilation) received ribavirin and palivizumab. All patients recovered without complications and with no persistent RSV infection. However, bronchiolitis obliterans (BOS) staging worsened in 6 patients during the mean follow-up of 45 months. Our data suggest that mild RSV infections in LTRs might evolve favorably in the absence of specific anti-viral therapy. However, this observation needs confirmation in a large clinical trial specifically investigating the development of BOS in untreated vs treated patients.


Glyphosate-induced lipid metabolism disorder contributes to hepatotoxicity in juvenile common carp.
Residues of glyphosate (GLY) are widely detected in aquatic systems, raising potential environmental threats and public health concerns, but the mechanism underlying GLY-induced hepatotoxicity in fish has not been fully elucidated yet. This study was designed to explore the hepatotoxic mechanism using juvenile common carp exposed to GLY for 45 d, and plasma and liver samples were collected at 15 d, 30 d, and 45 d to analyze the assays. First, GLY-induced hepatic damage was confirmed by serum liver damage biomarker and hepatic histopathological analysis. Next, changes in oxidative stress biomarkers, gene expression levels of pro- and anti-inflammatory cytokines, and lipid metabolism-related parameters in collected samples were analyzed to clarify their roles in GLY-induced hepatic damage. Data showed that oxidative stress was an early event during GLY exposure, followed by hepatic inflammatory response. Lipid metabolism disorder was a late event during GLY exposure, as evidenced by overproduced hepatic free fatty acids, enhanced lipogenesis-related gene expression levels, reduced lipolysis-related gene expression levels, and resultant hepatic lipid accumulation. Collectively, these findings demonstrate that GLY induces hepatotoxicity in fish through involvement of oxidative stress, inflammatory response, and lipid metabolism disorder, which are intimately interrelated with each other during GLY exposure.


Nutrition management for individuals with noninsulin-dependent diabetes mellitus in the 1990s: a review by the Diabetes Care and Education dietetic practice group.
Noninsulin-dependent diabetes mellitus (NIDDM), or Type II diabetes, is characterized by two primary defects: insulin resistance and insulin secretion. The two major goals of management of NIDDM are to achieve near normal metabolic control and to prevent/delay the microvascular and macrovascular complications of diabetes. Nutrition, exercise, and, if necessary, medication are the three primary treatment modalities used in NIDDM. Treatment regimens need to be individualized and developed with consideration for diabetes management goals and quality-of-life issues. Lean individuals with NIDDM should be encouraged to maintain their body weight and modify food composition and eating pattern to minimize glucose excursions. The primary treatment goal for an obese individual with NIDDM is weight loss. The process of teaching nutrition and meal planning involves developing a cooperative alliance, gathering information, setting realistic goals, intervention, and maintaining change. Nutrition intervention involves providing information in stages, beginning with "survival skill" information and progressing to in-depth information. The dietitian's responsibility is to promote continuity of learning by introducing new ideas and concepts and altering the learning environment. Dietitians can expand their role in the 1990s to that of a diabetes educator taking a leadership role to ensure that the individual with NIDDM receives comprehensive and individualized care.


Design of Experiment (DoE) as a Tool for the Optimization of Source Conditions in SEC-ESI-MS of Functional Synthetic Polymers Synthesized via ATRP.
Design of experiment (DoE) is applied to establish the optimum ionization conditions for analyzing synthetic polymers via coupled size exclusion chromatography electrospray ionization mass spectrometry (SEC-ESI-MS) yielding maximum ionization efficiency. The ion source conditions were optimized with regard to the ionization efficiency, the amount of fragmentation, as well as the formation of salt adducts. A D-optimal experimental design was employed for this purpose and the recorded data were evaluated by a quadratic response surface model, accounting for possible interactions between the individual source settings. It was established that the ionization efficiency can be improved by up to one order of magnitude without compromising the softness of the ionization process and that optimal ionization conditions are found at similar source settings regardless of the charge state. The present optimization exercise therefore provides a hands-on guide for the use of experimental design to determine optimum ionization conditions during the SEC-ESI-MS of functional polymers.


Bariatric surgery: is admission to the intensive care unit necessary?
The purpose of this study was to determine the place of stay at postoperative and to verify medical-surgical complications that would justify admission to the intensive care unit, including death. Cross-over, prospective, open study that evaluated 120 patients who were submitted to primary bariatric surgery by video laparoscopy from May 2007 to April 2008 in a tertiary hospital. The Aldrete Kroulik index was used for release from the post-anesthesia recovery room and to define where the patient should be routinely referred for postoperative. Among the 120 patients, 83 were women and 37 men with a mean age ranging from 35.4 ± 10.5 years (18 to 66 years), body mass index 45.6 ± 10.5. The time between hospital admission and start of surgery was 140.7 ± 81.8 minutes, surgery time was 105 ± 28.6 minutes, time of post-anesthesia recovery room was between 125 ± 38 minutes and length of hospital stay was 47.7 ± 12.4 hours, with 100% of the patients walking in 24 hours. The Aldrete and Kroulik index in the post-anesthesia recovery room achieved scores of 10 to 120 minutes in all patients, with a 100% survival . Using the Aldrete and Kroulik index in the post-anesthesia of gastric bypass by video laparoscopy in primary bariatric surgery, no patient was admitted in intensive care unit and no major complication was observed.


