The role of endoscopic Doppler US in patients with peptic ulcer bleeding.
Stigmata of recent hemorrhage are important prognostic signs for patients with ulcer bleeding, but these are subjective findings. This study evaluated the additional diagnostic value of Doppler US assessment in patients with a bleeding peptic ulcer. A prospective, multicenter study was performed of patients with ulcer bleeding. Stigmata of recent hemorrhage were classified according to the Forrest classification, after which the ulcer was assessed by using an endoscopic Doppler US system. Patients with a Forrest Ib-IIb ulcer with a positive Doppler signal received endoscopic therapy. Patients with a Forrest IIc-III ulcer with a positive Doppler signal were allocated randomly to endoscopic therapy or no therapy. No ulcer without a Doppler signal was treated. A total of 80 patients were enrolled. Of the Forrest Ib-IIb ulcers, 82% had a positive Doppler signal. Of the Forrest IIc-III ulcers, 53% had a positive Doppler signal. There was no difference in the rates of recurrent bleeding, surgery, or mortality between the group with Forrest Ib-IIb ulcers and between the Forrest IIc-III group with and without Doppler signal, but there was little power in the sample size to detect differences. Bleeding recurred in 3 patients without a Doppler signal. Recurrent bleeding was more frequent in the group in which a Doppler signal was still present immediately after endoscopic therapy (3/11 vs. 1/27; p=0.06). This study did not substantiate a role for endoscopic Doppler US when this was added to the Forrest classification for making clinical decisions in patients with ulcer bleeding.


Predicting early positive change in multisystemic therapy with youth exhibiting antisocial behaviors.
This study examined individual and family characteristics that predicted early positive change in the context of Multisystemic Therapy (MST). Families (n = 185; 65% male; average youth age 15 years) receiving MST in community settings completed assessments at the outset of treatment and 6-12 weeks into treatment. Early positive changes in youth antisocial behavior were assessed using the caregiver report on the Child Behavior Checklist Externalizing Behaviors subscale and youth report on the Self-Report Delinquency Scale. Overall, families showed significant positive changes by 6-12 weeks into treatment; these early changes were maintained into midtreatment 6-12 weeks later. Families who exhibited clinically significant gains early in treatment were more likely to terminate treatment successfully compared with those who did not show these gains. Low youth internalizing behaviors and absence of youth drug use predicted early positive changes in MST. High levels of parental monitoring and low levels of affiliation with deviant peers (mechanisms known to be associated with MST success) were also associated with early positive change.


Sex Chromosome Evolution: So Many Exceptions to the Rules.
Genomic analysis of many nonmodel species has uncovered an incredible diversity of sex chromosome systems, making it possible to empirically test the rich body of evolutionary theory that describes each stage of sex chromosome evolution. Classic theory predicts that sex chromosomes originate from a pair of homologous autosomes and recombination between them is suppressed via inversions to resolve sexual conflict. The resulting degradation of the Y chromosome gene content creates the need for dosage compensation in the heterogametic sex. Sex chromosome theory also implies a linear process, starting from sex chromosome origin and progressing to heteromorphism. Despite many convergent genomic patterns exhibited by independently evolved sex chromosome systems, and many case studies supporting these theoretical predictions, emerging data provide numerous interesting exceptions to these long-standing theories, and suggest that the remarkable diversity of sex chromosomes is matched by a similar diversity in their evolution. For example, it is clear that sex chromosome pairs are not always derived from homologous autosomes. In addition, both the cause and the mechanism of recombination suppression between sex chromosome pairs remain unclear, and it may be that the spread of recombination suppression is a more gradual process than previously thought. It is also clear that dosage compensation can be achieved in many ways, and displays a range of efficacy in different systems. Finally, the remarkable turnover of sex chromosomes in many systems, as well as variation in the rate of sex chromosome divergence, suggest that assumptions about the inevitable linearity of sex chromosome evolution are not always empirically supported, and the drivers of the birth-death cycle of sex chromosome evolution remain to be elucidated. Here, we concentrate on how the diversity in sex chromosomes across taxa highlights an equal diversity in each stage of sex chromosome evolution.


HuD binds to three AU-rich sequences in the 3'-UTR of neuroserpin mRNA and promotes the accumulation of neuroserpin mRNA and protein.
Neuroserpin is an axonally secreted serine protease inhibitor expressed in the nervous system that protects neurons from ischemia-induced apoptosis. Mutant neuroserpin forms have been found polymerized in inclusion bodies in a familial autosomal encephalopathy causing dementia, or associated with epilepsy. Regulation of neuroserpin expression is mostly unknown. Here we demonstrate that neuroserpin mRNA and the RNA-binding protein HuD are co-expressed in the rat central nervous system, and that HuD binds neuroserpin mRNA in vitro with high affinity. Gel-shift, supershift and T1 RNase assays revealed three HuD-binding sequences in the 3'-untranslated region (3'-UTR) of neuroserpin mRNA. They are AU-rich and 20, 51 and 19 nt in length. HuD binding to neuroserpin mRNA was also demonstrated in extracts of PC12 pheochromocytoma cells. Additionally, ectopic expression of increasing amounts of HuD in these cells results in the accumulation of neuroserpin 3'-UTR mRNA. Furthermore, stably transfected PC12 cells over-expressing HuD contain increased levels of both neuroserpin mRNAs (3.0 and 1.6 kb) and protein. Our results indicate that HuD stabilizes neuroserpin mRNA by binding to specific AU-rich sequences in its 3'-UTR, which prolongs the mRNA lifetime and increases protein level.


Stimulation of the blue light phototropic receptor NPH1 causes a transient increase in cytosolic Ca2+.
Blue light regulates plant growth and development, and three photoreceptors, CRY1, CRY2, and NPH1, have been identified. The transduction pathways of these receptors are poorly understood. Transgenic plants containing aequorin have been used to dissect the involvement of these three receptors in the regulation of intracellular Ca2+. Pulses of blue light induce cytosolic Ca2+ transients lasting about 80 s in Arabidopsis and tobacco seedlings. Use of organelle-targeted aequorins shows that Ca2+ increases are limited to the cytoplasm. Blue light treatment of cry1, cry2, and nph1 mutants showed that NPH1, which regulates phototropism, is largely responsible for the Ca2+ transient. The spectral response of the Ca2+ transient is similar to that of phototropism, supporting NPH1 involvement. Furthermore, known interactions between red and blue light and between successive blue light pulses on phototropic sensitivity are mirrored in the blue light control of cytosolic Ca2+ in these seedlings. Our observations raise the possibility that physiological responses regulated by NPH1, such as phototropism, may be transduced through cytosolic Ca2+.


Effects of warning and information labels on consumption of full-fat, reduced-fat, and no-fat products.
Participants in a taste test study were randomly assigned to 1 of 3 groups: warning label (e.g., "In this product, 90% of the calories come from fat. Warning: The U.S. Surgeon General has determined that eating high fat food increases your risk of heart disease."), information label (e.g., "In this product, 90% of the calories come from fat."), and no label. Participants rated how much they wanted to taste full-, reduced-, and no-fat cream cheeses, and they chose 1 type to eat. People in the warning- and no-label groups wanted to taste the full-fat product more than those in the information-label group. People in the warning- and information-label groups were less likely to eat the full-fat product than those in the no-label group. People reacted to the warning label but avoided the full-fat product. For products with credible and familiar risks, information labels may be more effective than warning labels because they don't arouse reactance.


Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans.
The ability of the human fungal pathogen Cryptococcus neoformans to adapt to variable copper (Cu) environments within the host is key for successful dissemination and colonization. During pulmonary infection, host alveolar macrophages compartmentalize Cu into the phagosome and C. neoformans Cu-detoxifying metallothioneins, MT1 and MT2, are required for survival of the pathogen. In contrast, during brain colonization the C. neoformans Cu+ importers Ctr1 and Ctr4 are required for virulence. Central for the regulation and expression of both the Cu detoxifying MT1/2 and the Cu acquisition Ctr1/4 proteins is the Cu-metalloregulatory transcription factor Cuf1, an established C. neoformans virulence factor. Due to the importance of the distinct C. neoformans Cu homeostasis mechanisms during host colonization and virulence, and to the central role of Cuf1 in regulating Cu homeostasis, we performed a combination of RNA-Seq and ChIP-Seq experiments to identify differentially transcribed genes between conditions of high and low Cu. We demonstrate that the transcriptional regulation exerted by Cuf1 is intrinsically complex and that Cuf1 also functions as a transcriptional repressor. The Cu- and Cuf1-dependent regulon in C. neoformans reveals new adaptive mechanisms for Cu homeostasis in this pathogenic fungus and identifies potential new pathogen-specific targets for therapeutic intervention in fungal infections.


Immunological detection of proteins phosphorylated at tyrosine in cells stimulated by growth factors or transformed by retroviral-oncogene-coded tyrosine kinases.
The receptors for polypeptide growth factors and proteins coded by oncogenes of the src family are endowed with protein kinase activity and share the uncommon property of autophosphorylating at tyrosine residues. It is unclear whether the tyrosine kinase activity is also directed towards other targets of physiological significance. In this work, phosphotyrosine antibodies were used to detect, by Western blots and immunoprecipitation, proteins phosphorylated at tyrosine in fibroblasts either stimulated by growth factors (PDGF and EGF) or transformed by oncogene-coded tyrosine kinases. In stimulated cells the antibodies detected the autophosphorylated receptors, but only trace amounts of other proteins phosphorylated at tyrosine. In fibroblasts transformed by retroviral oncogenes (v-src, v-abl, v-fps or v-fes) proteins other than the corresponding oncogene-coded kinase, were found. A p70 was found to be heavily phosphorylated in fibroblasts transformed by v-src, v-fes and v-fps. A p130 and a p36 were found in cells transformed by v-src and v-abl. A unique p70 was phosphorylated in v-abl-transformed fibroblasts. These proteins were also phosphorylated in vitro in an immunocomplex kinase reaction. This reaction was blocked by the specific kinase inhibitors. These data strongly suggest that tyrosine kinases phosphorylate protein targets other than themselves. These targets are barely detectable in normal cells stimulated by growth factors, where the kinase activity is triggered rapidly and transiently. By contrast, a number of intracellular proteins phosphorylated at tyrosine accumulate in cells transformed by v-onc-coded kinases, endowed with constitutive and non-regulated enzymatic activity.


Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function.
Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. These alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. We tested whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by hepatocyte growth factor and insulin-like growth factor-1 invade the scarred myocardium and generate myocytes and coronary vessels improving the hemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful chemoattractant of CPCs, and insulin-like growth factor-1 promotes their proliferation and survival. Injection of CPCs or growth factors led to the replacement of approximately 42% of the scar with newly formed myocardium, attenuated ventricular dilation and prevented the chronic decline in function of the infarcted heart. Cardiac repair was mediated by the ability of CPCs to synthesize matrix metalloproteinases that degraded collagen proteins, forming tunnels within the fibrotic tissue during their migration across the scarred myocardium. New myocytes had a 2n karyotype and possessed 2 sex chromosomes, excluding cell fusion. Clinically, CPCs represent an ideal candidate cell for cardiac repair in patients with chronic heart failure. CPCs may be isolated from myocardial biopsies and, following their expansion in vitro, administered back to the same patients avoiding the adverse effects associated with the use of nonautologous cells. Alternatively, growth factors may be delivered locally to stimulate resident CPCs and promote myocardial regeneration. These forms of treatments could be repeated over time to reduce progressively tissue scarring and expand the working myocardium.


Nanotheranostics: A Possible Solution for Drug-Resistant Staphylococcus aureus and their Biofilms?
Staphylococcus aureus is a notorious pathogen that colonizes implants (orthopedic and breast implants) and wounds with a vicious resistance to antibiotic therapy. Methicillin-resistant S. aureus (MRSA) is a catastrophe mainly restricted to hospitals and emerged to community reservoirs, acquiring resistance and forming biofilms. Treating biofilms is problematic except via implant removal or wound debridement. Nanoparticles (NPs) and nanofibers could combat superbugs and biofilms and rapidly diagnose MRSA. Nanotheranostics combine diagnostics and therapeutics into a single agent. This comprehensive review is interpretative, utilizing mainly recent literature (since 2016) besides the older remarkable studies sourced via Google Scholar and PubMed. We unravel the molecular S. aureus resistance and complex biofilm. The diagnostic properties and detailed antibacterial and antibiofilm NP mechanisms are elucidated in exciting stories. We highlight the challenges of bacterial infections nanotheranostics. Finally, we discuss the literature and provide "three action appraisals". (i) The first appraisal consists of preventive actions (two wings), avoiding unnecessary hospital visits, hand hygiene, and legislations against over-the-counter antibiotics as the general preventive wing. Our second recommended preventive wing includes preventing the adverse side effects of the NPs from resistance and toxicity by establishing standard testing procedures. These standard procedures should provide breakpoints of bacteria's susceptibility to NPs and a thorough toxicological examination of every single batch of synthesized NPs. (ii) The second appraisal includes theranostic actions, using nanotheranostics to diagnose and treat MRSA, such as what we call "multifunctional theranostic nanofibers. (iii) The third action appraisal consists of collaborative actions.


Recent progress, perspectives, and issues of engineered PD-L1 regulation nano-system to better cure tumor: A review.
Currently, immune checkpoint blockade (ICB) therapies that target the programmed cell death ligand-1 (PD-L1) have been used as revolutionary cancer treatments in the clinic. Apart from restoring the antitumor response of cytotoxic T cells by blocking the interaction between PD-L1 on tumor cells and programmed cell death-1 (PD-1) on T cells, PD-L1 proteins were also newly revealed to possess the capacity to accelerate DNA damage repair (DDR) and enhance tumor growth through multiple mechanisms, leading to the impaired efficacy of tumor therapies. Nevertheless, current free anti-PD-1/PD-L1 therapy still suffered from poor therapeutic outcomes in most solid tumors due to the non-selective tumor accumulation, ineludible severe cytotoxic effects, as well as the common occurrence of immune resistance. Recently, nanoparticles with efficient tumor-targeting capacity, tumor-responsive prosperity, and versatility for combination therapy were identified as new avenues for PD-L1 targeting cancer immunotherapies. In this review, we first summarized the multiple functions of PD-L1 protein in promoting tumor growth, accelerating DDR, as well as depressing immunotherapy efficacy. Following this, the effects and mechanisms of current clinically widespread tumor therapies on tumor PD-L1 expression were discussed. Then, we reviewed the recent advances in nanoparticles for anti-PD-L1 therapy via using PD-L1 antibodies, small interfering RNA (siRNA), microRNA (miRNA), clustered, regularly interspaced, short palindromic repeats (CRISPR), peptide, and small molecular drugs. At last, we discussed the challenges and perspectives to promote the clinical application of nanoparticles-based PD-L1-targeting therapy.


Variation of class I HLA antigen expression among platelet density cohorts: a possible index of platelet age?
Platelet alloantigens and other surface markers were studied in platelet cohorts of different mean density, using monoclonal and polyclonal probes. High density (HD) platelets expressed 12% more P1A1 molecules (46,942) than low density (LD) platelets (41,892). However, LD platelets carried 42% more HLA-A2 molecules (6,267 +/- 184) than HD platelets (4,406 +/- 232) (P less than .01) and 55% more class I HLA antigens (17,034 +/- 2,062 v 11,007 +/- 2,190) (P = .05). The platelet subpopulations did not differ in their content of glycoprotein (GP)IIb/IIIa complex or Baka antigen. The difference in expression of class I HLA antigens on HD and LD platelets is consistent with two possibilities: either class I HLA molecules are acquired from plasma or they are released into plasma as platelets age in circulation. Accordingly, class I HLA molecules may provide a useful marker of platelet age.


Interplay between mast cells and lymphatic vessels in different molecular types of breast cancer.
The particularities of lymphangiogenesis in different molecular types of breast cancer are virtually unknown and the contribution of microenvironment to this process has been ever less investigated. In the present study, we evaluated the relationships between lymphatic microvessel density (LMVD), mast cell density (MCD) and the different molecular subtypes of breast cancer. Molecular classification of breast tumors by immunohistochemistry was followed by the detection of mast cells and lymphatic vessels on the same slide by immunohistochemical double-stain method, using the lymphatic endothelial cell marker D2-40 and the mast cell tryptase. Mast cells and lymphatic vessels were simultaneously counted in the tumoral and peritumoral areas and results were compared with the molecular type, grade, lymphovascular invasion and lymph node status. Significant positive correlations were found between peritumoral MCD and LMVD for the luminal type-A breast cancers (p=0.025) and also for basal-like carcinomas (p=0.029). Moreover, a significant positive correlation was found between peritumoral and intratumoral MCD for basal-like carcinomas (p=0.009) and for overall MCD and LMVD. Low or inverse correlations between MCD and LMVD were also observed in other molecular subtypes of breast cancer. Our results strongly support that mast cells in the tumor microenvironment are keyplayers, involved in the development of tumor lymphatic vessels for some molecular subtypes of breast cancer.


Effects of dihydropyridine calcium channel modulators on cardiac sodium channels.
To investigate whether cardiac sodium channels have dihydropyridine (DHP) receptors we studied the effects of the optically pure (greater than 95%) enantiomers of the DHPs PN200-110 and BAY-K 8644 and the racemic DHP nitrendipine (NTD). Whole cell and single-channel sodium currents were recorded from cultured ventricular cells of neonatal rats using the patch-clamp method. NTD reduced cardiac sodium currents in a voltage-dependent manner. Inhibitory effects were due to an increase in traces without activity. The unit conductance remained unchanged. At negative holding potentials, NTD transiently increased the probability of channel opening. Both (+) and (-) PN 200-110 blocked sodium channels, although the (-) isomer was about one order of magnitude less effective. The blocking effects were voltage dependent. (+) BAY-K 8644 had similar blocking effects. (-) BAY-K 8644 produced an increase in sodium currents due to an increased frequency of channel openings and a marked prolongation of open time without any significant change in unit conductance. The DHPs have effects on cardiac sodium whole cell and single-channel currents that appear identical to and are as stereospecific as their effects on cardiac calcium currents, although the concentrations required are larger. In contrast the inwardly rectifying potassium channel (IK1) is unaffected by these DHPs. We conclude that functionally equivalent DHP receptors are present in cardiac sodium and calcium channels but not potassium channels and take this as evidence of the homology between sodium and calcium channels.


