Sex-dependent differences in animal cognition.
The differences in cognitive processes driven by biological sex are the issues that have gotten growing attention recently. Considering the increasing population suffering from various cognitive impairments and the development of therapeutic strategies, it is essential that we recognize the mechanisms responsible for discrepancies observed in male and female learning and memory functions. In this review, we discuss recent reports from preclinical studies on rodents regarding selected cognitive domains to explore the state of knowledge on sex-dependent differences and point to challenges encountered during such research. We focus on spatial, recognition, and emotional memory, as well as on executive functions, such as attention, cognitive flexibility, and working memory. This review will help to acknowledge sex-related differences in cognition and indicate some fields that lack sufficient data.


Student dietitians' experiences with dietary compliance.
The majority of students (91%; no. = 10) thought that following a modified diet was a very valuable experience. The student who did not think the assignment was valuable had been following a diet similar to that assigned, although she did not report this on the pre-test diet evaluation form. Overall, students thought they were better able to identify what it was like to make major dietary changes, especially when those changes are imposed by someone else. They had an increased awareness of the feelings of deprivation that patients might experience when foods become restricted. The students also believed that they would be more understanding when counseling patients and make more diligent efforts to individualize the diet as much as possible. Some thought they had a better understanding of noncompliance and would now be more empathic toward their patients. Assessing the changes required and the degree of difficulty experienced helped the students bring what had been learned conceptually to a conscious awareness.


Small organic molecules act as a trigger in an "unzippering" mechanism to facilitate carbon nanotube dispersion.
In binary dispersing agents system, the contribution and roles of different sized molecules to carbon nanotubes (CNTs) dispersion remain unclear, which hinders the understanding of the environmental behaviour and risks of CNTs. This study compared the dispersion of CNTs by m-nitrobenzoic acid (NBA), trans-cinnamic acid (TCA), tannic acid (TA), and their mixtures. The dispersion efficiency of CNTs significantly reduced with the increased solid-phase concentration (Qe) of TA due to the adsorption of TA on newly exposed CNTs surfaces. However, the CNTs dispersion efficiency by NBA or TCA was independent of Qe because the dispersed CNTs surface was completely occupied by NBA or TCA without new exposed sites available for subsequent adsorption. The mixture of NBA or TCA with TA significantly enhanced the dispersion efficiency of CNTs, indicating a synergistic effect of CNTs dispersion. The addition of NBA or TCA decreased the hydrodynamic diameter of CNTs dispersed by TA, which indicated that NBA or TCA facilitated TA wedging into CNTs bundles for more complete separation of CNTs. This study highlighted the triggering effect of small molecules in the "unzippering" mechanism for improving the dispersing efficiency of CNTs by large molecules.


The construction and destruction of gold nanoparticle assembly at liquid-liquid interface for Cd2+ sensing.
The analyte-induced aggregation of plasmonic nanoparticles (NPs) in the bulk solution have been widely employed in optical sensors. However, in trace detection, the slow diffusion kinetics of NPs and the ultralow concentration of analytes significantly limit the binding opportunity of the analytes, thus impose penalties on the sensitivity, reproducibility and response time of the sensors. Herein, we propose a novel sensing method with two working modes that based on the construction/destruction of NP arrays at the liquid-liquid interface (LLI). For the turning-on mode, the emulsion state of the two immiscible liquid phases and specific binding between Cd2+ and cysteine (Cys) assemble NPs into a liquid plasmonic mirror at the LLI whose reflectance has a positive relationship with the concentration of Cd2+. For the turning-off mode, the assembled NP arrays are intentionally destructed with the introduction of Cd2+ which aggregates neighboring NPs, reduces the interfacial reflectance. Compared with the conventional bulk aggregation method in a single phase, the NPs here that scavenge Cd2+ in the aqueous phase are condensed onto the LLI, boosting the local NP concentration and the diffusion kinetics for several orders. The prototypes achieve the limit of detection as 29.3 ± 0.03 μg L-1, and are applicable in real-life samples.


NO dioxygenase- and peroxidase-like activity of Arabidopsis phytoglobin 3 and its role in Sclerotinia sclerotiorum defense.
Phytoglobin 3 appears to be ubiquitous in plants, yet there has been dearth of evidence for their potent physiological functions. Previous crystallographic studies suggest a potential NO dioxygenase like activity of Arabidopsis phytoglobin 3 (AHb3). The present work examined the in vivo function of AHb3 in plant physiology and its role in biotic stress using Arabidopsis- Sclerotinia sclerotorium pathosystem. The gene was found to be ubiquitously expressed in all plant tissues, with moderately increased expression in roots. Its expression was induced upon NO, H2O2 and biotic stress. A C-terminal tagged GFP version of the wild type protein revealed its enhanced accumulation in the guard cells. AHb3-GFP was found to be partitioned majorly into the nucleus while residual amounts were present in the cytoplasm. The loss of function AHb3 mutant exhibited reduced root length and fresh weight. AHb3 knockout lines also displayed enhanced susceptibility towards the S. sclerotiorum. Interestingly, these lines displayed enhanced ROS accumulation upon pathogen challenge as suggested by DAB staining. Furthermore, enhanced/decreased NO accumulation in AHb3 knockout/overexpression lines upon treatment with multiple NO donors suggests a potent NO dioxygenase like activity for the protein. Taken together, our data indicate that AHb3 play a crucial role in regulating root length as well as in mediating defense response against S. sclerotiorum, possibly by modulating NO and ROS levels.


The significance of structured parental educational intervention on childhood atopic dermatitis: a randomized controlled trial.
Parental education is important in managing childhood chronic diseases. The aim of the study was to evaluate the effects of a short-term structured educational programme for parents of children with moderate to severe atopic dermatitis ( AD), aged 3 months to 7 years, on the clinical course of AD, parental stress, anxiety and the quality of family life. One hundred thirty-four parents with AD children were recruited in a randomized controlled clinical trial at the Outpatient Unit of Pediatric Dermatology, Children's Hospital in Zagreb. The primary outcome was change in the severity of eczema measured using SCORing AD (SCORAD) and Patient Oriented (PO) SCORAD index, changes of symptom scores for pruritus and sleep disturbance. Secondary outcomes included change in stress level according to the Perceived Stress Scale (PSS); change in anxiety level according to State Trait Anxiety Inventory (STAI) and change in the quality of family life according to the Croatian version of the Family Dermatology Life Quality Index (FDLQI). Participants in the intervention group had a significantly lower SCORAD (P = 0.000), PO SCORAD (P = 0.000) index, pruritus (P = 0.000), sleep disturbance (P = 0.001), level of perceived stress (P = 0.024) and anxiety as a state (P = 0.42) than those in the control group at the second visit. After the educational programme, participants in the intervention group had a significantly lower impact of AD on the total quality of family life (P = 0.006). We found a statistically significant difference between the two groups with respect to additional education received between the visits. The control group had acquired significantly more additional education (P = 0.007). There was no significant difference between groups in the amount of corticosteroid used. Our structured educational programme had a positive effect on AD severity, quality of family life, parental stress and anxiety.


Bilateral peripheral corneal infiltrates after simultaneous myopic laser in situ keratomileusis.
We describe a patient with multiple superior corneal infiltrates in both eyes, separated from the limbus by an intervening clear zone, that appeared 1 day after uneventful laser in situ keratomileusis. The overlying epithelium was intact, and the flap and interface were uninvolved. Based on these features, a clinical diagnosis of sterile corneal infiltrates was made and the eyes were treated with topical antibiotics and steroids. The infiltrates resolved during the ensuing weeks without corneal scarring. Good visual acuity was maintained. Recognition of this benign complication is important because aggressive corneal scrapings are not required. The infiltrates appear to be immunogenic in origin, although the exact etiopathogenesis is not clear.


Catalyst-free chemoselective N-tert-butyloxycarbonylation of amines in water.
[Structure: see text] Catalyst-free N-tert-butyloxycarbonylation of amines in water is reported. The N-t-Boc derivatives were formed chemoselectively without any isocyanate, urea, N,N-di-t-Boc, and O/S-t-Boc as side products. Chiral amines, esters of alpha-amino acids, and beta-amino alcohol afforded optically pure N-t-Boc derivatives. Amino alcohol and 2-aminophenol afforded the N-t-Boc derivative without oxazolidinone formation. Selectivity was observed during competition of aromatic amine vs aliphatic amine, amine vs amino acid ester, amine vs amino alcohol, and primary amine vs secondary amine.


Determination of steroid hormones in biological and environmental samples using green microextraction techniques: an overview.
Residues of steroid hormones have become a cause for concern because they can affect the biological activity of non-target organisms. Steroid hormones are a potential risk for wildlife and humans through the consumption of contaminated food or water. Their determination requires extraction and clean-up steps, prior to detection, to reach low concentration levels. In recent years, a great effort has been made to develop new analytical methodologies, such as microextraction techniques, that reduce environmental pollution. Researchers have modified old methods to incorporate procedures that use less-hazardous chemicals or that use smaller amounts of them. They are able to do direct analysis using miniaturised equipment and reduced amounts of solvents and wastes. These accomplishments are the main objectives of green analytical chemistry. In this overview, we focus on microextraction techniques for the determination of steroid hormones in biological (e.g., human urine, human serum, fish, shrimp and prawn tissue and milk) and environmental (e.g., wastewaters, surface waters, tap waters, river waters, sewage sludges, marine sediments and river sediments) samples. We comment on the most recent applications in sorptive-microextraction modes, such as solid phase microextraction (SPME) with molecularly imprinted polymers (MIPs), in-tube solid-phase microextraction (IT-SPME), stir-bar sorptive extraction (SBSE) and microextraction in packed sorbent (MEPS). We also describe liquid-phase microextraction (LPME) approaches reported in the literature that are applied to the determination of steroid hormones.


The historical character of human nature in Freud's theories.
In Freud' theories of human development, human nature is described and analyzed as essentially historical. At the core of human history is the restructuring of the sexual instinct and the death instinct (or its unique form as destructive impulses). The conscious, asked-for shaping of these two instincts, under the rule of the "reality principle", forms the basis of human society at all stages. This conscious restructuring has also unintended, unasked-for results, which are part of the historically developing human nature. The historical choice has been the building of human society as a social complex based on the de-eroticization of both the individual and society. Freud suggested that the historical process of changing human nature and maintaining the achieved new structure has mainly been an enterprise of enlightened political elite, which has imposed (in all societies) the various elements of the new nature upon the ordinary people. Human history is essentially a deed of the political sphere. In viewing human nature as consisting of both asked-for and unasked-for results of human conscious purposeful activity Freud belongs to the same historical school as Marx.


