Reassessing the Importance of PrEP Use Given Reduced Sex During the COVID-19 Pandemic: Perspectives From a Sample of Young Sexual Minority Men.
Research has begun to examine sexual behavior during the COVID-19 pandemic using quantitative methods, but less is known about the context surrounding these changes using qualitative methods, including corresponding changes in risk reduction methods. This qualitative study, guided by the Integrated Behavioral Model, examines the pandemic's impact on PrEP adherence among young men who have sex with men in Chicago. PrEP-using participants from a cohort study were recruited into a 90-day diary study measuring sexual behaviors and PrEP use. Between April and September 2020, a subset of participants was recruited for qualitative interviews (n = 28) exploring prevention strategies, including the impact of the pandemic. Although most were highly adherent pre-pandemic, many took fewer pills or discontinued during the pandemic due to decreased sex. Findings suggest the importance of counseling for PrEP reinitiation as "seasons of HIV risk" increase, as well as use of telehealth as a facilitator of PrEP use throughout the pandemic.


[Impact of antioxidative therapy on the activity of salivary glutathione-dependent enzymes in patients with fluorosis].
Fluorosis caused by long-term intake of high fluoride levels is characterized by clinical bone and tooth manifestations. The adverse impact of high fluoride intake was also observed in soft tissues. Although fluorosis is irreversible it could be prevented by appropriate and timely interventions through the understanding of the process at biochemical and molecular levels. Increased production of reactive oxygen forms and lipid peroxidation are considered to play an important role in the pathogenesis of chronic fluoride toxicity. Saliva is a biological fluid of the human organism may be a reflection of the metabolic state. Salivary indices are clinical diagnostic indicators. The purpose of this investigation was to comparatively study the salivary antioxidative defense system, including glutathione, glutathione reductase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase in adult patients with fluorosis before and after complex antioxidative therapy. Analysis indicated that there was a negative correlation between the level of glutathione and the clinical characteristics of the disease in patients with fluorosis. There was a direct relationship between the activity of glutathione-S-transferase and the clinical manifestations in the patients. These results reflected dose-dependent fluoride intoxication and metabolic imbalance. The imbalanced salivary antioxidative defense system was in part corrected by complex antioxidative therapy.


The Multidimensional Self-Control Scale (MSCS): Development and validation.
Trait self-control is important for well-being and mental and physical health. Most extant measures of self-control are limited in that they do not account for the multidimensionality and specificity of the trait. The aim of this study was to develop and validate a multidimensional and hierarchical scale of self-control in a full and a short version. The development of the Multidimensional Self-Control Scale (MSCS) and the Brief Multidimensional Self-Control Scale (BMSCS) was based on focus groups, a pilot, a main, and a validation sample (total N = 2,409). The 29-item MSCS consists of 6 first-order factors (Procrastination, Attentional Control, Impulse Control, Emotional Control, Goal Orientation, and Self-Control Strategies), 2 second-order factors (Inhibition and Initiation), and a third-order self-control factor. The 8 items in BMSCS provides a general trait self-control score. Findings from exploratory and confirmatory factor analyses supported the structures across samples, and internal consistency was acceptable. Assessment for acquiescence and sex differences indicated no major impacts on the scales. Strong convergent validity was observed with the Self-Control Scale (SCS) and the Brief Self-Control Scale (BSCS), as well as to other similar concepts. The MSCS subscales discriminated well between each other. Assessment of incremental validity of the MSCS over SCS, when controlling for sex and personality, showed significant increases in explained variance when predicting habits, hardiness, and life satisfaction. Similar significant results were observed for the BMSCS over the BSCS. Overall, results indicate that the new scales are useful measures that integrate recent theoretical and empirical findings of trait self-control. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Amniotic membranes in the treatment of necrotizing fasciitis complicating vulvar herpes virus infection.
Necrotizing fasciitis of the vulva developed in an immunocompromised patient with chronic myelogenous leukemia, apparently from secondarily infected herpes simplex lesions. In addition to surgical debridements and broad-spectrum intravenous antibiotic therapy, the wound was treated using specially prepared amniotic membranes as a wound dressing. The patient died on hospital day 65 because of complications of her immunocompromised state, with autopsy findings of disseminated cytomegalovirus. However, use of amniotic membranes as a wound dressing appeared to be beneficial.