Diterpene alkaloids from the roots of Aconitum moldavicum and assessment of Nav 1.2 sodium channel activity of aconitum alkaloids.
A new aconitane alkaloid, 1-O-demethylswatinine (1), was isolated from the root of Aconitum moldavicum together with the known compounds cammaconine (2), columbianine (3), swatinine (4), gigactonine (5), delcosine (6), lycoctonine (7), and ajacine (8). The structures were established by means of HRESIMS, 1D and 2D NMR spectroscopy, including 1H-1H COSY, NOESY, HSQC, and HMBC experiments, resulting in complete 1H-NMR chemical shift assignments for 1-4. The effects of the isolated compounds 4-8, together with eighteen other Aconitum diterpene and norditerpene alkaloids with different skeletal types and substitution patterns, were studied on Nav 1.2 channels by the whole-cell patch clamp technique, using the QPatch-16 automated patch clamp system. Pyroaconitine, ajacine, septentriodine, and delectinine demonstrated significant Nav 1.2 channel inhibition (57-42 %) at 10 µM concentration; several other compounds (acovulparine, acotoxicine, hetisinone, 14-benzoylaconine-8-O-palmitate, aconitine, and lycoctonine) exerted moderate inhibitory activity (30-22 %), while the rest of the tested alkaloids were considered to be inactive. On the basis of these results and by exhaustive comparison of data of previously published computerized QSAR studies on diterpene alkaloids, certain conclusions on the structure-activity relationships of Aconitum alkaloids concerning Nav 1.2 channel inhibitory activity are proposed.


Exploring the Concept of Healing Spaces.
Evidence-based design (EBD) research has demonstrated the power of environmental design to support improved patient, family, and staff outcomes and to minimize or avoid harm in healthcare settings. While healthcare has primarily focused on fixing the body, there is a growing recognition that our healthcare system could do more by promoting overall wellness, and this requires expanding the focus to healing. This article explores how we can extend what we know from EBD about health impacts of spatial design to the more elusive goal of healing. By breaking the concept of healing into antecedent components (emotional, psychological, social, behavioral, and functional), this review of the literature presents the existing evidence to identify how healthcare spaces can foster healing. The environmental variables found to directly affect or facilitate one or more dimension of healing were organized into six groups of variables-homelike environment, access to views and nature, light, noise control, barrier-free environment, and room layout. While there is limited scientific research confirming design solutions for creating healing spaces, the literature search revealed relationships that provide a basis for a draft definition. Healing spaces evoke a sense of cohesion of the mind, body, and spirit. They support healing intention and foster healing relationships.


Molecular characterization and in vitro differentiation of feline progenitor-like amniotic epithelial cells.
While amniotic mesenchymal cells have been isolated and characterized in different species, amniotic epithelial cells (AECs) have been found only in humans and horses and are recently considered valid candidates in regenerative medicine. The aim of this work is to obtain and characterize, for the first time in the feline species, presumptive stem cells from the epithelial portion of the amnion (AECs) to be used for clinical applications. In our study, we molecularly characterized and induced in vitro differentiation of feline AECs, obtained after enzymatic digestion of amnion. AECs displayed a polygonal morphology and the mean doubling time value was 1.94 ± 0.04 days demonstrating the high proliferating capacity of these cells. By RT-PCR, AECs expressed pluripotent (Oct4, Nanog) and some mesenchymal markers (CD166, CD44) suggesting that an epithelial-mesenchymal transition may occur in these cells that lack the hematopoietic marker CD34. Cells also showed the expression of embryonic marker SSEA-4, but not SSEA-3, as demonstrated by immunocytochemistry and flow cytometry. Moreover, the possibility to use feline AECs in cell therapies resides in their low immunogenicity, due to the absence of MHC-II antigen expression. After induction, AECs differentiated into the mesodermic and ectodermic lineages, demonstrating high plasticity. In conclusion, feline AECs appear to be a readily obtainable, highly proliferative, multipotent and non-immunogenic cell line from a source that may represent a good model system for stem cell biology and be useful in allogenic cell-based therapies in order to treat tissue lesions, especially with loss of substance.


C60-SIMS imaging of nanoparticles within mammalian cells.
To achieve successful drug delivery via nanoparticles the interactions between the nanoparticle and the chemistry of the surrounding biological environment is of central importance. A thorough understanding of these interactions is necessary in order to better elucidate information regarding drug pathways and mechanisms of action in treatment protocols. As such, it is important to identify the location of the nanoparticle, the state of its functionalization, as well as any changes in the cellular environment. The use of cluster secondary ion mass spectrometry (SIMS) using C60 (+) primary ions makes simultaneous acquisition of this information possible. Here, SIMS has been successfully used to chemically image gold nanoparticles (AuNPs) within a model, single cell system involving macrophage-like RAW 264.7 cells. The macrophage-like properties of this cell line make it extremely well-suited for cell-uptake studies. Both AuNPs and two pharmaceutical compounds, amiodarone and elacridar, were successfully imaged within a cellular system using cluster SIMS. To verify that SIMS can also be used to detect functionalization and nanoparticles simultaneously, fluorophore-functionalized AuNPs were studied as a model system. The fluorescent characteristics of these functionalized nanoparticles enabled the visual confirmation of the presence and location of the particles within the cell.


Learning to manage vasoactive drugs-A qualitative interview study with critical care nurses.
Being a nurse in an intensive care unit entails caring for seriously ill patients. Vasoactive drugs are one of the tools that are used to restore adequate circulation. Critical care nurses often manage and administer these potent drugs after medical advice from physicians. To describe the experiences of critical care nurses learning to manage vasoactive drugs, and to highlight the competence required to manage vasoactive drugs. Twelve critical care nurses from three hospitals in Sweden were interviewed. Qualitative content analysis was applied. The theme "becoming proficient requires accuracy, practice and precaution" illustrated how critical care nurses learn to manage vasoactive drugs. Learning included developing cognitive, psychomotor, and effective skills. Sources for knowledge refers to specialist education combined with practical exercises, collegial support, and accessible routine documents. The competence required to manage vasoactive drugs encompassed well-developed safety thinking that included being careful, in control, and communicating failures. Specific skills were required such as titrating doses, being able to analyse and evaluate the technological assessments, adapting to the situation, and staying calm. Learning to manage vasoactive drugs requires a supportive introduction for novices, collegial support, lifelong learning, and a culture of safety.


Epstein-Barr virus induces normal B cell responses but defective suppressor T cell responses in patients with systemic lupus erythematosus.
Epstein-Barr virus (EBV) is a polyclonal B cell activator, independent of helper T cells, which induces the generation of suppressor T cells in vivo and in vitro. Given the complexity of the immunologic abnormalities in patients with systemic lupus erythematosus (SLE), we used EBV as a tool to examine the following questions: a). Are SLE B cells primarily defective? and b). Does EBV stimulate the generation of suppressor activity from SLE T cells? It was found that B cells from SLE patients infected with EBV in vitro generate plaque-forming cell (PFC) responses that are similar to those raised by normal B cells infected with EBV within the first 14 days of culture. T cells from SLE patients, in contrast to T cells from normal individuals, cultured with autologous B cells plus EBV fail to develop the expected normal decrement of PFC during the late phase of the in vitro culture (day 14). However, B cells from SLE patients are susceptible to suppression as mixed cultures of SLE B cells and normal allogeneic T cells showed a pattern of PFC response to EBV similar to that of the co-culture of normal B cells with normal T cells. T cells from SLE patients, in analogous mixed cell cultures, failed to suppress either normal B cells or allogeneic SLE B cells. The above experiments indicate that the B cells are not intrinsically defective in SLE patients; rather, a specific T cell abnormality contributes to the lack of normal immunoregulation of certain B cell responses in SLE.


Race and ethnicity in the COVID-19 Critical Care Consortium: demographics, treatments, and outcomes, an international observational registry study.
Improving access to healthcare for ethnic minorities is a public health priority in many countries, yet little is known about how to incorporate information on race, ethnicity, and related social determinants of health into large international studies. Most studies of differences in treatments and outcomes of COVID-19 associated with race and ethnicity are from single cities or countries. We present the breadth of race and ethnicity reported for patients in the COVID-19 Critical Care Consortium, an international observational cohort study from 380 sites across 32 countries. Patients from the United States, Australia, and South Africa were the focus of an analysis of treatments and in-hospital mortality stratified by race and ethnicity. Inclusion criteria were admission to intensive care for acute COVID-19 between January 14th, 2020, and February 15, 2022. Measurements included demographics, comorbidities, disease severity scores, treatments for organ failure, and in-hospital mortality. Seven thousand three hundred ninety-four adults met the inclusion criteria. There was a wide variety of race and ethnicity designations. In the US, American Indian or Alaska Natives frequently received dialysis and mechanical ventilation and had the highest mortality. In Australia, organ failure scores were highest for Aboriginal/First Nations persons. The South Africa cohort ethnicities were predominantly Black African (50%) and Coloured* (28%). All patients in the South Africa cohort required mechanical ventilation. Mortality was highest for South Africa (68%), lowest for Australia (15%), and 30% in the US. Disease severity was higher for Indigenous ethnicity groups in the US and Australia than for other ethnicities. Race and ethnicity groups with longstanding healthcare disparities were found to have high acuity from COVID-19 and high mortality. Because there is no global system of race and ethnicity classification, researchers designing case report forms for international studies should consider including related information, such as socioeconomic status or migration background. *Note: "Coloured" is an official, contemporary government census category of South Africa and is a term of self-identification of race and ethnicity of many citizens of South Africa.


[Intra-operative complications and causes of conversion during aortofemoral reconstruction through mini-laparotomy].
Results of 269 reconstructive operations on infrarenal aorta (among them 30 - for aneurysms) applied using mini-laparotomy (abdominal midsection 5-10 cm) were analyzed. Complexities during the operation occurred in 12,6% of patients; among them complications were observed in 4.8%. In 7.1% of cases it resulted in conversion of access. With accumulation of experience frequency of complications decreased from 6.1 to 3.8% (p=0,616) and frequency of conversions - from 12.2 to 3.2% (p=0.017). Comparison with group of 162 patients operated using standard laparotomy showed that despite rather more frequent complexities with infrarenal aorta reconstruction from mini-access (12.6% against 9.4%, p=0.505) amount of complications didn't differ significantly (4.8% and 5.6% respectively, p=0.930). Authors consider abdominal aorta reconstruction from mini-access to be a safe operation.