Diverging in vitro inflammatory responses toward Streptococcus uberis in mouse macrophages either preconditioned or continuously treated with β-hydroxybutyrate.
Hyperketonemia is a common condition in early-lactation dairy cows that has been associated with an increase in the risk of infectious disease. Recent mouse studies have elucidated an anti-inflammatory effect of the ketone body β-hydroxybutyrate (BHB). Therefore, the objective of this study was to determine whether BHB altered inflammatory responses in macrophages challenged with the common mastitis pathogen Streptococcus uberis. A secondary objective was to determine whether the inflammatory response to the S. uberis challenge was dependent on whether BHB was present in the medium during the challenge (i.e., preconditioned vs. continuous treatment). Two cell culture experiments were conducted. In the first experiment, mouse macrophages (RAW 264.7 line) were preconditioned with BHB (0, 0.6, 1.2, and 1.8 mM) for 24 h; the medium was then replaced with a standard cell culture medium, and the cells were challenged or not with S. uberis for an additional 6 h. In the second experiment, a similar protocol was used; however, cells were preconditioned with BHB (0, 0.6, 1.2, and 1.8 mM) for 24 h, the medium was replaced with fresh medium containing the same concentration of BHB, and cells were either challenged or not with S. uberis for 6 h. In both experiments, relative transcript abundance of cell membrane receptors (Tlr2 and Gpr109a), cytokines (Il1b, Il10, Tnf, and Tgfb1), and chemokines (Cxcl2 and Ccl5) were determined using quantitative real-time PCR and normalized against the geometric mean of Hprt and B2m. Data were analyzed using a linear mixed model, and orthogonal contrasts were conducted to examine the effect of S. uberis challenge and BHB treatment. Streptococcus uberis activated the macrophages, noted by greater transcript abundance of analyzed genes. Intriguingly, in both experiments, the S. uberis challenge increased expression of Gpr109a, which encodes a receptor that is ligated by BHB. Paradoxically, preconditioning macrophages with BHB increased transcript abundance of the immunosuppressive cytokine Tgfb1 and increased that of the neutrophil chemoattractant Cxcl2. Preconditioning decreased Tlr2 and tended to decrease Il10 transcript abundance. In opposition to the preconditioning experiment, continuous treatment of BHB during the S. uberis challenge linearly increased abundance of Tlr2 and Il10 transcripts. Continuous BHB treatment also increased expression of Il1b. In conclusion, BHB treatment altered macrophage inflammatory responses during an S. uberis challenge; however, the direction of this response was dependent on whether BHB was added to the medium during the S. uberis challenge. Future studies should be conducted using bovine macrophages and in vivo approaches to examine BHB effects during an S. uberis challenge.


Immunosuppression with antithymocyte globulin in renal transplantation: better long-term graft survival.
We analyzed the impact of antithymocyte globulin (ATG) in renal transplantation. We retrospectively studied 1217 recipients performed from July 83 to December 03. ATG-Fresenius-S (ATG-F) was used for induction therapy in 492 patients (40.4%; group I) and compared with group II, 725 patients (59.6%), without antilymphocyte induction. Groups were comparable in terms of recipient gender and race distribution; time on dialysis; cause of renal disease; number of human leukocyte antigen (HLA) mismatches; donor age, gender, and creatinine; and cold ischemia time. Patients with ATG-F were younger (35.8 +/- 13.8 vs 38.9 +/- 12.5 years, P < .001), more frequently hypersensitized (10% vs 3%, P < .001), and had more second transplants (15.7% vs 5.8%, P < .001). The incidence of acute rejection episodes was lower among ATG-F patients (23.6% vs 32.1%, P = .004). Admission time and incidence of delayed graft function (DGF) were similar in the two groups. Graft survival at 1, 5, 10, and 15 years was 88.9%, 80.7%, 71.3%, and 64.9% in group I and 86.4%, 77.4%, 60.7%, and 48.4% in group II (P = .003). The difference in patient survival over the same follow-up did not reach statistical significance. Multivariate analysis showed that the risk of graft failure was higher for those who did not receive ATG-F (HR = 1.51; 95% CI, 1.14 to 2.00; P = .004). Donor age and DGF were also independent predictors of graft failure. Our results showed a better long-term graft survival among patients who received ATG-F, despite their higher immunological risk. The absence of induction with ATG-F, donor age, and DGF were independent risk factors for graft failure.


The diagnostic value of alpha-fetoprotein in infants and children with teratomas: a questionnaire survey in Japan.
Serum alpha-fetoprotein (AFP) values in 61 infants and children with mature, immature, or malignant teratoma were analyzed in comparison with the normal ranges of AFP. AFP was within the normal ranges in 23 of 24 mature teratomas, and higher than the upper border of the normal ranges in 31 of 32 malignant teratomas. The number of immature teratomas studied here was very small. These results suggest that the diagnostic value of AFP would seem very high even in infancy and childhood, if data are compared with the normal ranges. This conclusion appears particularly noticeable because the authors had once made a preliminary report on this subject in which they concluded that the differentiation between benign and malignant teratoma by AFP would be impossible under the age of 2 mo.


Autophagy-physiology and pathophysiology.
"Autophagy" is a highly conserved pathway for degradation, by which wasted intracellular macromolecules are delivered to lysosomes, where they are degraded into biologically active monomers such as amino acids that are subsequently re-used to maintain cellular metabolic turnover and homeostasis. Recent genetic studies have shown that mice lacking an autophagy-related gene (Atg5 or Atg7) cannot survive longer than 12 h after birth because of nutrient shortage. Moreover, tissue-specific impairment of autophagy in central nervous system tissue causes massive loss of neurons, resulting in neurodegeneration, while impaired autophagy in liver tissue causes accumulation of wasted organelles, leading to hepatomegaly. Although autophagy generally prevents cell death, our recent study using conditional Atg7-deficient mice in CNS tissue has demonstrated the presence of autophagic neuron death in the hippocampus after neonatal hypoxic/ischemic brain injury. Thus, recent genetic studies have shown that autophagy is involved in various cellular functions. In this review, we introduce physiological and pathophysiological roles of autophagy.


Implication of Changes in the Imaging Measurements after Mechanically Aligned Total Knee Arthroplasty.
Imaging measurements allow assessment of the mechanical alignment before and after total knee arthroplasty (TKA). The changes in radiographic parameters in each period of time within 1 year after TKA has been poorly understood. The purpose of this study was to examine the timing and causes of imaging changes in lower extremity force lines after total knee arthroplasty with mechanical alignment. A total of 93 mechanically-aligned TKA were radiographically examined before, 3 days, 3 months, and 1 year after surgery. Radiographic parameters included hip-knee angle (HKA), lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), knee joint line orientation (KJLO), ankle joint line orientation (AJLO), the knee joint line relative to ankle joint line angle (KJLTA) and midpoints of the ankle distance (MAD). Paired t-test were used to analyze the changes of these imaging parameters, By establishing a simple tibial model, the time points of changes in the imaging parameters after TKA was determined, with an attempt to understand the post-TKA changes in these imaging parameters. Statistically significant differences were found between the preoperative data and the data measured 3 days after surgery in HKA, LDFA, MPTA, MAD, KJLTA, AJLO (P < 0.05) while KJLO exhibited no significant difference (P = 0.089). There existed significant differences between the data measured 3 days and the measurements taken 3 months after operation in HKA, MPTA, KJLTA, KJLO, AJLO (P < 0.05), whereas LDFA and MAD showed no significant difference (P > 0.05). Significant differences were revealed between the data measured 3 months and those collected 1 year after surgery in LDFA, MPTA, AJLO, KJLTA (P < 0.05) but HKA, KJLO, AJLO showed no significant differences (P > 0.05). The tibial model was made to look into the changes in postoperative imaging parameters. ΔMAD and postoperative AJLO were calculated to verify the model and hypothesis. Postoperative changes in radiographic parameters and tibial models showed that the lower extremities were in an unnatural state within 1 year after TKA. The changes in the lower extremities force line were the results of the gradual adaptation of the lower extremities to TKA and the lateral swing of the extremities (3°) after surgery. Imaging data 1 year after surgery should be taken into account in the explanation of post-TKA changes in lower limb force lines.


Research agenda for mass gatherings: a call to action.
Public health research is essential for the development of effective policies and planning to address health security and risks associated with mass gatherings (MGs). Crucial research topics related to MGs and their effects on global health security are discussed in this review. The research agenda for MGs consists of a framework of five major public health research directions that address issues related to reducing the risk of public health emergencies during MGs; restricting the occurrence of non-communicable and communicable diseases; minimisation of the effect of public health events associated with MGs; optimisation of the medical services and treatment of diseases during MGs; and development and application of modern public health measures. Implementation of the proposed research topics would be expected to provide benefits over the medium to long term in planning for MGs.


NGF protects dorsal root ganglion neurons from oxaliplatin by modulating JNK/Sapk and ERK1/2.
The involvement of the Mitogen-Activated Protein Kinases (MAPKs) family in platinum derivative-induced peripheral neuropathy has already been demonstrated. In particular, it has been evidenced that in Dorsal Root Ganglion (DRG) neurons prolonged exposure to oxaliplatin (OHP) induces early activation of p38 and ERK1/2, which mediate neuronal apoptosis, while the neuroprotective action of JNK/Sapk is downregulated by the drug treatment. In this study, the exposure of OHP-treated neurons to a neuroprotective stimulus, represented by a high dose of NGF, counteracts OHP-induced neuronal mortality. This effect was achieved by restoring the MAPK activation existing in untreated control cells. Increased viability occurred also after the administration of retinoic acid (RA), a pro-differentiative agent able to activate both JNK/Sapk and ERK1/2. The use of specific chemical inhibitors of MAPKs confirms the importance of this class of proteins for the neuroprotective pathway, since they reverse the protective effect. In summary, our findings assess the validity of MAPKs as the target of neuroprotective therapies during chemotherapeutic treatment. Moreover they also describe a double role for ERK1/2, depending on cellular stimulation, since it mediates neuronal apoptosis after OHP exposure. However, it is also important, as is JNK/Sapk, in preserving the correct cellular differentiation that is pivotal for neuronal survival.


