Mitogen-induced genes are subject to multiple pathways of regulation in the initial stages of T-cell activation.
The delivery of a mitogenic signal to T cells via any one of several cell surface molecules elicits a variety of intracellular responses, some or all of which regulate subsequent gene expression events. The expression of nine novel mitogen-induced genes in response to various T-cell-activating agents was examined to evaluate the diversity of pathways which regulate such genes. The relative contribution of distinct secondary signals, individually or together, to mitogen-stimulated gene induction and the capability of individual genes to respond to the sometimes divergent signals generated from different cell surface structures is addressed. The activation of T cells with mitogenic monoclonal antibodies directed against the CD2 or CD3 cell surface molecules, or with phytohemagglutinin, induced all nine genes. Thus, stimulation by fully mitogenic agents regardless of cell surface-binding specificity correlated with the expression of all of the genes studied. However, heterogeneous patterns of gene expression, encompassing five regulatory classes, were revealed by the use of phorbol 12-myristate 13-acetate, calcium ionophore, and anti-CD28 monoclonal antibody, agents which mediated only a subset of intracellular events and thus an incomplete mitogenic signal. Interleukin-2 and two novel lymphokines represented one regulatory class that appeared to require unique transcriptional activation signals relative to the other mitogen-induced genes. As demonstrated in the accompanying paper (P. F. Zipfel, S. G. Irving, K. Kelly, and U. Siebenlist, Mol. Cell. Biol. 9:1041-1048, 1989), the immediate transcriptional response of T cells to mitogenic stimulation is quite complex, involving numerous genes beyond those which have been previously described. Furthermore, the discrimination of several regulatory phenotypes among these nine genes suggests that a multiplicity of signaling pathways extends from the cell surface to the level of transcription.


Classification of Prevention in Sports Medicine and Epidemiology.
It is today recognized that a large share of manifestations of ill health associated with sports participation is preventable and that a focus should be on implementation of effective prevention programs. One hindrance for implementation of effective preventive measures in sports medicine may be that an update of preventive frameworks to the current health challenges has not been performed. We introduce classifications of prevention that are adjusted to the health challenges faced by sports participants in the present day. To enable more precise characterizations of preventive measures, we find it necessary to describe them in two dimensions. In one dimension, pathological developments in the body are used as a basis for classification of preventive measures, while the other dimension classifies prevention on the grounds of epidemiological risk indicators. We conclude that longitudinal research combining diagnostic procedures, surveillance, and targeted interventions is needed to enable the introduction of prevention programs for athletes in the beginning of their sporting career at the pre-diagnostic stage, as well as suitable prevention measures for the adult elite athletes. A more distinct classification of prevention supports a specific and cost-effective planning and translation of sports injury prevention and safety promotion adjusted to the delivery settings, various injury types, and different groups of athletes. The present classifications constitute an additional conceptual foundation for such efforts.


All-trans-retinoic acid inhibition of transforming growth factor-β-induced collagen gel contraction mediated by human Tenon fibroblasts: role of matrix metalloproteinases.
Scarring and contraction of the conjunctiva are common complications of many ocular diseases. We investigated the effects of all-trans-retinoic acid (ATRA) on the contractility of human Tenon's capsule fibroblasts (HTFs) cultured in a three-dimensional collagen gel. HTFs were cultured in a three-dimensional gel of type I collagen and in the absence or presence of transforming growth factor (TGF)-β, ATRA, or an inhibitor of matrix metalloproteinases (MMPs). Collagen gel contraction was evaluated by measurement of gel diameter. The release of MMPs and tissue inhibitors of metalloproteinases (TIMPs) into culture supernatants was assessed by immunoblot analysis and gelatin zymography. The release of lactate dehydrogenase activity from HTFs was measured with a colorimetric assay kit. ATRA inhibited TGF-β-induced collagen gel contraction mediated by HTFs in a concentration- and time-dependent manner. TGF-β induced the release of MMP-1, MMP-2 and MMP-3 by HTFs, and ATRA inhibited these effects of TGF-β on MMP-1 and MMP-3 release. ATRA also stimulated TIMP-1 release from HTFs in the presence of TGF-β. Furthermore, TGF-β-induced collagen gel contraction was blocked by the MMP inhibitor GM6001. ATRA did not exhibit cytotoxicity for HTFs. ATRA inhibited TGF-β-induced collagen gel contraction mediated by HTFs, likely in part by attenuating the production of MMP-1 and MMP-3 and by stimulating the production of TIMP-1. ATRA may therefore prove to be of clinical value for inhibition of scar formation in the conjunctiva.


Metallic elements and oxides and their relevance to Laurentian Great Lakes geochemistry.
The Laurentian Great Lakes are the most studied system in lake geochemistry and have well-preserved chronological profiles. Metals play numerous critical roles in natural and anthropogenic characteristics of lake ecosystems, so patterns in the historical records of metals from sedimentary cores provide important information about environmental baselines and human impacts. Relevant studies of Great Lakes geochemistry are listed, and we follow with encyclopedic descriptions of metals and their oxides in the lakes. These descriptions include likely natural and anthropogenic sources of elements, their known history from previous paleoecological studies, and their status as potential contaminants of concern. Despite the well-studied geology of the Great Lakes catchment, sourcing elements was sometimes difficult due to materials often being moved long distances by glaciation and the global prevalence of atmospheric pollutants. We summarized available information on metals and their roles as geochemical indicators in the Great Lakes.


A RICKETTSIAL INFECTION IN CANADIAN VOLES.
From apparently normal voles captured on Grosse Isle, Province of Quebec, Canada, an infective agent has been grown in embryonated eggs, and by inoculation an inapparent infection was established in voles, mice, guinea pigs, hamsters, and rats. No growth of the agent was obtained in the absence of living cells, and the manner of its development in the yolk sac of embryonated eggs, as well as morphological, epidemiological, and pathogenic features, indicates a rickettsial nature. The inability to transmit infection by either cage or intrauterine contact points to a vector, and mites are shown to have a probable part in the epidemiology. Mice infected with the vole agent resist lethal doses of the Karp strain of scrub typhus, and certain epidemiological, morphological, and immunological features support the relationship indicated by the mouse tests. It is therefore concluded that voles on this island have an inapparent infection due to a rickettsia that may be related to the rickettsia of scrub typhus.


Baseline T-lymphocyte subset absolute counts can predict both outcome and severity in SARS-CoV-2 infected patients: a single center study.
The aim of this study was to evaluate the role of baseline lymphocyte subset counts in predicting the outcome and severity of COVID-19 patients. Hospitalized patients confirmed to be infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were included and classified according to in-hospital mortality (survivors/nonsurvivors) and the maximal oxygen support/ventilation supply required (nonsevere/severe). Demographics, clinical and laboratory data, and peripheral blood lymphocyte subsets were retrospectively analyzed. Overall, 160 patients were retrospectively included in the study. T-lymphocyte subset (total CD3+, CD3+ CD4+, CD3+ CD8+, CD3+ CD4+ CD8+ double positive [DP] and CD3+ CD4- CD8- double negative [DN]) absolute counts were decreased in nonsurvivors and in patients with severe disease compared to survivors and nonsevere patients (p < 0.001). Multivariable logistic regression analysis showed that absolute counts of CD3+ T-lymphocytes < 524 cells/µl, CD3+ CD4+ < 369 cells/µl, and the number of T-lymphocyte subsets below the cutoff (T-lymphocyte subset index [TLSI]) were independent predictors of in-hospital mortality. Baseline T-lymphocyte subset counts and TLSI were also predictive of disease severity (CD3+ < 733 cells/µl; CD3+ CD4+ < 426 cells/µl; CD3+ CD8+ < 262 cells/µl; CD3+ DP < 4.5 cells/µl; CD3+ DN < 18.5 cells/µl). The evaluation of peripheral T-lymphocyte absolute counts in the early stages of COVID-19 might represent a useful tool for identifying patients at increased risk of unfavorable outcomes.


Kidney Biomarkers and Decline in eGFR in Patients with Type 2 Diabetes.
Biomarkers may improve identification of individuals at risk of eGFR decline who may benefit from intervention or dialysis planning. However, available biomarkers remain incompletely validated for risk stratification and prediction modeling. We examined serum cystatin C, urinary kidney injury molecule-1 (uKIM-1), and urinary neutrophil gelatinase-associated lipocalin (UNGAL) in 5367 individuals with type 2 diabetes mellitus and recent acute coronary syndromes enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. Baseline concentrations and 6-month changes in biomarkers were also evaluated. Cox proportional regression was used to assess associations with a 50% decrease in eGFR, stage 5 CKD (eGFR<15 ml/min per 1.73 m2), or dialysis. eGFR decline occurred in 98 patients (1.8%) over a median of 1.5 years. All biomarkers individually were associated with higher risk of eGFR decline (P<0.001). However, when adjusting for baseline eGFR, proteinuria, and clinical factors, only baseline cystatin C (adjusted hazard ratio per 1 SD change, 1.66; 95% confidence interval, 1.41 to 1.96; P<0.001) and 6-month change in urinary neutrophil gelatinase-associated lipocalin (adjusted hazard ratio per 1 SD change, 1.07; 95% confidence interval, 1.02 to 1.12; P=0.004) independently associated with CKD progression. A base model for predicting kidney function decline with nine standard risk factors had strong discriminative ability (C-statistic 0.93). The addition of baseline cystatin C improved discrimination (C-statistic 0.94), but it failed to reclassify risk categories of individuals with and without eGFR decline. The addition of cystatin C or biomarkers of tubular injury did not meaningfully improve the prediction of eGFR decline beyond common clinical factors and routine laboratory data in a large cohort of patients with type 2 diabetes and recent acute coronary syndrome. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_01_16_CJASNPodcast_18_3_G.mp3.


Cutting edge: progesterone directly upregulates vitamin d receptor gene expression for efficient regulation of T cells by calcitriol.
The two nuclear hormone receptor ligands progesterone and vitamin D (vit.D) play important roles in regulating T cells. The mechanism that connects these two hormones in regulating T cells has not been established. In this study, we report that progesterone is a novel inducer of vit.D receptor (VDR) in T cells and makes T cells highly sensitive to calcitriol. At the molecular level, the induction by progesterone is mediated by two progesterone receptor-binding elements in the intron region after the first noncoding exon of the human VDR gene. Increased expression of VDR by progesterone allows highly sensitive regulation of T cells by vit.D even when vit.D levels are suboptimal. This novel regulatory pathway allows enhanced induction of regulatory T cells but suppression of Th1 and Th17 cells by the two nuclear hormones. The results have significant ramifications in effective regulation of T cells to prevent adverse immune responses during pregnancy.