Association Between Patterns of Alcohol Use and Short-Term Risk of Suicide Attempt Among Patients With and Without Reported Suicidal Ideation.
To evaluate the association between patterns of alcohol use and short-term risk of suicide attempt among patients with and without reported suicidal ideation. Kaiser Permanente Washington electronic health record data were used to identify mental health visits (1/1/2010-6/30/2015) with documented assessments for unhealthy alcohol use (AUDIT-C) and suicidal ideation (PHQ-9 ninth question). Logistic regression fit using generalized estimating equations were used to conduct visit-level analyses, accounting for correlation between individuals' assessments. Separate models evaluated the association between (1) level of alcohol consumption and (2) frequency of heavy episodic drinking (HED), in combination with suicidal ideation (any vs none), with suicide attempt within 90 days following each visit. Primary models adjusted for age, gender, race/ethnicity and visit year. Of 59,705 visits (43,706 unique patients), 372 (0.62%) were followed by a suicide attempt within 90 days. The risk of suicide attempt was significantly higher for patients reporting suicidal ideation across all levels of alcohol consumption compared to patients reporting low-level alcohol use and no suicidal ideation, particularly high-level use (OR 9.77, 95% CI, 6.23-15.34). Similarly, risk of suicide attempt was higher for patients reporting suicidal ideation across all levels of HED relative to those reporting no HED or suicidal ideation, particularly HED monthly or more (OR 6.80, 95% CI 4.77-9.72). Among patients reporting no suicidal ideation, no associations were observed. Findings underscore the potential value of offering alcohol-related care to patient reporting suicidal ideation. Additional strategies are needed to identify suicide risk among those reporting no suicidal ideation.


A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA.
To describe a large, multicenter prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the use of such a study in investigating the natural history of RA development. A total of 1,058 FDRs, none of whom met the American College of Rheumatology criteria for RA, were enrolled in a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit were described for these FDRs, and the relationship was examined between genetic factors, autoantibodies, inflammation, and joint disease. Fifty-five percent of the FDRs had > or =1 copy of the shared epitope, 20% had > or =1 copy of the PTPN22 polymorphism, and approximately 16% were positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic citrullinated peptide antibody. IgM-RF positivity is associated with > or =1 tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% CI] 1.27-4.89; P < 0.01) and elevated C-reactive protein (CRP) levels (OR 5.31, 95% CI 1.45-19.52; P = 0.01). FDRs without RA demonstrate high prevalences of genetic risk factors and RA-related autoantibodies. Additionally, an RF association with tender joints and elevated CRP levels suggests that autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic and epidemiologic factors and the development of RA-related autoimmunity.


[Total aortic arch replacement for severe atherosclerotic aortic aneurysms;consecutive 135 cases study].
We study the validity of surgical procedure for total aortic arch replacement according to the atherosclerosis in the aortic arch. From 2007 to June 2013, Consecutive 185 patients underwent total aortic arch replacement for thoracic aortic anuerysm. We studied 135 patients[96 males 72.1 year(38~89year)]except emergency operation. We assessed the atherosclerosis in the aortic arch by preoperative enhanced computed tomography (CT)scan and intraoperative epiaortic echocardiography. Based on the degree of atherosclerosis in the aortic arch, we divided into 2 groups:group 1(G1)included 97 patients with mild or moderate atherosclerosis and group 2 (G2) 38 patients with severe atherosclerosis. We used ascending aorta as arterial cannulation site in G1 and axillary artery with 8 mm graft in G2 .We compared with both groups for preoperative comorbidities and outcomes( mortality and stroke). Three patients died in the hospital (2%). In-hospital neurological events occurred in 12 patients, including major stroke in 4 patients, minor stroke in 4 patients and asymptomatic convulsion in 4 patients, although they were transient and clear before discharge except major stroke. There were no statistically significant differences in preoperative characteristics, cardiopulmonary bypass, brain protection, mortality, and neurological events between the 2 groups. There was a statistically difference in operation time( 388.8 minutes vs 448.5 minutes, p<0.01), intensive care unit( ICU) stay( 3.1 day vs 6.5 days, p<0.05) and hospital stay( 19.2 days vs 28.0 days, p<0.05). We selected surgical procedure for total aortic arch replacement (TAR) according to atherosclerosis in the aortic arch. Although the rate of stroke was largely acceptable, we much need to be improved in prevention of stroke.


The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications.
The re-emergence (i.e. 'breakthrough') of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre-clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non-adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid-cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub-threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long-term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients.


[Münchausen syndrome by proxy].
Münchausen syndrome by proxy (also known as factitious disorder by proxy) is a psychiatric disorder which consists of fabricating or inducing illness in a child, usually by his mother. The motivation for the perpetrator's behavior is receivng satisfaction from the investigations and treatments that the child receives and from the medical environment, as part of a unique mental disturbance. External incentives for the behavior (such as economic gain) are absent. During the last few years about 20 cases of Münchausen syndrome by proxy were diagnosed in our ward. We describe a few less typical cases of patients with Münchausen syndrome by proxy. In all cases the offender, the mother, had only secondary education and no medical background. The socioeconomic background was variable. Recognition of the syndrome and a high index of clinical suspicion are needed in order to diagnose the disorder. Suspicious signs and symptoms include prolonged and illogical course of disease, odd complications, exacerbation that appear just before discharge from the hospital and symptoms that occur only in the presence of a specific care giver. Münchausen syndrome by proxy is not very rare. It appears in all ethnic groups, socioeconomic status and educational backgrounds.


On some necessary and sufficient conditions for a recurrent neural network model with time delays to generate oscillations.
In this paper, the existence of oscillations for a class of recurrent neural networks with time delays between neural interconnections is investigated. By using the fixed point theory and Liapunov functional, we prove that a recurrent neural network might have a unique equilibrium point which is unstable. This particular type of instability, combined with the boundedness of the solutions of the system, will force the network to generate a permanent oscillation. Some necessary and sufficient conditions for these oscillations are obtained. Simple and practical criteria for fixing the range of parameters in this network are also derived. Typical simulation examples are presented.


Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction.
Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case-control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68-6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13-71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05-5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26-3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.


Smoking-related attitudes and clinical practices of medical personnel in Minnesota.
Effective clinic-based, smoking-cessation activities are not widely implemented. To compare and contrast the smoking-cessation attitudes and clinical practices of five types of primary healthcare team members. From July to October 2002, a cross-sectional survey was mailed to randomly selected primary care physicians (MDs), advanced practice nurses (APRNs), registered nurses (RNs), licensed practical nurses (LPNs), and medical assistants (MAs). Factors associated with limited smoking-cessation service delivery. The overall response rate was 68% (n =3021). Most respondents reported that patients' smoking status was consistently documented at their clinic (79%); other system prompts were less common (30%). Many respondents reported documenting smoking status or recommending quitting; few reported consistently assessing, assisting, or arranging follow-up. The mean rank of smoking cessation as an important preventive service among nine preventive services declined from MDs (1.9) to APRNs (2.5), RNs (3.4), LPNs (4.2), and MAs (4.6). Smoking prevalence increased from 1% in MDs to 3% APRNs, 9% RNs, 17% LPNs, and 22% MAs. Those who reported no consistent smoking-cessation service delivery were more likely to be RNs, LPNs, or MAs, currently smoke, and work more hours. They were less likely to consider patients receptive to cessation messages, to consider themselves qualified to counsel on smoking, or to work in clinics that had smoking-cessation guidelines or system prompts such as chart reminders. Smoking-cessation service delivery may be enhanced if educational offerings, system changes, and training include all clinical staff members.


Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation.
The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for <20 years, 1.2 for >40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.


Salinomycin in cancer: A new mission for an old agent.
Salinomycin is a monocarboxylic polyether ionophore isolated from Streptomyces albus that has been used for more than 30 years as an agricultural antibiotic to prevent coccidiosis in poultry and to improve nutrient absorption and feed efficiency in ruminants and swine. As a inonophore with strict selectivety for alkali ions and a strong preference for potassium, salinomycin interferes with transmembrane potassium potential and promotes the efflux of K+ ions from mitochondria and cytoplasm. Salinomycin has recently been shown to kill human cancer stem cells and to inhibit breast cancer growth and metastasis in mice. Salinomycin is also able to induce massive apoptosis in human cancer cells of different origins that display multiple mechanisms of drug and apoptosis resistance. Salinomycin activates an unconventional pathway of apoptosis in human cancer cells that may contribute to the breakdown of apoptosis resistance. The ability of salinomycin to effectively kill both cancer stem cells and apoptosis-resistant cancer cells may define the compound as a novel and effective anticancer agent.


Gaucher's disease: a clinical, morphological and biochemical study of a Nigerian family.
Two Nigerian sibling presented with progressive hepato-splenomegaly in infancy from which they subsequently died. Morphological investigations carried out showed that the children had Gaucher's disease. Leucocyte B-glucocerebrosidase activities from the parents of the two siblings and also from one surviving sibling were found to be only about 50% of the enzyme activities in control subjects while hexosaminidase and B-glucuronidase activities were within normal limits. There results showed that the three surviving relatives are heterozygotes and also provided a strong supporting evidence that the deceased children had Gaucher's disease. The occurence of this disease in African children living in Kenya, Uganda, the Congo and Nigeria, and in Black Americans suggest that this biochemical abnormality is not as rare in the Negroid race as has been believed hitherto, and may be widespread on the African continent.


Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic.
Diallyl sulfide (DAS) is a flavor compound derived from garlic and is sequentially converted to diallyl sulfoxide (DASO) and diallyl sulfone (DASO(2)) by cytochrome P(450) 2E1 (CYP2E1). These compounds have been shown to reduce the incidence of a multitude of chemically induced tumors in animal models. The impediment of phase I activation of these carcinogens is hypothesized to be accountable for the reduction in tumor incidence. Indeed, DAS, DASO and DASO(2) are competitive inhibitors of CYP2E1. DASO(2), in addition, is a suicide inhibitor of CYP2E1. These compounds have been shown to reduce carbon tetrachloride-, N-nitrosodimethylamine- and acetaminophen-induced toxicity in rodents. All three chemicals are substrates for CYP2E1. The protective effect was observed when the organosulfur compounds were given before, during or soon after chemical treatment. DAS and DASO(2) inhibited the bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and related lung tumorigenesis in A/J mice. Because CYP2E1 does not play a key role in NNK activation, the inhibition of other CYP enzymes active in NNK metabolism is likely. DAS also has been shown to induce other CYP and phase II enzymes as well as decrease hepatic catalase activity. All of these effects are observed at concentrations much higher than what is normally ingested by humans. The biological activities of garlic and its related compounds at lower concentrations that mimic human consumption remain to be studied further.


Making Clinical Practice Guidelines Pragmatic: How Big Data and Real World Evidence Can Close the Gap.
Clinical practice guidelines (CPGs) have become ubiquitous in every field of medicine today but there has been limited success in implementation and improvement in health outcomes. Guidelines are largely based on the results of traditional randomised controlled trials (RCTs) which adopt a highly selective process to maximise the intervention's chance of demonstrating efficacy thus having high internal validity but lacking external validity. Therefore, guidelines based on these RCTs often suffer from a gap between trial efficacy and real world effectiveness and is one of the common reasons contributing to poor guideline adherence by physicians. "Real World Evidence" (RWE) can complement RCTs in CPG development. RWE-in the form of data from integrated electronic health records-represents the vast and varied collective experience of frontline doctors and patients. RWE has the potential to fill the gap in current guidelines by balancing information about whether a test or treatment works (efficacy) with data on how it works in real world practice (effectiveness). RWE can also advance the agenda of precision medicine in everyday practice by engaging frontline stakeholders in pragmatic biomarker studies. This will enable guideline developers to more precisely determine not only whether a clinical test or treatment is recommended, but for whom and when. Singapore is well positioned to ride the big data and RWE wave as we have the advantages of high digital interconnectivity, an integrated National Electronic Health Record (NEHR), and governmental support in the form of the Smart Nation initiative.


Expression of Hedgehog ligand and signal transduction components in mutually distinct isocitrate dehydrogenase mutant glioma cells supports a role for paracrine signaling.
Hedgehog (Hh) signaling regulates the growth of malignant gliomas by a ligand-dependent mechanism. The cellular source of Sonic Hh ligand and mode of signaling have not been clearly defined due to the lack of methods to definitively identify neoplastic cells in glioma specimens. Using an antibody specific for mutant isocitrate dehydrogenase protein expression to identify glioma cells, we demonstrate that Sonic Hh ligand and the pathway components Patched1 (PTCH1) and GLI1 are expressed in neoplastic cells. Further, Sonic Hh ligand and its transcriptional targets, PTCH1 and GLI1, are expressed in mutually distinct populations of neoplastic cells. These findings support a paracrine mode of intratumoral Hh signaling in malignant gliomas.


[Physicochemical properties of the Newcastle group bacteriophages].
Physico-chemical properties of dysentery therapeutic-prophylactic Newcastle phages H-I, H-5, H-10, H-22 were studied. The morphology of the phage particles is described; their molecular weight and buoyant density in CsCl were determined by ultracentrifugation. The type of nucleic acids (DNA) was determined. By all the above characteristics and their chemical composition, bacteriophages of the Newcastle group approach T-even phages.


Diabetes and the prostate.
Here we discuss the interactions between prostatic health and diabetes. Diabetes may be associated with changes in prostatic anatomy, physiology, clinical morbidity, and clinical outcomes. Certain glucose-lowering drugs may impact prostatic health, and some prostato-tropic medications can influence glycaemic control. One should be vigilant for symptoms and signs of prostate health in diabetes.


Sequencing and de novo assembly of the Asian clam (Corbicula fluminea) transcriptome using the Illumina GAIIx method.
The Asian clam (Corbicula fluminea) is currently one of the most economically important aquatic species in China and has been used as a test organism in many environmental studies. However, the lack of genomic resources, such as sequenced genome, expressed sequence tags (ESTs) and transcriptome sequences has hindered the research on C. fluminea. Recent advances in large-scale RNA-Seq enable generation of genomic resources in a short time, and provide large expression datasets for functional genomic analysis. We used a next-generation high-throughput DNA sequencing technique with an Illumina GAIIx method to analyze the transcriptome from the whole bodies of C. fluminea. More than 62,250,336 high-quality reads were generated based on the raw data, and 134,684 unigenes with a mean length of 791 bp were assembled using the Velvet and Oases software. All of the assembly unigenes were annotated by running BLASTx and BLASTn similarity searches on the Nt, Nr, Swiss-Prot, COG and KEGG databases. In addition, the Clusters of Orthologous Groups (COGs), Gene Ontology (GO) terms and Kyoto Encyclopedia of Gene and Genome (KEGG) annotations were also assigned to each unigene transcript. To provide a preliminary verification of the assembly and annotation results, and search for potential environmental pollution biomarkers, 15 functional genes (five antioxidase genes, two cytochrome P450 genes, three GABA receptor-related genes and five heat shock protein genes) were cloned and identified. Expressions of the 15 selected genes following fluoxetine exposure confirmed that the genes are indeed linked to environmental stress. The C. fluminea transcriptome advances the underlying molecular understanding of this freshwater clam, provides a basis for further exploration of C. fluminea as an environmental test organism and promotes further studies on other bivalve organisms.


dsRNA uptake and persistence account for tissue-dependent susceptibility to RNA interference in the migratory locust, Locusta migratoria.
RNA interference (RNAi) by introducing double-stranded RNA (dsRNA) is a powerful approach to the analysis of gene function in insects; however, RNAi responses vary dramatically in different insect species and tissues, and the underlying mechanisms remain poorly understood. The migratory locust, a destructive insect pest and a hemimetabolic insect with panoistic ovaries, is considered to be a highly susceptible species to RNAi via dsRNA injection, but its ovary appears to be completely insensitive. In the present study, we showed that dsRNA persisted only briefly in locust haemolymph. The ovariole sheath was permeable to dsRNA, but injected dsRNA was not present in the follicle cells and oocytes. The lack of dsRNA uptake into the follicle cells and oocytes is likely to be the primary factor that contributes to the ineffective RNAi response in locust ovaries. These observations provide insights into tissue-dependent variability of RNAi and help in achieving successful gene silencing in insensitive tissues.


Sex-ratio optimization with helpers at the nest.
In many cooperatively breeding animals, offspring produced earlier in life assist their parents in raising subsequent broods. Such helping behaviour is often confined to offspring of one sex. Sex-allocation theory predicts that parents overproduce offspring of the helping sex, but the expected degree of sex-ratio bias was thought to depend on specific details of female and male life histories, hampering empirical tests of the theory. Here we demonstrate the following two theories. (i) If all parents produce the same sex ratio, the evolutionarily stable sex ratio obeys a very simple rule that is valid for a general class of life histories. The rule predicts that the expected sex-ratio bias depends on the product of only two parameters which are relatively easily measured: the average number of helping offspring per nest and the relative contribution to offspring production per helper. (ii) If the benefit of helping varies between parents, and parents facultatively adjust the sex ratio accordingly, then the population sex ratio is not necessarily biased towards the helping sex. For example, in line with empirical evidence, if helpers are produced under favourable conditions and parents do not adjust their clutch size to the number of helpers, then a surplus of the non-helping sex is expected.


The role of diffusible molecules in regulating the cellular differentiation of Dictyostelium discoideum.
A central problem in developmental biology is to understand how morphogenetic fields are created and how they act to direct regionalized cellular differentiation. This goal is being pursued in organisms as diverse as moulds, worms, flies, frogs and mice. Each organism has evolved its own solution to the challenge of multicellularity but there appear to be common underlying principles and, once pattern formation is fully understood in any system, some general truths seem certain to be revealed. As a non-obligate metazoan, Dictyostelium discoideum has proven a particularly tractable system in which to identify and characterize cellular morphogens. Cyclic AMP and ammonia stimulate prespore cell differentiation and ammonia plays an additional role in repressing terminal cellular differentiation. Differentiation Inducing Factor (DIF) acts to direct prestalk cell differentiation and adenosine may play a synergistic role in repressing prespore cell differentiation. This review summarizes the evidence for these interactions and describes a number of models which show how this small repertoire of diffusible molecules, acting in concert, may direct the formation of a differentiated structure.