Estrogenic Effect of Scoparia dulcis (Linn) Extract in Mice Uterus and In Silico Molecular Docking Studies of Certain Compounds with Human Estrogen Receptors.
Scoparia dulcis Linn. is reported to be used by women of Assam and Arunachal Pradesh in northeast India for treating menstrual disorders. Scoparia dulcis contains compounds that bind with estrogen receptors (ERα and ERβ) evidenced by increased PCNA in endometrial epithelium. Crude extract was orally administered at the dose of 500 mg/kg body weight/day to the female mice (60-70 days old) in five different groups. Each group containing six females included: (I) cyclic control, (II) cyclic extract treated, (III) Ovariectomized (OVX)-vehicle treated (Control), (IV) OVX-E2 treated (V) OVX- extract treated. Extract was administered for eight days to the cyclic groups and three days to the OVX groups. PCNA was detected immunohistochemically in uterine tissues and signals were analyzed by Image J software (NIH, USA). Compounds were separated by GC-MS and identified using NIST. In silico molecular docking studies was performed with human estrogen receptors (ERα and ERβ). Molecular dynamics (MD) simulations of the best interacting compound was done using gromacs. The results showed cell proliferation in the uterine endometrium evidenced by PCNA. Two phytocompounds, Octadecanoic acid and methyl stearate showed binding affinity with ERα and ERβ. Scoparia dulcis contains compounds having binding affinity with ERα and ERβ. The present study is the first report on compounds from Scoparia dulcis showing binding affinity with human estrogen receptors which may have biological effect on female reproduction.


In vitro studies of haematopoietic colony-forming capacity of human fetal liver cells at exposure to cytotoxic and immunomodulatory drugs.
Intrauterine transplantation with haematopoietic stem cells (SC) as a treatment for immunological, haematological and metabolic inherited disorders has not been effective in fetuses with a normal immunological status. Inhibition of the fetal haematopoiesis or immunosuppression might therefore be a therapeutic alternative in fetal SC transplantation. The aim of the present study was to evaluate the effects of drugs that might be considered as therapeutic options in fetal transplantations on the colony-forming capacity of fetal haematopoietic SC. Fetal liver cells were incubated with doxorubicin, daunorubicin, antithymocyte-globulin (ATG), OKT-3 (Orthoclone) and betamethasone. The effects of these drugs on colony formation by fetal hematopoietic SC were evaluated. Colony-forming capacity assays were cultured during 10 days after drug incubation on day 1 and evaluated for differences in number of colonies compared to unexposed cells. For betamethasone, similar studies were performed with adult bone marrow. A significant reduction in fetal liver haematopoietic colony formation of BFU-E, CFU-GM and CFU- GEMM was detected when 0.1 M doxorubicin (p < 0.05) and 0.5 microM daunorubicin (p < 0.05) were added. OKT-3 (5 microg/ml) and ATG (4 microg/ml) significantly reduced BFU-E, CFU-GM and CFU-GEMM (p < 0.05). A concentration of 0.2 microg/ml betamethasone caused a significant reduction of BFU-E, CFU-GM and CFU-GEMM (p < 0.05). The drugs investigated in this in vitro study were capable to different degrees to decrease the colony-forming capacity of fetal haematopoietic progenitor cells. Whether this strategy will become an alternative in fetal SC transplantations is an open question and further studies are required to elucidate the potential use of these drugs in fetal transplantation.


Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway.
Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can occur through either an electrophilic or non-electrophilic mechanism. To date, most of the research has focused on electrophilic Nrf2 activators, but there is increasing interest in non-electrophilic modulators of Nrf2. This Digest examines the current selection of small molecules that modulate Nrf2 through non-electrophilic mechanisms, and it highlights new opportunities for this important therapeutic target.


CAPS2 deficiency affects environmental enrichment-induced adult neurogenesis and differentiation/survival of newborn neurons in the hippocampal dentate gyrus.
Hippocampal adult neurogenesis is observed in the subgranular zone of the dentate gyrus (DG), and is associated with hippocampal memory formation and several psychiatric disorders including autism spectrum disorder (ASD). Calcium-dependent activator protein for secretion 2 (CAPS2) is a candidate gene related to ASD, and is highly expressed in the hippocampal DG region, with Caps2 knockout (KO) mice exhibiting ASD-like behavior. Accordingly, CAPS2 is potentially associated with hippocampal adult neurogenesis, the relationship between CAPS2 and adult neurogenesis has not yet been investigated. Here, we determined whether deficit of the Caps2 gene affects hippocampal adult neurogenesis and maturation of newborn neurons. To induce adult neurogenesis, we used the environmental enrichment (EE) condition. Both wild-type (WT) and Caps2 KO mice were housed in control or EE conditions for 3 or 14days. Hippocampal levels of brain-derived neurotrophic factor (BDNF) can be used as a physiological EE conditioned marker, and were increased at 14days in the EE condition in both WT and KO mice. Newborn cells during control and EE conditions were labeled by BrdU, and the labeled cells co-immunostained with the immature and mature neuron markers, calretinin (CR) and NeuN. The ratio of CR/BrdU and NeuN/BrdU double positive cells to all of BrdU positive cells were significantly increased in WT mice housed in the EE condition for 14days compared with the control condition. Whereas KO mice in the EE condition showed no significant increase of newborn neurons. These findings suggest that CAPS2 deficiency strongly impairs hippocampal adult neurogenesis and maturation of newborn neurons.


The Impact of Tumor Cell-Intrinsic Expression of Cyclic GMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) on the Infiltration of CD8+ T Cells and Clinical Outcomes in Mismatch Repair Proficient/Microsatellite Stable Colorectal Cancer.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8+ T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS-/STING-) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS+/STING+) in tumor cells. The frequency of cGAS+/STING+ cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8+ and/or CD4+ T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC.


Analysis of halonitriles in drinking water using solid-phase microextraction and gas chromatography-mass spectrometry.
Halonitriles are a class of nitrogen-containing disinfection by-products (DBPs) that have been reported to be more toxic and carcinogenic than the regulated DBPs. While haloacetonitriles (HANs) are often measured in drinking waters, there is little information on the formation, characteristics, and occurrence of other, higher molecular weight halonitriles. Halopropionitriles and halobutyronitriles have been predicted to be highly toxic and carcinogenic, and may have sufficient potency and selectivity to account for epidemiological associations of chlorinated and chloraminated water with adverse health effects. This paper reports on the development, optimisation, and validation of a simple, robust, and sensitive analytical method for the determination of halonitriles in waters, as well as the application of the method to study the formation and characteristics of halonitriles. This is the first reported method development for analysis halopropionitriles and halobutyronitriles, and the first study on their formation and occurrence as DBPs in drinking waters. The new method uses headspace solid-phase microextraction to extract the halonitriles from water, which are then analysed using gas chromatography-mass spectrometry (HS SPME/GC-S). The method demonstrated good sensitivity (detection limits: 0.9-80 ng L⁻¹) and good precision (repeatability: 3.8-12%), and is linear over three orders of magnitude. Matrix effects from raw drinking water containing organic carbon (4.1 mg L⁻¹) were shown to be negligible in the analysis of halonitriles. The optimised method was used to study the stability and persistence of halonitriles in aqueous samples, and the formation and occurrence of halonitriles in waters. Results from laboratory-scale disinfection experiments showed that haloacetonitriles were formed in chlorinated and chloraminated samples, but 2,2-dichloropropionitrile was only measured in chloraminated samples. Results from surveys of several drinking water distribution systems confirmed the laboratory findings.


Adenotonsillotomy Versus Adenotonsillectomy in Pediatric Obstructive Sleep Apnea: An RCT.
Adenotonsillectomy (ATE) is a well-established and effective treatment of pediatric obstructive sleep apnea (OSA). In recent years, a more conservative method, adenotonsillotomy (ATT), has gained popularity because it is associated with less postoperative morbidity. Yet no previous randomized study has compared these 2 methods regarding their effectiveness in treating pediatric OSA in terms of polysomnographic data, which was the primary aim of this study. The hypothesis was that ATT is noninferior to ATE after 1 year. Seventy-nine children, aged 2 to 6 years, with OSA (Apnea-Hypopnea Index [AHI] 5-30) were randomized to ATT (n = 40) or ATE (n = 39). Polysomnography (PSG) and questionnaire OSA-18 were assessed at baseline and 1 year postsurgery. Mean difference between groups in the primary outcome, change in AHI, was 0.83, 95% confidence interval -3.2 to 4.9, not exceeding the noninferiority margin of 5. After ATE, AHI decreased from median 12.7 (interquartile range 8.3-19.1) to 2.0 (1.2-3.1) and after ATT from 15.8 (8.5-21.2) to 4.0 (1.2-5.1). For both groups, significant improvements of PSG and OSA-18 questionnaire outcomes were observed, with no significant differences between groups. Five children (13%) in the ATT group needed repeated surgery for tonsil regrowth and recurrence of OSA. The results suggest that ATT is noninferior to ATE in treating pediatric OSA regarding PSG outcomes after 1 year. ATT could be considered an alternative to ATE for treatment of pediatric OSA. However, after ATT, there is a nonnegligible risk of recurrence of OSA, and this should be taken into account when selecting surgical method.


Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials.
Epidemiologic studies have shown inconsistent conclusions about the effect of ulinastain treatment for acute respiratory distress syndrome (ARDS). It is necessary to perform a meta-analysis of ulinastatin's randomized controlled trials (RCTS) to evaluate its efficacy for treating ARDS. We searched the published RCTs of ulinastatin treatment for ARDS from nine databases (the latest search on April 30th, 2017). Two authors independently screened citations and extracted data. The meta-analysis was performed using Rev. Man 5.3 software. A total of 33 RCTs involving 2344 patients satisfied the selection criteria and were included in meta-analysis. The meta-analysis showed that, compared to conventional therapy, ulinastatin has a significant benefit for ARDS patients by reducing mortality (RR = 0.51, 95% CI:0.43~0.61) and ventilator associated pneumonia rate (RR = 0.50, 95% CI: 0.36~0.69), and shortening duration of mechanical ventilation (SMD = -1.29, 95% CI: -1.76~-0.83), length of intensive care unit stay (SMD = -1.38, 95% CI: -1.95~-0.80), and hospital stay (SMD = -1.70, 95% CI:-2.63~-0.77). Meanwhile, ulinastatin significantly increased the patients' oxygenation index (SMD = 2.04, 95% CI: 1.62~2.46) and decreased respiratory rate (SMD = -1.08, 95% CI: -1.29~-0.88) and serum inflammatory factors (tumor necrosis factor-α: SMD = -3.06, 95% CI:-4.34~-1.78; interleukin-1β: SMD = -3.49, 95% CI: -4.64~-2.34; interleukin-6: SMD = -2.39, 95% CI: -3.34~-1.45; interleukin-8: SMD = -2.43, 95% CI: -3.86~-1.00). Ulinastatin seemly showed a beneficial effect for ARDS patients treatment and larger sample sized RCTs are needed to confirm our findings.


Comparison of outcomes for patients with acute myeloid leukemia undergoing haploidentical stem cell transplantation in first and second complete remission.
There was no consensus on whether prognostic advantages existed when transplant conducted at first complete remission (CR1) stage than at second complete remission (CR2) stage for patients with AML who received haploidentical hematological stem cell transplantation (haplo-HSCT). In 768 consecutive AML patients who received haplo-HSCT from January 2014 to December 2017, a 1:2 ratio matched-pair analysis was performed, 69 patients who in CR2 group and 138 CR1 patients were enrolled. Hematopoietic recovery, graft versus host disease (GVHD), relapse, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) were compared in two groups, and further evaluated in low-, intermediate-, and high-risk subgroups. The cumulative incidences of 30-day myeloid recovery and 90-day platelet recovery were comparable in CR1 and CR2 groups. The cumulative incidences of grade II-IV and grade III-IV aGVHD were not significantly different. The cumulative incidences of relapse at 3-year and 5-year in these two groups were 12.4% versus 11.6% (P = 0.880) and 12.4% versus 17.5% (P = 0.322). The cumulative incidences of TRM at 3-year and 5-year were both 10.9% versus 23.2% (P = 0.019). The probability of DFS at 3-year and 5-year were 76.7% versus 65.2% (P = 0.029) and 76.7% versus 59.3% (P = 0.009). The probability of OS at 3-year and 5-year were 81.8% versus 68.1% (P = 0.026) and 76.7% versus 59.3% (P = 0.026). In the intermediate-risk group, TRM was lower in CR1 group, DFS and OS of CR1 group were superior to CR2 group. In conclusion, haplo-HSCT at CR1 stage was of better prognosis for intermediate-risk AML patients than at CR2 stage.


Selective elimination of breast cancer surgery in exceptional responders: historical perspective and current trials.
With improvements in chemotherapy regimens, targeted therapies, and our fundamental understanding of the relationship of tumor subtype and pathologic complete response (pCR), there has been dramatic improvement in pCR rates in the past decade, especially among triple-negative and human epidermal growth factor receptor 2-positive breast cancers. Rates of pCR in these groups of patients can be in the 60 % range and thus question the paradigm for the necessity of breast and nodal surgery in all cases, particularly when the patient will be receiving adjuvant local therapy with radiotherapy. Current practice for patients who respond well to neoadjuvant chemotherapy (NCT) is often to proceed with the same breast and axillary procedures as would have been offered women who had not received NCT, regardless of the apparent clinical response. Given these high response rates in defined subgroups among exceptional responders it is appropriate to question whether surgery is now a redundant procedure in their overall management. Further, definitive radiation without surgical resection with or without systemic therapy has been proven effective for several other malignant disease sites including some stages of esophageal, anal, laryngeal, prostate, cervical, and lung carcinoma. The main impediments for potential elimination of surgery have been the fact that prior and current standard and functional breast imaging methods are incapable of accurate prediction of residual disease and that integrating percutaneous biopsy of the breast primary and nodes following NCT may circumvent this issue. This article highlights historical attempts at omission of surgery following NCT in an earlier era, the current status of breast and nodal imaging to predict residual carcinoma, and ongoing and planned trials designed to identify appropriate patients who might be selected for clinical trials designed to test the safety of selected elimination of breast cancer surgery in percutaneous image-guided biopsy-proven exceptional responders to NCT.


Negative Stress Test Is Not Always Negative: Revisiting the Clinical Implications of Balanced Ischemia.
Myocardial perfusion imaging with technetium (99mTc) sestamibi often aids in the diagnosis of coronary artery disease. This diagnostic tool is highly important in dictating future clinical decision-making and determining whether patients may benefit from revascularization. However, it is not completely sensitive and may be unreliable in diagnosing coronary artery disease in patients with balanced perfusion deficits. Here, we present the case of a 45-year-old male with severe coronary artery disease and false-negative myocardial perfusion imaging.


Erythropoietin in cardiovascular diseases.
Several studies showed that anaemia is commonly observed in patients with Chronic Heart Failure (CHF) and is associated with worsened symptoms and survival. When anaemia in these patients is treated with erythropoietin (EPO), a significant improvement in cardiac function and symptoms was observed. Although it was originally believed that EPO specifically acted on haematopoietical cells, recent evidence demonstrated several non-haematopoietical effects. Ischaemia/reperfusion experiments in rat heart and brain showed large infarct reduction when treated with EPO. Other effects of EPO are related to its pro-angiogenic effects on endothelial cells, which could be of potential value in patients with ischaemic heart disease. These preclinical findings suggest that EPO may have potential effects in cardiovascular disease beyond correction of haemoglobin levels.


Relationship between the velocity of illusory hand movement and strength of MEG signals in human primary motor cortex and left angular gyrus.
We studied the relationship between the velocity of movement illusion and the activity level of primary motor area (M1) and of the left angular gyrus (AG) in humans. To induce illusory movement perception, we applied co-vibration at different frequencies on tendons of antagonistic muscle groups. Since it is well established that the velocity of illusory movement is related to the difference in vibration frequency applied to two antagonistic muscles, we compared magnetoencephalography (MEG) signals recorded in two conditions of co-vibration: in the "fast illusion" condition a frequency difference of 80 Hz was applied on the tendons of the right wrist extensor and flexor muscle groups, whereas in the "slow illusion" condition a frequency difference of 40 Hz was applied on the same muscle groups. The dipole strength, reflecting the activity level of structures, was measured over M1 and the left AG in two different time-periods: 0-400 and 400-800 ms in each condition. Our results showed that the activity level of the AG was similar in both conditions whatever the time-period, whereas the activity level of M1 was higher in the "fast illusion" condition compared to the "slow illusion" condition from 400 ms after the vibration onset only. The data suggest that the two structures differently contributed to the perception of illusory movements. Our hypothesis is that M1 would be involved in the coding of cinematic parameters of the illusory movement but not the AG.


Leveraging fine-mapping and multipopulation training data to improve cross-population polygenic risk scores.
Polygenic risk scores suffer reduced accuracy in non-European populations, exacerbating health disparities. We propose PolyPred, a method that improves cross-population polygenic risk scores by combining two predictors: a new predictor that leverages functionally informed fine-mapping to estimate causal effects (instead of tagging effects), addressing linkage disequilibrium differences, and BOLT-LMM, a published predictor. When a large training sample is available in the non-European target population, we propose PolyPred+, which further incorporates the non-European training data. We applied PolyPred to 49 diseases/traits in four UK Biobank populations using UK Biobank British training data, and observed relative improvements versus BOLT-LMM ranging from +7% in south Asians to +32% in Africans, consistent with simulations. We applied PolyPred+ to 23 diseases/traits in UK Biobank east Asians using both UK Biobank British and Biobank Japan training data, and observed improvements of +24% versus BOLT-LMM and +12% versus PolyPred. Summary statistics-based analogs of PolyPred and PolyPred+ attained similar improvements.


Bubblegrams reveal the inner body of bacteriophage φKZ.
Dense packing of macromolecules in cellular compartments and higher-order assemblies makes it difficult to pick out even quite large components in electron micrographs, despite nominally high resolution. Immunogold labeling and histochemical procedures offer ways to map certain components but are limited in their applicability. Here, we present a differential mapping procedure, based on the physical principle of protein's greater sensitivity to radiation damage compared with that of nucleic acid.


PUVA-induced pigmented macules: a case involving palmoplantar skin.
A patient with palmoplantar psoriasis received a local treatment regimen of psoralens with long-wave ultraviolet A radiation (PUVA). After approximately 12 months of treatment, she developed hyperpigmented macules on her palms and soles. A biopsy showed changes consistent with PUVA-induced pigmented macules, as well as pronounced pigmentary incontinence. No cytologic atypia was noted. PUVA-induced pigmented macules should now be included in the differential diagnosis of palmoplantar hyperpigmented macules.


Modulation of 5-fluorouracil metabolism by thymidine. In vivo and in vitro studies on RNA-directed effects in rat liver and hepatoma.
The effects of thymidine (TdR) co-administration on the cytotoxicity and incorporation of 5-fluorouracil (5-FU) into RNA of various tissues was studied in rats bearing an ascites hepatoma (AH 130). The role of pyrimidine degradation in determining the modulating effects of TdR on the formation of FU-RNA was studied in hepatocytes and AH 130 cells in vitro. TdR (500 mg/kg) potentiated the antitumour effect of 5-FU (150 mg/kg) and also increased host toxicity as judged by changes in body weight. TdR given alone did not significantly affect tumour growth and body weight gain. Examination of the effect of TdR on the incorporation of 5-FU into RNA revealed a differential modulation of RNA-directed toxicity in different tissues. Incorporation of 5-FU into RNA in tumour and bone marrow was increased 2- and 4-fold, respectively. In spleen and kidney the incorporation increased by approximately 50%, but the values did not reach statistical significance. In contrast, the incorporation into RNA of liver and intestinal mucosa was decreased to ca 35% of the control. TdR at concentrations of 40 microM-40 mM progressively inhibited the degradation of 5-FU and decreased the incorporation of 5-FU into RNA of hepatocytes in vitro. In AH 130 cells in vitro TdR did not significantly influence the metabolism of 5-FU and the incorporation into RNA. These results demonstrate that the enhanced incorporation of 5-FU into tumour RNA in vivo after pretreatment with TdR is related not to local effects on the tumour cells but rather to an increased bioavailability of the drug. Although co-administration of TdR did not selectively enhance the antitumour effect of 5-FU, a differential toxicity in host tissues was indicated by the modulated incorporation of 5-FU into RNA.


