A systematic analysis of miRNA transcriptome in Marek's disease virus-induced lymphoma reveals novel and differentially expressed miRNAs.
Marek's disease is a lymphoproliferative neoplastic disease of the chicken, which poses a serious threat to poultry health. Marek's disease virus (MDV)-induced T-cell lymphoma is also an excellent biomedical model for neoplasia research. Recently, miRNAs have been demonstrated to play crucial roles in mediating neoplastic transformation. To investigate host miRNA expression profiles in the tumor transformation phase of MDV infection, we performed deep sequencing in two MDV-infected samples (tumorous spleen and MD lymphoma from liver), and two non-infected controls (non-infected spleen and lymphocytes). In total, 187 and 16 known miRNAs were identified in chicken and MDV, respectively, and 17 novel chicken miRNAs were further confirmed by qPCR. We identified 28 down-regulated miRNAs and 11 up-regulated miRNAs in MDV-infected samples by bioinformatic analysis. Of nine further tested by qPCR, seven were verified. The gga-miR-181a, gga-miR-26a, gga-miR-221, gga-miR-222, gga-miR-199*, and gga-miR-140* were down-regulated, and gga-miR-146c was up-regulated in MDV-infected tumorous spleens and MD lymphomas. In addition, 189 putative target genes for seven differentially expressed miRNAs were predicted. The luciferase reporter gene assay showed interactions of gga-miR-181a with MYBL1, gga-miR-181a with IGF2BP3, and gga-miR-26a with EIF3A. Differential expression of miRNAs and the predicted targets strongly suggest that they contribute to MDV-induced lymphomagenesis.


Borrelia burgdorferi-associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a.
We report two patients with low-grade malignant primary cutaneous B cell lymphoma in association with Borrelia burgdorferi infection. Extracutaneous manifestations were ruled out by standard staging procedures. Infection with Borrelia burgdorferi was confirmed by cultivation from lesional skin in both patients. In the first patient skin lesions cleared completely after pulse therapy with cefotaxime, whereas in the second patient antibiotic treatment failed. In this patient, however, skin lesions completely cleared after intralesional injection of interferon alfa-2a. Antibiotic treatment or intralesional injection of interferon alfa-2a should be considered as a first-line treatment of Borrelia burgdorferi-associated primary cutaneous B cell lymphoma before more aggressive conventional therapeutic modalities (e.g., radiation therapy) are applied.


Effects of graded return-to-work: a propensity-score-matched analysis.
Graded work exposure is deemed to have a therapeutic effect. In Germany, graded return-to-work (GRTW) is therefore frequently used following a rehabilitation program if workers are still unable to perform full job duties. The aim of the analyses was to determine long-term effects on disability pension and regular employment. Analyses were performed with longitudinal administrative data. Patients aged 18-60 years who attended an orthopedic, cardiac, oncological, or psychosomatic rehabilitation between January and June 2007 were eligible to participate in a GRTW scheme. The effects of GRTW were analyzed by a propensity-score-matched comparison of patients with and without GRTW. Outcomes were disability pension rates, regular income, and the duration of receiving welfare benefits due to sickness absence and unemployment up to the end of 2009. The propensity-score-matched sample comprised 1875 patients on GRTW and 1875 matched controls not undergoing GRTW. The probability of a disability pension was decreased by about 40% among GRTW patients [5.4% versus 8.6%; hazard rate ratio (HR) 0.62, 95% confidence interval (95% CI) 0.49-0.80]. The three-year income (2007-2009) was EUR12 920 higher (95% CI EUR10 054-15 786) in the GRTW group. The duration of receiving welfare benefits due to sickness absence and unemployment was significantly reduced. Graded work exposure supports labor participation and reduces the risk of permanent work disability.


Study of the first blastomeres in Coho salmon (Oncorhynchus kisutch).
Summary There is a lack of information on the morphology of the first blastomeres that could be used as a diagnostic tool for the first stages of embryonic development for Coho salmon. The purpose of this investigation, therefore, was to characterize morphometrically the first blastomeres of Coho salmon (Oncorhynchus kisutch). In total, 660 embryonic discs from a pool of eggs that had been fertilized and incubated at 5°C and after 19 h of incubation were extracted and photographed. Of these, 20 microphotographs of blastodiscs of normal appearance were analyzed morphologically (control blastodiscs: CB) and 100 random microphotographs from the whole group were classified as either symmetrical or asymmetrical according to their morphology and then compared with the CB. The length and width of each blastomere and the proportions of length and width were measured to determine symmetry in the embryos at the 4-cell stage. Seven categories were created to characterize the blastomeres: 38% normal (G1); 26% unequal (G2); 10% 'pie-shaped' (G3); 10% amorphous (G4); 8% with three equal and one unequal blastomere (G5); 6% 'clover-shaped' blastomeres (G7), and 3% with inclusions. The mean of the proportions of lengths and widths of the groups of blastomeres that were measured was 0.87 ± 0.08 and 0.85 ± 0.07, respectively. The morphometric results that were obtained in this investigation are compared with the results observed by other authors for teleostei and are discussed.


Distribution of staphylococcal cassette chromosome mec types among methicillin-resistant coagulase negative staphylococci in central Iran.
Methicillin-resistant coagulase-negative staphylococci (MR-CoNS) are important nosocomial pathogens. They may serve as a reservoir of SCCmec, the genomic island encoding amongst other methicillin resistance. This study was designed to determine the distribution of different SCCmec types from MR-CoNS isolated from clinical specimens in a tertiary hospital in central Iran, having high frequency of nosocomial methicillin-resistant staphylococcal infections. We evaluated isolates from patients attending the Vali-Asr Hospital located in the center of Iran, from February to December 2012. Multiplex PCR was performed for SCCmec typing. For isolates in which SCCmec could not be typed directly, additional ccr and mec complex analyses were performed. Totally, 70 MR-CoNS isolates, comprising of 47 S. epidermidis strains (67%), 10 S. saprophyticus (14.3%), 9 S. hemolyticus (13%) and 4 S. lugdunensis (5.7%) were identified. Thirty-nine were characterized as type IVa 19 (27%), type III 11 (16%), type II 7 (10%) and type V 2 (3%). Only 20 isolates (28.6%) carried the ccr complex, while the current methods could not characterize the 11 remaining isolates. A high level of SCCmec genetic diversity was found among MR-CoNS isolates. MR-CoNS may act as a reservoir of SCCmec IV for MRSA. This issue should be taken into consideration seriously.


Self-Powered Programmable van der Waals Photodetectors with Nonvolatile Semifloating Gate.
Tunable photovoltaic photodetectors are of significant relevance in the fields of programmable and neuromorphic optoelectronics. However, their widespread adoption is hindered by intricate architectural design and energy consumption challenges. This study employs a nonvolatile MoTe2/hexagonal boron nitride/graphene semifloating photodetector to address these issues. Programed with pulsed gate voltage, the MoTe2 channel can be reconfigured from an n+-n to a p-n homojunction and the photocurrent transition changes from negative to positive values. Scanning photocurrent mapping reveals that the negative and positive photocurrents are attributed to Schottky junction and p-n homojunction, respectively. In the p-n configuration, the device demonstrates self-driven, linear, rapid response (∼3 ms), and broadband sensitivity (from 405 to 1500 nm) for photodetection, with typical performances of responsivity at ∼0.5 A/W and detectivity ∼1.6 × 1012 Jones under 635 nm illumination. These outstanding photodetection capabilities emphasize the potential of the semifloating photodetector as a pioneering approach for advancing logical and nonvolatile optoelectronics.


EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma.
Enhancer of zeste homolog 2 (EZH2) promotes carcinogenesis by epigenetically silencing tumor suppressor genes. We studied EZH2 expression by immunohistochemistry in a large series of non-small cell lung carcinomas (NSCLC) in association with tumor characteristics and patient outcomes. EZH2 immunohistochemistry expression was analyzed in 265 normal and premalignant bronchial epithelia, 541 primary NSCLCs [221 squamous cell carcinomas (SCC) and 320 adenocarcinomas] and 36 NSCLCs with paired brain metastases. An independent set of 91 adenocarcinomas was also examined. EZH2 expression was statistically correlated with clinico-pathological information, and EGFR/KRAS mutation status. EZH2 expression was significantly (P < 0.0001) higher in SCCs compared with adenocarcinomas and in brain metastasis relative to matched primary tumors (P = 0.0013). EZH2 expression was significantly (P < 0.0001) elevated in bronchial preneoplastic lesions with increasing severity. In adenocarcinomas, higher EZH2 expression significantly correlated with younger age, cigarette smoking, and higher TNM stage (P = 0.02 to P < 0.0001). Higher EZH2 expression in adenocarcinoma was associated with worse recurrence-free survival (RFS; P = 0.025; HR = 1.54) and overall survival (OS; P = 0.0002; HR = 1.96). Furthermore, lung adenocarcinomas with low EZH2 levels and high expression of the lineage-specific transcription factor, TTF-1, exhibited significantly improved RFS (P = 0.009; HR = 0.51) and OS (P = 0.0011; HR = 0.45), which was confirmed in the independent set of 91 adenocarcinomas. In lung, EZH2 expression is involved in early pathogenesis of SCC and correlates with a more aggressive tumor behavior of adenocarcinoma. When EZH2 and TTF-1 expressions are considered together, they serve as a prognostic marker in patients with surgically resected lung adenocarcinomas.


A randomized trial of two treatments for mild traumatic brain injury: 1 year follow-up.
The purpose of this study was to provide 1 year follow-up data to a previous paper that compared single-session (SS) treatment to treatment-as-needed (TAN) outcomes for mild traumatic brain injury (MTBI) survivors at 3 months post-injury. Participants were 105 adults with MTBI who were recruited from consecutive admissions to two hospital emergency wards, and randomly assigned to either the SS or TAN modality. No group differences in outcome were evident at 12 months post-injury. As well, improvements seen in the groups after 3 months were maintained at 12 months. As improvements between 3 and 12 months were negligible, self-reported improvement after a treated MTBI typically occurred within the first 3 months. Brief educational intervention given soon after MTBI appears to be as helpful as more intensive treatment for most MTBI survivors for at least 12 months post-injury.