Demographic and Cardiovascular Risk Factors Associated with Drug Use in Truck Drivers in the State of São Paulo, Brazil: A Cross-Sectional Study.
The aim of the study is to analyze the association between risk factors for the health of truck drivers and previous use of illicit drugs. A cross-sectional study examined the data from 2071 truck drivers between 2010 and 2016. Demographic variables, risk factors for cardiovascular disease (CVD) and the use of illicit drugs were analyzed. The stepwise logistic regression model was used for the adjusted analysis. The dependent variable was the previous use of illicit drugs, and independent variables were those with p < 0.1 at a bivariate analysis. The average age of the truck drivers was 42.27 ± 11.07 years, and the previous use of illicit drugs was reported or detected in 388 (18.7%) drivers. Compared to non-users, drug users were younger (37.25 ± 9.45 vs. 43.43 ± 11.1 years; p < 0.001) and single (43.3% vs. 28.4%; p < 0.001). The independent variables for illicit drugs were age (OR = 0.93 (95% CI: 0.91-0.95; p < 0.001)), smoking (OR = 2.18 (95% CI: 1.39-3.44; p = 0.001)), alcohol consumption (OR = 1.626 (95% CI: 1.06-2.49; p = 0.026)) and driving hours per day (OR = 1.08 (95% CI: 1.01-1.15; p = 0.012)). Users of illicit drugs had multiple risk factors for CVD and traffic accidents.


Fabrication of planar organic nanotransistors using low temperature thermal nanoimprint lithography for chemical sensor applications.
A new fabrication process for the patterning of organic semiconductors at the nanoscale has been developed using low temperature thermal nanoimprint lithography and the details of this process are discussed. Novel planar nanotransistors have been fabricated and characterized from poly(3-hexylthiophene) (P3HT) and we demonstrate the feasibility of using such devices as highly sensitive chemical sensors.


VZV gB endocytosis and Golgi localization are mediated by YXXphi motifs in its cytoplasmic domain.
The cytoplasmic domains of many membrane proteins contain sorting signals that mediate their endocytosis from the plasma membrane. VZV gB contains three consensus internalization motifs within its cytoplasmic domain: YMTL (aa 818-821), YSRV (aa 857-860), and LL (aa 841-842). To determine whether VZV gB is internalized from the plasma membrane, and whether these motifs are required for its endocytosis, we compared the internalization of native gB to that of gB containing mutations in each of the predicted internalization motifs. VZV gB present on the surface of transfected cells associated with clathrin and was efficiently internalized to the Golgi apparatus within 60 min at 37 degrees C. VZV gB containing the mutation Y857 failed to be internalized, while gB-Y818A was internalized but did not accumulate in the Golgi. These data indicate that the internalization of VZV gB, and its subsequent localization to the Golgi, is mediated by two tyrosine-based sequence motifs in its cytoplasmic domain.


Safer transurethral resection of the prostate: coagulating intermittent cutting reduces hemostatic complications.
Transurethral resection of the prostate (TURP) is still the gold standard for the surgical treatment of symptomatic benign prostatic hyperplasia. However, the associated morbidity and blood loss remain concerns. A coagulating intermittent cutting (CIC) device with constant voltage pulses and controlled pulse intervals was recently developed. The impact of CIC on bleeding and blood transfusion rates as well as the occurrence of the TUR syndrome were investigated. From January 2000 to July 2002, 271 consecutive patients with symptomatic benign prostatic hyperplasia underwent TURP with the CIC device. In addition to blood transfusion rates, serum hemoglobin and electrolytes were determined in all patients immediately before and after TURP. The mortality rate in the 271 patients subjected to TURP was 0.0%. Mean decrease in hemoglobin after TURP was 1.08 mg/dl. Intraoperative and postoperative blood transfusions were required in 7 patients (2.6%), and clinical signs of the transurethral resection syndrome were noted in 1.1% of patients. Coagulating intermittent cutting dramatically improves the safety of TURP by decreasing intraoperative and postoperative blood loss, and the rate of blood transfusions. With this blood sparing device we anticipate a lower incidence of hemostatic complications from TURP.


Compulsive hoarding: an interpretative phenomenological analysis.
This project aimed to explore the experiences of people who compulsively hoard and how they make sense of their own hoarding behaviours. A total of 11 compulsive hoarders were recruited and interviewed using a simple semi-structured interview format, designed for the purposes of the study. The resulting transcribed interviews were analyzed using interpretive-phenomenological analysis. Four super-ordinate discrete, but interacting, themes were found: (1) childhood factors; (2) the participants' relationship to their hoarded items; (3) cognitive and behavioural avoidance of discard; and (4) the impact of hoarding on self, others and the home environment. The themes as a whole described people entrapped in massively cluttered physical environments of their own making. Efforts at discard appeared consistently sabotaged by cognitive/behavioural avoidance, thereby creating maintaining factors of associated personal distress and environmental decline. The results are discussed in the context of the extant evidence concerning hoarding, the distinct contribution made by the current results and the identified methodological shortcomings of the research approach.