Is there a correlation between taurine levels and xenobiotic-induced perturbations in protein synthesis?: a study with tetracycline in rats.
Changes in urinary levels of taurine have been reported in rats following treatment with various xenobiotics including those which alter protein synthesis and/or are hepatotoxic. This paper reports on the time course of the urinary elevation of taurine following treatment of rats with tetracycline (50, 150 and 200 mg.kg-1). Maximum taurine excretion occurred 8-12 h following dosing. Serum albumin and total protein were significantly lower after 24 h (200 mg.kg-1). The increase in urinary taurine was dose-related and reflected in the raised serum levels of taurine 24 h after dosing. Serum and urinary protein and [3H]-leucine incorporation into acid precipitable protein in liver and muscle were reduced by tetracycline (100, 150 and 200 mg.kg-1) 10 h after dosing. The reduction in protein synthesis was correlated with increased urinary and serum levels of taurine at 10 h. The use of taurine as a non-invasive marker of protein synthesis is discussed.


WITHDRAWN: Fracture line morphology of greater tuberosity fragments of Neer 3 and 4 part proximal humerus fractures.
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IGAxBSA composite for assessing disease severity and response in patients with atopic dermatitis.
Accurate assessment of atopic dermatitis (AD) severity is critical when initiating and monitoring therapy. Use of existing research tools such as the Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD) is complex and time-consuming in clinical practice. A previous analysis found the product of validated Investigator's Global Assessment (vIGA) and affected body surface area (BSA) to be an accurate and practical tool for routine assessment of paediatric AD. To evaluate the IGAxBSA composite as an alternative to EASI or SCORAD for assessment of AD disease severity and disease responsiveness. The relationship between IGAxBSA, EASI and SCORAD was assessed in a post hoc analysis of pooled data from the dupilumab clinical trial programme in adult and paediatric patients with moderate-to-severe AD who had received dupilumab or placebo, with or without topical corticosteroids (TCS). The trials are registered at ClinicalTrials.gov and EudraCT: LIBERTY AD SOLO 1 (NCT02277743, 2014-001198-15), LIBERTY AD SOLO 2 (NCT02277769, 2014-002619-40), LIBERTY AD SOLO-CONTINUE (NCT02395133, 2014-003384-38), LIBERTY AD CHRONOS (NCT02260986, 2013-003254-24), LIBERTY AD CAFÉ (NCT02755649, 2015-002653-35), LIBERTY AD ADOL (NCT03054428, 2015-004458-16), LIBERTY AD PEDS (NCT03345914, 2016-004997-16), LIBERTY AD OLE (NCT01949311, 2013-001449-15) and LIBERTY AD PEDS OLE (NCT02612454, 2015-001396-40). Using datapoints from pooled dupilumab randomized controlled trials (n = 3473) and open-label extension trials (n = 3045), we found that IGAxBSA correlated well with EASI and SCORAD, irrespective of treatment group and race (white, Asian, black). IGAxBSA correlated better with objective measures (EASI, SCORAD) than with patient- or caregiver-reported subjective measures. IGAxBSA correlated strongly with EASI and SCORAD in assessing disease change over time (r = 0·90, r = 0·76, respectively; P < 0·0001), and concordance between IGAxBSA-50/75/90 and EASI-50/75/90 was excellent (88-94%). IGAxBSA is a valid alternative for assessment of AD disease severity and response over time, compared with EASI or SCORAD in patients with AD, irrespective of race.


Isolation methods, proliferation, and adipogenic differentiation of adipose-derived stem cells from different fat depots in bovines.
The adipose-derived stem cells (ASCs) are a valuable resource for regenerative medicine and essential materials for research in fat deposition. However, the isolation procedure of ASCs has not been standardized and needs to be harmonized; differences in proliferation and adipogenic differentiation of ASCs obtained from different fat depots have not been well characterized. In the present study, we compared the efficiency of ASCs isolation by enzymatic treatment and explant culture methods and the proliferation ability and adipogenic differentiation potential of ASCs isolated from subcutaneous and visceral fat depots. The explant culture method was simple and with no need for expensive enzymes while the enzymatic treatment method was complex, time consuming and costly. By the explant culture method, a larger number of ASCs were isolated from subcutaneous and visceral fat depots. By contrast, fewer ASCs were obtained by the enzymatic treatment method, especially from visceral adipose. ASCs isolated by the explant culture method performed well in cell proliferation and adipogenic differentiation, though they were slightly lower than those by the enzymatic treatment method. ASCs isolated from visceral depot demonstrated higher proliferation ability and adipogenic differentiation potential. In total, the explant culture method is simpler, more efficient, and lower cost than the enzymatic treatment method for ASCs isolation; compared with visceral adipose, subcutaneous adipose is easier to isolate ASCs; however, the visceral ASCs are superior to subcutaneous ASCs in proliferation and adipogenic differentiation.


Comparison between multimodal and intraoperative opioid free anesthesia for laparoscopic sleeve gastrectomy: a prospective, randomized study.
Anesthesia for laparoscopic sleeve gastrectomy and perioperative management remains a challenge. Several clinical studies indicate that opioid-free anesthesia (OFA) may be beneficial, but there is no consensus on the most optimal anesthesia technique in clinical practice. The aim of our study was to assess the potential benefits and risks of intraoperative OFA compared to multimodal analgesia (MMA) with remifentanil infusion. In a prospective, randomized study, we analyzed 59 patients' data. Primary outcome measures were oxycodone consumption and reported pain scores (numerical rating scale, NRS) at 1, 6, 12, and 24th hours after surgery. Postoperative sedation on the Ramsay scale, nausea and vomiting on the PONV impact scale, desaturation episodes, pruritus, hemodynamic parameters, and hospital stay duration were also documented and compared. There were no significant differences in NRS scores or total 24-h oxycodone requirements. In the first postoperative hour, OFA group patients needed an average of 4.6 mg of oxycodone while the MMA group 7.72 mg (p = 0.008, p < 0.05 statistically significant). The PONV impact scale was significantly lower in the OFA group only in the first hour after the operation (p = 0.006). Patients in the OFA group required higher doses of ephedrine 23.67 versus 15.69 mg (p = 0.039) and more intravenous fluids 1160 versus 925.86 ml (p = 0.007). The mode of anesthesia did not affect the pain scores or the total dose of oxycodone in the first 24 postoperative hours. Only in the first postoperative hour were an opioid-sparing effect and reduction of PONV incidence seen in the OFA group when compared with remifentanil-based anesthesia. However, patients in the OFA group showed significantly greater hemodynamic lability necessitating higher vasopressor doses and more fluid volume.


A reducing environment stabilizes HIF-2alpha in SH-SY5Y cells under hypoxic conditions.
Accumulating evidence suggests that hypoxia-inducible factor-2 (HIF-2) is important for the cellular response to hypoxia. However, it is not clear how HIF-2 is regulated under hypoxic conditions. We investigated kinetic changes in redox status and HIF-2alpha accumulation in hypoxic SH-SY5Y cells. Our results demonstrated that hypoxia caused a reducing environment and increased HIF-2alpha protein levels. Experiments with redox modulations (N-acetylcysteine and l-buthionine sulfoximine) confirmed that a reducing environment induced HIF-2alpha accumulation while an oxidizing environment decreased it. In addition, experiments with SOD mimic, catalase, and exogenous H2O2 provided evidence that the presence of H2O2 down-regulated the amount of HIF-2alpha protein. This study offers novel evidence supporting redox status regulation of HIF-2alpha accumulation under hypoxic conditions.


Fibroblast-activating factor production by interleukin (IL)-2 dependent T-cell clones from rheumatoid arthritis patients and normal donors.
T cells spontaneously responsive to interleukin (IL)-2 were cloned from the peripheral blood (PBL) or synovial fluid (SFL) lymphocyte populations obtained from patients with rheumatoid arthritis (RA) or from normal PBL. The clones were compared for their capacities to produce fibroblast-activating factors (FAFs) which support the growth of RA synovial fibroblasts. Clones derived from all sources produced FAFs following mitogen stimulation, but SFL clones synthesized significantly higher levels of FAF activity. Physicochemical characterization of the FAFs suggested that SFL- and PBL-derived clones produced similar factors. It was also demonstrated that interferon-gamma and IL-2 did not contribute to the FAF activity of the clone supernatants. These results demonstrate that a subpopulation of activated lymphocytes which are present in increased numbers in the rheumatoid joint can produce factors which influence rheumatoid synovial cell growth.


Paperless migrants and Norwegian general practitioners.
In Norway, the rights of paperless migrants are restricted. We wished to investigate the extent to which Norwegian general practitioners give treatment to this group and their grounds for doing so, as well as to identify the health problems that were presented. In 2010, an online questionnaire was distributed to 3 994 general practitioners who were members of the Norwegian Medical Association. Altogether 1 027 GPs responded. Of these, 237 (23 %) reported to have treated paperless migrants. Mental problems, pregnancy-related issues and respiratory ailments were the most frequently reported reasons for contact. Of the 237 GPs who reported to have treated paperless migrants, altogether 166 (70 %) stated that they would continue to receive these patients. The fact that most of the GPs who had treated paperless migrants would continue to receive this patient group and thus provide health services beyond this group's entitlements, we regard as a wish to comply with the Code of Ethics for Norwegian doctors.


Caregiver experiences of social support following stroke.
Informal caregivers need to support their loved ones while performing caregiving responsibilities. A phenomenological qualitative study was done to understand the role of social support accessible for stroke caregivers. The respondents were enrolled from different organizations or support groups who were conducting activities specifically for stroke victims and/or their caregivers. Data collection was concluded after 10 participants were interviewed as no new major themes were discovered. Hence, saturation of data was obtained with a sample of 10 respondents. Two themes were identified from the interviews: "Response to Stroke" and "Stress and Coping". Categories in theme one "Response to Stroke" were "Work Life Balance", "Reaction of Other People or Family to Stroke", and "Expectations and Responsibility from Caregivers". Categories in theme two "Stress and Coping" were "Impact of Stroke on Abilities of Victim", "Stressors and Concerns for the Caregivers", "Strategies used by Caregivers to Cope with Stress", and "Role of Support Group and Social Support to Stroke Caregiver and Care Recipient". Stroke can lead to stress that can alter the responsibilities of caregivers of stroke victims. The role of social support and support groups was found to be critical for family caregivers to cope with caregiving issues.