Bedside Immune Monitoring: An Automated Immunoassay Platform for Quantification of Blood Biomarkers in Patient Serum within 20 Minutes.
This Article presents an automated, compact, and self-contained system for sensitive quantitative detection of blood biomarkers. A disposable microfluidic chip, prefilled with biomarker-specific reagents and magnetic beads, can be processed fully automatically by a readout platform, enabling an immunoassay-based analysis with a processing time from sample incubation to signal analysis of 20 min. Novel concepts for on-chip vortexing of the magnetic beads and on-chip reagent storage and actuation were developed. A lens-free photodiode readout system represents a cost-efficient approach for detecting the chemiluminescent signal. IL-8 spiked serum samples were measured with a high reproducibility and a limit of detection of 2.05 pg·mL-1. The system was validated with undiluted serum samples collected from trauma patients at the intensive care unit. The developed platform demonstrated good correlation with the clinical reference method, and the clinical trajectory course of IL-8 could be sufficiently followed. With an automated assay approach and an easily adaptable protocol, this portable platform has the potential to be utilized as a universal instrument for analyzing proteins in small sample volumes (<25 μL) in point-of-care settings.


[When is interventional therapy necessary for carotid stenosis?].
Stenoses of the internal carotid artery are common. 20-30% of ischaemic cerebrovascular events are due to atherosclerotic lesions of carotid arteries. For many years endarterectomy has been a method for prevention of cerebral ischaemia. There is confusion about how carotid stenosis should be measured on angiograms. Since the results of clinical trials based on different measurement methods are applied to routine clinical practice, the various measurement methods must be comparable. We must know which one was used, and how to convert them by a simple arithmetical equation. Carotid endarterectomy appears to be highly beneficial in patients with recent hemispheric transient ischaemic attacks or non-disabling stroke and ipsilateral high-grade stenosis (> or = 60-70%) of the internal carotid artery. Even asymptomatic patients with high-grade stenosis benefit to some extent from surgery, and the beneficial effects correlate directly with the degree of stenosis. Endarterectomy in moderate symptomatic stenosis (50-69%) yields only a moderate reduction in stroke risk. In stenosis < 50% there is no benefit. Decisions about endarterectomy should take into account the natural history of stroke in carotid stenosis, surgical skills, and the individual patient's risk factors.


Psychiatric disorders in youth with medically unexplained chest pain versus innocent heart murmur.
To examine the prevalence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition psychiatric disorders in youth with chest pain compared with a control sample with innocent heart murmur. We assessed youth ages 8 to 17 years who were examined in cardiology settings for medically unexplained chest pain (n=100) or innocent heart murmur (n=80). We conducted semi-structured interviews and assessed medical history, quality of life, and disability. Youth with chest pain had a higher prevalence of psychiatric disorders compared with youth with murmur (74% versus 47%, χ(2)=13.3; P<.001). Anxiety disorders predominated, although major depression was also more common in the chest pain group (9% versus 0%; Fisher exact tests; P<.01). Onset of psychiatric disorders generally preceded chest pain. Patterns were similar for boys and girls and for children and adolescents. Chest pain was associated with poorer quality of life and with pain-related disability for youth with co-morbid psychiatric disorder. In childhood and adolescence, medically unexplained chest pain is associated with a high prevalence of psychiatric disorders. Systematic mental health screening may improve detection and enhance treatment of these patients.


Effects of marginal iodine deficiency during pregnancy: iodide uptake by the maternal and fetal thyroid.
Iodide uptake by the thyroid is an active process. Iodine deficiency and pregnancy are known to influence thyroid hormone metabolism. The aim of this study was to clarify the effects of iodine deficiency and pregnancy on iodide uptake by the thyroid. Radioiodide was injected intravenously into nonpregnant and 19-day pregnant rats receiving a normal or marginally iodine-deficient diet. The uptake of radioiodide by the thyroid was measured continuously for 4 h. The absolute iodide uptake by the maternal and fetal thyroid glands at 24 h was calculated by means of the urinary specific activity. Pregnancy resulted in a decrease in the absolute thyroidal iodide uptake. Marginal iodine deficiency had no effect on the absolute iodide uptake by the maternal thyroid. The decreased plasma inorganic iodide was compensated by an increase in thyroidal clearance. A similar compensation was not found for the fetus; the uptake of iodide by the fetal thyroid decreased by 50% during marginal iodine deficiency. This can lead to diminished thyroid hormone production, which will have a negative effect on fetal development, especially of the brain.


Diversity and subcellular distribution of archaeal secreted proteins.
Secreted proteins make up a significant percentage of a prokaryotic proteome and play critical roles in important cellular processes such as polymer degradation, nutrient uptake, signal transduction, cell wall biosynthesis, and motility. The majority of archaeal proteins are believed to be secreted either in an unfolded conformation via the universally conserved Sec pathway or in a folded conformation via the Twin arginine transport (Tat) pathway. Extensive in vivo and in silico analyses of N-terminal signal peptides that target proteins to these pathways have led to the development of computational tools that not only predict Sec and Tat substrates with high accuracy but also provide information about signal peptide processing and targeting. Predictions therefore include indications as to whether a substrate is a soluble secreted protein, a membrane or cell wall anchored protein, or a surface structure subunit, and whether it is targeted for post-translational modification such as glycosylation or the addition of a lipid. The use of these in silico tools, in combination with biochemical and genetic analyses of transport pathways and their substrates, has resulted in improved predictions of the subcellular localization of archaeal secreted proteins, allowing for a more accurate annotation of archaeal proteomes, and has led to the identification of potential adaptations to extreme environments, as well as phyla-specific pathways among the archaea. A more comprehensive understanding of the transport pathways used and post-translational modifications of secreted archaeal proteins will also facilitate the identification and heterologous expression of commercially valuable archaeal enzymes.


Evaluation of the release of dioxins and PCBs during kiln-firing of ball clay.
Ball clay is known to be naturally contaminated with high levels of polychlorinated di-benzo-p-dioxins (PCDDs). This study evaluated the potential for PCDD, polychlorinated dibenzofuran (PCDF) and polychlorinated biphenyl (PCB) release during the kiln firing of ball clay in an art studio. Toxic equivalence (TEQ) were calculated using World Health Organization (WHO) 2005 toxic equivalence factors (TEF) and congener concentrations. Ten bags of commercial ball clay were found to have an average TEQ of 1,370 nanograms/kilogram (ng kg(-1)) dry weight (dw), almost exclusively due to PCDDs (99.98% of TEQ). After firing, none of the 29 dioxin-like analytes was measured above the limits of detection (LOD) in the clay samples. Air samples were taken during firings using both low-flow and high-flow air samplers. Few low-flow air samples contained measurable levels of dioxin congeners above the LOD. The mean TEQ in the high volume air samples ranged from 0.07 pg m(-3) to 0.21 pg m(-3) when firing ball clay, and was 0.11 pg m(-3) when no clay was fired. These concentrations are within the range measured in typical residences and well-controlled industrial settings. The congener profiles in the high-flow air samples differed from the unfired clay; the air samples had a considerable contribution to the TEQ from PCDFs and PCBs. Given that the TEQs of all air samples were very low and the profiles differed from the unfired clay, it is likely that the PCDDs in dry ball clay were destroyed during kiln firing. These results suggest that inhalation of volatilized dioxins during kiln firing of dry ball clay is an unlikely source of exposure for vocational and art ceramicists.


The long-lasting Ascaris suum antigens in the lungs shapes the tissue adaptation modifying the pulmonary architecture and immune response after infection in mice.
Ascariasis is the most prevalent helminth affecting approximately 819 million people worldwide. The acute phase of Ascariasis is characterized by larval migration of Ascaris spp., through the intestinal wall, carried to the liver and lungs of the host by the circulatory system. Most of the larvae subsequently transverse the lung parenchyma leading to tissue injury, reaching the airways and pharynx, where they can be expectorated and swallowed back to the gastrointestinal tract, where they develop into adult worms. However, some larvae are trapped in the lung parenchyma inciting an inflammatory response that causes persistent pulmonary tissue damage long after the resolution of infection, which returns to tissue homeostasis. However, the mechanism by which chronic lung disease develops and resolves remains unknown. Here, using immunohistochemistry, we demonstrate that small fragments and larval antigens of Ascaris suum are deposited and retained chronically in the lung parenchyma of mice following a single Ascaris infection. Our results reveal that the prolonged presence of Ascaris larval antigens in the lung parenchyma contributes to the persistent immune stimulation inducing histopathological changes observed chronically following infection, and clearly demonstrate that larval antigens are related to all phases of tissue adaptation after infection: lung injury, chronic inflammation, resolution, and tissue remodeling, in parallel to increased specific humoral immunity and the recovery of lung function in mice. Additional insight is needed into the mechanisms of Ascaris antigen to induce chronic immune responses and resolution in the host lungs following larval migration.


Electrostatic Interactions Govern Extreme Nascent Protein Ejection Times from Ribosomes and Can Delay Ribosome Recycling.
The ejection of nascent proteins out of the ribosome exit tunnel, after their covalent bond to transfer-RNA has been broken, has not been experimentally studied due to challenges in sample preparation. Here, we investigate this process using a combination of multiscale modeling, ribosome profiling, and gene ontology analyses. Simulating the ejection of a representative set of 122 E. coli proteins we find a greater than 1000-fold variation in ejection times. Nascent proteins enriched in negatively charged residues near their C-terminus eject the fastest, while nascent chains enriched in positively charged residues tend to eject much more slowly. More work is required to pull slowly ejecting proteins out of the exit tunnel than quickly ejecting proteins, according to all-atom simulations. An energetic decomposition reveals, for slowly ejecting proteins, that this is due to the strong attractive electrostatic interactions between the nascent chain and the negatively charged ribosomal-RNA lining the exit tunnel, and for quickly ejecting proteins, it is due to their repulsive electrostatic interactions with the exit tunnel. Ribosome profiling data from E. coli reveals that the presence of slowly ejecting sequences correlates with ribosomes spending more time at stop codons, indicating that the ejection process might delay ribosome recycling. Proteins that have the highest positive charge density at their C-terminus are overwhelmingly ribosomal proteins, suggesting the possibility that this sequence feature may aid in the cotranslational assembly of ribosomes by delaying the release of nascent ribosomal proteins into the cytosol. Thus, nascent chain ejection times from the ribosome can vary greatly between proteins due to differential electrostatic interactions, can influence ribosome recycling, and could be particularly relevant to the synthesis and cotranslational behavior of some proteins.