Diabetic patients with severe sepsis admitted to intensive care unit do not fare worse than non-diabetic patients: a nationwide population-based cohort study.
We sought to examine whether type 2 diabetes increases the risk of acute organ dysfunction and of hospital mortality following severe sepsis that requires admission to an intensive care unit (ICU). Nationwide population-based retrospective cohort study of 16,497 subjects with severe sepsis who had been admitted for the first time to an ICU during the period of 1998-2008. A diabetic cohort (n = 4573) and a non-diabetic cohort (n = 11924) were then created. Relative risk (RR) of organ dysfunctions, length of hospital stay (LOS), 90-days hospital mortality, ICU resource utilization and hazard ratio (HR) of mortality adjusted for age, gender, Charlson-Deyo comorbidity index score, surgical condition and number of acute organ dysfunction, were compared across patients with severe sepsis with or without diabetes. Diabetic patients with sepsis had a higher risk of developing acute kidney injury (RR, 1.54; 95% confidence interval (CI), 1.44-1.63) and were more likely to be undergoing hemodialysis (15.55% vs. 7.24%) in the ICU. However, the diabetic cohort had a lower risk of developing acute respiratory dysfunction (RR = 0.96, 0.94-0.97), hematological dysfunction (RR = 0.70, 0.56-0.89), and hepatic dysfunction (RR = 0.77, 0.63-0.93). In terms of adjusted HR for 90-days hospital mortality, the diabetic patients with severe sepsis did not fare significantly worse when afflicted with cardiovascular, respiratory, hepatic, renal and/or neurologic organ dysfunction and by numbers of organ dysfunction. There was no statistically significant difference in LOS between the two cohorts (median 17 vs. 16 days, interquartile range (IQR) 8-30 days, p = 0.11). Multiple logistic regression analysis to predict the occurrence of mortality shows that being diabetic was not a predictive factor with an odds ratio of 0.972, 95% CI 0.890-1.061, p = 0.5203. This large nationwide population-based cohort study suggests that diabetic patients do not fare worse than non-diabetic patients when suffering from severe sepsis that requires ICU admission.


Hypochondriasis: difficulties in diagnosis and management.
The hypochondriacal patient presents numerous frustrations for the physician. The typical hypochondriac is a middle-aged person dominated by a preoccupation with bodily symptoms. Bereavement, serious life failures, and severe blows to self-esteem put patients at high risk for somatization. Hypochondrisis has been cited as a symptom of masked depression, early paranoid schizophrenia, and dementia and/or delirium. A careful diagnostic work-up with attention to any correctable psychiatric illness sets the stage for regularly scheduled, long-term supportive therapy.


Lupinus mutabilis Edible Beans Protect against Bacterial Infection in Uroepithelial Cells.
Lupinus mutabilis is a South American herb with edible beans, known to reduce serum glucose levels in diabetic patients. Furthermore, L. mutabilis contains phytochemicals known to decrease bacterial load. Based on the increased urinary tract infections experienced among patients with diabetes, we investigated the effect of L. mutabilis on bladder epithelial cells in the protection of E. coli infection during normal and high glucose concentrations. We did not observe any direct antibacterial effect by L. mutabilis extract. Instead we observed an influence on the host cells, with indirect impact on bacteria and their possibility of causing infection. L. mutabilis extract decreased adhesion to bladder epithelial cells of uropathogenic bacteria, including drug-resistant strains. Moreover, uroplakin1a, involved in adhesion, was downregulated while the antimicrobial peptide RNase 7 was upregulated in L. mutabilis treated cells irrespectively of glucose concentration. This supports an early effect fighting bacteria. Additionally, L. mutabilis prevented bacterial biofilm formation, which is used by bacteria to evade the immune system and antibiotics. In summary, L. mutabilis protects against bacterial infection in uroepithelial cells by preventing adhesion through alteration of the cell surface, increasing antimicrobial peptide expression, and reducing biofilm formation. Together, this promotes bacterial clearance, suggesting that L. mutabilis as extract or as a dietary item can contribute to the prevention of urinary tract infections, which is of importance in an era of increasing antibiotic resistance.


Treatment of male and female spontaneously hypertensive rats with TNF-α inhibitor etanercept increases markers of renal injury independent of an effect on blood pressure.
Hypertension remains the leading risk factor for cardiovascular disease. Young females tend to be protected from hypertension compared with age-matched males. Although it has become increasingly clear that the immune system plays a key role in the development of hypertension in both sexes, few studies have examined how cytokines mediate hypertension in males versus females. We previously published that there are sex differences in the levels of the cytokine tumor necrosis factor (TNF)-α in spontaneously hypertensive rats (SHR). The goal of this study was to test the hypothesis that TNF-α inhibition with etanercept will lower BP in male and female SHR. However, as male SHR have a more pro-inflammatory status than female SHR, we further hypothesize that males will have a greater decrease in BP with TNF-α inhibition than females. Young adult male and female SHR were administered increasing doses of the TNF-α inhibitor etanercept or vehicle twice weekly for 31 days and BP was continuously measured via telemetry. Following treatment, kidneys and urine were collected and analyzed for markers of inflammation and injury. Despite significantly decreasing renal TNF-α levels, renal phospho-NFκB and urinary MCP-1 excretion, etanercept did not alter BP in either male or female SHR. Interestingly, treatment with etanercept increased urinary excretion of protein, creatinine and KIM-1 in both sexes. These results indicate that TNF-α does not contribute to sex differences in BP in SHR but may be vital in the maintenance of renal health.


Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health.
Glutamine together with glucose is essential for body's homeostasis. It is the most abundant amino acid and is involved in many biosynthetic, regulatory and energy production processes. Several membrane transporters which differ in transport modes, ensure glutamine homeostasis by coordinating its absorption, reabsorption and delivery to tissues. These transporters belong to different protein families, are redundant and ubiquitous. Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature. Function of glutamine transporters is studied in cells over-expressing the transporters or, more recently in proteoliposomes harboring the proteins extracted from animal tissues or over-expressed in microorganisms. The role of the glutamine transporters is linked to their transport modes and coupling with Na(+) and H(+). Most transporters share specificity for other neutral or cationic amino acids. Na(+)-dependent co-transporters efficiently accumulate glutamine while antiporters regulate the pools of glutamine and other amino acids. The most acknowledged glutamine transporters belong to the SLC1, 6, 7, and 38 families. The members involved in the homeostasis are the co-transporters B0AT1 and the SNAT members 1, 2, 3, 5, and 7; the antiporters ASCT2, LAT1 and 2. The last two are associated to the ancillary CD98 protein. Some information on regulation of the glutamine transporters exist, which, however, need to be deepened. No information at all is available on structures, besides some homology models obtained using similar bacterial transporters as templates. Some models of rat and human glutamine transporters highlight very similar structures between the orthologs. Moreover the presence of glycosylation and/or phosphorylation sites located at the extracellular or intracellular faces has been predicted. ASCT2 and LAT1 are over-expressed in several cancers, thus representing potential targets for pharmacological intervention.


Hazardous effects of effluent from the chrome plating industry: 70 kDa heat shock protein expression as a marker of cellular damage in transgenic Drosophila melanogaster (hsp70-lacZ).
Hazardous effects of an effluent from the chrome plating industry were examined by exposing transgenic Drosophila melanogaster (hsp70-lacZ) to various concentrations (0.05, 0.1, 1.0, 10.0, and 100.0 micro L/mL) of the effluent through diet. The emergence pattern of adult flies was affected, along with impaired reproductive performance at the higher dietary concentrations of the effluent. Interestingly, the effect of the effluent was more pronounced in male than in female flies. The effect of the effluent on development of adult flies was concurrent with the expression pattern of the heat shock protein 70 gene (hsp70), both in larval tissues and in the reproductive organs of adult flies. We observed a dose- and time-dependent expression of hsp70 in third instar larvae exposed for different time intervals. Absence of hsp70 expression in larvae exposed to 0.1 micro L/mL of the effluent indicated that this is the highest nontoxic concentration for Drosophila. The stress gene assay in the reproductive organs of adult flies revealed hsp70 expression in the testis of male flies only. However, trypan blue dye exclusion tests in these tissues indicate tissue damage in the male accessory gland of adult flies, which was further confirmed by ultrastructural observations. In the present study we demonstrate the utility of transgenic Drosophila as an alternative animal model for evaluating hazardous effects of the effluent from the chrome plating industry and further reveal the cytoprotective role of hsp70 and its expression as an early marker in environmental risk assessment.


Correlations between plasma levels of opioid peptides and adrenal androgens in prepuberty and puberty.
In 139 prepubertal children and in 38 pubertal adolescents plasma levels of ACTH, cortisol, beta-lipotropin (BLPH), beta-endorphin (BEP) and dehydroepiandrosterone sulphate (DHAS) were determined by specific radioimmunoassays directly (steroids) or after plasma purification (peptides). ACTH and cortisol concentrations remain stable during both prepuberty and puberty, while DHAS levels constantly increased from 5 to 16 years. Both BLPH and BEP increase from early infancy to late prepuberty when they reach adult values. During puberty both opioids remain constantly within the adult range. BLPH and BEP concentrations were significantly correlated to those of DHAS throughout prepuberty. These data suggest a possible role of BLPH and BEP in and/or other proopiocortin-related peptides in the development of adrenarche, while the lack of particular changes in these peptide levels during sexual maturation seems to exclude their role in gonadarche and pubertal development.


[Evolution of vaccine poliovirus strains].
The paper considers different aspects of the molecular evolution of poliovirus vaccine strains: mutational and recombinant variability; mechanisms of fixation of occurring genetic changes. Matters concerning the policy of vaccination of the population against poliomyelitis are covered.


Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?
Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis.