Current Practice Patterns Among Members of the American Urological Association for Male Genitourinary Lichen Sclerosus.
To determine the practice patterns of urologists who treat male genitourinary lichen sclerosus (MGU-LS) via a national web-based survey distributed to American Urological Association members. A 20-question survey was collected from a random sample of American Urological Association members. Respondents answered questions on their practice patterns for MGU-LS diagnosis, treatment of symptomatic urethral stricture disease, surveillance, and follow-up. In total, 309 urologists completed the survey. The majority of respondents reported practicing more than 20+ years (37.5%) within an academic (31.7%) or group practice (31.1%) setting. The majority of respondents saw 3-5 men with MGU-LS per year (32.7%). The most common locations of MGU-LS involvement included the glans penis (66.2%), foreskin (26.3%), and/or the urethra (5.8%). Respondent first-line treatment for urethral stricture disease was direct visual internal urethrotomy (26.6%) and second-line treatment was referral to subspecialist (38.4%). After controlling for the number of patients evaluated with MGU-LS per year, those with reconstructive training were more likely to perform a primary urethroplasty for men with symptomatic urethral stricture disease (adjusted odds ratio 13.1, 95% confidence interval 5.1-33.8, P < .001). They were also more likely to counsel men on the associated penile cancer risks (adjusted odds ratio 4.6, 95% confidence interval 1.7-12.5, P < .01). Reconstructive urologists evaluate the most number of patients with MGU-LS and are more likely to perform primary urethroplasty for urethral stricture disease. Men with MGU-LS should be referred to a reconstructive urologist to understand the full gamut of treatment options.


Heat shock (hsp70) and resistance proteins in non-small cell lung carcinomas.
The aim of the study was to prove whether or not an association exists between the heat shock protein 70 (hsp70) and drug resistance. Tumor samples of 90 patients with previously untreated non-small lung carcinomas were investigated immunohistochemically for expression of resistance related proteins. Additionally, resistance to doxorubicin was determined using a short term test. No association between resistance related proteins. Additionally, resistance to doxorubicin was determined using a short term test. No association between resistance to doxorubicin and hsp70 was found. Of 63 resistant tumors, 33 showed low and 30 high hsp70 expression. Of the 26 sensitive tumors, 11 had low and 16 had high hsp70 expression. No relationship could be found between P-glycoprotein which is related to multidrug resistance and hsp70 expression or between hsp70 expression and expression of topoisomerase II, thymidylate synthase and metallothionein. On the other hand, a trend was noted for tumors with high glutathione S-transferase-pi expression to show high hsp70 expression. In addition, there was a significant relationship between hsp70 and catalase positivity. These data indicate that heat shock and stress promote intracellular oxidative damage and catalase is necessary for protection.


Left ventricular diastolic function in hypertrophic cardiomyopathy: assessment by radionuclide angiography.
Diastolic left ventricular function was studied in 20 patients with obstructive hypertrophic cardiomyopathy, 10 with apical hypertrophic cardiomyopathy, and 20 control subjects. The left ventricular time-activity curve was filtered using Fourier expansion with 4 harmonics. The first and second derivatives of the filtered curve were used to define various parameters of the left ventricle. Isovolumic relaxation period and time to peak filling rate were prolonged in obstructive hypertrophic cardiomyopathy and apical hypertrophic cardiomyopathy (101.56 +/- 44.81 msec, 105.19 +/- 45.27 versus 72.19 +/- 29.36 (CS) P less than 0.05; 169.70 +/- 50.73 msec, 173.83 +/- 50.53 versus 138.02 +/- 29.54 (CS) P less than 0.05, respectively). Rapid filling period, diastasis, atrial contraction period, time to peak filling rate-isovolumic relaxation period, and filling fraction of diastasis were not significantly different in these groups. Fasting filling fraction was 11% lower in hypertrophic groups than in control subjects. The filling fraction of atrial contribution was 12% higher in hypertrophic groups. We conclude: Isovolumic relaxation period, rapid filling phase, and diastasis atrial contraction period can be clearly defined by this technique. Impaired relaxation is an important determinant of decreased left ventricular filling in patients with obstructive hypertrophic cardiomyopathy and apical hypertrophic cardiomyopathy. Prolonged time to peak filling rate is mainly due to increased isovolumic relaxation period in hypertrophic patients. Atrial contraction contributes to more stroke volume in patients with hypertrophic cardiomyopathy.


The Association Between Obesity and Weight Loss Intention Weaker Among Blacks and Men than Whites and Women.
Although obesity is associated with weight loss intention, the magnitude of this association may differ across various populations. Using a nationally representative data of the United States, this study tested the variation of the association between obesity and weight loss intention based on race and gender. Data came from the National Survey of American Life (NSAL), 2001-2003, which enrolled 5,810 nationally representative sample of adults (3,516 African Americans, 1,415 Caribbean Blacks, and 879 Non-Hispanic Whites). Socio-demographics, body mass index (BMI), and weight loss intention were measured. We fitted logistic regression models in the pooled sample with weight loss intention as outcome, obesity (BMI > 30) as predictor, while the effect of covariates were controlled. To test our moderation hypotheses, we entered race * obesity and gender * obesity interactions to the model. Although the association between obesity and weight loss intention was significant among both race and gender groups, the magnitude of the association between obesity and weight loss intention was larger for women than men and Whites than Blacks. That means individuals with obesity have less intention for weight loss if they are Black or men. The link between obesity and weight loss intention depends on race and gender. Weight loss intention may not increase in response to obesity among Blacks and men, compared to Whites and women. Healthy weight programs in the United States may benefit from tailoring based on race and gender.


Assessment of the 1693 tsunami wave generation and propagation simulation based on multiple focal mechanism scenarios for recent disaster mitigation in eastern sicily, Italy.
The 1693 tsunami was the most extensive earthquake-tsunami event in Sicily, submerging Catania, Augusta, and Syracuse. However, the earthquake rupture, water level, arrival time, and furthest inundation distance of the tsunami waves are not yet known. This study aims to investigate the tsunamigenic source, run-up height, furthest inundation distance, and arrival time of the 1693 tsunami waves on the east coast of Sicily. Moreover, the assessment of tsunami-prone zones was also conducted based on worst-case earthquake-tsunami scenarios. Numerical modeling was applied by proposing six offshore focal mechanism scenarios using the shallow water equation in Delft3D and Delft Dashboard. The input parameters include length, width, strike, dip, slip, rake, and depth of the earthquake rupture. Meanwhile, the tsunami wave propagation onshore utilized XBeach and ArcGIS, considering the maximum run-up height, surface roughness analyzed from land use maps, slope, river existence, and coastline from Digital Terrain Model (DTM) identification. The results indicate that the worst possible impact of the 1693 tsunami was generated by an earthquake with a magnitude of Mw 7.13. The maximum water level, furthest inundation distance, and arrival time achieved 7.7 m, 318 m, and 9 min after wave generation offshore, respectively. This simulation is consistent with the discovery of 1693 tsunami deposits at a distance of less than 400 m from the coastlines of Augusta and Syracuse, but it is above the estimated furthest inundation distance in previous studies, which only reached around 100 m-200 m from the eastern coastline of Sicily. The results of the study are reliable as they align with the 1697 historical document where seawater inundated San Filippo Square, Catania.


Surgical Management of Congenital Diaphragmatic Hernia.
Congenital diaphragmatic hernia (CDH) is a challenging surgical disease that requires complex preoperative, perioperative, and postoperative care. Survival depends on successful reduction and repair of the defect, and numerous complex decisions must be made regarding timing and preparation for surgery. This review describes the challenges and controversies inherent to surgical CDH care and provides recommendations for management based on the most recent evidence.


Reproducibility of continuous glucose monitoring results under real-life conditions in an adult population: a functional data analysis.
Continuous glucose monitoring systems (CGM) are a very useful tool to understand the behaviour of glucose in different situations and populations. Despite the widespread use of CGM systems in both clinical practice and research, our understanding of the reproducibility of CGM data remains limited. The present work examines the reproducibility of the results provided by a CGM system in a random sample of a free-living adult population, from a functional data analysis approach. Functional intraclass correlation coefficients (ICCs) and their 95% confidence intervals (CI) were calculated to assess the reproducibility of CGM results in 581 individuals. 62% were females 581 participants (62% women) mean age 48 years (range 18-87) were included, 12% had previously been diagnosed with diabetes. The inter-day reproducibility of the CGM results was greater for subjects with diabetes (ICC 0.46 [CI 0.39-0.55]) than for normoglycaemic subjects (ICC 0.30 [CI 0.27-0.33]); the value for prediabetic subjects was intermediate (ICC 0.37 [CI 0.31-0.42]). For normoglycaemic subjects, inter-day reproducibility was poorer among the younger (ICC 0.26 [CI 0.21-0.30]) than the older subjects (ICC 0.39 [CI 0.32-0.45]). Inter-day reproducibility was poorest among normoglycaemic subjects, especially younger normoglycaemic subjects, suggesting the need to monitor some patient groups more often than others.


Mismatch repair proteins play a role in ATR activation upon temozolomide treatment in MGMT-methylated glioblastoma.
The methylation status of the O6-methylguanine methyltransferase (MGMT) gene promoter has been widely accepted as a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ). In the absence of promoter methylation, the MGMT enzyme removes O6-methylguanine (O6-meG) lesions. In the setting of MGMT-promoter methylation (MGMT-), the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Our group reported that loss of MGMT expression via MGMT promoter silencing modulates activation of ataxia telangiectasia and RAD3 related protein (ATR) in response to TMZ treatment, which is associated with synergistic tumor-cell killing. Whether or not MMR proteins are involved in ATR activation in MGMT-cells upon alkylation damage remains poorly understood. To investigate the function of MMR in ATR activation, we created isogenic cell lines with knockdowns of the individual human MMR proteins MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutS homolog 3 (MSH3), MutL homolog 1 (MLH1), and PMS1 homolog 2 (PMS2). Here, we demonstrate that MSH2, MSH6, MLH1 and PMS2, specifically, are involved in the activation of the ATR axis after TMZ exposure, whereas MSH3 is likely not. This study elucidates a potential mechanistic understanding of how the MMR system is involved in ATR activation by TMZ in glioblastoma cells, which is important for targeting MMR-mutated cancers.