From Mice to Men: Generation of Human Blastocyst-Like Structures In Vitro.
Advances in the field of stem cell-based models have in recent years lead to the development of blastocyst-like structures termed blastoids. Blastoids can be used to study key events in mammalian pre-implantation development, as they mimic the blastocyst morphologically and transcriptionally, can progress to the post-implantation stage and can be generated in large numbers. Blastoids were originally developed using mouse pluripotent stem cells, and since several groups have successfully generated blastocyst models of the human system. Here we provide a comparison of the mouse and human protocols with the aim of deriving the core requirements for blastoid formation, discuss the models' current ability to mimic blastocysts and give an outlook on potential future applications.


Looking across Scales in Disease Ecology and Evolution.
AbstractOver the past few decades, it has become clear that ecological and evolutionary dynamics are influenced by processes operating across spatial and temporal scales. Processes that operate on small spatial scales have the potential to influence dynamics at much larger scales; for example, a change in the physiology of a primary producer can alter primary productivity in an ecosystem. Similarly, evolution-a process that historically was thought of as occurring at longer timescales-can influence ecological dynamics and vice versa. The importance of considering multiple scales is broadly true in ecology and evolution, and it is especially important for studies of disease ecology and evolution. Yet characterizing the scales at which individual studies operate is surprisingly challenging, as we (re)discovered while trying to characterize articles published in this journal over the past three decades. However, while it is difficult to determine where one scale ends and another begins, it is also clear that work that spans across a spectrum can yield insights that could not be gleaned from a narrower focus. To demonstrate this, we highlight studies previously published in this journal that show the value of working across scales. We then introduce the six articles that comprise this Focused Topic section. Together, these articles present systems, theory, and methods that provide important insights that could not have been obtained from studying a single scale in isolation.


The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated-Interferon versus Entecavir Therapy.
To explore the role of natural killer (NK) cells in the process of hepatitis B virus (HBV) clearance and whether their phenotype is related to antiviral treatment outcome in chronic hepatitis B (CHB) patients. We performed a single-center prospective cohort study to analyze changes of NK cells at weeks 12 and 24 from baseline in CHB patients who received PEGylated-interferon- (PEG-IFN-) α-2a versus entecavir. The frequencies of NK, CD56bright, CD56dim, IFNAR2+, NKp46+, NKp46bright, and NKp46dim NK cells and mean fluorescence intensity (MFI) of receptors NKp46 and IFNAR2 on the surface of NK cells were measured. Subgroup analyses were performed by comparing treatment responders versus nonresponders with aforementioned parameters in each group. In PEG-IFN-α-treated patients, posttreatment CD56bright NK cell frequency increased, but CD56dim NK cell frequency decreased. Additionally, receptor NKp46 and IFNAR2 expression enhanced. In entecavir-treated patients, although NK cell frequency increased, CD56bright and CD56dim NK cell frequencies and IFNAR2 expression did not differ between baseline and posttreatment. In subgroup analyses, posttreatment CD56bright NK cell frequency and IFNAR2 expression significantly increased in PEG-IFN-α responders from baseline, while changes were absent in PEG-IFN-α nonresponders and entecavir treatment responders. Among patients with HBV viremia after entecavir therapy, NK cell frequency significantly increased, whereas NKp46bright and IFNAR2+ NK frequency and IFNAR2 MFI significantly decreased at 12 and 24 weeks from baseline. In CHB patients, PEG-IFN-α treatment significantly enhanced NK cell frequency and function when compared to entacavir. Positive treatment responses to either interferon or entecavir were associated with NK cell function improvement. This trial is registered with clinical trial registration no. NCT03208998.