Thiolumazines as Heavy-Atom-Free Photosensitizers for Applications in Daylight Photodynamic Therapy: Insights from Ultrafast Excited-State Dynamics.
Finding appropriate photosensitizers (PSs) for daylight photodynamic therapy (dPDT) applications is extremely challenging, even though heavy-atom-free photosensitizers (HAFPSs) such as thiocarbonyl-modified nucleobases have shown a ray of hope. Few attempts have been made to find alternative natural products for dPDT applications. Pteridine heterocycles consisting of a pyrazine ring and a pyrimidine ring, such as lumazine, which exhibit many structural similarities to the alloxazine ring of the flavin molecule, could be an option for HAFPSs. The photophysical and quantum mechanical studies of the thio-modified lumazines revealed that sequential thiomodifications in lumazine result in a bathochromic shift. Additionally, higher tissue penetration depths were observed for thiolumazines. The fluorescence quenching in the case of thiomodified lumazines was explained using triplet state formation, whereas the contribution from the photoinduced electron transfer process cannot be ignored. It was also noticed that a strong one-photon absorption influenced the two-photon absorption (TPA) process, leading to a self-focusing effect in the visible spectral region. The higher tissue penetration and larger TPA cross section are the hallmark characteristics of the thiolumazines to be considered as potential HAFPSs for dPDT applications.


Diet in autism and associated disorders.
A dietitian discusses the theory that peptides with opioid activity may cause or trigger autism. The use of an exclusion diet to treat autism is explained, weighing the potential benefits against some of the practical difficulties of keeping to a strict exclusion diet. The use of nutritional supplements is described. An abnormal gut flora has also been implicated in autism and the use of probiotics and prebiotics in improving the integrity of the gut mucosa is also discussed.


A multi-objective optimization framework with rule-based initialization for multi-stage missile target allocation.
This paper investigates a novel multi-objective optimization framework for the multi-stage missile target allocation (M-MTA) problem, which also widely exists in other real-world complex systems. Specifically, a constrained model of M-MTA is built with the trade-off between minimizing the survivability of targets and minimizing the cost consumption of missiles. Moreover, a multi-objective optimization algorithm (NSGA-MTA) is proposed for M-MTA, where the hybrid encoding mechanism establishes the expression of the model and algorithm. Furthermore, rule-based initialization is developed to enhance the quality and searchability of feasible solutions. An efficient non-dominated sorting method is introduced into the framework as an effective search strategy. Besides, the genetic operators with the greedy mechanism and random repair strategy are involved in handling the constraints with maintaining diversity. The results of numerical experiments demonstrate that NSGA-MTA performs better in diversity and convergence than the excellent current algorithms in metrics and Pareto front obtained in 15 scenarios. Taguchi method is also adopted to verify the contribution of proposed strategies, and the results show that these strategies are practical and promotive to performance improvement.


Beneficial effect of lycopene on anti-diabetic nephropathy through diminishing inflammatory response and oxidative stress.
Lycopene is widely used for nutritional supplementation, but the potential benefits in diabetic nephropathy (DN) remains unknown. This study aimed to highlight the therapeutic prospect of lycopene against streptozotocin (STZ)-induced kidney injury in mice. During the process of the experiments, biochemical kits were employed to determine the diabetes-metabolic parameters in STZ-lesioned mice. Routine pathological and ultrastructural observations were screened for the histological changes of kidney tissue. Moreover, immunohistochemical staining was used to investigate the inflammatory conditions expressed in kidney tissue. Furthermore, intrarenal heme oxygenase 1 (HO-1) mRNA level was assayed via RT-PCR and Western blot analyses. The results showed that lycopene alleviated the lesioned signs of DN mice induced by STZ, accompanied with the increase in body weight, reduced serum concentrations of blood sugar and low-density lipoprotein cholesterol (LDL-C), elevated high-density lipoprotein cholesterol (HDL-C) level, and the decrease in urine protein content. In addition, oxidative defense patterns in the kidneys of DN mice were ameliorated, as shown in augmented bioactivities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and in turn lowered malondialdehyde (MDA) content. The immunohistochemical experiment exhibited that lycopene intake contributed to attenuation of nuclear factor-kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α) expressions in kidney tissue. Moreover, intrarenal HO-1 level was up-regulated in the presence of lycopene. Our findings provide the evidence that lycopene protects kidney cells from STZ-induced lesions via inhibiting NF-κB signal pathway for anti-inflammation and attenuating oxidative stress for anti-dysmetabolism.


The modulus of fibroblast-populated collagen gels is not determined by final collagen and cell concentration: Experiments and an inclusion-based model.
The fibroblast-populated collagen lattice is an attractive model tissue for in vitro studies of cell behavior and as the basis for bioartificial tissues. In spite of its simplicity-containing only collagen and cells-the system is surprisingly difficult to describe mechanically because of the ability of the cells to remodel the matrix, including compaction at short times and synthesis and/or degradation (and cell proliferation) at longer times. The objectives of this work were to measure the equilibrium modulus of fibroblast-populated gels with different collagen and cell concentrations, and to use that characterization as the basis for a theoretical model that could be used to predict gel mechanics based on conditions. Although many observations were as expected (e.g., the gel compacts more when there are more cells in it, and the gel is stiffer when there is more collagen in it), an unexpected result arose: the final modulus of the gel was not dependent solely on the final composition. Even if it compacted more than a gel that was originally at a high collagen concentration, a gel that started at a low collagen concentration remained less stiff than the higher-concentration gel. In light of these results and experimental studies by others, we propose a model in which the gel compaction is not homogeneous but consists instead of extreme densification near the cells in an otherwise unchanged matrix. By treating the dense regions as spherical inclusions, we used classical composite material theory to develop an expression for the modulus of a compacted gel based on the initial collagen density and the final inclusion (i.e., cell) density. The new model fit the data for moderately compacted gels well but broke down, as expected, for larger volume fractions at which the underlying model assumptions did not apply.