The formation of phosphatidylcholine oxidation products by stimulated phagocytes.
Phagocytic cells produce a variety of oxidants as part of the immune defence, which react readily both with proteins and lipids, and could contribute to the oxidation of low density lipoprotein in atherosclerosis. We have investigated the oxidation of phospholipid vesicles by neutrophils and mononuclear cells, to provide a model of lipid oxidation in the absence of competing protein. Phorbol 12-myristate 13-acetate-stimulated neutrophils were incubated with phospholipid vesicles containing dipalmitoyl phosphatidylcholine, palmitoyl-arachidonoyl phosphatidylcholine (PAPC) and stearoyl-oleoyl phosphatidylcholine, before extraction of the lipids for analysis by HPLC coupled to electrospray mass spectrometry. The formation of monohydroperoxides (814 m/z) and bishydroperoxides (846 m/z) of PAPC was observed. However, the major oxidized product occurred at 828 m/z,and was identified as 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine. These products were also formed in incubations where the neutrophils were replaced by mononuclear cells, and the amounts produced per million cells were similar. These results show that following oxidative attack by phagocytes stimulated by PMA, intact phospholipid oxidation products can be detected. The identification of an epoxyisoprostane phospholipid as the major product of phagocyte-induced phospholipid oxidation is novel, and in view of its inflammatory properties has implications for phagocyte involvement in atherogenesis.


In the wake of a possible mistake: Security motivation, checking behavior, and OCD.
In previous experiments, OCD washers did not differ significantly from controls in their initial level of activation in response to the potential threat of contamination; however, they were less able to reduce their activation by engaging in hand-washing, suggesting that the key problem in OCD is a faulty stopping mechanism. The main objectives of the present experiments were to develop a similar experimental paradigm for investigating checking behavior, and to use it to test the hypothesis that a faulty stopping mechanism also underlies OCD checking. Participants sorted pills under the guise of beta testing a new medication system and then were given suggestions of the possibility of having made mistakes with potentially serious consequences. Later, participants engaged in a 90-s checking period and an unlimited period of checking. At baseline and three other times during the experiment, security motivation was measured with respiratory sinus arrhythmia (RSA) and subjective ratings of confidence. Experiment 1 established the parameters of the paradigm in non-patient participants, and Experiment 2 contrasted OCD checkers with OCD washers and non-patients. Results for both subjective and physiological measures of security motivation closely replicated previous findings for washing behavior. Groups did not differ significantly in initial activation, but the OCD checkers were unable to reduce their activation by engaging in period of checking that was ample for returning controls to baseline. The sample size for the patient groups was modest. These results lend further support to the security-motivation theory of OCD.


The cell cycle of symbiotic Chlorella. II. The effect of continuous darkness.
When green hydra were grown in continuous darkness the mean cell size of their symbiotic algae was smaller than when grown in light and numbers of algae per digestive cell were reduced. The former was due to a reduction in size at which the algae divided, and the latter to a loss of synchrony of algal mitosis with that of digestive cells after transfer to darkness. Eventually, algal mitosis regained synchrony with that of digestive cells. Division synchrony was not lost in reinfected hydra (with lower than normal numbers of algae per cell) transferred to darkness; this, and the observation that synchrony in normal animals transferred to darkness was regained when algal numbers per cell had fallen to a new, lower level, suggested that the initial inhibition of algal mitosis was due to competition for a limited supply of heterotrophically required metabolites. When dark-grown hydra were returned to light there was no delay in algal division and a steady increase in the size of dividing cells, suggesting that the smaller division size in darkness was not due simply to the critical size for division being set at a lower value. In light, algal division size varied with frequency of host feeding, but this had less effect on algal division size in darkness. It is suggested that the critical cell size that algae must attain before being able to complete the cell cycle is the same in light and darkness, but in light mitosis is restricted by some exogenous factor so that algae grow beyond the critical size without dividing. In darkness both algal cell growth and division are dependent on exogenously supplied metabolites, and cell growth rather than the division factor is limiting. The precise nature of the restriction on algal division remains unknown.


Demographic, criminal, and psychiatric factors related to inmate suicide.
A review of 19 studies suggests that it may be feasible to identify prisoners with suicide risk on the basis of demographic, psychiatric, and criminal characteristics. The present study aimed to identify combinations of characteristics that are capable of identifying potential suicide victims. Characteristics of 95 suicide victims in the Dutch prison system were compared with those of a random sample of 247 inmates in ten jails. Combinations of indicators for suicide risk were also tested for their capability of identifying 209 suicides in U.S. jails and 279 prison suicides in England and Wales. A combination of six characteristics (age 40+, homelessness, history of psychiatric care, history of drug abuse, one prior incarceration, violent offence) was capable of correctly classifying 82% of the Dutch suicide victims (82% specificity). Less powerful combinations correctly classified 53% of the U.S. suicides and 47% of the U.K. suicides. It is concluded that a set of demographic and criminal characteristics and indicators of psychiatric problems is useful for the identification of suicide risk in jails and prisons.


Ultrafast photoinduced charge separation in metal-semiconductor nanohybrids.
Hybrid nano-objects formed by two or more disparate materials are among the most promising and versatile nanosystems. A key parameter in their properties is interaction between their components. In this context we have investigated ultrafast charge separation in semiconductor-metal nanohybrids using a model system of gold-tipped CdS nanorods in a matchstick architecture. Experiments are performed using an optical time-resolved pump-probe technique, exciting either the semiconductor or the metal component of the particles, and probing the light-induced change of their optical response. Electron-hole pairs photoexcited in the semiconductor part of the nanohybrids are shown to undergo rapid charge separation with the electron transferred to the metal part on a sub-20 fs time scale. This ultrafast gold charging leads to a transient red-shift and broadening of the metal surface plasmon resonance, in agreement with results for free clusters but in contrast to observation for static charging of gold nanoparticles in liquid environments. Quantitative comparison with a theoretical model is in excellent agreement with the experimental results, confirming photoexcitation of one electron-hole pair per nanohybrid followed by ultrafast charge separation. The results also point to the utilization of such metal-semiconductor nanohybrids in light-harvesting applications and in photocatalysis.


Follicular morphological characteristics may be associated with invasion in follicular thyroid neoplasms with papillary-like nuclear features.
The newly proposed nomenclature and diagnostic criteria for encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), could improve the consistency and accuracy of diagnosing this entity. Diagnosis of NIFTP requires evaluation of the complete tumor border or capsule. The presence of tumor invasion in follicular thyroid neoplasms with papillary-like nuclear features has been recently discussed by many authors. In this study, we examined the predictive value and association of follicular morphological characteristics with the tumor invasion. In addition, we analyzed the association between tumor encapsulation and molecular profile in EFVPTC/NIFTP cases. A total of 106 cases of FVPTC were included in the study. The tumors were grouped based on the presence of tumor capsule and characteristics of tumor border, as 1) completely encapsulated tumors without invasion, 2) encapsulated tumors with invasion, 3) infiltrative tumors without a capsule. Clinicopathological features, histomorphological features [nuclear criteria, minor diagnostic features, follicles oriented perpendicular to tumor border/capsule (FOPBC)] and molecular alterations in BRAF, NRAS, and KRAS genes were evaluated. FOPBC were significantly more frequently seen in encapsulated tumors with invasion (p = 0.008). The nuclear features were not associated with the presence of encapsulation and characteristics of tumor border. BRAF mutation was more frequent in infiltrative tumors, while NRAS mutation was more frequent in encapsulated tumors, but the results were not statistically significant (p = 0.917). In conclusion, FOPBC histomorphological feature may be associated with tumor invasion in EFVPTC/NIFTP. Additionally, BRAF/KRAS/NRAS mutation analysis may prevent inadequate treatment in these patients.


The chemical composition and the content of volatile oil: potential factors that can contribute to the oxidative stability of Nigella sativa L. crude oil.
The crude oil of Nigella sativa L. (Black cumin) has well-known nutraceutical and pharmaceutical properties. The oil is prone to rapid oxidative deterioration because of its high content of poly-unsaturated fatty acids. In the current investigation, different cold-pressed crude oils of N. sativa were examined for their composition of fatty acids and oxidative stability. The data obtained were correlated with the chemical composition and content of volatile oils, which correspond to each crude oil. Results indicated that different crude oils have the same fatty acid composition, and linoleic acid was the major constituent (60.0-61.7%). Though, the oxidative stability index of the crude oils was different ranging from 2.5 hr to 26.9 hr, as revealed by the Rancimate test at 100°C and airflow rate of 20 ml/min. The results showed that there is a straightforward correlation between the volatile oil content and the oxidative stability of the corresponding parent crude oil. In addition, high γ-terpinene content in the constitution of volatile oil can also be another contributing factor for enhancing the oxidative stability of the crude oil. The data presented here draw attention to some important factors that may guide the nutraceutical and food supplement processors in their screening for the highest quality of Nigella crude oils with maximum health benefits.