Intrathecal tramadol versus intrathecal fentanyl for visceral pain control during bupivacaine subarachnoid block for open appendicectomy.
Profound side-effects following intrathecal use of local anesthetics as the sole drugs of choice make spinal anesthesia for open appendicectomy uncommon. The aim of this study was to evaluate the effectiveness of intra-operative analgesia produced by intrathecal tramadol and fentanyl during bupivacaine spinal anesthesia for open appendicectomy. A prospective randomized study was performed. A total of 186 American Society of Anesthesiologists 1 or 11 patients scheduled for emergency open appendicectomy were analyzed. Group FB ( n = 62) received intrathecal fentanyl 25 μg plus 3 ml of 0.5% hyperbaric bupivacaine, Group SB ( n = 62) received 0.5 ml normal saline plus 3 ml of 0.5% hyperbaric bupivacaine and Group TB ( n = 62) received intrathecal tramadol 25 mg plus 3 ml of 0.5% hyperbaric bupivacaine. Visual analog scale scores and frequency of subjective symptoms among patients in the three groups formed the primary outcome measure of this study. Effective intraoperative sensory block was achieved in 100% of patients in group FB and TB while 29 (46.8%) patients in group SB had ineffective sensory block ( P = 0.0001). The pain free period was significantly longer in patients in Group FB than Group SB and TB. Mean time for Group FB with regard to first analgesic request was 304.73 ± 67.91 min, Group SB was 146.59 ± 36.62 and Group TB was 238.39 ± 61.28 min. Incidence of complications were comparable among the three groups. This study showed that intrathecal tramadol (25 mg) can safely replace intrathecal fentanyl (25 μg) in the management of visceral pain and discomfort during subarachnoid block for appendicectomy.


The role of gut microbiota in immune homeostasis and autoimmunity.
Keeping a delicate balance in the immune system by eliminating invading pathogens, while still maintaining self-tolerance to avoid autoimmunity, is critical for the body's health. The gut microbiota that resides in the gastrointestinal tract provides essential health benefits to its host, particularly by regulating immune homeostasis. Moreover, it has recently become obvious that alterations of these gut microbial communities can cause immune dysregulation, leading to autoimmune disorders. Here we review the advances in our understanding of how the gut microbiota regulates innate and adaptive immune homeostasis, which in turn can affect the development of not only intestinal but also systemic autoimmune diseases. Exploring the interaction of gut microbes and the host immune system will not only allow us to understand the pathogenesis of autoimmune diseases but will also provide us new foundations for the design of novel immuno- or microbe-based therapies.


High Curie temperature and carrier mobility of novel Fe, Co and Ni carbide MXenes.
Two-dimensional (2D) magnets with room temperature ferromagnetism and semiconductors with moderate band gap and high carrier mobility are highly desired for applications in nanoscale electronics and spintronics. By performing the first-principles calculations, we investigate novel Fe, Co, Ni carbide based pristine (M2C) and functionalized (M2CT2, T: F, O, OH) MXenes. Our calculations show that Fe2C, Co2C, Ni2C, Fe2CF2, Fe2CO2, Fe2C(OH)2, Co2CF2, Co2C(OH)2 and Ni2CF2 are dynamically and mechanically stable. More importantly, Fe2C, Co2C, Fe2CF2 and Fe2C(OH)2 exhibit intrinsic ferromagnetism (magnetic moments 2-5μB per unit cell). Monte Carlo simulations suggest high Curie temperatures of 590 and 920 K for Fe2C and Fe2CF2, respectively, at the HSE06 level owing to the large spin magnetic moments and strong ferromagnetic coupling. Based on the deformation potential theory, we predict high and anisotropic hole mobility (0.2-1.4 × 104 cm2 V-1 s-1) for semiconducting Fe2CO2 and Co2C(OH)2. Additionally, Ni2CF2 demonstrates highly anisotropic electron mobility together with a direct band gap. Our results further show the effectiveness of surface functionalization in modulating the electronic and magnetic properties and broadening the properties of MXenes to achieve long-range intrinsic ferromagnetism well above room temperature and high carrier mobility.