Pore Engineering for One-Step Ethylene Purification from a Three-Component Hydrocarbon Mixture.
Ethylene production from C2 hydrocarbon mixtures through one separation step is desirable but challenging because of the similar size and physical properties of acetylene, ethylene, and ethane. Herein, we report three new isostructural porous coordination networks (NPU-1, NPU-2, NPU-3; NPU represents Northwestern Polytechnical University) that are sustained by 9-connected nodes based upon a hexanuclear metal cluster of composition [Mn6(μ3-O)2(CH3COO)3]6+. NPU-1/2/3 exhibit a dual cage structure that was systematically fine-tuned in terms of cage size to realize selective adsorption of C2H2 and C2H6 over C2H4. Dynamic breakthrough experiments demonstrated that NPU-1 produces ethylene in >99.9% purity from a three-component gas mixture (1:1:1 C2H2/C2H4/C2H6). Molecular modeling studies revealed that the dual adsorption preference for C2H2 and C2H6 over C2H4 originates from (a) strong hydrogen-bonding interactions between electronegative carboxylate O atoms and C2H2 molecules in one cage and (b) multiple non-covalent interactions between the organic linkers of the host network and C2H6 molecules in the second cage.


Surgical treatment of metastatic tumors of the long bones.
With improvements in chemotherapy, endocrine therapy and radiotherapy, the development of a pathological fracture does not indicate a terminal stage for a neoplasm patient, since survival rates have increased over the years. A review has been undertaken of thirty-nine cases of long-bone metastases treated surgically at Taichung Veterans General Hospital in the past 11 years. Pathological fractures and impending fractures were managed with open reduction and internal fixation with different methods, dependent upon the lesion site. Methylmethacrylate was used to fill the bone defect and strengthen the internal fixation. Radiotherapy was given post-operatively to complying patients. One patient died post-operatively. Eight cases were lost to post-operative follow-up. Four cases are still living. The remaining 26 cases survived for a median of 149 days (range 32-1220 days). Results in relief of pain and for restoration of limb function were good. Since long bone metastases with pathological fracture predictably causes disability for patients, the authors recommend aggressive surgery to improve their quality of life.


Pancuronium attenuates associated hemodynamic and transcutaneous oxygen tension changes during nursery procedures.
Intermittent increases in blood pressure (BP) associated with motor activity have been implicated in the pathogenesis of intraventricular hemorrhage in premature infants. Inhibition of motor activity by pancuronium administration has also been shown to stabilize cerebral blood flow velocity (CBFV) and BP patterns. The purpose of this study was to determine whether administration of pancuronium to ill premature infants would attenuate changes in BP and transcutaneous oxygen tension (TcPO2) and the variability of CBFV pattern associated with common nursery procedures. Fourteen premature infants in the study were given a single dose of pancuronium bromide at a dose of 0.1 mg/kg intravenously. BP and TcPO2 changes were monitored during nursery procedures, that is, during radial artery blood gas sampling and a head ultrasonographic/Doppler procedure, before and during pancuronium therapy. During arterial blood gas sampling, mean percent increase in BP was significantly greater (32% +/- 21%) before pancuronium administration compared with 21% +/- 13% during pancuronium use (p < 0.05). Mean percent changes in TcPO2 were -30% +/- 21% and 5.8% +/- 7.2% before and during pancuronium use, respectively (p < 0.05). Similar significant changes in BP and TcPO2 were observed with a head ultrasonographic/Doppler procedure. Coefficients of variation of systolic and mean CBFV also decreased significantly during pancuronium therapy. We observed short-term benefits with pancuronium use on vascular dynamics and oxygenation during nursery procedures. Further studies are needed to evaluate the use of pancuronium in preterm babies supported by mechanical ventilation during the first few days of life for possible prevention of intraventricular hemorrhage, the pathophysiologic mechanism of which may be related to hemodynamic and biochemical derangement.


Partial primary structure of the alpha and beta chains of human tumor T-cell receptors.
The T-cell receptor for antigen (Ti) was purified from the human tumor cell line HPB-ALL. Amino-terminal sequence analysis of an acid-cleaved peptide of the Ti alpha chain showed that it is highly homologous to a putative murine alpha chain recently described. Amino-terminal sequence analysis of the Ti beta chain revealed that it shares 50 percent homology with the Ti beta chain amino acid sequences from two other human T-cell tumors. Nucleotide sequence analysis of a complementary DNA clone encoding the Ti beta chain from the HPB-MLT cell line showed that this chain represents a second human constant region gene segment and suggested that it arises from direct joining of the variable and joining gene segments without any intervening D region sequences.


Microchromosomes are building blocks of bird, reptile, and mammal chromosomes.
Microchromosomes, once considered unimportant shreds of the chicken genome, are gene-rich elements with a high GC content and few transposable elements. Their origin has been debated for decades. We used cytological and whole-genome sequence comparisons, and chromosome conformation capture, to trace their origin and fate in genomes of reptiles, birds, and mammals. We find that microchromosomes as well as macrochromosomes are highly conserved across birds and share synteny with single small chromosomes of the chordate amphioxus, attesting to their origin as elements of an ancient animal genome. Turtles and squamates (snakes and lizards) share different subsets of ancestral microchromosomes, having independently lost microchromosomes by fusion with other microchromosomes or macrochromosomes. Patterns of fusions were quite different in different lineages. Cytological observations show that microchromosomes in all lineages are spatially separated into a central compartment at interphase and during mitosis and meiosis. This reflects higher interaction between microchromosomes than with macrochromosomes, as observed by chromosome conformation capture, and suggests some functional coherence. In highly rearranged genomes fused microchromosomes retain most ancestral characteristics, but these may erode over evolutionary time; surprisingly, de novo microchromosomes have rapidly adopted high interaction. Some chromosomes of early-branching monotreme mammals align to several bird microchromosomes, suggesting multiple microchromosome fusions in a mammalian ancestor. Subsequently, multiple rearrangements fueled the extraordinary karyotypic diversity of therian mammals. Thus, microchromosomes, far from being aberrant genetic elements, represent fundamental building blocks of amniote chromosomes, and it is mammals, rather than reptiles and birds, that are atypical.


(E)-1-(4-Bromo-phen-yl)-3-(2,4,6-trimethoxy-phen-yl)prop-2-en-1-one.
The mol-ecule of the title chalcone derivative, C(18)H(17)BrO(4), is twisted, the dihedral angle between the 4-bromo-phenyl and 2,4,6-trimethoxy-phenyl rings being 39.17 (6)°. The three meth-oxy groups are oriented in two different conformations whereby two meth-oxy groups are coplanar, whereas the third is twisted with respect to the attached benzene ring [C-O-C-C torsion angles of -2.84 (18), -2.80 (18) and -9.31 (18)°]. Weak intra-molecular C-H⋯O inter-actions generate two S(5) and one S(6) ring motifs. In the crystal structure, mol-ecules are linked into supra-molecular sheets parallel to the bc plane by weak C-H⋯O inter-actions. These sheets are stacked along the a axis. The crystal structure is further stabilized by weak C-H⋯π inter-actions.


Cell motility and migration as determinants of stem cell efficacy.
Stem cells` (SC) functional heterogeneity and its poorly understood aetiology impedes clinical development of cell-based therapies in regenerative medicine and oncology. Recent studies suggest a strong correlation between the SC migration potential and their therapeutic efficacy in humans. Designating SC migration as a denominator of functional SC heterogeneity, we sought to identify highly migrating subpopulations within different SC classes and evaluate their therapeutic properties in comparison to the parental non-selected cells. We selected highly migrating subpopulations from mesenchymal and neural SC (sMSC and sNSC), characterized their features including but not limited to migratory potential, trophic factor release and transcriptomic signature. To assess lesion-targeted migration and therapeutic properties of isolated subpopulations in vivo, surgical transplantation and intranasal administration of MSCs in mouse models of glioblastoma and Alzheimer's disease respectively were performed. Comparison of parental non-selected cells with isolated subpopulations revealed superior motility and migratory potential of sMSC and sNSC in vitro. We identified podoplanin as a major regulator of migratory features of sMSC/sNSC. Podoplanin engineering improved oncovirolytic activity of virus-loaded NSC on distantly located glioblastoma cells. Finally, sMSC displayed more targeted migration to the tumour site in a mouse glioblastoma model and remarkably higher potency to reduce pathological hallmarks and memory deficits in transgenic Alzheimer's disease mice. Functional heterogeneity of SC is associated with their motility and migration potential which can serve as predictors of SC therapeutic efficacy. This work was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and by the IZEPHA grant.


Monitoring airway pressure: a new standard.
This article is the fifth of a series designed to help nurse anesthetists appreciate the clinical applications of equipment and monitoring systems. In this issue, the author describes the most recent American Society for Testing and Materials (ASTM) standard requirements for airway pressure monitoring and outlines the most important reasons for monitoring high, sustained and subatmospheric airway pressure.


Influence of reward expectation on visuospatial processing in macaque lateral prefrontal cortex.
The lateral prefrontal cortex (LPFC) has been implicated in visuospatial processing, especially when it is required to hold spatial information during a delay period. It has also been reported that the LPFC receives information about expected reward outcome. However, the interaction between visuospatial processing and reward processing is still unclear because the two types of processing could not be dissociated in conventional delayed response tasks. To examine this, we used a memory-guided saccade task with an asymmetric reward schedule and recorded 228 LPFC neurons. The position of the target cue indicated the spatial location for the following saccade and the color of the target cue indicated the reward outcome for a correct saccade. Activity of LPFC was classified into three main types: S-type activity carried only spatial signals, R-type activity carried only reward signals, and SR-type activity carried both. Therefore only SR-type cells were potentially involved in both visuospatial processing and reward processing. SR-type activity was enhanced (SR+) or depressed (SR-) by the reward expectation. The spatial discriminability as expressed by the transmitted information was improved by reward expectation in SR+ type. In contrast, when reward information was coded by an increase of activity in the reward-absent condition (SR- type), it did not improve the spatial representation. This activity appeared to be involved in gaze fixation. These results extend previous findings suggesting that the LPFC exerts dual influences based on predicted reward outcome: improvement of memory-guided saccades (when reward is expected) and suppression of inappropriate behavior (when reward is not expected).