Automatic tractography and segmentation using finsler geometry based on higher-order tensor fields.
We focus on three-dimensional higher-order tensorial (HOT) images using Finsler geometry. In biomedical image analysis, these images are widely used, and they are based on the diffusion profiles inside the voxels. The diffusion information is stored in the so-called diffusion tensor D. Our objective is to present new methods revealing the architecture of neural fibers in presence of crossings and high curvatures. After tracking the fibers, we achieve direct 3D image segmentation to analyse the brain's white matter structures. To deal with the construction of the underlying fibers, the inverse of the second-order diffusion tensor D, understood as the metric tensor D-1, is commonly used in DTI modality. For crossing and highly curved fibers, higher order tensors are more relevant, but it is challenging to find an analogue of such an inverse in the HOT case. We employ an innovative approach to metrics based on higher order tensors to track the fibers properly. We propose to feed the tracked fibers as the internal initial contours in an efficient version of 3D segmentation. We propose a brand-new approach to the inversion of a diffusion HOT, and an effective way of fiber tracking in the Finsler setting, based on innovative classification of the individual voxels. Thus, we can handle complex structures with high curvatures and crossings, even in the presence of noise. Based on our novel tractography approach, we also introduce a new segmentation method. We feed the detected fibers as the initial position of the contour surfaces to segment the image using a relevant active contour method (i.e., initiating the segmentation from inside the structures). This is a pilot work, enhancing methods for fiber tracking and segmentation. The implemented algorithms were successfully tested on both synthetic and real data. The new features make our algorithms robust and fast, and they allow distinguishing individual objects in complex structures, even under noise.


Prevalence of benign, atypical, and malignant breast lesions in populations at different risk for breast cancer. A forensic autopsy study.
A forensic autopsy series of 519 women more than 14 years old was studied for prevalence of benign, atypical, and occult malignant breast lesions. The women included Anglos (non-Hispanic whites), Hispanics, and American Indians from New Mexico and Eastern Arizona. These three ethnic/racial groups are at markedly different risk for the development of breast cancer (Anglo 89 of 100,000 women per year, Hispanic 45.5, and American Indian 24.9. There were striking ethnic/racial and age-related differences in both the prevalence and magnitude of all forms of nonproliferative and proliferative fibrocystic disease. The various subsets of fibrocystic disease were highly associated with each other. Such lesions as apocrine metaplasia, sclerosing adenosis, and lobular microcalcification showed as much difference according to ethnic/racial background and age as the more common cystic change and duct epithelial hyperplasia. Atypical lobular and ductal hyperplasia, carcinoma in situ, and occult invasive carcinoma were uncommon and also occurred in ethnic/racial groups in a pattern that parallels the cancer risk in those groups.


Shockwave therapy differentially stimulates endothelial cells: implications on the control of inflammation via toll-Like receptor 3.
Shock wave therapy (SWT) reportedly improves ventricular function in ischemic heart failure. Angiogenesis and inflammation modulatory effects were described. However, the mechanism remains largely unknown. We hypothesized that SWT modulates inflammation via toll-like receptor 3 (TLR3) through the release of cytosolic RNA. SWT was applied to human umbilical vein endothelial cells (HUVECs) with 250 impulses, 0.08 mJ/mm(2) and 3 Hz. Gene expression of TLR3, inflammatory genes and signalling molecules was analysed at different time points by real-time polymerase chain reaction. SWT showed activation of HUVECs: enhanced expression of TLR3 and of the transporter protein for nucleic acids cyclophilin B, of pro-inflammatory cytokines cyclophilin A and interleukin-6 and of anti-inflammatory interleukin-10. No changes were found in the expression of vascular endothelial cell adhesion molecule. SWT modulates inflammation via the TLR3 pathway. The interaction between interleukin (IL)-6 and IL-10 in TLR3 stimulation can be schematically seen as a three-phase regulation over time.


Papillary fibroelastoma prolapsing into the left ventricular outflow tract: diagnosis using three-dimensional TEE.
A 72-year-old woman was admitted to our hospital with exertional dyspnea and atrial tachycardia due to atypical atrial flutter. Comprehensive three-dimensional transesophageal echocardiography (3D-TEE) with offline reconstruction of the dataset (Siemens Foursight TEE, Erlangen, Germany) allowed visualization of the origin of the tumor and gave important additional information about the tumor: the tumor surface was floppy, it had the appearance of a "sea anemone", and it was attached to the endocardium of the head of the papillary muscle by a short stalk. The tumor was assessed to be 1.9 × 1.4 × 0.9 cm, and a prolapsing of the tumor into the left ventricular outflow tract during systole was demonstrated.A tumor size of 8 × 10 mm and an infiltration of the head of the anterior papillary muscle were found during surgery. The histopathological findings were typical for a papillary fibroelastoma (PFE) with involvement of the head of the papillary muscle.Our case indicates that a PFE might be difficult to distinguish from myxoma by echocardiography. Thus, the multimodal imaging approach and the three-dimensional visualization of the surface, the localization, and the attachment of the tumor to the head of a papillary muscle were very helpful for the identification of a fibroelastoma in this particular case.


Improving Collaboration Between Youth Peer Support Workers and Non-peer Colleagues in Child and Adolescent Mental Health Services.
The involvement of youth peer workers (YPSWs) in child and adolescent mental health services (CAMHS) stimulates hope, destigmatization, and more culturally and developmentally appropriate support. Nevertheless, the collaboration between YPSWs and non-peer colleagues remains challenging, as it requires services to embed a new type of expert into practice. To stimulate the involvement of YPSWs in practice, this study reports on 27 semi-structured interviews with YPSWs and non-peer colleagues to provide insight into the barriers and facilitators in the collaboration process. The study took place in the Netherlands. A total of 10 interviews with YPSWs, and 17 interviews with non-peer colleagues in different healthcare occupations in CAMHS were conducted. Overall, the participants perceived relatively more barriers compared to facilitators in the collaboration process. Barriers to operate efficiently with YPSWs in multidisciplinary teams included: condescending attitudes and professional stigma towards YPSWs; concerns for YPSW boundaries; bureaucratic and clinical language usage by non-peer colleagues; conflicts due to different sets of expertise; and, lack of role clarity and guidelines for YPSWs. To improve the partnership between YPSWs and non-peer colleagues, participants described the importance of supervision and monitoring of YPSW activities. Moreover, participants also stressed the need for clear guidelines, and introduction and evaluation sessions to facilitate the collaboration process. While YPSWs seem to be an asset to CAMHS, there are a number of barriers to overcome. To overcome these barriers, organizational commitment, supervision (especially from peer colleagues), flexibility by non-peer colleagues, training non-peer staff to support YPSWs, and consistent evaluation of the implementation of YPSWs in services is recommended.


Bimodal distribution of serum trypotphan level.
Serum levels of total L-tryptophan (L-TP) were determined before and during treatment in patients suffering from endogenous depression, who were treated with L-TP, 6 g daily, and unilateral electroconvulsive therapy (ECT). The gaussian curve of initial L-TP concentrations changed into a bimodal distribution during treatment. The patients with initially lower L-TP levels also had lower L-TP levels during the treatment, thus forming the low-concentration group within the bimodal distribution. In the patients with higher initial concentrations, the L-TP levels increased to a much greater degree, forming the high-concentration group. Patients in this group needed a larger number of ECT's, probably owing to L-TP's property of shortening the seizure duration. No other background data or clinical variables showed significant differences between the groups. It is suggested that the bimodality of L-TP levels is genetically determined.


Pathology of mycobacteriosis in birds.
Avian mycobacteriosis is a disease that affects companion, captive exotic, wild, and domestic birds. The disease in birds is generally caused by Mycobacterium avium subsp avium but more than 10 other species of mycobacteria infect birds. Oral route of infection appears to be the primary mode of transmission. In some cases, the extensive involvement of the respiratory system suggests an airborne mode of transmission. Molecular diagnostic techniques have improved the ability to confirm the disease. Avian mycobacteriosis is an important veterinary and economic risk in birds and mammals. Exposure of humans to infected birds may cause a zoonotic infection.


Fine structural changes in the gastro-intestinal tract of the hypoxic puppy: a study of natural history.
The present study demonstrates that a 2 hr period of sustained hypoxia results in a focally destructive process, a process which resolves by 5 days. That the changes described in earlier work are not overwhelming to the animal suggest that an early, focal, and reversible stage of the development of acute enterocolitis in the puppy can be described with the aid of electron microsocpy.


Clustering approach to quantify long-term spatio-temporal interactions in epileptic intracranial electroencephalography.
Abnormal dynamical coupling between brain structures is believed to be primarily responsible for the generation of epileptic seizures and their propagation. In this study, we attempt to identify the spatio-temporal interactions of an epileptic brain using a previously proposed nonlinear dependency measure. Using a clustering model, we determine the average spatial mappings in an epileptic brain at different stages of a complex partial seizure. Results involving 8 seizures from 2 epileptic patients suggest that there may be a fixed pattern associated with regional spatio-temporal dynamics during the interictal to pre-post-ictal transition.


Enhancement of antioxidant activity of levan through the formation of nanoparticle systems with metal ions.
Levan, a natural polymer, is widely used in biomedical applications, such as antioxidants, anti-inflammatory, and anti-tumor. The present study aimed to enhance the antioxidant activity of levan by combining it with various metal ions in the nanoparticle (NP) system. Levansucrase encoding gene from Bacillus licheniformis BK1 has been inserted into an expression vector and the obtained recombinant was labeled as Lsbl-bk1 (accession number MF774877.1). That enzyme was used for in vitro levan synthesis in 12% (w/v) sucrose as a substrate and about 4.28 mg/mL of levan was obtained. Levan-based metal ion NPs were synthesized using the coprecipitation method. In the production of NPs, levan acts as a reducing and stabilizing agent. Four types of levan-based metal ion NPs were synthesized, namely, levan-Fe2+ NPs, levan-Cu+ NPs, levan-Co2+ NPs, and levan-Zn2+ NPs. The transmission electron microscopy (TEM) technique was applied to visualize the size and shape of the synthesized levan-metal NPs. All levan-based metal ion NPs have a particle size of less than 100 nm, and even levan-Cu+ and levan-Zn2+ have particle sizes less than 50 nm. Levan-Fe2+ NPs and levan-Cu+ NPs exhibited prominent antioxidant activity with an inhibition level of up to 88% and 95%, respectively. And the inhibition level of two metal ion NPs had about 33%-40% higher antioxidant activity compared with the inhibition level of levan only. The two levan-metal ion NPs, therefore, have future prospects to be developed as the new formulation for the antioxidant drugs.