Association between miscarriage and cardiovascular disease in a Scottish cohort.
To assess if miscarriage, whether consecutive or not, is associated with an increased risk of subsequent cardiovascular disease. A cohort study was performed using women with at least one miscarriage or live birth recorded from 1950 to 2010 in the Aberdeen Maternity and Neonatal Databank. The exposed groups consisted of women with non-consecutive, two consecutive or three or more consecutive miscarriages; the unexposed group consisted of all women with at least one live birth and no miscarriages. Women were linked to Scottish Morbidity Records for hospital admissions for cardiovascular conditions, cardiac surgery and death registrations. Main outcome measures were ischaemic heart disease, cerebrovascular disease and a composite outcome of any disease of circulatory system. A sensitivity analysis was performed dividing the women into those who had one, two or three or more miscarriages irrespective of whether these events were consecutive or not. After excluding women with pre-existing hypertension, type 1 diabetes mellitus, kidney disease and 'disease of circulatory system', 60,105 women were analysed; 9419 with non-consecutive, 940 with two consecutive, 167 with three or more consecutive miscarriages and 49,579 with no miscarriage. In the multivariate analyses, a significant association was found between ischaemic heart disease and women with two (HRs 1.75 (95% CI 1.22 to 2.52)) or three or more (HR 3.18 (95% CI 1.49 to 6.80)) consecutive miscarriages. Similar patterns of risk were observed in the sensitivity analysis. Women with a history of two or more miscarriages, irrespective of whether consecutive or not, appear to have an increased risk of ischaemic heart disease.


Polar and nonpolar atomic environments in the protein core: implications for folding and binding.
Hydrophobic interactions are believed to play an important role in protein folding and stability. Semi-empirical attempts to estimate these interactions are usually based on a model of solvation, whose contribution to the stability of proteins is assumed to be proportional to the surface area buried upon folding. Here we propose an extension of this idea by defining an environment free energy that characterizes the environment of each atom of the protein, including solvent, polar or nonpolar atoms of the same protein or of another molecule that interacts with the protein. In our model, the difference of this environment free energy between the folded state and the unfolded (extended) state of a protein is shown to be proportional to the area buried by nonpolar atoms upon folding. General properties of this environment free energy are derived from statistical studies on a database of 82 well-refined protein structures. This free energy is shown to be able to discriminate misfolded from correct structural models, to provide an estimate of the stabilization due to oligomerization, and to predict the stability of mutants in which hydrophobic residues have been substituted by site-directed mutagenesis, provided that no large structural modifications occur.


Consensus and tools needed to measure health care emergency management capabilities.
There is no widely accepted, validated framework of health care emergency management capabilities (HEMCs) that can be used by facilities to guide their disaster preparedness and response efforts. We reviewed the HEMCs and the evaluation methods used by the Veterans Health Administration, The Joint Commission, the Institute of Medicine Metropolitan Medical Response System committee, the Department of Homeland Security, and the Department of Health and Human Services to determine whether a core set of HEMCs and evaluative methods could be identified.Despite differences in the conceptualization of health care emergency management, there is considerable overlap among the agencies regarding major capabilities and capability-specific elements. Of the 5 agencies, 4 identified occupant safety and continuity of operations as major capabilities. An additional 5 capabilities were identified as major by 3 agencies. Most often the differences were related to whether a capability should be a major one versus a capability-specific element (eg, decontamination, management of resources). All of the agencies rely on multiple indicators and data sources to evaluate HEMCs. Few performance-based tools have been developed and none have been fully tested for their reliability and validity. Consensus on a framework and tools to measure HEMCs is needed.