Assignment of absolute configurations of highly flexible linear diterpenes from the brown alga Bifurcaria bifurcata by VCD spectroscopy.
Correct assignment of the stereogenic centers of highly flexible linear diterpenes (LDs) is challenging. Herein we report the first application of VCD spectroscopy for the absolute configuration determination of LDs of algal origin and provide experimental and computational procedures, such as a fragmentation approach, which will facilitate the use of VCD spectroscopy for configuration assignments of LDs.


Some clinical properties of Octocaine 200 (2 per cent lidocaine with epinephrine 1:200,000).
This study utilizes healthy volunteers to determine, via electronic pulp tester, such basic clinical parameters as time of onset and duration of action for an infiltration and mandibular block utilizing the recently available local anesthetic preparation, 2 per cent lidocaine with 1:200,000 epinephrine (Octocaine 200). This study showed Octocaine 200 to be both safe and efficacious, producing times of onset and duration within the clinically useful range. The rationale for vasoconstrictor use in dentistry is also reviewed.


How accurate are published recurrence rates after rectal prolapse surgery? A meta-analysis of individual patient data.
The literature shows wide variations of recurrence rates (RRs) after abdominal surgery for rectal prolapse. The aim of this meta-analysis was to evaluate the accuracy of published RRs. An electronic search was performed with no restrictions. Inclusion criterion was abdominal surgery in at least 10 adults with follow-up evaluation of any length of time. Two reviewers screened 1669 references. A total of 190 investigators were asked to provide individual patient data that should be the same used at the time their reports were written. The RR was estimated by actuarial analysis. Investigators were asked for comments on results. Individual patient data from 6 reports published with 273 patients (186 women, 87 men) with a median age of 54 years (range, 18-88 y) were available. Abdominal surgery included mobilization with pexy (88%), with additional resection (7%), or mobilization only (5%). There were 16 recurrences at a median follow-up period of 3.94 years (range, .05-15.11 y). The effect of age (hazard ratio [HR], 2.010; P = .3443), sex (HR, 2.070; P = .4260), surgical technique (HR, .743; P = .7669), and publication (HR, 1.014; P = .8747) on RR was not significant. Two publications reported a RR of 0. In another report, the published and estimated RRs of 15% did not differ. Published RRs differed from estimated RRs in 3 reports (2.5% vs 4%; 7% vs 54%; and 9.6% vs 36%). The pooled odds ratios of 6 reports revealed a borderline significant difference between the published and estimated RRs (P = .066). Published RRs differed by as much as 47% from the RRs estimated by actuarial analysis depending on event definition and how the data were censored.


Gap junctional communication promotes apoptosis in a connexin-type-dependent manner.
Gap junctions (GJs) have been described to modulate cell death and survival. It still remains unclear whether this effect requires functional GJ channels or depends on channel-independent effects of connexins (Cx), the constituents of GJs. Therefore, we analysed the apoptotic response to streptonigrin (SN, intrinsic apoptotic pathway) or to α-Fas (extrinsic apoptotic pathway) in HeLa cells expressing Cx43 as compared with empty vector-transfected (CTL) cells. Apoptosis assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining was significantly higher in HeLa-Cx43 compared with HeLa-CTL cells. Moreover, the cleavage of caspase-7 or Parp occurred earlier in HeLa-Cx43 than in HeLa-CTL cells. Comparative analysis of the effect of two further (endothelial) Cx (Cx37 and Cx40) on apoptosis revealed that apoptosis was highest in HeLa-Cx43 and lowest in HeLa-Cx37 cells, and correlated with the GJ permeability (assessed by spreading of a GJ-permeable dye and locally induced Ca(2+) signals). Pharmacologic inhibition of GJ formation in HeLa-Cx43 cells reduced apoptosis significantly. The role of GJ communication was further analysed by the expression of truncated Cx43 proteins with and without channel-forming capacity. Activation of caspases was higher in cells expressing the channel-building part (HeLa-Cx43NT-GFP) than in cells expressing the channel-incompetent C-terminal part of Cx43 (HeLa-Cx43CT-GFP) only. A hemichannel-dependent release and, hence, paracrine effect of proapoptotic signals could be excluded since the addition of a peptide (Pep)-blocking Cx43-dependent hemichannels (but not GJs) did not reduce apoptosis in HeLa-Cx43 cells. Treatment with SN resulted in a significant higher increase of the intracellular free Ca(2+) concentration in HeLa-Cx43 and HeLa-Cx43NT-GFP cells compared with HeLa-CTL or HeLa-Cx43CT-GFP cells, suggesting that Ca(2+) or a Ca(2+)-releasing agent could play a signalling role. Blocking of inositol triphosphate receptors reduced the SN-induced Ca(2+) increase as well as the increase in apoptosis. Our observations suggest that Cx43 and Cx40 but not Cx37 promote apoptosis via gap junctional transfer of pro-apoptotic signals between cells.


Sex differences in a landmark environmental re-orientation task only during the learning phase.
Sex differences are consistently reported in human navigation. Indeed, to orient themselves during navigation women are more likely to use landmark-based strategies and men Euclidean-based strategies. The difference could be due to selective social pressure, which fosters greater spatial ability in men, or biological factors. And the great variability of the results reported in the literature could be due to the experimental setting more than real differences in ability. In this study, navigational behaviour was assessed by means of a place-learning task in which a modified version of the Morris water maze for humans was used to evaluate sex differences. In using landmarks, sex differences emerged only during the learning phase. Although the men were faster than the women in locating the target position, the differences between the sexes disappeared in delayed recall.


Dairy consumption and risk of stroke in Swedish women and men.
Epidemiological studies of the associations of low-fat dairy and specific dairy food consumption with risk of stroke are sparse. Our aim was to examine the association between consumption of total, low-fat, full-fat, and specific dairy foods and risk of stroke in a prospective cohort study. We followed 74,961 Swedish women and men who were free from cardiovascular disease and cancer and who completed a 96-item food frequency questionnaire in 1997. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. During a mean follow-up of 10.2 years, we ascertained 4089 cases of stroke, including 3159 cerebral infarctions, 583 hemorrhagic strokes, and 347 unspecified strokes. Consumption of low-fat dairy foods was inversely associated with risk of total stroke (P for trend=0.03) and cerebral infarction (P for trend=0.03). The multivariable relative risks for the highest compared with the lowest quintile of low-fat dairy consumption were 0.88 (95% CI, 0.80-0.97) for total stroke and 0.87 (95% CI, 0.78-0.98) for cerebral infarction. Consumption of total dairy, full-fat dairy, milk, sour milk/yogurt, cheese, and cream/crème fraiche was not associated with stroke risk. These results suggest that low-fat dairy consumption is inversely associated with the risk of stroke.


"The Top Priority Is a Healthy Baby": Narratives of Health, Disability, and Abortion in Online Pregnancy Forum Discussions in the US and China.
The introduction of cell-free DNA prenatal genetic screening has rekindled discussion of ethical and social questions surrounding prenatal testing, perceptions of disability, and abortion. The growing use of prenatal genetic screening presents a unique opportunity to assess decision-making around new methods of prenatal testing; especially as there is little available research comparing individual and cultural differences that affect a pregnant woman's decision-making on prenatal testing. We performed a content analysis of online pregnancy forums in the United States and Mainland China. Content from January 2012 to December 2013 was identified through search methodologies and refined to remove duplication. China-based content was translated by a native Mandarin speaker. We used qualitative analysis methods to identify common themes in the dataset. There were 333 English responses and 519 Mandarin responses. Three main themese were identified in the data: decision making factors, attitude towards the pregnancy, and attitudes towards abortion. Women's narratives reflected how broader social forces can have an impact on intimate personal decision-making. Women in the Mandarin dataset evoked stronger narratives of community and/or family decision-making in pregnancy and were more accepting of the possibility of abortion in the event of a finding of fetal abnormality. Narrative in the English dataset more frequently evoked ideas of unconditional love, regardless of fetal diagnosis, but also acknowledged much stronger support services for individuals with disability and less awareness of stigma. These results highlight the necessity of awareness around how broader cultural and social factors can consciously or unconsciously impact women's decisions and highlight potential focus areas for future counseling efforts.


Which wound cuts deeper: loss of an only child or loss of a spouse? An examination of bereavement in older adults within a Chinese cultural context.
This study aimed to examine whether the loss of spouse had similar impacts on psychological well-being as the loss of the only child, and whether the presence of one mitigated the absence of the other. We used data from a 2013 survey conducted in Shanghai, China. The sample included 1,200 older adults aged 60+, and 200 adults aged 45+ who lost their only child. Psychological well-being consisted of three dimensions: depression, loneliness, and life satisfaction. We applied logistic regression models to assess the impact of loss of spouse or children on psychological well-being. We further tested whether the impact differed by gender and whether social support mediated the relationship. Participants who have at least one living child but lost their spouse had less psychological distress than those who have a living spouse but lost their only child. This effect appeared to be stronger in women than in men. Social support mediated the relationship between bereavement and loneliness among women. The findings suggested the loss of the only child is a more devastating event than the loss of spouse in Chinese adults. The loss of the only child is a major chronic stressor that has cumulative negative effect on psychological well-being.


Effect of pH on substrate and inhibitor kinetic constants of human liver alanine aminopeptidase. Evidence for two ionizable active center groups.
The presence of at least two ionizable active center groups has been detected by a study of the effect of pH upon catalysis of hydrolysis of L-alanyl-beta-naphthylamide by human liver alanine aminopeptidase and upon the inhibition of hydrolysis by inhibitors and substrate analogs. Octanoic acid, octylamine, and peptide inhibitors have been found to be competitive inhibitors and are therefore thought to bind the active center. L-Phe was previously shown to bind the active center since it was found to be a competitive inhibitor of the hydrolysis of tripeptide substrates (Garner, C. W., and Behal, F. J. (1975), Biochemistry 14, 3208). A plot of pKm vs. pH for the substrate L-Ala-beta-naphthylamide showed that binding decreased below pH 5.9 and above 7.5, the points at which the theoretical curve undergoes an integral change in slope. These points are interpreted as the pKa either of substrate ionizable groups or binding-dependent enzyme active center groups. Similar plots of pKm vs. pH for L-alanyl-p-nitroanilide (as substrate) and pKi vs. pH for L-Leu-L-Leu-L-Leu and D-Leu-L-Tyr (as inhibitors) gave pairs fo pKa values of 5.8 and 7.4, 6.0 and 7.5, and 5.7 and 7.5, respectively. All the above substrates (and D-Leu-L-Tyr) have pKa values near 7.5; therefore, the binding-dependent group with a pKa value near 7.5 is possibly this substrate group. Similar plots of pKi vs. pH for the inhibitors L-Phe, L-Met, L-Leu, octylamine, and octanoic acid had only one bending point at 7.7, 7.6, 7.4, 6.3, and 5.9, respectively. Amino acid inhibitors, octylamine, and octanoic acid have no groups with pKa values between 5 and 9. These data indicate that there are two active center ionizable groups with pKa values of approximately 6.0 and 7.5 which are involved in substrate binding or inhibitory amino acid binding but not in catalysis since Vmax was constant at all pH values tested.