Presence of emerging contaminants in baby food.
Food safety becomes imperative when it aims to protect infants. The objective of this study was to investigate the presence of emerging contaminants of which some act as endocrine-disruptors in baby food. Persistent organic pollutants (POPs), perfluoroalkyl substances (PFASs), parabens and antibiotics were analysed in 112 baby food of different categories (meat, fish, vegetables, fruit, cheese). As regard POPs, PFASs and antibiotics, no residues were detected, while one sample showed methyl-paraben (4.14 ng g-1), whereas another three contained propyl-paraben (median 1.70 ng g-1). Special attention must be paid on parabens metabolites, as 4-hydroxybenzoic acid, the principal parabens metabolite, was detected in all samples (median 176.7 ng g-1). It may be present as a degradation product, but also, it can be released from vegetables and fruits during food processing. It is recommended to collect more data on natural vs non-natural occurrence of parabens and metabolites to evaluate the exposure of sensitive population vs ADI published by the European Food Safety Authority and European Medicines Agency.


T cell stimulation via the erythrocyte receptor. Synergism between monoclonal antibodies and phorbol myristate acetate without changes of free cytoplasmic Ca++ levels.
We observed that certain E-receptor antibodies (CD2 antibodies) can induce proliferation of resting human T cells in the presence of PMA, while other CD2 antibodies fail to have such an effect. The same CD2 antibodies that were mitogenic in the presence of PMA (9.6, X11, VIT13), but not the nonreactive ones, were also able to induce T cell proliferation via the so-called alternative pathway of T cell activation, i.e., when added pairwise in certain combinations to T cells in the absence of PMA. While the simultaneous addition of two comitogenic CD2 antibodies (9.6 or X11 plus VIT13) or the addition of a single nonmitogenic CD3 antibody (VIT3) led to a clearcut elevation of intracellular Ca++ levels, no such effect could be observed after the addition of one CD2 antibody alone. Even in the presence of PMA, one comitogenic CD2 antibody alone was unable to trigger a significant Ca++ response, although this combination induced a proliferative response. These data indicate that, distinguishable by their influence on free cytoplasmic Ca++, there are two different mechanisms of T cell activation via CD2. While simultaneous triggering with two antibodies leads to cell proliferation preceded by an increase of Ca++ levels, stimulation with one antibody plus PMA results in proliferation without a measurable early Ca++ response. We conclude that T cells treated by certain CD2 antibodies alone already recognize an activation signal probably unrelated to Ca++ homeostasis, a signal that can further be developed by PMA to result in a completely developed proliferative response.


Posterior Shoulder Dislocation Associated With the Head (Splitting) and Humeral Neck Fracture: Impact of Understanding Radiologic Signs and Experience With an Extended Deltopectoral Approach.
In this paper, our main objective was to emphasize the competency of extended deltopectoral exposure, enforced with the supraspinatus and subscapularis detachment, to gain access to the entire head. The second important point in this paper was to underline the importance of the knowledge that is necessary for interpreting classic radiologic signs of posterior fracture-dislocation of the shoulder. A 47-year-old woman fell down directly onto her shoulder while she was skiing. She was diagnosed with posterior shoulder dislocation, associated with fracture of the head (head splitting) and humeral neck fracture, with the aid of plain radiographs and computed tomographic results. The patient was treated with open reduction and internal fixation of the fracture, through the extended deltopectoral approach, which was augmented with rotator cuff detachment. At the 1-year follow-up, x-rays showed stable fixation with good evidence of healing. One year after the surgery, the patient had no pain, and she regained most of her functionality in her right shoulder with 140 to 150 degrees of lateral elevation (abduction), 140 to 150 degrees of forward flexion , internal rotation hand at T12 vertebra (slightly restricted). These results showed good functionality, with a painless shoulder at the 1-year follow-up. The "double shadow" and "lightbulb" signs are indicative of posterior shoulder fracture-dislocation, and augmented (with the detachment of supraspinatus and subscapularis tendons) traditional deltopectoral incision is suitable for managing these kinds of difficult fracture dislocations.


Helicobacter pylori infection with a duodenal ulcer in a 6-year-old boy.
A 6-year-old boy was hospitalized because of dark feces and facial pallor of 1 weeks duration. Other gastrointestinal symptoms, including vomiting and abdominal pain, were absent, but he felt dizziness when standing and fatigue on effort. Hematologic studies revealed iron-deficiency anemia, and endoscopy showed gastric erosions and a duodenal ulcer. All test results for Helicobacter pylori infection, including H. pylori antigen in stool, anti-H. pylori IgG immunoassay in serum, and the (13)C-urea breath test, were positive. Because an H. pylori-associated gastric ulcer had been diagnosed with endoscopy in the patients father 3 years earlier, father-son transmission was suspected. The patient was treated with triple-agent eradication therapy (proton pump inhibitor [lansoprazol], amoxicillin, and clarithromycin) for 2 weeks. One month after therapy was completed, eradication of H. pylori was confirmed by negative results on the stool antigen test. Peptic ulcer disease can occur in young children, as in this case. The stool antigen test kit is a useful and reliable method that can be used even in preschool children to diagnose H. pylori infection.