Clinico-histopathological correlation of symptomatic left main coronary artery electrocardiographic ischemia pattern in a young child with hypertrophic cardiomyopathy.
The specific electrocardiographic (ECG) pattern of left main coronary artery ischemia is exceptionally rare in children and under recognized. Occasional reports are bereft of a detailed mechanistic ECG description and limited to dissection, spasm, or anomalous origin of the left main coronary artery. An association with pediatric hypertrophic cardiomyopathy (HCM) is hitherto unreported. We furbish a detailed electrocardiographic description of this entity in the unusual setting of a 4-year-old child with HCM with a restrictive phenotype and exertional symptoms consistent with myocardial ischemia. Heart transplant was performed for this rare indication. Histopathology of the explanted heart in particular revealed left main coronary artery narrowing and provided us with a unique window of opportunity to correlate with clinical findings. The pathophysiology was also likely exacerbated by diffuse sub endocardial ischemia in the milieu of left ventricular hypertrophy with elevated end diastolic pressures. We anticipate that this illustrative case will help contextualize this as well as pediatric scenarios in which the 'left main ischemia' ECG pattern can be encountered and foster an accurate electrocardiographic recognition of this entity in children.


Increased expression and function of glutamate transporters in multiple sclerosis.
Recent studies have shown that glutamate excitotoxicity may be a component in the etiology of multiple sclerosis (MS). Glutamate transporters determine the levels of extracellular glutamate and are essential to prevent excitotoxicity. We have analyzed here the expression of the glutamate transporters EAAT1, EAAT2 and EAAT3 in control and in MS optic nerve samples. We observed an overall increase in the level of the glutamate transporters EAAT1 and EAAT2 mRNA and protein. In turn, functional assays showed that glutamate uptake was also increased in MS samples. Furthermore, glutamate transporter increases were mimicked in rat optic nerves treated with excitotoxic levels of glutamate. Together, these results indicate that enhanced expression of glutamate transporters in MS constitutes a regulatory response of glial cells to toxic levels of glutamate in the CNS during inflammation and neurodegeneration.


Creating interactive, web-based and data-enriched maps with the Systems Biology Graphical Notation.
The Systems Biology Graphical Notation (SBGN) is an emerging standard for the uniform representation of biological processes and networks. By using examples from gene regulation and metabolism, this protocol shows the construction of SBGN maps by either manual drawing or automatic translation using the tool SBGN-ED. In addition, it discusses the enrichment of SBGN maps with different kinds of -omics data to bring numerical data into the context of these networks in order to facilitate the interpretation of experimental data. Finally, the export of such maps to public websites, including clickable images, supports the communication of results within the scientific community. With regard to the described functionalities, other tools partially overlap with SBGN-ED. However, currently, SBGN-ED is the only tool that combines all of these functions, including the representation in SBGN, data mapping and website export. This protocol aims to assist scientists with the step-by-step procedure, which altogether takes ∼90 min.


SRTR program-specific reports on outcomes: a guide for the new reader.
Differences in outcomes indeed exist among transplant programs and organ procurement organizations (OPO). A growing set of tools are available from the Scientific Registry of Transplant Recipients (SRTR) to measure and assess these outcomes in the different phases of the transplant process. These tools are not intended to compare two individual programs, rather to help identify programs whose practices may need further scrutiny, to be either avoided, corrected or emulated. To understand which differences in outcomes might be due to underlying differences in populations served and which might be due to differences in treatment, it is important to compare outcomes to 'risk-adjusted' expected values. Further, it is important to recognize and assess the role that random chance may play in these outcomes by considering the p-value or confidence interval of each estimate. We present the reader with a basic explanation of these tools and their interpretation in the context of reading the SRTR Program-Specific Reports. We describe the intended audience of these reports, including patients, monitoring and process improvement bodies, payers and others such as the media. Use of these statistics in a way that reflects a basic understanding of these concepts and their limitations is beneficial for all audiences.


Biographical sketch: William John Little, FRCS (1810-1894).
This biographical sketch on William Little corresponds to the historic text, The Classic: Hospital for the Cure of Deformities: Course of Lectures on the Deformities of the Human Frame (1843), available at DOI 10.1007/s11999-012-2302-y .


Immunological method for prediction of progress in neurological deficit in patients with intracranial aneurysm rupture.
Skin tests of nonspecific antigens (immunoskin test Sevac) were performed on patients suffering from intracranial aneurysms, scheduled for surgical clipping. It was found that high antibody titre correlated well with the severity and progress of neurological deficit developing after surgery. This deficit was absent in patients who exhibited low antibody titre in response to the skin test before surgery. These results indicate that the immunological processes may play a role in the development of neurological deficit after neurosurgical procedures. Thus the skin test employed may have prognostic value in predicting neurological deficit following intracranial aneurysm surgery.


The influence of weather upon the activity of slugs.
The activity of slugs was measured by a catch per unit effort sampling system based upon night searching, and was related to the microclimatological conditions in the habitat by regression analysis. The activity of Arion hortensis Fér., Arion subfuscus (Drap.), Arion lusitanicus Mab., Milax budapestensis (Hazay), and of all slugs irrespective of species, was found to be best related to temperature and vapour pressure deficit. The relevance of these results to the application of effective methods for the control of slugs is discussed.


Aerosol size standards in the nanometer size range II. Narrow size distributions of polystyrene 3-11 nm in diameter.
A technique for generating charged aerosols of polystyrene (pSty) with narrow size distributions has been developed. It is based on electrospraying commercial narrow mass standards of pSty dissolved in l-methyl-2-pyrrolidone (NMP) seeded with the newly synthesized salt dimethyl ammonium formate. This salt imparts a much larger electrical conductivity than previously known NMP electrolytes, leading to higher quality sprays with greatly reduced attachment of impurities. Controlling the solute concentration enables forming polystyrene particles containing from one up to more than ten single polystyrene molecules, whereby 4 mass standards with molecular weights from 9200 up to 96,000 g/mol yield particles covering densely the diameter range from 3 to 11 nm. Combined mobility and mass measurement with a differential mobility analyzer and a mass spectrometer in tandem are carried out with a pSty sample 9200 amu in molecular weight. They fix directly the mass versus mobility relation near 9200 amu, and indirectly for the other standards and their clusters. The apparent particle density resulting from mobility versus mass data agrees with the bulk density of the polymer, indicating that the particles are dense and spherical. Although these standards have been studied only in gaseous suspension, their injection in liquids such as water where pSty is insoluble should keep them spherical.


Hypothermic circulatory arrest in the treatment of thoracic aortic lesions.
The use of hypothermic circulatory arrest has been established in the treatment of aortic arch lesions. We recently used this method of arrest in the treatment of 10 consecutive patients with thoracic aortic lesions. Seven of these patients had dissecting aneurysms of the ascending aorta with extension into the aortic arch. One patient had a mycotic aneurysm of the arch, and 2 patients had arteriosclerotic aneurysms of the ascending aorta and entire aortic arch. All patients were supported and cooled with cardiopulmonary bypass. Circulatory arrest was maintained for periods of 21 to 63 minutes. All 10 patients survived the operative procedure. Nine patients remained intact neurologically. Renal function returned to baseline in all patients. Average blood replacement was 2.9 units. All patients have experienced an excellent surgical result. The average follow-up is 21.1 months. The technique facilitates a surgical approach to these lesions and appears to be the safest form of vital-organ preservation.


Update: The diagnosis and management of dengue virus infection in North America.
Dengue is a mosquito-transmitted infection that poses significant global health risks for travelers and individuals living in the tropics and subtropics. The reported global incidence has increased dramatically in the past century, with dengue now ranking as the most common cause of febrile illness in travelers. While sporadic cases have been reported within the southern United States since 1980, autochthonous outbreaks have now been described in Hawaii, St. Croix (US Virgin Islands), along the Texas-Mexico border, and, most recently, in Key West, Florida. Although many infections are mild or asymptomatic, 5-10% of patients may experience hemorrhagic disease, with shock and even death. Laboratory identification commonly involves serologic and nucleic acid amplification methods. Due to rising incidence worldwide, physicians should be familiar with the clinical manifestations, laboratory diagnosis, and management of this illness.


BMP2 induces osteogenic differentiation through ACKR3 in mesenchymal stem cells.
In recent years, bone loss related diseases have attracted more and more attention, such as osteoporosis and osteonecrosis of the femoral head exhibited symptoms of osteopenia or insufficient bone mass in a certain stage. Mesenchymal stem cells (MSCs), which can be induced to differentiate into osteoblasts under certain conditions can provide a new solution bone disease. Herein, we deciphered the possible mechanism by which BMP2 drives the transduction of MSCs to the osteoblast lineage through ACKR3/p38/MAPK signaling. The levels of ACKR3 in femoral tissues of samples from humans with different ages and sexes were measured firstly and found that ACKR3 protein levels increase with age. In vitro cellular assays showed that ACKR3 inhibits BMP2-induced osteo-differentiation and promotes adipo-differentiation of MSCs, whereas siACKR3 exhibited the opposite effects. In vitro embryo femur culture experiment showed that inhibition of ACKR3 enhanced BMP2-induced trabecular bone formation in C57BL6/J mouse. In terms of molecular mechanisms, we found that p38/MAPK signaling might play the key role. ACKR3 agonist TC14012 suppressed the phosphorylation of p38 and STAT3 in BMP2 induced MSCs differentiation. Our findings suggested that ACKR3 might be a novel therapeutic target for the treatment of bone-associated diseases and bone-tissue engineering.