Urinary Neutrophil Gelatinase-Associated Lipocalin Is Excellent Predictor of Acute Kidney Injury in Septic Elderly Patients.
Elderly is the main age group affected by acute kidney injury (AKI). There are no studies that investigated the predictive properties of urinary (u) NGAL as an AKI marker in septic elderly population. This study aimed to evaluate the efficacy of uNGAL as predictor of AKI diagnosis and prognosis in elderly septic patients admitted to ICUs. We prospectively studied elderly patients with sepsis admitted to ICUs from October 2014 to November 2015. Assessment of renal function was performed daily by serum creatinine and urine output. The level of uNGAL was performed within the first 48 hours of the diagnosis of sepsis (NGAL1) and between 48 and 96 hours (NGAL2). The results were presented using descriptive statistics and area under the receiver operating characteristic curve (AUC-ROC) and p value was 5%. Seventy-five patients were included, 47 (62.7%) developed AKI. At logistic regression, chronic kidney disease and low mean blood pressure at admission were identified as factors associated with AKI (OR=0.05, CI=0.01-0.60, p=0.045 and OR=0.81, CI=0,13-0.47; p=0.047). The uNGAL was excellent predictor of AKI diagnosis (AUC-ROC >0.95, and sensitivity and specificity>0.89), anticipating the AKI diagnosis in 2.1±0.3 days. Factors associated with mortality in the logistic regression were presence of AKI (OR=2.14, CI=1.42-3.98, p=0.04), chronic obstructive pulmonary disease (OR = 9.37, CI =1.79-49.1, p=0.008) and vasoactive drugs (OR=2.06, CI=0.98-1.02, p=0.04). The accuracy of NGALu 1 and 2 as predictors of death was intermediate, with AUC-ROC of 0.61 and 0.62; sensitivity between 0.65 and 0.77 and specificity lower than 0.6. The uNGAL was excellent predictor of AKI in septic elderly patients in ICUs and can anticipate the diagnosis of AKI in 2.1 days.


Importance of microcirculatory disturbances in the pathogenesis of pancreatitis.
Pancreatic microvascular control is a complex physiological process which is incompletely understood. Blood flow in the pancreas is altered by a large number of endogenous and exogenous factors in the context of acute and chronic pancreatitis. The frequency of progression from acute pancreatitis to a chronic form is a controversial question. In acute pancreatitis reductions in blood flow and alterations of microvascular integrity resulting in impaired tissue oxygenation play an important part in the progression and possibly the initiation of the disease. Endothelin and nitric oxide are believed to be two of the most effective vasoactive mediators. The beneficial effect of therapeutic strategies affecting vasoactive mediators is confirmed in experimental studies. Chronic disease is associated with decreased pancreatic blood flow and histological changes in the vasculature in both patients and animal models. Further studies are needed to clarify whether ischemia in chronic pancreatitis is more important in perpetuating the disease or as primary cause of the inflammatory processes.


Involvement of two endonuclease III homologs in the base excision repair pathway for the processing of DNA alkylation damage in Saccharomyces cerevisiae.
DNA base excision repair (BER) is initiated by DNA glycosylases that recognize and remove damaged bases. The phosphate backbone adjacent to the resulting apurinic/apyrimidinic (AP) site is then cleaved by an AP endonuclease or glycosylase-associated AP lyase to invoke subsequent BER steps. We have used a genetic approach in Saccharomyces cerevisiae to determine whether or not AP sites are blocks to DNA replication and the biological consequences if AP sites persist in the genome. We previously reported that yeast cells deficient in the two AP endonucleases (apn1 apn2 double mutant) are extremely sensitive to killing by a model DNA alkylating agent methyl methanesulfonate (MMS) and that this sensitivity can be reduced by deleting the MAG1 3-methyladenine DNA glycosylase gene. Here we report that in the absence of the AP endonucleases, deletion of two Escherichia coli endonuclease III homologs, NTG1 and NTG2, partially suppresses MMS-induced killing, which indicates that the AP lyase products are deleterious unless they are further processed by an AP endonuclease. The severe MMS sensitivity seen in AP endonuclease deficient strains can also be rescued by treatment of cells with the AP lyase inhibitor methoxyamine, which suggests that the product of AP lyase action on an AP site is indeed an extremely toxic lesion. In addition to the AP endonuclease interactions, deletion of NTG1 and NTG2 enhances the mag1 mutant sensitivity to MMS, whereas overexpression of MAG1 in either the ntg1 or ntg2 mutant severely affects cell growth. These results help to delineate alkylation base lesion flow within the BER pathway.


[Clinical reasoning and decision-making in practice. A patient with loss of vision and painful legs].
A 69-year-old man was admitted to the Department of Ophthalmology with bilateral loss of vision. For a few months he had also had shooting pains in both legs and instability of gait. Neurological examination showed loss of vision bilaterally and minor sensory disturbances of the legs with diminished tendon reflexes. As extensive further examination showed no specific abnormalities, the tentative diagnosis 'arteriitis temporalis' was made. Despite treatment with corticosteroids his condition deteriorated. Only after a repeat medical history had been taken did it become clear that in the past he had had homosexual contact with a number of partners. This increased the likelihood of a sexually transmitted disease in the differential diagnosis. In the meantime the results from serological tests became known: there were strongly elevated titres for syphilis in both serum and cerebral spinal fluid. Eventually the patient was diagnosed with neurosyphilis with ocular involvement and tabes dorsalis. He recovered almost completely in a few months after treatment with doxycycline.


Relationship of visit-to-visit and ambulatory blood pressure variability to vascular function in African Americans.
Visit-to-visit clinic blood pressure variability (BPV) and 24-h BPV have both been identified as independent risk factors for cardiovascular (CV) morbidity and mortality; however, the mechanisms contributing to the increased CV risk as yet are unclear. The purpose of this study was to assess the relationship between BPV and endothelial function in a cohort of putatively healthy African Americans. A total of 36 African Americans who were sedentary, non-diabetic, non-smoking, free of CV and renal disease and not on antihypertensive medication followed an American Heart Association low fat, low salt diet for 6 weeks. Upon completion of the 6-week dietary stabilization period, participants underwent 24-h ambulatory BP monitoring and had their office blood pressure (BP) measured on 3 separate days. Right brachial artery diameter was assessed at rest, during reactive hyperemia (flow-mediated vasodilation: FMD), and after nitroglycerin administration (nitroglycerin-mediated vasodilation: NMD). Participants classified as having decreased endothelial function according to either %FMD or the FMD/NMD ratio had significantly higher 24-h BPV and a trend for higher visit-to-visit BPV when compared with participants with normal endothelial function. Continuous variable analyses revealed a significant positive association between NMD and 24-h diastolic BPV (DBPV). Visit-to-visit systolic BPV (SBPV), 24-h SBPV and 24-h DBPV were all negatively associated with the FMD/NMD ratio. All relationships remained significant after adjustment for age, body mass index and mean BP levels. These results may suggest that BPV is increased in African Americans with decreased endothelial function and is associated with the vascular smooth muscle response to nitric oxide.


YAP/TAZ are Activated by Mechanical and Hormonal Stimuli in Myometrium and Exhibit Increased Baseline Activation in Uterine Fibroids.
Uterine fibroids (UFs) are benign myometrial neoplasms. The mechanical environment activates signaling through the Hippo pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) in other fibrotic disorders. Here, we assess the differences in YAP/TAZ responsiveness to signals in UF compared with myometrium (Myo). Matched samples of UF and Myo were collected. Atomic force microscopy (AFM) was used to determine in situ stiffness. Cells were plated sparsely on hydrogels or at confluence. Ten nanomolars of estradiol (E2) and 100 nM progesterone (P4) were used. Immunostaining for YAP/TAZ and extracellular matrix (ECM) proteins was performed. Cells were incubated with control or YAP1 (YAP)/WWTR1 (TAZ) small interfering RNA (siRNA). Real time qPCR was completed for connective tissue growth factor (CTGF). Cells were treated with verteporfin (a YAP inhibitor) or Y27632 (a ROCK inhibitor), and ECM gene expression was analyzed. Paired t test and Wilcoxon sign-rank test were used. AFM-measured tissue stiffness and YAP/TAZ nuclear localization in situ and in confluent cells were higher in UF compared with Myo (p < 0.05). Decreasing substrate stiffness reduced YAP/TAZ nuclear localization for both Myo and UF (p = 0.05). Stimulating cells with E2 or P4 increased YAP/TAZ nuclear localization, but only in Myo (p = 0.01). UFs had increased FN, COLI, and COLIII deposition. Following siRNA targeting, CTGF was found to be statistically decreased. Verteporfin treatment reduced cell survival and reduced FN deposition. Treatment with Y27632 demonstrated better cell tolerance and a reduction in ECM deposition. The mechanosensitive pathway may be linked to YAP/TAZ function and involved in transducing fibroid growth.


Regulatory focus and self-determination motives interact to predict students' nutrition-habit intentions.
Regulatory focus (Higgins, 1997) and self-determination (Deci & Ryan, 2000) are two motivation theories widely applied in health-intervention research but never conjointly, despite sharing a number of theoretical similarities. In three studies (N = 578), we investigated how university students' self-determination motives to act upon their nutrition interact with induced regulatory focus and regulatory-message framing to predict their behaviors or intentions to improve their eating habits. Results revealed a fit between extrinsic motives and prevention focus: Intention increased with extrinsic motives in a prevention but not a promotion focus. The effect of intrinsic motives, however, was independent of the focus, which suggests that these motives drive intention and behavior independently of external cues. Hence, the results advocate for simultaneously taking into consideration self-determination and regulatory focus when planning a health intervention relying on motivation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Enhanced brain expression of genes related to cell proliferation and neural differentiation is associated with cortisol receptor expression in fishes.
Stress enhances or inhibits neurogenesis in mammals and some fish species. The link between the two processes is still unclear. Most studies have been performed in very specific stressful or altered environments. Despite the known inter-individual divergence in coping abilities within populations, the relationship between the stress axis and neurogenesis has never been addressed in unstressed individuals. Here we correlate brain expression of the pcna (proliferating cell nuclear antigen) and neurod1 (neurogenic differentiation factor 1) genes, two markers of neurogenesis, with transcripts of cortisol receptors in three fish species living in very distinct environments. Within the three species, individuals with the highest expression of neurogenesis genes were also those that expressed the high levels of cortisol receptors. Based on these correlations and the hypothesis that mRNA levels are proxies of protein levels, we hypothesize that within unstressed animals, individuals sensitive to cortisol perceive a similar environment to be more stimulating, leading to increased neurogenesis. Although it is difficult to determine whether it is sensitivity to cortisol that affects neurogenesis capacities or the opposite, the proposed pathway is a potentially fruitful avenue that warrants further mechanistic experiments.