Proline and glycinebetaine ameliorated NaCl stress via scavenging of hydrogen peroxide and methylglyoxal but not superoxide or nitric oxide in tobacco cultured cells.
Efficient detoxification of the reactive oxygen species, nitric oxide (NO) and methylglyoxal (MG), provides protection against NaCl-induced damage in plants. To elucidate the protective mechanisms of proline and glycinebetaine (betaine) against NaCl stress, intracellular levels of hydrogen peroxide (H(2)O(2)), superoxide (O(2)(-)), NO, and MG were investigated in tobacco Bright Yellow-2 cells. The Levels of H(2)O(2), O(2)(-), NO and MG were higher in the short-term and long-term NaCl-stressed cells than in the non-stressed cells, whereas the O(2)(-) level was higher in the long-term stressed cells. Exogenous proline and betaine decreased the H(2)O(2) level in both the short-term and the long-term NaCl-stressed cells and the MG level in the long-term NaCl-stressed cells, but did not change the O(2)(-) or NO levels. Under salt stress, both proline and betaine increased the transcription levels of glutathione peroxidase, which can contribute to the reduction of H(2)O(2). In conclusion, proline and betaine mitigated salt stress via reduction of H(2)O(2) accumulation during short-term incubation and via reduction of the accumulation of H(2)O(2) and MG during long-term incubation.


Human Cytomegalovirus Cell Tropism and Host Cell Receptors.
In the 1970s-1980s, a striking increase in the number of disseminated human cytomegalovirus (HCMV) infections occurred in immunosuppressed patient populations. Autopsy findings documented the in vivo disseminated infection (besides fibroblasts) of epithelial cells, endothelial cells, and polymorphonuclear leukocytes. As a result, multiple diagnostic assays, such as quantification of HCMV antigenemia (pp65), viremia (infectious virus), and DNAemia (HCMV DNA) in patient blood, were developed. In vitro experiments showed that only low passage or endothelial cell-passaged clinical isolates, and not laboratory-adapted strains, could reproduce both HCMV leuko- and endothelial cell-tropism, which were found through genetic analysis to require the three viral genes UL128, UL130, and UL131 of the HCMV UL128 locus (UL128L). Products of this locus, together with gH/gL, were shown to form the gH/gL/pUL128L pentamer complex (PC) required for infection of epithelial cells/endothelial cells, whereas gH/gL and gO form the gH/gL/gO trimer complex (TC) required for infection of all cell types. In 2016, following previous work, a receptor for the TC that mediates entry into fibroblasts was identified as PDGFRα, while in 2018, a receptor for the PC that mediates entry into endothelial/epithelial cells was identified as neuropilin2 (Nrp2). Furthermore, the olfactory receptor family member OR14I1 was recently identified as a possible additional receptor for the PC in epithelial cells. Thus, current data support two models of viral entry: (i) in fibroblasts, following interaction of PDGFRα with TC, the latter activates gB to fuse the virus envelope with the cell membrane, whereas (ii) in epithelial cells/endothelial cells, interaction of Nrp2 (and OR14I1) with PC promotes endocytosis of virus particles, followed by gB activation by gH/gL/gO (or gH/gL) and final low-pH entry into the cell.


Demographic details, risk factors, microbiological profile, and clinical outcomes of pediatric infectious keratitis cases in North India.
To study the demographic details, risk factors, microbiological profile, and clinical outcomes of pediatric infectious keratitis cases in North India. This retrospective case series included review of medical records of pediatric patients (0-16 years) diagnosed with infectious keratitis in a tertiary care center of North India during December 2011 to January 2017 was done. Demographic details, predisposing factors, microbiological investigations, and clinical outcomes were analyzed. In this time period, 104 eyes of 104 children had a diagnosis of infectious keratitis. Culture was obtained for all 104 eyes and was positive in eighty eight eyes (84.2%). The most common causative factor was trauma, seen in 77 eyes (74%). Bacteria was the most common agent isolated in culture (54.2%) followed by fungi (40.8%) and acanthamoeba (2.1%). Successful healing of the keratitis with appropriate medical treatment occurred in 84 (80.7%) eyes, while 13 (12.5%) eyes required therapeutic keratoplasty. Of the 80 eyes with documentation of both preliminary and final visual acuity, improvement of two lines was seen in 35 eyes (43.7%), stayed the same in and worsened in 17 eyes (21%). Mean time to resolution of infection on medical treatment for bacteria was 23.65 ± 4.78 days, fungi 32 ± 5.19 days, and acanthamoeba 53.67 ± 4.78 days. Gram positive organism is the most common etiological agent of keratitis in children in our study population which is in contrast to pediatric infective keratitis study conducted by Aruljyothi et al. in South India (2011--2013). Though less in number than bacterial keratitis, fungus also remains an important causative agent. Along with early diagnosis and immediate medical intervention, it is important to identify regional profile of organisms and risk factors for good visual and anatomical outcome.


Loss of porphyrins from solution during analysis: effect of sample pH and matrix on porphyrin quantification in urine by "high-performance" liquid chromatography.
We report the effect of sample matrix and pH on quantification of porphyrins by HPLC with fluorimetric detection. For aqueous solutions of pH less than 2.5, HPLC peak heights of the porphyrins increased with decreasing pH, reaching a plateau at pH less than 1.0. This loss of porphyrins from solutions with pH greater than 1.0 appeared to be due to a combination of microprecipitation and aggregation effects. No such "pH effect" was observed for urine samples supplemented with mixed-porphyrin standards. Addition of trace amounts of albumin to aqueous solutions also decreased these pH-related losses. These findings suggest a porphyrin-protein interaction that prevents microprecipitation and aggregation processes. We conclude that standard solutions of porphyrins for HPLC analysis should be prepared in a urine matrix. If aqueous solutions are used, then the pH must be adjusted to less than 1.0. Urine samples from normal individuals require only adjustment of pH to less than 2 before analysis; however, porphyric urines requiring dilution should be prepared with porphyrin-free urine diluent.