Response of exogenous melatonin on transcription and metabolism of soybean under drought stress.
Amino acid metabolism is an important factor in regulating nitrogen source assimilation and source/sink transport in soybean. Melatonin can improve plant stress resistance, but whether it affects amino acid metabolism is not known. Therefore, this study investigated whether exogenous melatonin had an effect on amino acid metabolism of soybean under drought conditions and explored its relationship with yield. The treatments were normal water supply treatment (WW), drought stress treatment (D), drought stress and melatonin treatment group (D + M), sprayed with 100 μmol/L melatonin. The effects of melatonin on amino acid metabolism and grain filling were studied by physiological and omics experiments using Kangxian 9 (drought-sensitive variety) and Suinong 26 (drought-resistant variety) soybean cultivars. The results showed that drought stress decreased the activity of carbon and nitrogen metabolizing enzymes, which inhibited the accumulation of dry matter and protein, and decreased the yield. In the drought-sensitive soybean variety, glycoenzymes and amino acid synthetases synthetic genes were upregulated in melatonin-treated soybeans, hence carbon and nitrogen metabolism enzyme activity increased, increasing the carbohydrate and amino acid contents simultaneously. This resulted in higher dry matter and yield than drought-stressed soybean not treated with melatonin. In the drought-resistant variety, the grain weight per plant increased by 7.98% and 6.57% in 2020 and 2021, respectively, while it increased by 23.20% and 14.07% in the drought-sensitive variety during the respective years. In conclusion, melatonin treatment can enhance the activity of nitrogen and carbon metabolism and amino acid content by upregulating the expression of soybean metabolic pathway and related genes, thus increasing the yield of soybean under drought stress.


Uridine Diphosphate Promotes Rheumatoid Arthritis Through P2Y6 Activation.
BACKGROUND: Uridine diphosphate (UDP) is an extracellular nucleotide signaling molecule implicated in diverse biological processes via specific activation of pyrimidinergic receptor P2Y, G Protein-Coupled, 6 (P2Y6). There is very little knowledge about the function and mechanism of UDP in rheumatoid arthritis (RA). METHODS: This study used a quasi-targeted liquid chromatography-mass spectrometry (LC-MS) approach to investigate the unique expression of metabolites in RA synovial fluids (SF) (n = 10) with samples from osteoarthritis (OA) as controls (n = 10). RA fibroblast-like synoviocytes (FLSs) were collected from synovial tissues (n = 5) and cultured with UDP or MRS2578, a P2Y6 antagonist, and FLSs from OA were used as controls (n = 5). Rats with collagen-induced arthritis (CIA) were injected with UDP, MRS2578 or both (n = 9 for each group). P2Y6 expression was examined using real-time PCR, Western blotting and immunohistochemistry. Cell proliferation, apoptosis and migration of RA FLSs were measured using CCK-8 assay, real-time cell analysis, flow cytometry, wound healing assay and Transwell assay, respectively. The UDP levels in the culture medium, synovial fluid (n = 36) and peripheral blood (n = 36) of RA and CIA rats were measured using a Transcreener UDP Assay. Levels of proinflammatory cytokines were measured using a flow assay. Interleukin-6 (IL-6) levels were measured using ELISA and flow. RESULTS: LC-MS analysis detected significantly increased UDP levels in RA SF compared with OA SF, and the level was positively correlated with anticyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF)levels in RA. The increased UDP concentration was verified in the blood and synovial fluids of RA patients compared with samples from OA patients and healthy volunteers, respectively. UDP stimulated cell proliferation, migration and IL-6 secretion in RA FLSs and inhibited their apoptosis in culture, and MRS2578 inhibited these effects of UDP. UDP injection accelerated CIA and stimulated IL-6 production rather than other proinflammatory cytokines in the rat model, but simultaneous injection of MRS2578 suppressed these effects and alleviated CIA. P2Y6 expression was increased in RA and CIA synovial tissues. CONCLUSION: These results suggest that UDP is highly expressed in RA and stimulates RA pathogenesis by promoting P2Y6 activities to increase IL-6 production.


Microemulsions.
Water and oil can be made completely miscible by adding a sufficient amount of an amphiphilic compound, such as soap or a detergent. For historical reasons, such stable homogeneous solutions are called "microemulsions." In this article the term microemulsion is used in a more restrictive manner; at low concentrations of the amphiphile, mixtures of water, nonpolar solvents, and amphiphiles may separate into three coexisting liquid layers, namely, an aqueous phase, an amphiphile-rich phase, and an oil-rich phase. In the amphiphile-rich phase, which is the microemulsion in the narrower sense, one finds for thermodynamic reasons a maximum of the mutual solubility between water and oil, combined with a minimum of the interfacial tension between the aqueous and the oil-rich phase, properties that are of interest for both theory and application. The present state of art in this rapidly growing field of science is reviewed.


Clinical and molecular characteristics of malignant transformation of low-grade glioma in children.
To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children. The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval. Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% +/- 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient. The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.


Responsiveness of the Balance Evaluation Systems Test (BESTest) in People With Subacute Stroke.
The reliability and convergent validity of the Balance Evaluation Systems Test (BESTest) in people with subacute stroke have been established, but its responsiveness to rehabilitation has not been examined. The study objective was to compare the responsiveness of the BESTest with those of other clinical balance tools in people with subacute stroke. This was a prospective cohort study. Forty-nine people with subacute stroke (mean age=57.8 years, SD=11.8) participated in this study. Five balance measures-the BESTest, the Mini-BESTest, the Berg Balance Scale, the Postural Assessment Scale for Stroke Patients, and the Community Balance and Mobility Scale (CB&M)-were used to measure balance performance before and after rehabilitation or before discharge from the hospital, whichever came first. The internal responsiveness of each balance measure was classified with the standardized response mean (SRM); changes in Berg Balance Scale scores of greater than 7 were used as the external standard for determining the external responsiveness. Analysis of the receiver operating characteristic curve was used to determine the accuracy and cutoff scores for identifying participants with balance improvement. Participants received 13.7 days (SD=9.3, range=5-44) of physical therapy rehabilitation. The internal responsiveness of all balance measures, except for the CB&M, was high (SRM=0.9-1.2). The BESTest had a higher SRM than the Mini-BESTest and the CB&M, indicating that the BESTest was more sensitive for detecting balance changes than the Mini-BESTest and the CB&M. In addition, compared with other balance measures, the BESTest had no floor, ceiling, or responsive ceiling effects. The results also indicated that the percentage of participants with no change in scores after rehabilitation was smaller with the BESTest than with the Mini-BESTest and the CB&M. With regard to the external responsiveness, the BESTest had higher accuracy, sensitivity, specificity, and posttest accuracy than the Postural Assessment Scale for Stroke Patients and the CB&M for identifying participants with balance improvement. Changes in BESTest scores of 10% or more indicated changes in balance performance. A limitation of this study was the difference in the time periods between the first and the second assessments across participants. The BESTest was the most sensitive scale for assessing balance recovery in participants with subacute stroke because of its high internal and external responsiveness and lack of floor and ceiling effects.


Plastic deformation, wrinkling, and recovery in microgel multilayers.
Microgel multi-layer films assembled from anionic particles and linear polycation were prepared on elastomeric substrates and their self-healing properties studied. Dried films were imaged in situ during mechanical deformation and were determined to undergo plastic deformation in response to linear strain, leading to film buckling upon strain relaxation. Hydration leads to rapid reorganization of the film building blocks, permitting recovery of the film to the undamaged state. Additionally, films were determined to heal in the presence of high relative humidity environments, suggesting that film swelling and hydration is a major factor in the restoration of film integrity, and that full immersion in solvent is not required for healing. Films prepared from microgels with lower levels of acid content and/or polycation length, factors strongly connected to the charge density and presumably the connectivity of the film, also display self-healing characteristics.


A tissue-restricted cAMP transcriptional response: SOX10 modulates alpha-melanocyte-stimulating hormone-triggered expression of microphthalmia-associated transcription factor in melanocytes.
alpha-Melanocyte-stimulating hormone (MSH) utilizes cAMP to trigger pigmentation of melanocytes via activation of melanocyte-restricted microphthalmia-associated transcription factor (M-MITF) expression. M-MITF is a melanocyte-restricted helix-loop-helix transcription factor capable of transactivating promoters for multiple genes whose products modulate pigmentation. Although M-MITF promoter activation by MSH is known to occur through a conserved cAMP-response element (CRE), it remains unclear how this CRE exhibits such exquisitely tissue-restricted responsiveness. Here we show that cAMP-mediated CRE-binding protein activation of the M-MITF promoter requires a second DNA element located approximately 100 bp upstream, a site that is bound and activated by SOX10. Mutations in the SOX10 transcription factor, like MITF, results in a disorder known as Waardenburg Syndrome. The cAMP response of the M-MITF promoter was analyzed in melanoma and neuroblastoma cells (which are neural crest-derived but lack both M-MITF and SOX10 expression). M-MITF promoter responsiveness to cAMP was found to depend upon SOX10, and reciprocally, SOX10 transactivation was dependent upon the CRE. Ectopic SOX10 expression, in cooperation with cAMP signaling, activated the M-MITF promoter function and the expression of measurable endogenous M-MITF transcripts in neuroblastoma cells. SOX10dom, a mutant allele, failed to cooperate with cAMP in neuroblastoma cells and attenuated the cAMP responsiveness of the M-MITF promoter in melanoma cells. These observations demonstrate a means whereby the ubiquitous cAMP signaling machinery is harnessed to produce a highly tissue-restricted transcriptional response by cooperating with architectural factors, in this case SOX10.


Preparation for Old Age: The Role of Cultural Context and Future Perceptions.
Preparation for age-related changes is a central task in midlife and older age and a determinant of functioning and well-being in later life. If and how people prepare is influenced by societal and institutional circumstances and also by beliefs about aging and the future. We assessed domain-specific preparation for age-related changes in samples from three countries with high population aging but different premises regarding preparation, and analyzed data from N = 1,830 individuals aged 35-85 years from urban regions in Germany, the United States, as well as China (Hong Kong). Preparation was universally low in China, but the amount of differences between countries varied depending on life domain. While we found pronounced differences between all three countries for domains related to public provision (such as health care, work, and finances), East-West differences in preparation emerged for domains regarding social relations and end-of-life concerns. The concreteness of time perspective and future self-views mediated country differences in preparation. Our results speak for the culture-specificity of preparing for old age and we deliver evidence on psychological variables that might explain these differences.