Dose-response effect of L-citrulline on skeletal muscle damage after acute eccentric exercise: an in vivo study in mice.
Eccentric exercise may trigger mechanical stress, resulting in muscle damage that may decrease athletic performance. L-citrulline potentially prevents skeletal muscle damage after acute eccentric exercise. This study aimed to assess the dose-response effect of L-citrulline as a preventive therapy for skeletal muscle damage in mice after acute eccentric exercise. This is a controlled laboratory in vivo study with a post-test-only design. Male mice (BALB/c, n = 25) were randomized into the following groups: a normal control (C1) (n = 5); a negative control (C2) with downhill running and placebo intervention (n = 5); treatment groups: T1 (n = 5), T2 (n = 5), and T3 (n = 5), were subjected to downhill running and 250, 500, and 1,000 mg/kg of L-citrulline, respectively, for seven days. Blood plasma was used to determine the levels of TNNI2 and gastrocnemius muscle tissue NOX2, IL-6, and caspase 3 using ELISA. NF-κB and HSP-70 expressions were determined by immunohistochemistry. Skeletal muscle damage (plasma TNNI2 levels) in mice after eccentric exercise was lower after 250 and 500 mg/kg of L-citrulline. Further, changes in oxidative stress markers, NOX2, were reduced after a 1,000 mg/kg dose. However, a lower level of change has been observed in levels of cellular response markers (NF-κB, HSP-70, IL-6, and caspase 3) after administration of L-citrulline doses of 250, 500, and 1,000 mg/kg. L-citrulline may prevent skeletal muscle damage in mice after acute eccentric exercise through antioxidant effects as well as inflammatory and apoptotic pathways. In relation to dose-related effects, it was found that L-citrulline doses of 250, 500, and 1,000 mg/kg significantly influenced the expression of NF-κB and HSP-70, as well as the levels of IL-6 and caspase 3. Meanwhile, only doses of 250 and 500 mg/kg had an impact on TNNI2 levels, and the 1,000 mg/kg dose affected NOX2 levels.


Flashback to 2002: a retesting and reanalysis suggests an important role of DSA.
In 2002, Lee et al. published the first paper describing the effect of HLA antibodies on graft failure in kidney transplant patients, yet remained skeptical as to why some patient grafts were surviving years longer than others while testing positive for HLA antibodies. Through a retesting and reanalysis of these patient samples, we confirm the effect that HLA antibodies had on graft failure. Furthermore, our data suggests an explanation for the discrepancy in patient graft survival lasting significant periods of time with HLA antibodies. Through use of updated technology by Luminex testing, as opposed to the ELISA-based HLA screening used in 2002, we confirm that although patient grafts are surviving significant periods of time with HLA antibodies, these antibodiesare not DSA. Thus, grafts with non-DSA HLA antibodies are able to survive longer than grafts with DSA. The data also proposes that lower DSA MFI values are less detrimental to graft survival as well. Moreover, the recent data also suggests that Class I DSA leads to an even shorter graft survival than Class II only DSA.


[Spontaneous changes in cardiovascular functions in guinea pig fetuses].
During the last half of pregnancy, in fetal guinea pigs studied have been made on the blood pressure in the navelstring artery, the placental connection of the fetus remaining intact. During prolonged experiments, fetal circulation exhibited spontaneous fluctuations in the form of reversible bradycardia and the decrease in the blood pressure. These changes were not associated with motor activity of the fetus. Age peculiarities of these fluctuations reflected the degree of maturity of circulation control mechanisms during prenatal development of animals.


Changes in tail posture detected by a 3D machine vision system are associated with injury from damaging behaviours and ill health on commercial pig farms.
To establish whether pig tail posture is affected by injuries and ill health, a machine vision system using 3D cameras to measure tail angle was used. Camera data from 1692 pigs in 41 production batches of 42.4 (±16.6) days in length over 17 months at seven diverse grower/finisher commercial pig farms, was validated by visiting farms every 14(±10) days to score injury and ill health. Linear modelling of tail posture found considerable farm and batch effects. The percentage of tails held low (0°) or mid (1-45°) decreased over time from 54.9% and 23.8% respectively by -0.16 and -0.05%/day, while tails high (45-90°) increased from 21.5% by 0.20%/day. Although 22% of scored pigs had scratched tails, severe tail biting was rare; only 6% had tail wounds and 5% partial tail loss. Adding tail injury to models showed associations with tail posture: overall tail injury, worsening tail injury, and tail loss were associated with more pigs detected with low tail posture and fewer with high tails. Minor tail injuries and tail swelling were also associated with altered tail posture. Unexpectedly, other health and injury scores had a larger effect on tail posture- more low tails were observed when a greater proportion of pigs in a pen were scored with lameness or lesions caused by social aggression. Ear injuries were linked with reduced high tails. These findings are consistent with the idea that low tail posture could be a general indicator of poor welfare. However, effects of flank biting and ocular discharge on tail posture were not consistent with this. Our results show for the first time that perturbations in the normal time trends of tail posture are associated with tail biting and other signs of adverse health/welfare at diverse commercial farms, forming the basis for a decision support system.


Compromised margins following mastectomy for stage I-III invasive breast cancer.
We investigated factors associated with positive margins following mastectomy and the impact on outcomes. We identified 240 patients with stage I-III invasive breast cancer who underwent mastectomy from 1999 to 2009. Data included patient and tumor characteristics, pathologic margin assessment, and outcomes. Margin positivity was defined as the presence of in situ or invasive malignancy at any margin. Descriptive statistics were used for data summary and were compared using χ(2). Of the 240 patients, 132 (55%) had a simple mastectomy with sentinel lymph node biopsy and 108 (45%) had a modified radical mastectomy. Overall, 21 patients (9%) had positive margins, including 12 (57%) with one positive margin, 3 (14%) with two positive margins, and 6 (29%) with three or more positive margins. The most commonly affected margin was the deep margin (48% of patients). Eight of the 21 patients (38%) received adjuvant chest wall irradiation. There were no differences between patients who had a positive margin and those who did not with respect to patient age, race, percentage of in situ component, tumor size, tumor grade, lymphovascular invasion, or immunostain profile (P > 0.05 for all). None of the patients with positive margins experienced a local recurrence. Positive margins following mastectomy occurred in nearly 10% of our patients. No specific patient or tumor characteristics predicted a risk for having a positive margin. Despite the finding that only approximately 40% of patients received adjuvant radiation in the setting of a positive margin, no local recurrences have been observed.


Pancreatic expression of DOG1: a novel gastrointestinal stromal tumor (GIST) biomarker.
The cDNA microarray gene profile of gastrointestinal stromal tumors (GISTs) revealed that DOG1 (TMEM16A) gene was mostly expressed in these neoplasms. Immunohistochemically, DOG1 protein was found positive in a significant proportion of GISTs. However, normal tissues' expression of DOG1 is not yet completely studied. Our study intended to identify the DOG1 protein expression in normal adult and fetal tissues, in comparison with that of GISTs, using an anti-DOG1 polyclonal serum. Fourteen CD117/CD34-positive GIST cases were tested for DOG1. Tissue samples from autopsies of 15 human fetuses and 11 adults were tested immunohistochemically on simple or double staining with antibodies raised against: DOG1, insulin, glucagon, somatostatin, NK1, PGP9.5, chromogranin A, and synaptophysin. All the tested GISTs were positive for DOG1, with a membranous and cytoplasmic location. The normal tissues showed a distinct positivity for DOG1 only in the endocrine pancreas, in both fetal and adult ones. The other tissues tested showed a weak or negative reaction. The DOG1 staining pattern in the pancreas islets was granular, like that of neuroendocrine markers. The location of DOG1 expression in pancreatic islets was partly similar to neuroendocrine markers chromogranin A, PGP9.5, and synaptophysin. The positive cells were situated centrally, in the vicinity of insulin-bearing cells as seen on double staining. DOG1 positivity in fetal and adult pancreatic islets suggests the strong antibody affinity for neuroendocrine cells. Before making a final conclusion regarding the suitability of DOG1 as a new neuroendocrine marker, a large survey of neuroendocrine lesions must be undertaken, including carcinoid tumors of various sites and pancreatic endocrine tumors. To the best of our knowledge, this particular localization has not been reported yet for DOG1.


Guanylate cyclase-activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors.
Light adaptation of photoreceptor cells is mediated by Ca2+-dependent mechanisms. In darkness, Ca2+ influx through cGMP-gated channels into the outer segment of photoreceptors is balanced by Ca2+ extrusion via Na+/Ca2+, K+ exchangers (NCKXs). Light activates a G protein signaling cascade, which closes cGMP-gated channels and decreases Ca2+ levels in photoreceptor outer segment because of continuing Ca2+ extrusion by NCKXs. Guanylate cyclase-activating proteins (GCAPs) then up-regulate cGMP synthesis by activating retinal membrane guanylate cyclases (RetGCs) in low Ca2+ This activation of RetGC accelerates photoresponse recovery and critically contributes to light adaptation of the nighttime rod and daytime cone photoreceptors. In mouse rod photoreceptors, GCAP1 and GCAP2 both contribute to the Ca2+-feedback mechanism. In contrast, only GCAP1 appears to modulate RetGC activity in mouse cones because evidence of GCAP2 expression in cones is lacking. Surprisingly, we found that GCAP2 is expressed in cones and can regulate light sensitivity and response kinetics as well as light adaptation of GCAP1-deficient mouse cones. Furthermore, we show that GCAP2 promotes cGMP synthesis and cGMP-gated channel opening in mouse cones exposed to low Ca2+ Our biochemical model and experiments indicate that GCAP2 significantly contributes to the activation of RetGC1 at low Ca2+ when GCAP1 is not present. Of note, in WT mouse cones, GCAP1 dominates the regulation of cGMP synthesis. We conclude that, under normal physiological conditions, GCAP1 dominates the regulation of cGMP synthesis in mouse cones, but if its function becomes compromised, GCAP2 contributes to the regulation of phototransduction and light adaptation of cones.