Enzyme-histochemical staining of dermal lymphatic capillaries by guanylate cyclase.
Human foreskins were examined for enzyme-histochemical staining of microvessels using guanylate cyclase, an enzyme similar to adenylate cyclase. Like 5'-nucleotidase (which hydrolyzes 5'-adenosine monophosphate to adenosine), and adenylate cyclase (which converts adenosine triphosphate to cyclic AMP), guanylate cyclase selectively stains positive for lymphatic capillaries and therefore may be another useful histochemical marker to differentiate dermal lymph from blood capillaries.


Dopamine regulation of amiloride-sensitive sodium channels in lung cells.
Dopamine increases lung fluid clearance. This is partly due to activation of basolateral Na-K-ATPase. However, activation of Na-K-ATPase by itself is unlikely to produce large changes in transepithelial transport. Therefore, we examined apical and basolateral dopamine's effect on apical, highly selective sodium channels [epithelial sodium channels (ENaC)] in monolayers of an alveolar type 2 cell line (L2). Dopamine increased channel open probability (P(o)) without changing the unitary current. The D(1) receptor blocker SCH-23390 blocked the dopamine effect, but the D(2) receptor blocker sulpiride did not. The dopamine-mediated increase in ENaC activity was not a secondary effect of dopamine stimulation of Na-K-ATPase, since ouabain applied to the basolateral surface to block the activity of Na-K-ATPase did not alter dopamine-mediated ENaC activity. Protein kinase A (PKA) was not responsible for dopamine's effect since a PKA inhibitor, H89, did not reduce dopamine's effect. However, cpt-2-O-Me-cAMP, which selectively binds and activates EPAC (exchange protein activated by cAMP) but not PKA, increased ENaC P(o). An Src inhibitor, PP2, and the phosphatidylinositol-3-kinase inhibitor, LY-294002, blocked dopamine's effect on ENaC. In addition, an MEK blocker, U0126, an inhibitor of phospholipase A(2), and a protein phosphatase inhibitor also blocked the effect of dopamine on ENaC P(o). Finally, since the cAMP-EPAC-Rap1 pathway also activates DARPP32 (32-kDa dopamine response protein phosphatase), we confirmed that dopamine phosphorylates DARPP32, and okadaic acid, which blocks phosphatases (DARPP32), also blocks dopamine's effect. In summary, dopamine increases ENaC activity by a cAMP-mediated alternative signaling pathway involving EPAC and Rap1, signaling molecules usually associated with growth-factor-activated receptors.


A change in response to Bmp signalling precedes ectodermal fate choice.
Bone morphogenetic protein (Bmp) signalling plays a central role in the decision of ectoderm to adopt either neural or non-neural fates. The effects of this signalling are seen at mid-gastrulation in the activation of genes such as the Gata factors and the repression of genes such as the SoxB1 transcription factors in the non-neural regions. Using zebrafish embryos, we show that this Bmp signalling does not repress the expression of these same neural markers just 2-3 hours earlier. Since expression of the Bmp signalling effector, Smad1, only begins during early gastrulation, we tested the role of Smad1 and Smad5 (which is maternally expressed) in controlling gene expression both before and during gastrulation. This showed that the absence of Smad1 does not explain the lack of response of neural genes to Bmp signalling at early stages. However, these experiments showed that expression of the non-neural marker, gata2, is mediated by Smad5 in the absence of Smad1 at early stages, but is dependent upon Smad1 at later stages. Hence, we have shown a dynamic change in the molecular machinery underlying the Bmp response in the ectoderm during gastrulation stages of development.