Antibacterial activity and physical properties of glass-ionomer cements containing antibiotics.
This study evaluated the antibacterial effects, physical properties and bonding strengths of conventional glass-ionomer cements (GICs) containing antibiotics and determined the optimal concentration of antibiotics addition for use with the ART approach. Fuji IX GIC was used as a control. Three antibiotic mixtures, ciprofloxacin, metronidazole and minocycline, were added to powdered GIC (Fuji IX) to obtain concentration ratios of 1.5, 3.0 and 4.5% w/w. The antibacterial activity of each GIC was evaluated against Streptococcus mutans or Lactobacillus casei using agar-diffusion methods. The release of antibiotics was analyzed by high-performance liquid chromatography (HPLC). The compressive strength and bonding strength to dentin were measured and compared with those of control samples. The results were analyzed using the Mann-Whitney test and Wilcoxon test. All tested groups showed a significantly greater inhibition with growth of the selected bacteria in comparison to the control groups (p < 0.01). However, the 3% and 4.5% concentration ratios of antibiotics had significantly lower compressive strength and lower bond strength to dentin than the control group (p = 0.003). The GIC-containing antibiotics were effective in inhibiting S Mutans and L Casei. The addition of a 1.5% antibiotic mixture was optimal to giving appropriate physical and bonding properties.


Comparison of the Kansas City Cardiomyopathy Questionnaire and Minnesota Living With Heart Failure Questionnaire in Predicting Heart Failure Outcomes.
Patient-reported outcome measures (PROMs) are relevant independent outcomes in heart failure (HF) care and are predictive of subsequent hospitalization and death in HF. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) are the 2 most widely adopted PROMs specific to HF. We compared their prognostic abilities in a prospective cohort of HF patients. A prospective cohort of subjects from a single-center registry was analyzed with regard to baseline KCCQ and MLHFQ scores and the outcomes of death, transplant, or left ventricular assist device implantation and hospitalization. A total of 516 subjects with reduced left ventricular ejection fraction (HFrEF) and 151 subjects with preserved left ventricular ejection fraction (HFpEF) were included. Discrimination was assessed using c-statistics based on time-to-event analyses and receiver-operator curves. The additive contribution of MLHFQ was assessed through the change in c-statistic, incremental discrimination index, and category-free net reclassification index. Overall, KCCQ was superior to MLHFQ for predicting death/transplant/ventricular assist device (c-statistic 0.702 [0.666 to 0.738] and 0.658 [0.621 to 0.695] respectively, p value for difference <0.001) and hospitalization (c-statistic 0.640 [0.613 to 0.666] and 0.624 [0.597 to 0.651], respectively, p value for difference 0.022). However, this difference was statistically nonsignificant in the HFpEF group alone. When analyzing the additional prognostic information afforded by adding MLHFQ to KCCQ in the overall, HFrEF, and HFpEF groups there was no significant improvement, although adding KCCQ to MLHFQ did significantly improve risk stratification. Scoring based upon the abbreviated KCCQ-12 did not reduce the prognostic accuracy of KCCQ. In conclusion, KCCQ is more prognostic of death/transplant/left ventricular assist device and hospitalization than MLHFQ in a combined cohort of patients with HFrEF and HFpEF, although the effect in HFpEF was less pronounced. KCCQ should be the preferred PROM for patients with HF if prognostication is a desired goal of using the PROMs.


Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.
High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.


Long-term Results of the Open Latarjet Procedure for Recurrent Anterior Shoulder Instability in Patients Older Than 40 Years.
Subgroup analyses of the Latarjet procedure have suggested that age over 40 years is a risk factor for dislocation arthropathy. To analyze long-term results of the open Latarjet procedure for recurrent anterior shoulder dislocation in patients at least 40 years of age. Case series; Level of evidence, 4. A total of 39 consecutive patients (40 shoulders) with a mean age of 48 years (range, 40-66 years) at surgery were evaluated at a mean follow-up of 11.0 years (range, 8-16 years). Of these, 15 patients (38%) had undergone previous soft tissue stabilization surgery. Long-term results were assessed clinically and radiographically, including computed tomography scanning at final follow-up. No recurrence of dislocation was noted. Subluxation had occurred in 3 patients (8%), and apprehension persisted in 5 patients (13%). The total Walch-Duplay score averaged 89 points at the final follow-up, and the mean Subjective Shoulder Value (60%-91%) had improved significantly (P < .001). In total, 36 patients rated their result as excellent, 3 as good. Further, 6 patients (15%) underwent joint-preserving reoperation, and 1 patient (3%) had reverse total shoulder arthroplasty for severe dislocation arthropathy. Dislocation arthropathy was severe in 14 patients (37%) and had progressed by at least 2 grades in 17 patients (45%). Patients with severe dislocation arthropathy had already shown degenerative changes preoperatively as opposed to those who ultimately had no or moderate dislocation arthropathy (n = 24) (P < .001). Progression of dislocation arthropathy was associated with lateral (>1 mm) graft positioning (P < .001) and older age at surgery (r = 0.58; P < .001). The open Latarjet procedure for recurrent anterior shoulder instability in patients older than 40 years reliably restores stability and leads to high patient satisfaction. This procedure is, however, associated with a substantial rate of advanced but clinically mild symptomatic dislocation arthropathy, which is associated with the degree of preoperative joint degeneration, older age at surgery, and lateral graft placement.


Muscle Involvement in Amyotrophic Lateral Sclerosis: Understanding the Pathogenesis and Advancing Therapeutics.
Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.


Distinct antigenic characteristics of murine parietal yolk sac laminin.
Two monoclonal antibodies (LAM-A and LAM-B) specific for laminin from normal and neoplastic parietal yolk sac (PYS) cells were produced in rats immunized with a mouse yolk sac carcinoma cell line. Both antibodies immunoprecipitated the 400,000- and 200,000-Da chains of laminin and reacted with purified PYS laminin in ELISA. LAM-A reacted with mouse and rat PYS laminin, whereas LAM-B reacted only with mouse PYS laminin. Formaldehyde- and methanol-fixed adult and fetal somatic tissues were immunohistochemically unreactive with either of the two antibodies. In acetone-fixed tissue sections, both antibodies reacted weakly with some medullary tubules of the kidney, the follicular basement membrane of the ovaries, and the seminiferous tubules. The antibodies appear to react with the polypeptide determinants residing on the terminal portion of the long arm of laminin. It is concluded that laminin derived from normal or malignant PYS cells has distinct antigenic sites that are immunochemically not apparent in most other basement membranes.


[Structure of progressive forms of tick-borne encephalitis].
On the basis of long-term follow up (from 2 to 22 years) of 175 patients with various syndromes of progressive forms of tick-borne encephalitis (TBE), evaluation criteria of TBE progression are systematized. Two basic forms of disease progression are identified: amyotrophic and hyperkinetic, each of them breaking down into a series of leading syndromes. Important for characterizing progressive forms of tick-borne encephalitis (PFTBE) are the time when the disease began to progress and the pattern of progression as well as its stage and severity. PFTBE are correlated with the acute period syndromes. In long-term follow-up, 68% of patients with PFTBE display transformation of clinical forms of the disease, with the formation of the lateral amyotrophic sclerosis syndrome in the overwhelming majority of these patients.


Predictors of sustained walking among diabetes patients in managed care: the Translating Research into Action for Diabetes (TRIAD) study.
Although patients with diabetes may benefit from physical activity, few studies have examined sustained walking in this population. To examine the factors associated with sustained walking among managed care patients with diabetes. Longitudinal, observational cohort study with questionnaires administered 2.5 years apart. Five thousand nine hundred thirty-five patients with diabetes walking at least 20 minutes/day at baseline. The primary outcome was the likelihood of sustained walking, defined as walking at least 20 minutes/day at follow-up. We evaluated a logistic regression model that included demographic, clinical, and neighborhood variables as independent predictors of sustained walking, and expressed the results as predicted percentages. The absence of pain was linked to walking behavior, as 62% of patients with new pain, 67% with ongoing pain, and 70% without pain were still walking at follow-up (p = .03). Obese patients were less likely (65%) to sustain walking than overweight (71%) or normal weight (70%) patients (p = .03). Patients > or =65 years (63%) were less likely to sustain walking than patients between 45 and 64 (70%) or < or =44 (73%) years (p = .04). Only 62% of patients with a new comorbidity sustained walking compared with 68% of those who did not (p < .001). We found no association between any neighborhood variables and sustained walking in this cohort of active walkers. Pain, obesity, and new comorbidities were moderately associated with decreases in sustained walking. Whereas controlled intervention studies are needed, prevention, or treatment of these adverse conditions may help patients with diabetes sustain walking behavior.


Imaging of peptide adsorption to microfluidic channels in a plastic compact disc using a positron emitting radionuclide.
A method for studying peptide-surface interactions within microfluidic channels by radionuclide imaging is described. With the high surface area-to-volume ratio of channels in miniaturised devices, combined with low amounts of analyte, non-specific peptide adsorption is a critical issue. The objective of the study was therefore to develop a method capable of direct detection of adsorbed peptide within microfluidic channels. A micro-device consisting of channels moulded in a plastic compact disc was chosen for the study, together with two selected peptides of different lengths and isoelectric point (pI) values. A bifunctional chelator, DOTA, was attached to the peptide by conjugation and labelled with the short-lived positron emitting radionuclide 68Ga. Quantitative images of radiotracer distribution within the microfluidic channels were obtained using a PhosphorImager system. The power of the method was demonstrated by the ability to clearly measure changes in adsorption when varying a number of parameters that typically affect peptide adsorption. These included surface modifications, analyte concentration, pH, and ionic strength. Additionally, two quantification methods were developed and compared. Radionuclide imaging also permitted visualisation of adsorption and release processes in microchannel chromatographic columns. The results suggest that radionuclide imaging is a suitable tool not only for the study of peptide adsorption to the microchannels presented in this study but also as a versatile tool to measure peptide-surface interactions in a wide variety of miniaturised structures and devices.