Using stable and unstable profiles to deduce deformation limits of the air-water interface.
The shape of the air-water interface deformed by a van der Waals stress induced by a paraboloid shaped solid body is addressed and discussed. Emphasis is placed on the existence limit of solutions to the governing Euler-Lagrange equation for the equilibrium shape. Two legitimate solutions, one stable and one unstable, are found to converge at the existence limit, giving a numerical criterion for establishing critical physical conditions guaranteeing absolute stability. Insight is aided by a study of an analogous mechanical problem that exhibits very similar properties. Among numerical data produced are critical lower height limits of the paraboloid to the air-water surface and associated peak deformation heights and their dependencies on physical parameters. Of further interest to experimentalists in the surface force field are the variations in peak deformation height and total surface force on the solid as a function of position of the paraboloid, paraboloid geometry, and strength of the van der Waals stress.


Cloning, sequencing, and use as a molecular probe of a gene encoding an aminoglycoside 6'-N-acetyltransferase of broad substrate profile.
A gene coding for an aminoglycoside 6'-N-acetyltransferase that was able to modify amikacin was cloned from a plasmid isolated from a clinical strain of Enterobacter cloacae. Sequencing of a 955-bp segment which mediates the modifying activity revealed a single open reading frame of 432 nucleotides that predicted a polypeptide of 144 amino acid residues with a molecular weight of 16,021. Putative ribosomal binding sites and -10 and -35 sequences were located at the 5' end of the gene. The size of the polypeptide was confirmed through minicell analysis of the expression products of plasmids containing the sequence. The use of the gene as a molecular probe revealed its specificity toward strains harboring genes coding for related enzymes. This probe is therefore useful for epidemiological studies.


Pulling complexes out of complex diseases: Spinocerebellar Ataxia 7.
Spinocerebellar ataxia 7 (SCA7) is an incurable disease caused by expansion of CAG trinucleotide sequences within the Ataxin-7 gene. This elongated CAG tract results in an Ataxin-7 protein bearing an expanded polyglutamine (PolyQ) repeat. SCA7 disease is characterized by progressive neural and retinal degeneration leading to ataxia and blindness. Evidence gathered from investigating SCA7 and other PolyQ diseases strongly suggest that misregulation of gene expression contributes to neurodegeneration. In fact, Ataxin-7 is a subunit of the essential Spt-Ada-Gcn5-Acetltransferase (SAGA) chromatin modifying complex that regulates expression of a large number of genes. Here we discuss recent insights into Ataxin-7 function and, considering these findings, propose a model for how polyglutamine expansion of Ataxin-7 may affect Ataxin-7 function to alter chromatin modifications and gene expression.


[Effect of residential region, and educational and marital status on suicide: census-based negative binomial regression analysis].
Suicidal behaviour is a multicausal phenomenon, accordingly its occurence is determined, in a mutually non-exclusive manner, by several medical, sociodemographic, cultural and lifestyle factors. In the current study we investigated the effects of age, gender, marital and educational statuses and region of residence on the risk of completed suicide. Our raw data came from the census in 2011 and from the Demographic Register of the Hungarian Central Statistical Office. Negative binomial regression analyses were used to reveal the effects of our variables on suicide. We found that the risk of completed suicide varies significantly by gender, age, educational attainment, marital status, and region of residence. Effects of sociodemographic and region of residence variables on suicidal risk were strongly influenced by gender. Suicide risk was elevated for both men and women who are living in the Great Plain and also for women who are living in the region Central Hungary and men who are living in the region Northern Hungary. The thorough clarification of sociodemographic determinants of suicide is essential in the identification of endangered groups and it is the prerequisite of successful prevention as well.


Evaluation of a self-management plan for chronic obstructive pulmonary disease.
We hypothesized that the use of an Action Plan might assist self-management for patients with chronic obstructive pulmonary disease (COPD). A pilot process and randomized, controlled study were undertaken to evaluate an Action Plan that provided advice on management of usual care and exacerbations, together with a booklet on self-management. Fifty six subjects with COPD recruited through general practitioners (GPs) completed the 6 month study, 27 in the control group and 29 in the intervention group. The control group received usual care from their GP, and the intervention group received a booklet and Action Plan from their practice nurse plus a supply of prednisone and antibiotic from their GP. The two groups were demographically similar with a mean age of 68 yrs. The resources were well received by GPs, practice nurses and intervention group subjects. After 6 months, there were no differences in quality of life scores or pulmonary function. There were significant changes in self-management behaviour in the intervention group compared to controls. In response to deteriorating symptoms, 34 versus 7% (p=0.014) initiated prednisone treatment and 44 versus 7% (p=0.002) initiated antibiotics. Subjects in the intervention group readily adopted self-management skills but did not show any difference in quality of life or lung function parameters. A larger, prospective, controlled, clinical trial of this approach is warranted.


Chronic hepatotoxicity and intestinal bleeding in 1,2-dimethylhydrazine carcinogenesis in rats and mice.
The long term administration of dimethylhydrazine to mice induces severe hepatotoxic damage. Parenchymal cell pleomorphism and necrosis were later associated with reticulin collapse and bile duct proliferation. Withdrawing the drug after 17 weeks was followed by some improvement in the parenchymal cells but there was a chronic proliferative response tending towards early cirrhotic changes. The rats appeared relatively resistant to the hepatotoxic effects but unlike the mice the colon tumors arising in these animals bled frequently and could result in profound anemia.


Cholecystokinin potentiates dopamine-mediated behaviors: evidence for modulation specific to a site of coexistence.
Cholecystokinin coexists with dopamine in mesolimbic neurons in mammalian brain. When injected directly into the nucleus accumbens, cholecystokinin (CCK) potentiated dopamine (DA)-induced hyperlocomotion and apomorphine-induced stereotypy. These effects were not mimicked by nonsulfated CCK, but were blocked by proglumide, a putative CCK antagonist, as well as by antisera raised against sulfated CCK. CCK alone had no effect on locomotion or sterotypy, indicating that this peptide acts primarily as a modulator of DA-mediated behaviors in the mesolimbic pathway. In addition, CCK did not potentiate DA-induced hyperlocomotion or apomorphine-induced stereotypy when injected into the caudate nucleus, where CCK and DA are localized in separate neurons in rats. Facilitation of DA-mediated behaviors by CCK may represent a functional interaction specific to the neuromodulator-neurotransmitter coexistence phenomenon.


Prevalence of serum antibodies to Helicobacter pylori VacA and CagA and gastric diseases in Chile.
The objective of this study was to evaluate the prevalence of antibodies to Helicobacter pylori CagA and VacA proteins and correlate this prevalence with gastric diseases in colonised Chileans. The study was performed in 418 adults colonised with H. pylori: 316 with gastroduodenal pathology (152 duodenal ulcer, 14 gastric cancer and 150 gastritis patients) and 102 asymptomatic subjects. Serum IgG antibodies to H. pylori were determined by enzyme immunoassay (EIA). Antibodies to VacA and CagA proteins were detected by Western blotting. In a subgroup of the patients, the vacuolating activity was determined by HeLa cell assay and the CagA product was confirmed by PCR assay. IgG antibodies to both VacA and CagA proteins of H. pylori were found in 270 (85%) of 316 colonised gastric patients and in 72 (71%) of 102 asymptomatic subjects. Colonisation with virulent strains was significantly higher among duodenal ulcer and gastric cancer patients than in gastritis patients or asymptomatic subjects. Infections with VacA+/ CagA+ H. pylori strains is common in Chile but, in contrast to some Asian countries, this phenotype was more prevalent in isolates from patients with more severe gastric pathologies.


Repopulating Kupffer cells originate directly from hematopoietic stem cells.
Kupffer cells (KCs) originate from yolk-sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at a steady state and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adults remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. We first traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate-mapping mouse models, respectively. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC-depletion in mice. Finally, we traced the fate of hematopoietic stem cells (HSCs) in an HSC-specific fate-mapping mouse model, in the context of chronic liver inflammation induced by repeated carbon tetrachloride treatment. By using fate-mapping mouse models, we found no evidence that repopulating KCs originate from preexisting KCs or MOs and found that in response to KC-depletion, HSCs proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Then, in the chronic liver inflammation context, we confirmed that repopulating KCs originated directly from HSCs. Taken together, these findings provided in vivo fate-mapping evidence that repopulating KCs originate directly from HSCs, which presents a completely novel understanding of the cellular origin of repopulating KCs and shedding light on the divergent roles of KCs in liver homeostasis and diseases.


Radiotherapy treatment planning for testicular seminoma.
Virtually all patients with Stage I testicular seminoma are cured regardless of postorchiectomy management. For patients treated with adjuvant radiotherapy, late toxicity is a major concern. However, toxicity may be limited by radiotherapy techniques that minimize radiation exposure of healthy normal tissues. This article is an evidence-based review that provides radiotherapy treatment planning recommendations for testicular seminoma. The minority of Stage I patients who choose adjuvant treatment over surveillance may be considered for (1) para-aortic irradiation to 20 Gy in 10 fractions, or (2) carboplatin chemotherapy consisting of area under the curve, AUC = 7 × 1-2 cycles. Two-dimensional radiotherapy based on bony anatomy is a simple and effective treatment for Stage IIA or IIB testicular seminoma. Centers with expertise in vascular and nodal anatomy may consider use of anteroposterior-posteroanterior fields based on three-dimensional conformal radiotherapy instead. For modified dog-leg fields delivering 20 Gy in 10 fractions, clinical studies support placement of the inferior border at the top of the acetabulum. Clinical and nodal mapping studies support placement of the superior border of all radiotherapy fields at the top of the T12 vertebral body. For Stage IIA and IIB patients, an anteroposterior-posteroanterior boost is then delivered to the adenopathy with a 2-cm margin to the block edge. The boost dose consists of 10 Gy in 5 fractions for Stage IIA and 16 Gy in 8 fractions for Stage IIB. Alternatively, bleomycin, etoposide, and cisplatin chemotherapy for 3 cycles or etoposide and cisplatin chemotherapy for 4 cycles may be delivered to Stage IIA or IIB patients (e.g., if they have a horseshoe kidney, inflammatory bowel disease, or a history of radiotherapy).