Overexpression of endoglin (CD105) is associated with recurrence in radically resected gastric cancer.
The aim of this study was to examine the expression of endoglin (CD105) in resected gastric cancer and to evaluate the relationship between microvessel density (MVD) and tumor recurrence after surgery. One hundred and thirty-two patients who had undergone curative surgery for primary gastric cancer were immunohistochemically stained for CD105, and MVD was assessed based on the number of CD105-positive vessels. MMP-7 expression was also investigated to determine the relationship with MVD. High MVD was significantly correlated with worse relapse-free survival in all cases and stage I-II cases by log-rank test (p=0.0005 and p=0.0154, respectively). Furthermore, in stage I-II cases, high MVD was the only independent predictor for relapse-free survival by multivariate analysis of the Cox proportional hazard model [p=0.028; hazard ratio (HR)=4.582; 95% confidence interval (CI) 1.184-17.737]. Regarding the specific patterns of recurrence, high MVD was independently related to locoregional recurrence [p=0.011; odds ratio (OR)=15.208; 95% CI 1.886-122.662] and hematogenous recurrence (p=0.002; OR=5.718; 95% CI 1.875-17.442) by multivariate logistic analysis. However, the expression of MMP-7 or CD105 combined with MVD was associated with relapse-free survival, although these prognostic impacts were not maintained in multivariate analysis. In conclusion, MVD recognized by CD105 may be useful as a predictor for the recurrence of resected gastric cancer and may have a specific association with the development of locoregional and hematogenous recurrence.


Does Haber's law apply to human sensory irritation?
Irritation of the eyes, nose, and throat by airborne chemicals--also referred to as "sensory irritation"--is an important endpoint in both occupational and environmental toxicology. Modeling of human sensory irritation relies on knowledge of the physical chemistry of the compound(s) involved, as well as the exposure parameters (concentration and duration). A reciprocal relationship between these two exposure variables is postulated under Haber's law, implying that protracted, low-level exposures may be toxicologically equivalent to brief, high-level exposures. Although time is recognized as having an influence on sensory irritation, the quantitative predictions of Haber's Law have been addressed for only a handful of compounds in human experimental studies. We have conducted a systematic literature review that includes a semiquantitative comparison of psychophysical data extracted from controlled human exposure studies versus. the predictions of Haber's law. Studies containing relevant data involved exposures to ammonia (2), chlorine (2), formaldehyde (1), inorganic dusts such as calcium oxide (1), and the volatile organic compound 1-octene (1). With the exception of dust exposure, varying exposure concentration has a proportionally greater effect on sensory irritation than does changing exposure duration. For selected time windows, a more generalized power law model (c(n) x t = k) rather than Haber's law per se (c x t = k) yields reasonably robust predictions. Complicating this picture, however, is the frequent observation of intensity-time "plateauing," with time effects disappearing, or even reversing, after a relatively short period, depending on the test compound. The implications of these complex temporal dynamics for risk assessment and standard setting have been incompletely explored to date.


Punctate inner choroidopathy: a survey analysis of 77 persons.
To evaluate the demographic and clinical features of punctate inner choroidopathy (PIC). Noncomparative survey. Persons with PIC who were in contact with the PIC Society. A survey was designed and posted on the Web site of the PIC Society, and persons diagnosed with PIC were invited to participate. Seventy-seven persons with PIC completed the survey. Demographics, presenting symptoms, disease manifestations, treatment regimens, and ocular complications. Of the 77 participants who completed the survey, 90% were women, 97% Caucasian, and 85% myopic. The median age of participants was 30 years (range, 15-55). The median duration of disease at the time of survey completion was 3 years (range, <1-14). Reported presenting symptoms of PIC included scotomata (91%), blurred vision (86%), photopsias (73%), floaters (69%), photophobia (69%), metamorphopsia (65%), and loss of peripheral vision (26%). Eighty-five percent reported unilateral scotomata initially. Thirty-two percent of participants reported waxing and waning symptoms before treatment. The majority of participants (86%) had received treatment, most commonly with systemic (60%) and/or intraocular corticosteroids (22%). Fourteen percent of participants reported treatment with at least one immunosuppressive agent at some time during their disease. Sixty-nine percent had been diagnosed with choroidal neovascularization and 56% with subretinal fibrosis in at least one eye. In 75% of respondents, the onset of choroidal neovascularization occurred less than 1 year after the presenting symptoms of PIC, and in 79%, the onset of subretinal fibrosis occurred less than 1 year after the presenting symptoms. In this survey of 77 persons with PIC, the majority of respondents were young, myopic, Caucasian women, who experienced unilateral scotoma and blurred vision as initial symptoms. The ocular complications choroidal neovascularization and subretinal fibrosis were present in the majority of participants in at least one eye and typically occurred within the first year of initial symptoms.