Multiple-cost constraints for the design of tree-structured vector quantizers.
Minimizing the distortion subject to a cost constraint is fundamental in the design of tree-structured vector quantizers. Because of various competing cost measures, the use of single-cost constraints has led to undesirable results. The author studies the relationships among several cost functions and shows how multiple-cost constraints can be used to significantly improve tree design.


Morinda officinalis oligosaccharides ameliorate depressive-like behaviors in poststroke rats through upregulating GLUT3 to improve synaptic activity.
Poststroke depression (PSD) is one of the most common psychiatric diseases afflicting stroke survivors, yet the underlying mechanism is poorly understood. The pathophysiology of PSD is presumably multifactorial, involving ischemia-induced disturbance in the context of psychosocial distress. The homeostasis of glucose metabolism is crucial to neural activity. In this study, we showed that glucose consumption was decreased in the medial prefrontal cortex (mPFC) of PSD rats. The suppressed glucose metabolism was due to decreased glucose transporter-3 (GLUT3) expression, the most abundant and specific glucose transporter of neurons. We also found Morinda officinalis oligosaccharides (MOOs), approved as an antidepressive Chinese medicine, through upregulating GLUT3 expression in the mPFC, improved glucose metabolism, and enhanced synaptic activity, which ultimately ameliorated depressive-like behavior in PSD rats. We further confirmed the mechanism that MOOs induce GLUT3 expression via the PKA/pCREB pathway in PSD rats. Our work showed that MOOs treatment is capable of restoring GLUT3 level to improve depressive-like behaviors in PSD rats. We also propose GLUT3 as a potential therapeutic target for PSD and emphasize the importance of metabolism disturbance in PSD pathology.


Inhibition of curli assembly and Escherichia coli biofilm formation by the human systemic amyloid precursor transthyretin.
During biofilm formation, Escherichia coli and other Enterobacteriaceae produce an extracellular matrix consisting of curli amyloid fibers and cellulose. The precursor of curli fibers is the amyloidogenic protein CsgA. The human systemic amyloid precursor protein transthyretin (TTR) is known to inhibit amyloid-β (Aβ) aggregation in vitro and suppress the Alzheimer's-like phenotypes in a transgenic mouse model of Aβ deposition. We hypothesized that TTR might have broad antiamyloid activity because the biophysical properties of amyloids are largely conserved across species and kingdoms. Here, we report that both human WT tetrameric TTR (WT-TTR) and its engineered nontetramer-forming monomer (M-TTR, F87M/L110M) inhibit CsgA amyloid formation in vitro, with M-TTR being the more efficient inhibitor. Preincubation of WT-TTR with small molecules that occupy the T4 binding site eliminated the inhibitory capacity of the tetramer; however, they did not significantly compromise the ability of M-TTR to inhibit CsgA amyloidogenesis. TTR also inhibited amyloid-dependent biofilm formation in two different bacterial species with no apparent bactericidal or bacteriostatic effects. These discoveries suggest that TTR is an effective antibiofilm agent that could potentiate antibiotic efficacy in infections associated with significant biofilm formation.


Identification of differential gene expression in Brassica rapa nectaries through expressed sequence tag analysis.
Nectaries are the floral organs responsible for the synthesis and secretion of nectar. Despite their central roles in pollination biology, very little is understood about the molecular mechanisms underlying nectar production. This project was undertaken to identify genes potentially involved in mediating nectary form and function in Brassica rapa. Four cDNA libraries were created using RNA isolated from the median and lateral nectaries of B. rapa flowers, with one normalized and one non-normalized library being generated from each tissue. Approximately 3,000 clones from each library were randomly sequenced from the 5' end to generate a total of 11,101 high quality expressed sequence tags (ESTs). Sequence assembly of all ESTs together allowed the identification of 1,453 contigs and 4,403 singleton sequences, with the Basic Localized Alignment Search Tool (BLAST) being used to identify 4,138 presumptive orthologs to Arabidopsis thaliana genes. Several genes differentially expressed between median and lateral nectaries were initially identified based upon the number of BLAST hits represented by independent ESTs, and later confirmed via reverse transcription polymerase chain reaction (RT PCR). RT PCR was also used to verify the expression patterns of eight putative orthologs to known Arabidopsis nectary-enriched genes. This work provided a snapshot of gene expression in actively secreting B. rapa nectaries, and also allowed the identification of differential gene expression between median and lateral nectaries. Moreover, 207 orthologs to known nectary-enriched genes from Arabidopsis were identified through this analysis. The results suggest that genes involved in nectar production are conserved amongst the Brassicaceae, and also supply clones and sequence information that can be used to probe nectary function in B. rapa.


Nasal Cavity CT Imaging Contribution to the Diagnosis and Treatment of Choanal Atresia.
Background and Objectives: Choanal atresia is the most common congenital malformation of the nose. Materials and Methods: We have evaluated 24 CT images of children with choanal atresia treated at the Department of Pediatric Otorhinolaryngology FM CU and the NICD Bratislava (Slovakia). In accordance with the methodology used by Slovis et al. (1985), we have measured parameters related to anomalous development in the nasal cavity: vomer width, the width of soft atresia and the width of the air space of unilaterally developed choana. Results: In the group of 24 patients, 11 (46%) were male and 13 (54%) were female. The age of patients at the time of CT imaging varied. Associated syndromes had been manifested in 11 (46%) children, with 7 (29%) patients having CHARGE syndrome. In 13 (54%) cases it was a bone membranous type of atresia, in 8 (33%) cases a membranous type, and in 3 (13%) patients a bone type. Among the group of patients, unilateral disorder was present in 13 (54%) patients and bilateral in 11 (46%). Based on the Pearson's correlation test, we have found in the studied group that the width of the vomer correlates with age, and the vomer is wider in bone atresia than in the membranous ones. Based on determining the average vomer's width within the age groups 0-8 and >8-20, compared to the standard widths, we found that the vomer's widths reached the upper limits of the standard ±2 SD (cm) or even exceeded that limit. The same applies to the width in soft choanal atresia. On the other hand, the width of the developed choana in the case of unilateral atresia is almost standard. Conclusions: The above findings are the basis for selecting the appropriate type of surgery. Currently, the gold standard is the endoscopic fenestration. associated with posterior septotomy.


Predictors of long-term exercise adherence in a community-based sample of older women.
Few studies have examined long-term exercise adherence in older women. The purpose of this study was to assess predictors of adherence to an intervention involving walking and balance exercises. This was a randomized controlled trial with 2-year follow-up. Sedentary women (n = 137) aged > or =70 randomized to the exercise intervention were evaluated in their homes. The exercise prescription included walking 30 minutes per day 5 days per week and completing 11 balance exercises twice per week. The main outcome measure was exercise adherence of the intervention group only. The average number of minutes walked per week was 95.2 (SD 68.8); 17% walked the recommended 150 minutes or greater. The average number of times the balance exercises were done was 1.5 (SD 1.6) per week. Results of regression analysis for walking adherence showed clinical variables accounted for the greatest variance (17%) of all the blocks, and cognitive variables were second highest (12%). The final model explained 19% of the variance in predicting adherence to walking. Results of regression analysis for adherence to balance exercises showed health-related quality of life (HRQOL) variables accounted for the greatest variance (14%), followed by cognitive variables (12%). The final model explained 24% of the variance in predicting adherence to balance exercises. Adherence to exercise was below recommended goals, although this study demonstrated that sedentary women can adopt and continue regular exercise long term. Predictors of adherence varied with different forms of exercise. Individually tailored exercise interventions may be most amenable to older women.


Atelocollagen-templated fabrication of tangled fibrous silica.
Protein-templated structured silica and titania are fabricated via a biomimetic method based on the synergistic effect of amine/carboxyl complexes under ambient conditions. Atelocollagen-templated silica showed a tangled fibrous structure with a smooth surface. The number of carboxyl groups of a protein is an important factor for homogeneous silica growth.


Effects of zilpaterol hydrochloride on retail yields of subprimals from beef and calf-fed Holstein steers.
Retail cutting tests were conducted on subprimals from cattle fed zilpaterol hydrochloride (ZH) to determine if the improved carcass composition and red meat yield resulting from ZH feeding would translate into increased retail yields of ready-to-cook products. As part of a 3-phase study, selection of carcasses from Holstein steers was done once (fall 2008), followed by the collection of carcasses from beef-type steers on 2 separate occasions (beef study I: summer 2009; beef study II: spring 2010). Each of the 3 groups of steers was assigned previously to 1 of 2 treatments, treated (fed 8.3 mg/kg of ZH for 20 d) or control (not fed ZH). All steers were slaughtered and carcasses were fabricated in commercial beef-processing establishments. Only those carcasses grading USDA Choice or higher were used. Five subprimals were used for both the calf-fed Holstein study (n = 546 subprimals) and beef study I (n = 576 subprimals): beef chuck, chuck roll; beef chuck, shoulder clod; beef round, sirloin tip (knuckle), peeled; beef round, top round; and beef round, outside round (flat). Seven subprimals were used in beef study II (n = 138 subprimals): beef chuck, chuck roll; beef round, sirloin tip (knuckle), peeled; beef round, top round; beef round, eye of round; beef loin, strip loin, boneless; beef loin, top sirloin butt, boneless; and beef loin, tenderloin. A simulated retail market environment was created, and 3 retail meat merchandisers prepared retail cuts from each subprimal so salable yields and processing times could be obtained. Differences in salable yields were found for the calf-fed Holstein steer chuck rolls (96.54% for ZH vs. 95.71% for control; P = 0.0045) and calf-fed Holstein steer top rounds (91.30% for ZH vs. 90.18% for control; P = 0.0469). However, other than heavier subprimals and an increased number of retail cuts obtained, total salable yields measured on a percentage basis and processing times were mostly unaffected by ZH. Cutability advantages of feeding ZH are achieved primarily in the carcass-to-subprimal conversion rather than in the subprimal-to-retail conversion.