Determination of antiprotozoal drug mechanisms by metabolomics approaches.
The discovery, development and optimal utilization of pharmaceuticals can be greatly enhanced by knowledge of their modes of action. However, many drugs currently on the market act by unknown mechanisms. Untargeted metabolomics offers the potential to discover modes of action for drugs that perturb cellular metabolism. Development of high resolution LC-MS methods and improved data analysis software now allows rapid detection of drug-induced changes to cellular metabolism in an untargeted manner. Several studies have demonstrated the ability of untargeted metabolomics to provide unbiased target discovery for antimicrobial drugs, in particular for antiprotozoal agents. Furthermore, the utilization of targeted metabolomics techniques has enabled validation of existing hypotheses regarding antiprotozoal drug mechanisms. Metabolomics approaches are likely to assist with optimization of new drug candidates by identification of drug targets, and by allowing detailed characterization of modes of action and resistance of existing and novel antiprotozoal drugs.


Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis.
Dynamic processes are implicit in the catalytic function of all enzymes. To obtain insights into the relationship between the dynamics and thermodynamics of protein fluctuations and catalysis, we have measured millisecond time scale motions in the enzyme dihydrofolate reductase using NMR relaxation methods. Studies of a ternary complex formed from the substrate analog folate and oxidized NADP+ cofactor revealed conformational exchange between a ground state, in which the active site loops adopt a closed conformation, and a weakly populated (4.2% at 30 degrees C) excited state with the loops in the occluded conformation. Fluctuations between these states, which involve motions of the nicotinamide ring of the cofactor into and out of the active site, occur on a time scale that is directly relevant to the structural transitions involved in progression through the catalytic cycle.


Differential regulation of transforming growth factor beta-1 gene expression by glucocorticoids in human T and glial cells.
The inflammatory process in the brain requires bidirectional interaction of the immune and nervous systems. Evidently, astrocytic glial cells play an important role in facilitating this communication by releasing immunomodulators and cytokines. Expression of transforming growth factor beta-1 (TGF beta-1), a potent inhibitor of T cell function and glial cell proliferation, is highly regulated in T cells and is believed to be an important component in the molecular interaction between the immune and nervous systems. Comparative analysis of TGF beta-1 gene expression in human T and glial cells by Northern hybridization and S1 nuclease protection assay showed that dexamethasone (DM) caused a significant decrease in the basal and PMA-induced levels of TGF beta-1 mRNA in glial cells but not in T cells. This reduction correlated with a lower level of TGF beta-1 protein production. Transient transfection assay using deletion constructs of the 5' TGF beta-1 gene promoter-containing sequences between -453 and +11 bp identified a region spanning -160 to -60 bp as a potential sequence responsive to regulation by DM in T cells, whereas in glial cells, the overall transcriptional activity of the 5' TGF beta-1 promoter was reduced after DM treatment, but promoter activity within each construct remained constant in response to DM. Thus, a DM-responsive region could not be identified within the TGF beta-1 promoter in glial cells. These findings suggest that TGF beta-1 gene expression is differentially regulated by distinct regulatory elements in T and glial cells, and that extracellular stimulators, including glucocorticoids, can utilize the TGF beta-1-regulatory pathway to affect the functions of neural and immune cells.


Leveraging ancillary benefits from urban greenspace - a case study of St. Louis, Missouri.
Urban greenspace and green infrastructure are often cited for their many ecosystem services and benefits including stormwater management. However, the localized nature and limited range of effects of these benefits and the type of greenspace and green infrastructure, make planning and placement critical components to selecting for and maximizing desired benefits. Here, the authors test a framework to demonstrate a practical approach to simultaneously manage excess stormwater and maximize distribution of ecosystem services to underserved areas using spatial analysis. St. Louis was subdivided using census block polygons and polygons identified have combined sewer systems with high aggregate annual discharge. Additionally, indicators representing social, economic, and environmental characteristics, which have demonstrated effects from greenspace, were mapped to identify spatial distribution and overlap. The analysis identified one polygon that could promote multiple desired ecosystem services, while reducing annual discharge into combined sewers, and provide these services to an underserved demographic.


Ligand removal and photo-activation of CsPbBr3 quantum dots for enhanced optoelectronic devices.
Perovskite quantum dots have recently emerged as a promising light source for optoelectronic applications. However, integrating them into devices while preserving their outstanding optical properties remains challenging. Due to their ionic nature, perovskite quantum dots are extremely sensitive and degrade on applying the simplest processes. To maintain their colloidal stability, they are surrounded by organic ligands; these prevent efficient charge carrier injection in devices and have to be removed. Here we report on a simple method, where a moderate thermal process followed by exposure to UV in air can efficiently remove ligands and increase the photo-luminescence of the room temperature synthesized perovskite quantum dot thin films. Annealing is accompanied by a red shift of the emission wavelength, usually attributed to the coalescence and irreversible degradation of the quantum dots. We show that it is actually related to the relaxation of the quantum dots upon the ligand removal, without the creation of non-radiative recombining defects. The quantum dot surface, as devoid of ligands, is subsequently photo-oxidized and smoothened upon exposure to UV in air, which drastically enhances their photo-luminescence. This adequate combination of treatments improves by more than an order of magnitude the performances of perovskite quantum dot light emitting diodes.


Macrophage glucose-6-phosphate dehydrogenase stimulates proinflammatory responses with oxidative stress.
Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that regulates cellular redox potential. In this study, we demonstrate that macrophage G6PD plays an important role in the modulation of proinflammatory responses and oxidative stress. The G6PD levels in macrophages in the adipose tissue of obese animals were elevated, and G6PD mRNA levels positively correlated with those of proinflammatory genes. Lipopolysaccharide (LPS) and free fatty acids, which initiate proinflammatory signals, stimulated macrophage G6PD. Overexpression of macrophage G6PD potentiated the expression of proinflammatory and pro-oxidative genes responsible for the aggravation of insulin sensitivity in adipocytes. In contrast, when macrophage G6PD was inhibited or suppressed via chemical inhibitors or small interfering RNA (siRNA), respectively, basal and LPS-induced proinflammatory gene expression was attenuated. Furthermore, macrophage G6PD increased activation of the p38 mitogen-activated protein kinase (MAPK) and NF-κB pathways, which may lead to a vicious cycle of oxidative stress and proinflammatory cascade. Together, these data suggest that an abnormal increase of G6PD in macrophages promotes oxidative stress and inflammatory responses in the adipose tissue of obese animals.


Placers of cosmic dust in the blue ice lakes of greenland.
A concentration process occurring in the melt zone of the Greenland ice cap has produced the richest known deposit of cosmic dust on the surface of the earth. Extraterrestrial particles collected from this region are well preserved and are collectable in large quantities. The collected particles are generally identical to cosmic spheres found on the ocean floor, but a pure glass type was discovered that has not been seen in deep-sea samples. Iron-rich spheres are conspicuously rare in the collected material.


Effects of myocardial preservation on enzyme levels in serum and myocardium: a clinical study comparing cold crystalloid versus warm blood cardioplegia.
Enzyme activities have been recognized as one of the parameters in the assessment of the effects of various forms of myocardial preservation. However, comparisons between different methods of myocardial protection by the use of enzyme assay in clinical settings in uncommon. Twenty patients who underwent open-heart valve replacement were divided equally into two groups: intermittent perfusion of cold crystalloid (St. Thomas Hospital solution) with hypothermic cardiopulmonary bypass (CPB) (Group I) and continuous administration of warm blood cardioplegia with normothermic CPB (Group II). The groups were similar with respect to sex, age, body surface area and preoperative ventricular function. Blood samples were obtained from an indwelling radial arterial catheter or from the arterial end of the oxygenator. Biopsy specimens from the right atrium were obtained immediately before aortic declamping (ischemic period), and 30 minutes after crossclamp removal (reperfusion period). The cumulative release of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and its isoenzymes; linear correlation between (iso)-enzymes of each group and multivariate regression between blood potassium and serum enzymes were determined. The enzyme levels of myocardial specimens including ALT, AST, LDH, creatine phosphokinase (CK), superoxide dismutase (SOD), and malondialdehyde (MDA) were recorded and compared both between the two groups and within each group. No significant intergroup difference was found in the cumulative release of the serum (iso)-enzymes. Close relationships were found in all the correlation coefficients except for the CK-ALT couple in Group I. Neither were intergroup differences found in each parameter of the linear correlations between the (iso)-enzymes. A close correlation between blood potassium and serum enzymes was found in Group I rather than in Group II. Differences of enzyme levels of myocardial specimens between ischemic periods and reperfusion periods were also not statistically significant either within the group or between the groups. Judging from the results of enzyme assay, similar myocardial preservation effects against ischemia-reperfusion injuries could be obtained by either of the techniques of myocardial preservation.


Treatment resistance in severe unipolar depression: no association with psychotic or melancholic features.
Depressive subtypes generally have been neglected in research on treatment efficacy. We studied a sample of 699 severe unipolar depressed patients to detect any association between depressive features and treatment resistance. Participants were divided into psychotic (PSY, n = 90), melancholic (MEL, n = 430) and non-melancholic (n = 179) subjects according to clinical features. Formal diagnostic criteria (Mini International Neuropsychiatric Interview items), and items from 17-item Hamilton Rating Scale for Depression (HRSD17) were compared across groups. Non-responders were defined by a HRSD17 cut-off score of ≥17 after the last adequate antidepressant treatment. Treatment-resistant depression (TRD) was defined as the failure to respond to ≥2 adequate antidepressant trials. Non-linear regression models were designed to detect associations between depressive subtypes and TRD. PSY and MEL patients appeared to be more severely affected and to share some "core" melancholic symptoms. Both PSY and MEL patients reported a higher rate of seasonality. However, we found no clinical or illness course variable associated with TRD. Our results indicate that psychotic and melancholic depression share some "core" melancholia symptoms, while no distinguishing psychopathological feature appears to be associated with TRD in severely depressed patients.