Human anti-60 kD heat shock protein autoantibodies are characterized by basic features of natural autoantibodies.
Anti-human Hsp60 autoantibodies--known risk factor of atherosclerosis--were investigated in a mouse model and in samples of healthy subjects: polyreactivity, presence in cord blood samples of healthy newborns and life-long stability were tested. In IgM hybridoma panel from mouse spleens, polyreactivity of anti-Hsp60 autoantibodies was studied. In healthy pregnant women, umbilical vein and maternal blood samples were collected after childbirth, anti-Hsp-60 and -65 IgM and IgG levels were measured. Life-long stability of anti-Hsp-60 levels was studied on healthy patients during 5 years. ELISA was used in all studies. Polyreactivity of IgM clones of newborn mice and lifelong stability of these autoantibodies in healthy adults were established. IgM anti-Hsp60 autoantibodies in cord blood of healthy human infants were present, however, there was no correlation between maternal and cord blood IgM anti-Hsp60 concentrations. It is proposed that presence of anti-Hsp60 autoantibodies--as part of the natural autoantibody repertoire--may be an inherited trait. Level of anti-Hsp60 autoantibodies may be an independent, innate risk factor of atherosclerosis for the adulthood.


Novel probiotic Bifidobacterium bifidum CECT 7366 strain active against the pathogenic bacterium Helicobacter pylori.
Helicobacter pylori is considered one of the major risk factors underlying the development of gastritis and gastric and duodenal ulcers. Moreover, 50% of the population carries this bacterium, and consequently, when it is detected, eradication of H. pylori is strongly recommended. Regarding the use of probiotics as functional agents, several studies have shown that there is a direct relationship between the addition of certain probiotic bacteria and in vitro inhibition of H. pylori; however, in vivo studies showing bifidobacterial activity against H. pylori remain scarce. In this study, a Bifidobacterium bifidum strain which proved active in vitro against H. pylori has been isolated, with inhibition levels reaching 81.94% in the case of the supernatant and even 94.77% inhibition for supernatant purified by cationic exchange followed by an inverse phase. In vivo studies using a BALB/c mouse model have proved that this strain partially relieves damage to gastric tissues caused by the pathogen and also decreases the H. pylori pathogenicity ratio. This novel strain fulfills the main properties required of a probiotic (resistance to gastrointestinal juices, biliary salts, NaCl, and low pH; adhesion to intestinal mucus; and sensitivity to antibiotics). Furthermore, the absence of undesirable metabolites has been demonstrated, and its food safety status has been confirmed by acute ingestion studies in mice. In summary, the results presented here demonstrate that Bifidobacterium bifidum CECT 7366 can be considered a probiotic able to inhibit H. pylori both in vitro and in vivo.


Enhanced autophagy ameliorates cardiac proteinopathy.
Basal autophagy is a crucial mechanism in cellular homeostasis, underlying both normal cellular recycling and the clearance of damaged or misfolded proteins, organelles and aggregates. We showed here that enhanced levels of autophagy induced by either autophagic gene overexpression or voluntary exercise ameliorated desmin-related cardiomyopathy (DRC). To increase levels of basal autophagy, we generated an inducible Tg mouse expressing autophagy-related 7 (Atg7), a critical and rate-limiting autophagy protein. Hearts from these mice had enhanced autophagy, but normal morphology and function. We crossed these mice with CryABR120G mice, a model of DRC in which autophagy is significantly attenuated in the heart, to test the functional significance of autophagy activation in a proteotoxic model of heart failure. Sustained Atg7-induced autophagy in the CryABR120G hearts decreased interstitial fibrosis, ameliorated ventricular dysfunction, decreased cardiac hypertrophy, reduced intracellular aggregates and prolonged survival. To determine whether different methods of autophagy upregulation have additive or even synergistic benefits, we subjected the autophagy-deficient CryABR120G mice and the Atg7-crossed CryABR120G mice to voluntary exercise, which also upregulates autophagy. The entire exercised Atg7-crossed CryABR120G cohort survived to 7 months. These findings suggest that activating autophagy may be a viable therapeutic strategy for improving cardiac performance under proteotoxic conditions.