The Perinatal-Neonatal Care Journey for Parents of Preterm Infants: What Is Working and What Can Be Improved.
Preterm birth is traumatic for parents, but there are few reports of parents' views on how the healthcare journey can be improved. This secondary thematic analysis used focus group data from parent consultation on proposed neonatal services standards for Northern Ireland to discover parents' experiences and recommendations for the perinatal, neonatal, and home care phases. Parents of preterm infants (n = 40) described their healthcare journey as positive overall and were grateful for the caring and competent care providers they encountered. However, parents described experiences that varied in quality and family centeredness across the care journey from perinatal to home care. They noted inconsistencies in healthcare team communication and provider practices and reported receiving limited emotional and practical support at all phases. In the perinatal phase, parents described difficult situations of discovering medical problems leading to preterm birth. In the neonatal intensive care unit phase, they also experienced unmet needs for involvement in decision making, financial strain, and difficulty coping with transfers and discharge. Parents experienced emotional challenges and lack of support in the home care phase. Parents identified actions that health systems can take to improve the consistency of care and communication across all phases and settings to encourage better collaboration and transitions in care.


[Unconditional self-acceptance and self-compassion: another clinic for anorexia nervosa?]
People suffering from anorexia have a particular emotional and cognitive profile (altered body and self-perception, emotional dysregulation, perfectionism, obsessive traits), which the disorder can compensate for through emotional distancing strategies. Self-compassion and unconditional self-acceptance have been shown to have therapeutic effects on the barriers to recovery associated with this profile.


[Synthesis and cloning of artificial zein genes].
To investigate structure-function relationships in zein proteins and to develop an approach to the construction of mutant zeins of improved nutritional qualities, the chemical-enzymatic synthesis of a gene for zein cZ22B1 (22 kd) has been undertaken. This 806-base pair long DNA fragment consists of about 40 synthetic oligonucleotides, mostly 30-60-mers. The synthesis was planned with the use of a universal methodology for the artificial gene construction. The choice of appropriate sites for altering amino acid sequence and the possibility of obtaining by directed mutagenesis of the gene corresponding to modified zeins containing residues Trp and Lys in specified positions of the polypeptide chain is discussed.


A Comparison of the Periprosthetic Fracture Rate of Cemented and Cementless Total Knee Arthroplasties: An Analysis of Data From the National Joint Registry.
Periprosthetic fractures are serious complications of knee arthroplasty often requiring complex surgery. There is concern of increased periprosthetic fracture risk with cementless components given the reliance on interference fit for primary stability. It is unknown how the periprosthetic fracture risk compares between cemented and cementless total knee arthroplasties (TKAs). A total of 22,477 cemented and 22,477 cementless TKAs from the National Joint Registry and Hospital Episodes Statistics database were propensity score matched on patient and surgical factors. Cumulative periprosthetic fracture rates were calculated using Kaplan Meier analyses and compared with Cox regressions. Subgroup analyses were performed in different age, body mass index (BMI), and sex groups. The three-month fracture rate in the cemented and cementless TKA groups were 0.02 and 0.04%, respectively. At 10 years, the cumulative fracture rate after cemented TKA was 1.2%, and after cementless was 1.4%. During the study period there were no significant differences in fracture rates between cemented and cementless TKAs with a HR 1.14 (Confidence Interval 0.94 to 1.37, P=0.20) at 10-years postoperatively. There were no significant differences in fracture rates between fixation types on subgroup analyses of sex, BMI and age groups. Women were at risk factor for fracture in both cemented (Odds Ratio (OR) 2.35, P<0.001) and cementless TKAs (OR 2.97, P<0.001). The periprosthetic fracture rates following cemented and cementless TKA surgery are low being approximately 1.2 and 1.4% respectively at 10-years. There were no significant differences in periprosthetic fracture rates requiring readmission between cemented and cementless TKAs. III.


No decline in the risk of heart failure after incident atrial fibrillation: A community study assessing trends overall and by ejection fraction.
Patients with atrial fibrillation (AF) experience an increased risk of heart failure (HF). However, data are lacking on current trends in the risk of HF after AF. The purpose of this study was to describe the temporal trends in HF occurrence after AF in a community cohort of patients with incident AF from 2000 to 2013. Cox regression was used to examine the association of year of AF diagnosis with HF and the predictors of developing HF after AF. Among 3491 AF patients without prior HF, 750 (21%) developed incident HF over mean follow-up of 3.7 years. Among those with an echocardiogram, 422 (61%) had HF with preserved ejection fraction (HFpEF), and 270 (39%) had HF with reduced ejection fraction (HFrEF). After adjusting for demographics and comorbidities, the risk of developing HF did not change over time (hazard ratio [HR] (95% confidence interval [CI]) per year of AF diagnosis: 1.01 (0.98-1.03) overall; 1.00 (0.98-1.03) for HFpEF; 1.00 (0.96-1.03) for HFrEF). Increasing age, obesity, smoking, diabetes, chronic pulmonary disease, and renal disease were predictors of developing HF. Compared to the Olmsted County, Minnesota, population, a substantial excess risk of developing HF was observed after AF diagnosis [standardized morbidity ratio (95% CI): 9.60 (7.44-12.19), 2.13 (1.56-2.84), and 1.70 (1.34-2.14) at 90 days, 1 year, and 3 years after diagnosis]. In the community, HF is a frequent adverse outcome among patients with AF, and HFpEF is more common than HFrEF. The rates of HF after AF have not declined, thus highlighting the importance of continued efforts to improve outcomes in AF.


'He is just getting old, you know': the role of cultural and health beliefs in shaping the help-seeking process of family members caring for persons with dementia in Vietnam.
This study aims to examine the help-seeking process of family caregivers for persons with dementia (PWD) in Vietnam, and how health and cultural beliefs shape this process. Twenty family caregivers of PWD at a geriatric hospital in Northern Vietnam were recruited. A total of 30 face-to-face, semi-structured interviews, including 10 follow-up interviews, were conducted. Structural coding was used first to guide data analysis through four structural codes consistent with the four stages of the help-seeking model: (1) disease and symptom experience; (2) explanatory models for symptom appraisal; (3) decision to seek help; and (4) contact with the sources of help. Then thematic coding was used for more detailed and data-driven initial codes to emerge from the data. Cultural and health beliefs, particularly collectivist values, such as familism and filial piety, shaped each stage of Vietnamese family caregivers' help-seeking process. Caregivers experienced different PWD's symptoms and adopted a mixed explanatory model combining biomedical and folk beliefs to explain the causes of dementia. They highly valued independence, autonomy, devotion to their family, and self-sacrifice, making these values the driving force underlying their self-reliance regime in caregiving. Help-seeking was often delayed until caregivers considered the situation to be beyond their own capacity to manage independently. The family was always the primary informal source of support for caregivers, with additional help sought from friends, neighbors, and religious facilities. Health professionals, if available, were also an important formal source for medical advice. The results highlight the importance of culture and health beliefs in shaping caregivers' help-seeking process, and advocate the needs of service development targeting not only Vietnamese family caregivers for PWD, but also caregivers sharing similar collectivist culture in different areas. Interventions and services that are consistent with their values of self-sacrifice, devotion to family, autonomy, and self-reliance are much needed.


Socioeconomic status and age trajectories of health.
The cumulative advantage hypothesis suggests diverging socioeconomic status (SES) based gaps in health with age. However, previous studies yield inconsistent findings regarding the association between SES and health across the adult life span. Dealing with the issue of mortality selection bias, this study utilizes latent growth-curve modeling to comprehensively examine age trajectories of both physical and mental health by SES using panel data based on a national probability sample of 3617 US adults. We find that education- and income-based gaps in physical impairment and the education-based gap in depression diverge over time for all adult age groups, supporting the hypothesis of cumulative advantage. In contrast, we find that the income-based gap in depression converges in older age, supporting the hypothesis of age-as-leveler. Mortality selection bias is unlikely to be a major part of the explanation for the convergence. These results indicate that age-related patterns in health trajectories may differ by various dimensions of SES and health. Finally, we take into account persistence or change in income over time to examine the relationship between trajectories of income and health across adulthood, highlighting the importance of considering the temporal patterns of income in understanding age trajectories of health.


Clinical use of digitalis glycosides. An update.
Digitalis glycosides continue to place high on the list of prescribed drugs. Digoxin is 8th on prescriptions written in the United States in 1980, digitoxin 16th, and digitalis leaf 23rd. There is little doubt that most physicians continue to believe these drugs are useful. The application of more definite indications, smaller doses, and the recognition of the role of pharmacokinetics and drug interactions make use of the glycosides more challenging than ever before in 1985.


Distribution of sodium channels in chronically demyelinated spinal cord axons: immuno-ultrastructural localization and electrophysiological observations.
The immuno-ultrastructural localization of voltage-sensitive sodium channels was demonstrated within a central demyelinating lesion induced in the rat spinal cord by ethidium bromide/irradiation using polyclonal antibody 7493. Antibody 7493 has previously been shown to immunostain intensely axon membrane at nodes of Ranvier, and also perinodal astrocyte processes. At 25-35 days post injection/irradiation, the central portion of the demyelinating lesion is populated with chronically demyelinated axons and there is an absence of glial processes. Sodium channel immunoreactivity was not observed on the chronically demyelinated axolemma within this central portion of the lesion. Within the peripheral portion of the lesion demyelinated axons were occasionally abutted by astrocyte and Schwann cell processes. At these focal sites of apposition, the axon membrane displayed intense sodium channel immunoreactivity, while the abutting astrocyte and Schwann cell processes did not exhibit immunostaining. Also in the periphery of the lesion, some axons become ensheathed and myelinated by oligodendrocytes and Schwann cells. The axon membrane of circumferentially ensheathed axons displayed antibody 7493 immunostaining, and this immunoreactivity persisted on the axolemma until the ensheathing cytoplasmic processes compacted into myelin. Internodal axon membrane beneath the myelin sheath did not display sodium channel immunoreactivity, though (putative) developing nodal axon membrane adjacent to terminal paranodal loops exhibited robust sodium channel staining. Electrophysiological recordings within the ethidium bromide/irradiation lesion demonstrated that at least some axons conducted action potentials within the lesion, while others exhibited conduction block. These results indicate that there is a reorganization of sodium channels within the axon membrane of chronically demyelinated central axons.