Mutation spectrum of the retinoblastoma gene in osteosarcomas.
We have performed an intensive mutation survey of the Rb gene in 63 osteosarcomas. Loss of heterozygosity (LOH) at the Rb locus was analyzed by using polymerase chain reaction at four intronic polymorphic sites, and 62.9% (39 of 62) of tumors showed LOH. Mutation analysis of the Rb gene was performed by Southern blot for structural anomalies, polymerase chain reaction-single strand conformation polymorphism analysis followed by direct genomic sequencing for subtle mutations, and immunohistochemistry for protein expression. The frequencies of each type of abnormalities were: structural anomalies, 28.6% (18 of 63); subtle mutations, 6.0% (3 of 50); negative protein expression, 53.6% (30 of 56); 54.5% (18 of 33) of tumors with LOH at the Rb locus were proved to show negative Rb expression, while 50.0% (11 of 22) of tumors without LOH also showed negative Rb, indicating that LOH at the Rb locus in osteosarcoma will not necessarily correlate with the actual inactivation of the Rb gene at the protein level. Findings in primary tumors were correlated with clinical outcome, and the presence of LOH and DNA alterations of the Rb gene were proved to indicate poor prognosis.


Operative treatment of fractures in children is increasing. A population-based study from Finland.
Epidemiological data on the incidence of surgical treatment of pediatric fractures are sparse. Our aim was to determine the incidence of in-hospital-treated fractures and of the surgical treatment of these fractures in children and adolescents. National Discharge Register data on pediatric fractures (in patients younger than the age of eighteen years) treated in the hospital in Finland between 1997 and 2006 were evaluated. During the ten-year follow-up period, the incidence (per 100,000 persons) of fractures leading to hospitalization increased by 13.5% (from 319 in 1997 to 362 in 2006; p < 0.001). This change resulted mainly from an increase in the incidence of hospital-treated upper-extremity fractures (23% increase; from 189 in 1997 to 232 in 2006). The incidence of primary fracture surgery increased by 20% (from 237 in 1997 to 284 in 2006; p < 0.001). The incidences of surgery for upper-extremity, lower-extremity, and axial fractures increased by 28%, 3.9%, and 10.7%, respectively. Within the upper-extremity-fracture group, the incremental increase was mainly due to an increase in forearm fracture surgery (62% increase; from fifty-five in 1997 to eighty-nine in 2006) (p < 0.001). Operative treatment of children's fractures has increased markedly during the last ten years. Evidence-based medical and economic data supporting this change in practice are sparse.


Seasonal and Temporal Trends of Infectious Keratitis in Northern Vietnam.
The epidemiology of corneal ulcers in Vietnam has not been well characterized. In this report, we reviewed retrospectively the microbiological data of patients with a clinical diagnosis of corneal ulcer at the microbiology laboratory of Vietnam National Eye Hospital from January 1, 2010 to March 31, 2023. We observed a seasonal pattern for fungal and microsporidial keratitis, with an annual peak in November, and an inverse relationship between fungal keratitis and inclement weather. The November peak coincided with one of the major harvesting seasons in Vietnam. We also observed increasing numbers of microsporidial and Acanthamoeba keratitis cases in recent years. Knowledge of these trends are helpful in guiding empirical treatment of corneal infections and preventing corneal blindness.


Requirement for uracil-DNA glycosylase during the transition to late-phase cytomegalovirus DNA replication.
Cytomegalovirus gene UL114, a homolog of mammalian uracil-DNA glycosylase (UNG), is required for efficient viral DNA replication. In quiescent fibroblasts, UNG mutant virus replication is delayed for 48 h and follows the virus-induced expression of cellular UNG. In contrast, mutant virus replication proceeds without delay in actively growing fibroblasts that express host cell UNG. In the absence of viral or host cell UNG expression, mutant virus fails to proceed to late-phase DNA replication, characterized by rapid DNA amplification. The data suggest that uracil incorporated early during wild-type viral DNA replication must be removed by virus or host UNG prior to late-phase amplification and encapsidation into progeny virions. The process of uracil incorporation and excision may introduce strand breaks to facilitate the transition from early-phase replication to late-phase amplification.


Association of Genes, Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort.
The mitochondrial genome encodes for the synthesis of 13 proteins that are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process, and promoting the production of reactive oxidative species. To investigate the role of the OXPHOS pathway and mitochondrial genes in colorectal cancer (CRC) risk, we tested 185 mitochondrial SNPs (mtSNPs), located in 13 genes that comprise four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort Study. Using the sequence kernel association test, we examined the collective set of 185 mtSNPs, as well as subsets of mtSNPs grouped by mitochondrial pathways, complexes, and genes, adjusting for age, sex, principal components of global ancestry, and self-reported maternal race/ethnicity. We also tested for haplogroup associations using unconditional logistic regression, adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with CRC risk (P = 0.04). In mtSNP-subset analysis, the NADH dehydrogenase 2 (MT-ND2) gene in Complex I was associated with CRC risk at a P-value of 0.001 (q = 0.015). In addition, haplogroup T was associated with CRC risk (OR = 1.66, 95% CI: 1.19-2.33, P = 0.003). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups--African Americans, Asian Americans, Latinos, and Native Hawaiians. In summary, our findings suggest that variations in the mitochondrial genome and particularly in the MT-ND2 gene may play a role in CRC risk among European Americans, but not in other maternal racial/ethnic groups. Further replication is warranted and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to CRC risk.


[Determination of ochratoxin a in spices].
The method of determination of ochratoxin A in some spices: coriander, cloves, ginger, paprika, black pepper was described. Depending on kind of matrix, extraction with metanol/water (80/20) or with solution of 1% NaHCO3 and several variants of clean-up on IAC columns were investigated. The most useful extraction solvent appeared water solution of 1% NaHCO3. In case of cloves only, none of the methods of extraction and clean-up variants was appropriate. The mean recovery of the method, dependent on kind of sample, was 61-82% and RSD% 1.4 and 7.8. The estimated LOD and LOQ were 0.02 and 0.06 microg/kg, respectively. In samples of spice used for method preparation, ochratoxin A was detected on the level 3.4-4.6 microg/kg.


Clinical observation on application of Chinese materia medica after intralaryngeal microsurgery.
41 cases still showing various symptoms and signs after having been operated on for intralaryngeal conditions were treated with Yiqi Kaiyin Tang [symbol: see text] the vital energy replenishing and voice restoring decoction). The chief clinical manifestations were hoarseness of voice, lack of strength for speech, feeling of dryness and pain in the throat with foreign body sensation or burning sensation, and aphonia. The treatment lasted 15-60 days, resulting in cure in 19 cases, improvement in 16 cases, and no response in 6 cases, making a total effectiveness rate of 85.4%.


Late-pregnancy dysglycemia in obese pregnancies after negative testing for gestational diabetes and risk of future childhood overweight: An interim analysis from a longitudinal mother-child cohort study.
Maternal pre-conception obesity is a strong risk factor for childhood overweight. However, prenatal mechanisms and their effects in susceptible gestational periods that contribute to this risk are not well understood. We aimed to assess the impact of late-pregnancy dysglycemia in obese pregnancies with negative testing for gestational diabetes mellitus (GDM) on long-term mother-child outcomes. The prospective cohort study Programming of Enhanced Adiposity Risk in Childhood-Early Screening (PEACHES) (n = 1,671) enrolled obese and normal weight mothers from August 2010 to December 2015 with trimester-specific data on glucose metabolism including GDM status at the end of the second trimester and maternal glycated hemoglobin (HbA1c) at delivery as a marker for late-pregnancy dysglycemia (HbA1c ≥ 5.7% [39 mmol/mol]). We assessed offspring short- and long-term outcomes up to 4 years, and maternal glucose metabolism 3.5 years postpartum. Multivariable linear and log-binomial regression with effects presented as mean increments (Δ) or relative risks (RRs) with 95% confidence intervals (CIs) were used to examine the association between late-pregnancy dysglycemia and outcomes. Linear mixed-effects models were used to study the longitudinal development of offspring body mass index (BMI) z-scores. The contribution of late-pregnancy dysglycemia to the association between maternal pre-conception obesity and offspring BMI was estimated using mediation analysis. In all, 898 mother-child pairs were included in this unplanned interim analysis. Among obese mothers with negative testing for GDM (n = 448), those with late-pregnancy dysglycemia (n = 135, 30.1%) had higher proportions of excessive total gestational weight gain (GWG), excessive third-trimester GWG, and offspring with large-for-gestational-age birth weight than those without. Besides higher birth weight (Δ 192 g, 95% CI 100-284) and cord-blood C-peptide concentration (Δ 0.10 ng/ml, 95% CI 0.02-0.17), offspring of these women had greater weight gain during early childhood (Δ BMI z-score per year 0.18, 95% CI 0.06-0.30, n = 262) and higher BMI z-score at 4 years (Δ 0.58, 95% CI 0.18-0.99, n = 43) than offspring of the obese, GDM-negative mothers with normal HbA1c values at delivery. Late-pregnancy dysglycemia in GDM-negative mothers accounted for about one-quarter of the association of maternal obesity with offspring BMI at age 4 years (n = 151). In contrast, childhood BMI z-scores were not affected by a diagnosis of GDM in obese pregnancies (GDM-positive: 0.58, 95% CI 0.36-0.79, versus GDM-negative: 0.62, 95% CI 0.44-0.79). One mechanism triggering late-pregnancy dysglycemia in obese, GDM-negative mothers was related to excessive third-trimester weight gain (RR 1.72, 95% CI 1.12-2.65). Furthermore, in the maternal population, we found a 4-fold (RR 4.01, 95% CI 1.97-8.17) increased risk of future prediabetes or diabetes if obese, GDM-negative women had a high versus normal HbA1c at delivery (absolute risk: 43.2% versus 10.5%). There is a potential for misclassification bias as the predominantly used GDM test procedure changed over the enrollment period. Further studies are required to validate the findings and elucidate the possible third-trimester factors contributing to future mother-child health status. Findings from this interim analysis suggest that offspring of obese mothers treated because of a diagnosis of GDM appeared to have a better BMI outcome in childhood than those of obese mothers who-following negative GDM testing-remained untreated in the last trimester and developed dysglycemia. Late-pregnancy dysglycemia related to uncontrolled weight gain may contribute to the development of child overweight and maternal diabetes. Our data suggest that negative GDM testing in obese pregnancies is not an "all-clear signal" and should not lead to reduced attention and risk awareness of physicians and obese women. Effective strategies are needed to maintain third-trimester glycemic and weight gain control among otherwise healthy obese pregnant women.