Multi-center study regarding the risk factors for bleeding in gastrointestinal stromal tumor.
In spite of several case reports about gastrointestinal stromal tumor (GIST) complicated with hemorrhage, study regarding the risk factors of bleeding in this tumor is scanty. Therefore, we analyzed the clinical characteristics of bled GISTs and tried to find risk factors of bleeding by comparing with non-bled cases. Medical records of 49 bled GIST cases from 5 university hospitals in Korea between year 2001 to 2010 were compared with 96 non-bled cases. Whole pathological slides were reviewed by an experienced pathologist. Female predominance (58.6%) was noted and the mean age of the included patients was 58.4±13.1 years. In univariate analysis, location of jejunum, prolonged prothrombin time, presence of surface dimpling in CT, cellular pleomorphism and positivity of S100 was significantly dominant in the bled cases. Multivariate analysis showed significant differences in the location of jejunum (p=0.004, OR=3.533), prolonged prothrombin time (p=0003, OR=19.643), presence of surface dimpling (p=0.026, OR=6.250) in CT, and positivity of S100 (p=0.001, OR=12.941). Location of jejunum, prolonged prothrombin time, presence of surface dimpling in CT, and positivity of S100 are independent risk factors associated with bleeding in GI GIST patients.


Effects of Gamma Radiation on Single- and Multicomponent Organic Crystalline Materials.
Exploration of highly ionizing radiation damage to organic materials has mainly been limited to polymers and single-component organic crystals due to their use in coatings and scintillation detection. Additional efforts are needed to create new tunable organic systems with stability in highly ionizing radiation to rationally design novel materials with controllable chemical and physical properties. Cocrystals are a promising class of compounds in this area because of the ability to rationally design bonding and molecular interactions that could lead to novel material properties. However, currently it is unclear if cocrystals exposed to radiation will maintain crystallinity, stability, and physical properties. Herein, we report the effects of γ radiation on both single-component- and multicrystalline organic materials. After irradiation with 11 kGy dose both single- (trans-stilbene, trans-1,2-bis(4-pyridyl)ethylene (4,4'-bpe), 1,n-diiodotetrafluorobenzene (1,n-C6I2F4 ), 1,n-dibromotetrafluorobenzene (1,n-C6Br2F4 ), 1,n-dihydroxybenzene (1,n-C6H6O2 ) (where n = 1, 2, or 3)), and multicomponent materials (4,4'-bpe)·(1,n-C6I2F4 ), (4,4'-bpe)·(1,n-C6Br2F4 ), and (4,4'-bpe)·(1,n-C6H6O2 ) were analyzed and compared to their preirradiated forms. Radiation damage was evaluated via single-crystal- and powder-X-ray diffraction, Raman spectroscopy, differential scanning calorimetry, and solid-state fluorimetry. Single-crystal X-ray diffraction analysis indicated minimal changes in the lattice postirradiation, but additional crystallinity changes for bulk materials were observed via powder X-ray diffraction. Overall, cocrystalline forms with 4,4'-bpe were more stable than the related single-component systems and were related to the relative stability of the individual conformers to γ radiation. Fluorescence signals were maintained for trans-stilbene and 4,4'-bpe, but quenching of the signal was observed for the cocrystalline forms to varying degrees. Three of the single components, 1,2-diiodotetrafluorobenzene (1,2-C6I2F4 ), 1,4-diiodotetrafluorobenzene (1,4-C6I2F4 ), and 1,4-dibromotetrafluorobenzene (1,4-C6Br2F4 ), also underwent sublimation within an hour of exposure to air postirradiation. Further analysis using differential scanning calorimetry (DSC) and Raman spectroscopy attributed this phenomenon to removal of impurities adsorbed to the crystal surface during irradiation.


A UV-induced self-reinforced hydrogel based on in situ hydrophobic aggregation of strained 1,2-dithiolane rings.
A novel responsive hydrogel exhibiting self-reinforcement and self-healing capacity was developed based on the hydrophobic aggregation of strained 1,2-dithiolane rings. Oligomerization of 1,2-dithiolane within hydrophobic domains under UV irradiation not only reinforced the hydrogel but also maintained its dynamic cross-linked nature by converting the intraring dynamic S-S bond to an outer one.


Wide dissemination of linezolid-resistant Staphylococcus epidermidis in Greece is associated with a linezolid-dependent ST22 clone.
Dependence on linezolid was recently described as significant growth acceleration of linezolid-resistant Staphylococcus epidermidis (LRSE) isolates upon linezolid exposure. We investigated the possible contribution of linezolid dependence to LRSE dissemination in Greece. Linezolid resistance rates were estimated in six tertiary hospitals located throughout Greece between 2011 and 2013. Sixty-three randomly selected LRSE recovered in these hospitals during this period were studied. Growth curve analysis was conducted with and without linezolid. Clonality of the isolates was investigated by PFGE and MLST. During the study period, the LRSE rate in the participating hospitals rose significantly from 6.9% to 9% (P = 0.006); the increase was more prominent in ICUs (from 15.1% to 20.9%; P = 0.005). Forty-seven (74.6%) of the 63 LRSE, derived from all study hospitals, clearly exhibited linezolid dependence, growing significantly faster in the presence of 16 and 32 mg/L linezolid. Of note, 61 (96.8%) LRSE exhibited a single macrorestriction pattern and belonged to ST22, which included all linezolid-dependent LRSE. The remaining two LRSE belonged to unique STs. Five of six linezolid-dependent isolates tested also exhibited linezolid dependence upon exposure to 8 mg/L linezolid. Interestingly, five of six ST22 linezolid-non-dependent isolates tested developed linezolid dependence when linezolid exposure preceded growth analysis. The rapid LRSE dissemination in Greek hospitals threatens linezolid activity. The observation that most LRSE belonged to ST22 and expressed dependence on linezolid clearly implies that the spread of linezolid resistance should have been driven by this trait, which provided the LRSE with a selective advantage under linezolid pressure.