Reproductive characteristics and life-history relationships of starry smooth-hound Mustelus asterias in British waters.
The reproductive biology and other life-history parameters were investigated for Mustelus asterias in British waters, with specimens caught from both commercial fisheries and research-vessel surveys. In total, 504 specimens [238 males, 24-99 cm total length (LT) and 266 females, 28-124 cm LT] were examined, with further information collected from 238 uterine pups. The lengths at 50% maturity were estimated as 70·4 and 81·9 cm LT for males and females, respectively. Ovarian fecundity ranged from one to 28, and uterine fecundity from four to 20. The number, mass and LT of pups were positively correlated with maternal LT. Full-term pups ranged from 205 to 329 mm LT, and the smallest free-living fish caught was 24 cm LT . Parturition occurred in February in the western English Channel and during June to July in the eastern English Channel and southern North Sea, indicating either protracted spawning or asynchronous parturition for the stock as a whole. The reproductive cycle is thought to extend beyond 1 year. Developmental abnormalities observed included atresia in oocytes, uterine eggs that failed to develop, a partly developed pup and an abnormal male with a single aberrant clasper. Data relating to conversion factors, oocyte numbers and diameter and gonado-somatic and hepato-somatic indices are presented, and the seasonality of the reproductive cycle is discussed.


Glucocerebrosidase as a therapeutic target for Parkinson's disease.
Introduction: The association between Gaucher disease, caused by the inherited deficiency of glucocerebrosidase, and Parkinson's disease was first recognized in the clinic, noting that patients with Gaucher disease and their carrier relatives had an increased incidence of Parkinson's disease. Currently, mutations in glucocerebrosidase (GBA1) are the most common genetic risk factor for Parkinson's disease and dementia with Lewy bodies, with an inverse relationship between glucocerebrosidase and α-synuclein, a key factor in Parkinson pathogenesis. The hypothesis that therapeutic enhancement of brain glucocerebrosidase levels might reduce the aggregation, accumulation or spread of α-synuclein has spurred great interest in glucocerebrosidase as a novel therapeutic target.Area covered: This article explores the potential molecular mechanisms underlying the association between GBA1 mutations and Parkinson's disease and outlines therapeutic strategies to increase brain glucocerebrosidase, including gene therapy, targeted delivery of recombinant glucocerebrosidase to the brain, small-molecule chaperones to rescue mutant glucocerebrosidase, and small-molecule modulators to activate wild-type glucocerebrosidase.Expert opinion: Although an improved understanding of the mechanistic basis for GBA1-associated parkinsonism is essential, enhancing levels of brain glucocerebrosidase may have wide therapeutic implications. While gene therapy may ultimately be effective, less expensive and invasive small-molecule non-inhibitory chaperones or activators could significantly impact the disease course.


Small-molecule inhibition of Wnt signaling abrogates dexamethasone-induced phenotype of primary human trabecular meshwork cells.
Trabecular meshwork (TM) cells are the governing regulators of the TM structure. When the functionality of these cells is impaired, the structure of the TM is perturbed which often results in increased ocular hypertension. High intraocular pressure is the most significant risk factor for steroid-induced glaucoma. Dexamethasone (Dex)-induced phenotype of TM cells is widely utilized as a model system to gain insight into mechanisms underlying damaged TM in glaucoma. In this study, to assess the possible role of abnormal Wnt signaling in steroid-induced glaucoma, we analyzed the effects of small-molecule Wnt signaling modulators on Dex-induced expression extracellular matrix proteins of primary human TM cells. While Dex-treated TM cells exhibited increased collagen and fibronectin expression, we found that Wnt signaling inhibitor 3235-0367 suppressed these Dex-induced effects. We therefore propose that Wnt signaling plays an important role in Dex-mediated impairment of TM cell functions. Moreover, the use of small-molecule Wnt signaling inhibitors to treat TM cells may provide an opportunity of restoring TM tissue in steroid-induced glaucoma.


Rebleeding after traumatic hyphema.
We reviewed the medical records of 175 patients who were admitted between 1977 and 1984 with a diagnosis of traumatic hyphema to define the incidence of operative intervention for the treatment of complications related to rebleeding. Of the 156 patients admitted with primary hyphemas, 25 (16%) rebled during hospitalization. Seven of these 25 in-hospital rebleeds required surgical intervention. Nineteen other patients were admitted with ocular histories and examinations strongly suggestive of rebleeding prior to admission (secondary hyphema--presumed preadmission rebleed). Seven of these 19 eyes underwent surgery. Of the 175 eyes studied, only one eye that did not rebleed underwent surgery during the initial hospitalization. Fourteen (32%) of 44 eyes that rebled underwent operative intervention. Nine of these 14 patients were operated on under general anesthesia. Potential benefits of newer hyphema treatments, such as epsilon-aminocaproic acid, designed to prevent rebleeding should be weighed against not only the ocular risks of rebleeding but also the risks of general anesthesia.


Accelerated, free-breathing, noncontrast, electrocardiograph-triggered, thoracic MR angiography with stack-of-stars k-space sampling and GRASP reconstruction.
To develop an accelerated, free-breathing, noncontrast, electrocardiograph-triggered, thoracic MR angiography (NC-MRA) pulse sequence capable of achieving high spatial resolution at clinically acceptable scan time and test whether it produces clinically acceptable image quality in patients with suspected aortic disease. We modified a "coronary" MRA pulse sequence to use a stack-of-stars k-space sampling pattern and combined it with golden-angle radial sparse parallel (GRASP reconstruction to enable self-navigation of respiratory motion and high data acceleration. The performance of the proposed NC-MRA was evaluated in 13 patients, where clinical standard contrast-enhanced MRA (CE-MRA) was used as control. For visual analysis, two readers graded the conspicuity of vessel lumen, artifacts, and noise level on a 5-point scale (overall score index = sum of three scores). The aortic diameters were measured at seven standardized locations. The mean visual scores, inter-observer variability, and vessel diameters were compared using appropriate statistical tests. The overall mean visual score index (12.1 ± 1.7 for CE-MRA versus 12.1 ± 1.0 for NC-MRA) scores were not significantly different (P > 0.16). The two readers' scores were significantly different for CE-MRA (P = 0.01) but not for NC-MRA (P = 0.21). The mean vessel diameters were not significantly different, except at the proximal aortic arch (P < 0.03). The mean diameters were strongly correlated (R2 ≥ 0.96) and in good agreement (absolute mean difference ≤ 0.01 cm and 95% confidence interval ≤ 0.62 cm). This study shows that the proposed NC-MRA produces clinically acceptable image quality in patients at high spatial resolution (1.5 mm × 1.5 mm × 1.5 mm) and clinically acceptable scan time (~6 min).


Projection sites of medial preoptic area and ventral bed nucleus of the stria terminalis neurons that express Fos during maternal behavior in female rats.
Medial preoptic area (MPOA) and ventral bed nucleus of the stria terminalis (VBST) neurons are involved in maternal behavior, but the neural sites to which the maternally relevant neurons project have not been determined. Since MPOA and VBST neurons express Fos during maternal behavior, we used a double-labeling immunocytochemical procedure to detect both Fos and a retrograde tracer, wheat germ agglutinin (WGA), in order to determine where these Fos neurons project. On Day 4 postpartum, fully maternal females were separated from their litters. On Day 5, WGA was iontophoretically injected into one of the following regions known to receive MPOA and/or VBST input: Lateral septum, medial hypothalamus at the level of the ventromedial nucleus, lateral habenula, ventral tegmental area, retrorubral field, or periaqueductal gray. On Day 7, females received a 2-h test with either pups or candy, after which they were perfused and their brains were processed for the detection of Fos and WGA. As expected, females tested with pups had more Fos-containing neurons in the MPOA and VBST than did females tested with candy. After WGA injections into several brain sites, the number of double-labeled cells observed in the MPOA and VBST was greater for the maternal females when compared to the non-maternal females. Therefore, these results pinpointed neural circuits that were activated during maternal behavior. For the maternal females, Fos-containing neurons in the MPOA projected most strongly to the medial hypothalamus at the level of the ventromedial nucleus and to the lateral septum, while Fos-containing neurons in the VBST projected most strongly to the retrorubral field, ventral tegmental area, and medial hypothalamus. Although relatively few MPOA and VBST neurons which expressed Fos during maternal behavior projected to the periaqueductal gray, these Fos-expressing neurons made up a relatively large proportion of the MPOA and VBST projection to the periaqueductal gray. This study suggests that MPOA and VBST efferents project to a variety of regions to promote full maternal responsiveness.


Impact of inflammation on the osteoarthritic niche: implications for regenerative medicine.
Osteoarthritis (OA) is the most common form of arthritis worldwide and is the sixth leading cause of disability. It costs the UK economy approximately 1% of gross national product per annum. With an aging population, the cost of chronic conditions such as OA continues to rise. Historically, treatments for OA have been limited to painkillers, physiotherapy and joint injections. When these fail, patients are referred for joint replacement surgery. With the advent of tissue engineering strategies aimed at generating new bone and cartilage for repair of osteochondral defects, there has been considerable interest in exploiting these techniques to devise new treatments for OA. To date, little consideration has been given to the OA niche and attendant inflammatory milieu for any regenerative skeletal strategy. This review highlights the importance of understanding the osteoarthritic niche in order to modify existing tissue engineering and regenerative medicine strategies for the future treatment of OA.