Systematic review of factors associated with hope in family carers of persons living with chronic illness.
To identify factors associated with hope in family carers of persons living with chronic illness. A systematic review of quantitative and mixed method studies on hope in carers of persons living with chronic illness. Five electronic databases (Medline, Cumulative Index to Nursing and Allied Health Literature, Web of Science, ProQuest Dissertations and PsycINFO) were searched from inception to 13 July 2020. Inclusion criteria were the following: (a) study population of adult (18 years of age and older) carers of persons living with chronic illness, (b) hope was measured as a variable, (c) reported factors associated with hope, (d) employed either quantitative or mixed methods design, (e) written in English and (f) was published in peer reviewed journals. All included studies were evaluated for quality using the Mixed Method Appraisal Tool. Twenty-six studies were included in the systematic review. Quality of life, physical and mental health, life satisfaction and the hope of care recipients were found to be positively associated with hope. Carer's coping increased (self-efficacy and caregiver preparedness) as hope increased with a decrease in maladaptive coping strategies. Anxiety, depression, distress, grief and guilt were negatively associated with carers' hope. Carers' hope did not appear to be associated with carer or care-recipient demographic variables. Carers' hope appears to be associated with the carers' over all positive health. The factors associated with carers' hope provide potential areas to focus intervention development such as strategies that increase self-efficacy. More research is needed to clarify if factors such as stage of disease and resilience are associated with hope. Research on carers' hope assessment and intervention development should also focus on factors associated with hope. The findings underscore the need to assess and work with carers of persons living with chronic illness to enhance their hope.


Principles of conjugating quantum dots to proteins via carbodiimide chemistry.
The covalent coupling of nanomaterials to bio-recognition molecules is a critical intermediate step in using nanomaterials for biology and medicine. Here we investigate the carbodiimide-mediated conjugation of fluorescent quantum dots to different proteins (e.g., immunoglobulin G, bovine serum albumin, and horseradish peroxidase). To enable these studies, we developed a simple method to isolate quantum dot bioconjugates from unconjugated quantum dots. The results show that the reactant concentrations and protein type will impact the overall number of proteins conjugated onto the surfaces of the quantum dots, homogeneity of the protein-quantum dot conjugate population, quantum efficiency, binding avidity, and enzymatic kinetics. We propose general principles that should be followed for the successful coupling of proteins to quantum dots.


Cerebral Temperature Changes Accompanying Sexual Activity in the Male Rat.
Cerebral temperature was continuously recorded in male rats during sexual activity. The temperature showed a persistent increase in the presence of females and a relatively brief, rapid increase during sexual intromission. Cerebral temperature may be usable as a sensitive measure of immediate and persisting motivational effects of transitory and longterm conditions of stimulation.


[Nodular goiter and thyroid cancer].
The available literature data and the author's observations do not support the view that nodular goiter or adenoma constitute an indispensable stage of carcinogenesis in human thyroid gland. They also suggest that the chances of malignant transformation of single nodular formations in the thyroid gland are sometimes exaggerated. Therefore, radical approach to treatment of single nodular formations should be sometimes revised and indications for surgery may be limited to a reasonable degree.


[Weak androgens, their importance experimentally and clinically].
Antisera obtained for certain hormones possessed a high specific effect on homologous hormones. Radioimmunological methods were worked out for determination of these hormones in the blood serum of humans and animals. Clinical use of the above antisera for determination of dehydroepiandrosterone and androstenedione in humans revealed than it could be useful to determine dehydroepiandrosterone in some forms of hypogonadism. Androstenedione is often increased in female hirsutism.


Neurons in the caudal ventrolateral medulla mediate the somato-sympathetic inhibitory reflex response via GABA receptors in the rostral ventrolateral medulla.
In urethane-anesthetized rabbits, stimulation of the sural nerve, consisting of cutaneous afferents (A-fibers), evoked reflex responses consisting of an early small excitatory component followed by a prolonged inhibitory component in renal sympathetic nerve activity. Bilateral injections of GABA antagonist, bicuculline (4 nmol/site), into the rostral ventrolateral medulla (RVLM), where sympatho-excitatory reticulospinal neurons are located, attenuated the inhibitory component in a dose-dependent manner as well as the inhibition evoked by stimulation of the aortic nerve A-fibers (baroreceptor afferents). Bilateral injections of a neurotoxic agent, kainic acid (4 nmol/site, 3 sites/side), into the caudal ventrolateral medulla (CVLM), where sympatho-inhibitory neurons with axonal projection to the RVLM are located, diminished these sympatho-inhibitory responses. Therefore it is concluded that the sympatho-inhibition evoked by activation of somatic afferents was mediated by neurons in the CVLM and by GABA receptors in the RVLM, as was the sympatho-inhibition associated with the arterial baroreceptor reflex. Bilateral injections of kynurenic acid (4 nmol/site, 3 sites/side) into the CVLM did not affect the somato-sympathetic reflex response, but diminished the sympatho-inhibition produced by activation of the baroreceptor afferents. Sympatho-inhibitory neurons in the CVLM were activated by glutamate when baroreceptor afferents were activated, but another excitatory transmitter may participate in the somato-sympathetic reflex in the CVLM.


Isoliquiritigenin inhibits the growth of multiple myeloma via blocking IL-6 signaling.
Previous studies have suggested that isoliquiritigenin (ISL) has anti-carcinogenic activity in several kinds of solid tumors, however, little is known about the effects of ISL on hematologic malignancies. In this study, we investigated the effects of ISL on multiple myeloma (MM) cells both in vitro and in vivo. The results showed that ISL could inhibit the growth of MM cells and induce their apoptosis in time- and dose-dependent manners. ISL exhibited significant anti-tumor activity in MM xenograft models and synergistically enhanced the anti-myeloma activity of adriamycin. Further analysis demonstrated that ISL not only downregulated IL-6 expression but also significantly decreased levels of phosphorylated ERK and STAT3 and could inhibit phosphorylation levels of ERK and STAT3 induced by recombinant human IL-6, which are critical signaling proteins in IL-6 signaling regulation networks. Taken together, our findings suggested that ISL could inhibit the growth of MM via blocking IL-6 signaling and might serve as a promising therapeutic agent for treatment of MM.


Prevalence and genetic characterization of cephalosporin-resistant Enterobacteriaceae among dogs and cats in an animal shelter.
The prevalence of antimicrobial-resistant bacteria, especially cephalosporin-resistant Enterobacteriaceae, is a major concern for human and animal health. We investigated the prevalence of cephalosporin-resistant Enterobacteriaceae among sheltered dogs and cats with various backgrounds. Faecal samples or rectal swabs were collected from 151 dogs and 182 cats, and screened for the presence of antimicrobial-resistant bacteria. Isolates were characterized phenotypically and genotypically by pulsed-field gel electrophoresis, multi-locus sequence typing and phylogenetic grouping. The animal attributes related to bacterial carriage were statistically analysed. Cephalosporin-resistant Enterobacteriaceae was detected in 22 dogs (14.6%) and 20 cats (11.0%): 21 were extended-spectrum β-lactamase (ESBL)-producing, 20 were AmpC-producing, and 1 was both ESBL- and AmpC-producing. Their β-lactamase genes were varied and associated with humans, animals or other origins. The genes CTX-M-14 (n=9) and CMY-2 (n=9) were dominant, but CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-15, CTX-M-24, CTX-M-27, CTX-M-55 and DHA-1 genes were also detected. Genotyping of isolates revealed that β-lactamase-producing Enterobacteriaceae had high genetic diversity. Relationships between animals harbouring cephalosporin-resistant Enterobacteriaceae and individual attributes, such as sex and nutrition type, were detected, but there was no correlation between history of human association and the presence of the bacterium in either dogs or cats. We found several types of cephalosporin-resistant Enterobacteriaceae distributed among companion animals with a range of individual attributes and histories in Osaka, Japan. Companion animals may play a bridging role in the circulation of antimicrobial-resistant bacteria from humans and from other origins.


Legitimating State Capital: The Global Financial Professions and the Transnationalization of Chinese Sovereign Wealth.
Increasing Chinese investment has raised the spectre of strategic state influence in Europe, yet the transformative potential of state capital as a global phenomenon remains under-explored. This article sheds light on the dual imperatives of transnationalizing state capital wherein the movement of capital entails both profit maximization and the extra-profit interests of the state. State-capitalist entities such as sovereign wealth funds (SWFs) are both market-facing and politically driven, disrupting ideological norms surrounding the strictly safe-keeper role of the state in private capital accumulation. The authors draw on the case of the China Investment Corporation, China's premier SWF, to argue that the transnationalization of state capital is a process deeply embedded in the liberal international order, and that it signals the metamorphosis of global capitalism in palimpsest-like ways. The global financial professions, namely investment banking, corporate law and management consulting along with other advisory services, have legitimated state capital by normalizing its political origins through technocratic, expert-driven practice to the effect that it is treated as no different from private capital in global capital networks. The article identifies three logics of practice by which professionals legitimate state capital: adoption, alliance and recreation of financial practices that have facilitated the embeddedness of state capital in global markets.


LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotection.
Bacterial endotoxin lipopolysaccharide (LPS) is responsible for the multiorgan dysfunction that characterizes septic shock and is causal in the myocardial depression that is a common feature of endotoxemia in patients. In this setting the myocardial dysfunction appears to be due, in part, to the production of proinflammatory cytokines. A line of evidence also indicates that LPS stimulates autophagy in cardiomyocytes. However, the signal transduction pathway leading to autophagy and its role in the heart are incompletely characterized. In this work, we wished to determine the effect of LPS on autophagy and the physiological significance of the autophagic response. Autophagy was monitored morphologically and biochemically in HL-1 cardiomyocytes, neonatal rat cardiomyocytes, and transgenic mouse hearts after the administration of bacterial LPS or TNF-alpha. We observed that autophagy was increased after exposure to LPS or TNF-alpha, which is induced by LPS. The inhibition of TNF-alpha production by AG126 significantly reduced the accumulation of autophagosomes both in cell culture and in vivo. The inhibition of p38 MAPK or nitric oxide synthase by pharmacological inhibitors also reduced autophagy. Nitric oxide or H(2)O(2) induced autophagy in cardiomyocytes, whereas N-acetyl-cysteine, a potent antioxidant, suppressed autophagy. LPS resulted in increased reactive oxygen species (ROS) production and decreased total glutathione. To test the hypothesis that autophagy might serve as a damage control mechanism to limit further ROS production, we induced autophagy with rapamycin before LPS exposure. The activation of autophagy by rapamycin suppressed LPS-mediated ROS production and protected cells against LPS toxicity. These findings support the notion that autophagy is a cytoprotective response to LPS-induced cardiomyocyte injury; additional studies are needed to determine the therapeutic implications.