[Thalidomide therapy in patients with refractory or relapsed multiple myeloma].
We treated seven refractory or relapsed myeloma patients resistant to conventional chemotherapy with thalidomide. We started thalidomide at 100 mg daily and the dose was increased up to 300 mg if the patient could tolerate it. The patients were evaluated at four weeks and 12 mg of dexamethasone was added for four days when the patient failed to respond to thalidomide treatment. One patient was excluded from the study because of general fatigue. Two of the six patients responded to thalidomide alone and three of the remaining four patients responded to the combination with dexamethasone. The most common adverse effect was sleepiness which was seen in three patients. Two patients showed pancytopenia (Grade 3), constipation and skin eruption. Of the six patients four needed reduction of the thalidomide dose to 200 mg because of adverse effects. Plasma levels of TNF-alpha, IL-6, bFGF and VEGF were measured before and after four weeks. High plasma bFGF levels were seen in responding patients. In conclusion, treatment with thalidomide alone or in combination with dexamethasone is feasible and effective in refractory or relapsed myeloma patients. Further study is required to clarify the role of thalidomide in the therapeutic strategy for multiple myeloma.


Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma.
Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic disorders characterized by monoclonal plasma cell proliferation in the bone marrow in the absence of end-organ damage. Updated diagnostic criteria for these disorders, risk-stratification models to determine prognosis, and the current management of these two entities are discussed in this review.


The GluK1 (GluR5) Kainate/{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 reduces soman-induced seizures and neuropathology.
The possibility of mass exposure to nerve agents by a terrorist attack necessitates the availability of antidotes that can be effective against nerve agent toxicity even when administered at a relatively long latency after exposure, because medical assistance may not be immediately available. Nerve agents induce status epilepticus (SE), which can cause brain damage or death. Antagonists of kainate receptors that contain the GluK1 (formerly known as GluR5) subunit (GluK1Rs) are emerging as a new potential treatment for SE and epilepsy from animal research, whereas clinical trials to treat pain have shown that the GluK1/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] is safe and well tolerated. Therefore, we tested whether LY293558 is effective against soman-induced seizures and neuropathology, when administered 1 h after soman exposure, in rats. LY293558 stopped seizures induced by soman and reduced the total duration of SE, monitored by electroencephalographic recordings within a 24 h-period after exposure. In addition, LY293558 prevented neuronal loss in the basolateral amygdala (BLA) and the CA1 hippocampal area on both days 1 and 7 after soman exposure and reduced neuronal degeneration in the CA1, CA3, and hilar hippocampal regions, entorhinal cortex, amygdala, and neocortex on day 1 after exposure and in the CA1, CA3, amygdala, and neocortex on day 7 after exposure. It also prevented the delayed loss of glutamic acid decarboxylase-67 immuno-stained BLA interneurons on day 7 after exposure. LY293558 is a potential new emergency treatment for nerve agent exposure that can be expected to be effective against seizures and brain damage even with late administration.


Social cognitive bias increases loneliness both directly and by decreasing social connection in patients with schizophrenia.
While considerable emphasis has been put on investigating the mechanisms that drive reduced social connection in patients with schizophrenia (SCZ), recent studies have increasingly focused on the issue of loneliness in SCZ. As both social cognitive bias and self-reported empathy predict loneliness in non-clinical populations, the current study aims to examine the relationship between loneliness, reduced social connection and social cognitive biases, and self-reported empathy in SCZ. Ninety-three adult SCZ and sixty-six matched healthy individuals completed a battery of questionnaires measuring loneliness and social connection (Revised-UCLA Loneliness Scale, Lubben-Social Network Scale, Social Disconnectedness Scale), cognitive biases (Ambiguous Intentions Hostility Questionnaire, Davos Assessment of Cognitive Biases Scale, Cognitive Biases Questionnaire for psychosis) and self-reported empathy (Interpersonal Reactivity Index). Significant predictors of loneliness in SCZ were entered into two latent variables ("Social Threat Bias", "Social Connection"), and structural equation modeling was used to explore the direct and indirect relationships between Social Threat Bias, symptoms. and loneliness in SCZ. Patients reported higher levels of loneliness, cognitive biases and personal distress compared to controls. Furthermore, SCZ reported less social connection and perspective taking compared to controls. Structural equation modeling revealed that Social Threat Bias was linked to increased loneliness in SCZ both directly and indirectly via decreased social connection. Negative symptoms were directly linked with loneliness, while the association between affective symptoms and loneliness was mediated via Social Threat Bias. The results of the current study suggest that social threat bias should be considered while planning the interventions aimed to reduce loneliness in schizophrenia.