Prophylactic progesterone prevents adverse behavioural and neurocognitive effects of neonatal anaesthesia exposure in rat.
Evidence from animal models and human studies suggests an association between early general anaesthesia exposure and development of long-lasting neurocognitive problems including learning and memory impairments and an anxious phenotype. Because millions of children each year undergo procedures that require anaesthesia, it is important to investigate ways to protect the vulnerable developing brain. We evaluated whether progesterone treatment administered before general anaesthesia exposure could prevent long-term anaesthesia-induced neurocognitive and behavioural changes. Female and male Long-Evans rat pups were repeatedly exposed to 2 h of sevoflurane or control procedures at postnatal days 7, 10, and 13. Subcutaneous injections of progesterone or vehicle were administered immediately before general anaesthesia exposure or control procedures. Neurobehavioural and cognitive outcomes were evaluated using elevated plus maze and Morris water maze tests. Prophylactic progesterone treatment attenuated the chemokine (C-X-C motif) ligand 1 (CXCL1) response to sevoflurane exposure. Rats given vehicle treatment with general anaesthesia exposure exhibited increased anxiety on the elevated plus maze and learning and memory impairments on the Morris water maze. However, rats treated with progesterone before general anaesthesia lacked these impairments and performed in a similar manner to controls on both tasks. Progesterone attenuated the anaesthesia-induced, acute peripheral inflammatory response and prevented cognitive and behavioural alterations associated with early repeated general anaesthesia exposure. Importantly, our results suggest that progesterone treatments given before general anaesthesia may help to protect the developing brain.


Method for splitting low power laser beams.
A new method for producing parallel rays from a laser beam using a cylindrical lens and pinholes is presented. This method can produce a greater number of emergent rays than using a beam splitter.


Polymer nanoparticles containing tumor lysates as antigen delivery vehicles for dendritic cell-based antitumor immunotherapy.
Encapsulation of tumor-associated antigens in polymer nanoparticles (NP) is a promising approach to enhance efficiency of antigen delivery for anti-tumor vaccines. Head and neck squamous carcinoma (HNSCC) cell lines were initially used to generate tumor-associated antigens (TAA)-containing poly (lactic-co-glycolic acid) (PLGA) NP; encapsulation efficiency and release kinetics were profiled. Findings were adopted to entrap fresh tumor lysate from five patients with advanced HNSCC. To test the hypothesis that NP enhance antigen presentation, dendritic cell (DC) produced from patient blood monocyte precursors were loaded with either the un-encapsulated or NP-encapsulated versions of tumor lysates. These were used to stimulate freshly-isolated autologous CD8+ T cells. In four of five patients, anti-tumor CD8+ T cells showed significantly increased immunostimulatory IFN-γ (p=0.071) or decreased immmunoinhibitory IL-10 production (p=0.0004) associated with NP-mediated antigen delivery. The observations represent an enabling step in the production of clinically-translatable, inexpensive, highly-efficient, and personalized polymer-based immunotherapy for solid organ malignancies. Enhancing the antigen presentation may be a viable approach to increase the efficiency of tumor cell directed cytotoxicity via immune mechanisms. This study presents an example for this using head and neck cancer cell lines and nanotechnology-based encapsulated antigen presentation to dendritic cells. The observed CD8+ T-cell response was significantly enhanced. This method may pave the way to a highly efficient cancer cell elimination method with minimal to no toxicity.


Angioleiomyoma of the upper extremity.
To determine the outcomes of surgical excision in the management of angioleiomyomas of the upper extremity. We retrospectively reviewed the medical records of 26 patients undergoing a surgical excision of an angioleiomyoma in the upper extremity between 1975 and 2012, who had at least 1 year of follow-up. There were 12 men and 14 women, with an average age of 55 ± 20 years. The most common location was the hand (n = 14). The onset of symptoms was on average 6 ± 5 years before presentation. The most common problem was a painful mass (19 of 26 patients). Average tumor size was 10 ± 7 mm. Patients over the age of 60 years tended to have smaller tumors. There was no significant difference between average preoperative and postoperative grip strength in the affected and unaffected extremities. None of the lesions was diagnosed based on radiographic imaging. There was 1 postoperative complication. No recurrence was noted at an average 8.6-year follow-up (range, 1.0-21.0 y). Angioleiomyomas present as a small, painful masses that can be reliably treated with marginal surgical excision. Therapeutic IV.


Reversible regulation of metastasis by ROS-generating mtDNA mutations.
It has been controversial whether mtDNA mutations are responsible for oncogenic transformation (normal cells to develop tumors), and for malignant progression (tumor cells to develop metastases). To clarify this issue, we created trans-mitochondrial cybrids with mtDNA exchanged between mouse tumor cells that express different metastatic phenotypes. The G13997A mutation in the ND6 gene of mtDNA from high metastatic tumor cells reversibly controlled development of metastases by overproduction of reactive oxygen species (ROS), but did not control development of tumors. The mtDNA-mediated reversible control of metastasis reveals a novel function of mtDNA, and suggests that ROS scavengers may be therapeutically effective in suppressing metastasis.


[Effect of harmful chemical air impurities on some parameters of the oral cavity].
The paper describes guidelines for studying the role of harmful chemical air impurities at work in the development of diseases of the teeth and periodontium, by applying the nonparametric methods that can substantiate conclusions on the nature and mechanism of a cause-and-effect relation when the number of observations is limited.


Artificial receptor-functionalized nanoshell: facile preparation, fast separation and specific protein recognition.
This work combined molecular imprinting technology with superparamagnetic nanospheres as the core to prepare artificial receptor-functionalized magnetic nanoparticles for separation of homologous proteins. Using dopamine as a functional monomer, novel surface protein-imprinted superparamagnetic polydopamine (PDA) core-shell nanoparticles were successfully prepared in physiological conditions, which could maintain the natural structure of a protein template and achieved the development of molecularly imprinted polymers (MIPs) from one dimension to zero dimension for efficient recognition towards large biomolecules. The resultant nanoparticles could be used for convenient magnetic separation of homologous proteins with high specificity. The nanoparticles possessed good monodispersibility, uniform surface morphology and high saturation magnetization value. The bound amounts of template proteins measured by both indirect and direct methods were in good agreement. The maximum number of imprinted cavities on the surface of the bovine hemoglobin (Hb)-imprinted nanoshell was 2.21 x 10(18) g( - 1), which well matched their maximum binding capacity toward bovine Hb. Both the simple method for preparation of MIPs and the magnetic nanospheres showed good application potential in fast separation, effective concentration and selective biosensing of large protein molecules.


Controlling the elements: an optogenetic approach to understanding the neural circuits of fear.
Neural circuits underlie our ability to interact in the world and to learn adaptively from experience. Understanding neural circuits and how circuit structure gives rise to neural firing patterns or computations is fundamental to our understanding of human experience and behavior. Fear conditioning is a powerful model system in which to study neural circuits and information processing and relate them to learning and behavior. Until recently, technological limitations have made it difficult to study the causal role of specific circuit elements during fear conditioning. However, newly developed optogenetic tools allow researchers to manipulate individual circuit components such as anatomically or molecularly defined cell populations, with high temporal precision. Applying these tools to the study of fear conditioning to control specific neural subpopulations in the fear circuit will facilitate a causal analysis of the role of these circuit elements in fear learning and memory. By combining this approach with in vivo electrophysiological recordings in awake, behaving animals, it will also be possible to determine the functional contribution of specific cell populations to neural processing in the fear circuit. As a result, the application of optogenetics to fear conditioning could shed light on how specific circuit elements contribute to neural coding and to fear learning and memory. Furthermore, this approach may reveal general rules for how circuit structure and neural coding within circuits gives rise to sensory experience and behavior.


Paclitaxel-betulinic acid hybrid nanosuspensions for enhanced anti-breast cancer activity.
Paclitaxel-betulinic acid hybrid nanosuspensions (PTX-BA-NP) with increased anti-breast cancer activity were developed. The resultant nanosuspensions (NP) had a mean particle size of 282.54 ± 5.4 nm, a polydispersity index of approximately 0.242 ± 0.02, a zeta potential of -19.7 ± 0.19 mV and a redispersibility index of 103.3 ± 0.01%. The cumulative dissolution percentage of PTX coarse powder and PTX-BA-NP dried powder at 60 min were 15.4% and 90.8%, respectively. MCF-7 cell-based testing showed that treatment with PTX-BA-NP led to more PTX-BA-NP accumulation in the cytoplasm of breast cancer cells, less cell cycle arrest in the G2-M phase, more cell cycle arrest in the G0-G1 phase, more apoptosis-induced cell death and stronger inhibition of cell migration than paclitaxel nanosuspensions (PTX-NP). Biodistribution studies showed that tumor accumulation levels at 12 h in the PTX-BA-NP group were approximately 2.67- and 2.33-fold higher than the levels in the Taxol® and PTX-NP groups, respectively. In vivo antitumor efficacy demonstrated that PTX-BA-NP exerted the strongest tumor inhibition among the four groups, with a tumor inhibition rate of 47.79 ± 2.28%, followed by PTX-NP (35.05 ± 5.55%), Taxol® (22.67 ± 6.01%) and betulinic acid nanosuspension (BANP) (14.38 ± 6.02%). These findings indicate that PTX-BA-NP holds great promise for breast cancer therapy.