The Power of Systems Biology: Insights on Lupus Nephritis from the Accelerating Medicines Partnership.
The Accelerating Medicines Partnership (AMP) SLE Network united resources from academic centers, government, nonprofit, and industry to accelerate discovery in lupus nephritis (LN). The AMP SLE Network developed a set of protocols for high-throughput analyses to systematically study kidney tissue, urine, and blood in LN. This article summarizes approaches and results from phase 1 of AMP SLE Network effort, including single cell RNA-seq analysis of LN kidney biopsies, cellular and proteomic studies of LN urine, and mass cytometry immunophenotyping of blood cells. This work provides a framework to guide studies of the clinical implications of active cellular/molecular pathways in LN.


Prognostic immunophenotypic biomarker studies in diffuse large B cell lymphoma with special emphasis on rational determination of cut-off scores.
A number of biomarkers, particularly proteins that contribute to prognosis in diffuse large B cell lymphoma (DLBCL), have been identified. However, translation into accepted standards to predict survival has not yet been accomplished, primarily due to contradictory reports in the literature resulting from, among other factors, arbitrary methodologies used to set cut-off values for determining positivity. Some of these problems might be resolved by application of rational statistical methods for determination of cut-off scores. Herein, we critically address issues on in situ phenotypic prognostic tumor-related biomarkers in DLBCL with a particular and practical emphasis on tools for cut-off level determination, especially receiver operating characteristic curve analysis. Moreover, we candidly illustrate the application of these tools for efficient disease-specific survival prognostication on a tissue microarray collective of 240 primary DLBCL using the common prognostic biomarkers Bcl-2, Bcl-6, CD10, FOXP1, MUM1, and Cyclin E. Comparison of the results relative to disease-specific survival unequivocally showed the superior discriminatory power of the cut-off levels calculated by receiver operating curves and the Youden's index, compared to arbitrary cut-off values from the literature, advocating fundamental application of rational methods for determination of clinically relevant prognostic biomarkers' cut-off scores.


High-cost religion, religious switching, and health.
Previous research has devoted significant attention to understanding the link between health and personal religious beliefs and practices, typically finding that more religious people tend to have better health. However, almost no attention has been given to how switching religious groups or leaving religion altogether is related to self-reported health. Due to selection and causation mechanisms, switching from high-cost groups that are theologically and culturally exclusive could be associated with poor health more than switching from other religious groups. Using data from the 1972 through 2006 General Social Surveys, we examine the relationship between health and religious switching as moderated by the religious tradition of origin. We find that people who are raised and stay in high-cost sectarian groups, such as the Latter-day Saints and Jehovah's Witnesses, have better self-reported health than those raised and staying in other religious traditions. However, people who leave such groups are more likely to report worse health than those who leave other groups.


B-1b Cells Have Unique Functional Traits Compared to B-1a Cells at Homeostasis and in Aged Hyperlipidemic Mice With Atherosclerosis.
Immunoglobulin M (IgM) to oxidation specific epitopes (OSE) are inversely associated with atherosclerosis in mice and humans. The B-1b subtype of B-1 cells secrete IgM to OSE, and unlike B-1a cells, are capable of long-lasting IgM memory. What attributes make B-1b cells different than B-1a cells is unknown. Our objectives were to determine how B-1b cells produce more IgM compared to B-1a cells at homeostatic condition and to see the differences in the B-1a and B-1b cell distribution and IgM CDR-H3 sequences in mice with advanced atherosclerosis. Here, in-vivo studies demonstrated greater migration to spleen, splenic production of IgM and plasma IgM levels in ApoE-/-Rag1-/- mice intraperitoneally injected with equal numbers of B-1b compared to B-1a cells. Bulk RNA seq analysis and flow cytometry of B-1a and B-1b cells identified CCR6 as a chemokine receptor more highly expressed on B-1b cells compared to B-1a. Knockout of CCR6 resulted in reduced B-1b cell migration to the spleen. Moreover, B-1b cell numbers were significantly higher in spleen of aged atherosclerotic ApoE-/- mice compared to young ApoE-/- mice. Single cell sequencing results of IgHM in B-1a and B-1b cells from peritoneal cavity and spleen of atherosclerotic aged ApoE-/- mice revealed significantly more N additions at the V-D and D-J junctions, greater diversity in V region usage and CDR-H3 sequences in B-1b compared to B-1a cells. In summary, B-1b cells demonstrated enhanced CCR6-mediated splenic migration, IgM production, and IgM repertoire diversification compared to B-1a cells. These findings suggest that potential strategies to selectively augment B-1b cell numbers and splenic trafficking could lead to increased and more diverse IgM targeting OSE to limit atherosclerosis.


Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen.
Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID50], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nnHTN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design. IMPORTANCE The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nnHTN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope.


Loss of tritium from coprostanone derived from [1,2(n)-3H]cholesterol or [7(n)-3H]cholesterol.
After oral administration of a mixture of [1,2(n)-3H]cholesterol and [4-14C]cholesterol to a baboon, fecal coprostanone had a 46% lower 3H/14C ratio than the dose administered. Loss of 3H by enolization of the 3-ketone could account for the decrease in 3H/14C. If [7(n)-3H]cholesterol was administered instead of [1,2(n)-3H]cholesterol a 23% loss of 3H from coprostanone was found. Procedures requiring measurement of 3H-coprostanone derived from [1,2(n)-3H]- or [7(n)-3H]cholesterol could be seriously in error unless an appropriate correction for loss of 3H is made.