Risk and protective factors, longitudinal research, and bullying prevention.
This chapter presents the results from two systematic/meta-analytic reviews of longitudinal studies on the association of school bullying (perpetration and victimization) with adverse health and criminal outcomes later in life. Significant associations between the two predictors and the outcomes are found even after controlling for other major childhood risk factors that are measured before school bullying. The results indicate that effective antibullying programs should be encouraged. They could be viewed as a form of early crime prevention as well as an early form of public health promotion. The findings from a systematic/meta-analytic review on the effectiveness of antibullying programs are also presented. Overall, school-based antibullying programs are effective, leading to an average decrease in bullying of 20 to 23 percent and in victimization of 17 to 20 percent. The chapter emphasizes the lack of prospective longitudinal research in the area of school bullying, which does not allow examination of whether any given factor (individual, family,. or social) is a correlate, a predictor, or a possible cause for bullying. This has important implications for future antibullying initiatives, as well as implications for the refinement of theories of school bullying. It is necessary to extend the framework of the traditional risk-focused approach by incorporating the notion of resiliency and investigating possible protective factors against school bullying and its negative consequences.


Investigating the relation between imagery and perception: evidence from face priming.
The relation between imagery and perception was investigated in face priming. Two experiments are reported in which subjects either saw or imagined the faces of celebrities. They were later given a speeded perceptual test (familiarity judgement to pictures of celebrities) or a speeded imagery test (in which they were told the names of celebrities and asked to make a decision about their appearance). Seeing faces primed the perceptual test, and imaging faces primed the imagery test; however, there was no priming between seeing and imaging faces. These results show that perception and imagery can be dissociated in normal subjects. In two further experiments, we examined the effects of imaging faces on a subsequent face-naming task and on a task requiring familiarity judgements to partial faces. Both these tasks were facilitated by prior imaging of faces. These results are discussed in relation to those of McDermott & Roediger (1994), who found that imagery promoted object priming in a perceptual test involving naming partial line drawings. The implications for models of face recognition are also discussed.


[Cross-cultural adaptation of the Eating Disorder Examination into Spanish].
This study presents a cross-cultural adaptation into Spanish of the Eating Disorder Examination (EDE) by Fairburn and Cooper (1993). The original English version was adapted by means of a complex successive translation-backtranslation procedure. The final Spanish version was then applied to 50 patients with eating disorders (17 diagnosed for anorexia nervosa, 19 for bulimia nervosa, and 14 for binge eating disorder) and to 30 normal control subjects. The means and standard deviations of the group in the 4 subscales were similar to the data obtained by the normative studies of the original English version. The Spanish version also showed similarly high Cronbach alpha coefficients for reliability. As for discriminative validity, the subscales discriminated significantly between the clinical groups and the control group. The Spanish version of the EDE presents adequate psychometric properties, similar to the original version.


Risk factors for cerebral edema in diabetic ketoacidosis in a developing country: role of fluid refractory shock.
To study the clinical profile and risk factors of cerebral edema in children with diabetic ketoacidosis with specific reference to fluid refractory shock. Retrospective review of medical records. Twelve-bed pediatric intensive care unit of a teaching hospital. Seventy-seven patients admitted to pediatric intensive care unit with a diagnosis of diabetic ketoacidosis over 5 yrs. Medical records were reviewed, and data with respect to patients' age, clinical features, biochemical profile (blood glucose, osmolality, electrolytes, urea, creatinine, arterial pH, PaCO(2), and HCO(3) at admission, 6-12 hrs, 24 hrs, and beyond 24 hrs), cerebral edema, presence of sepsis and shock, treatment details, and primary outcome in terms of survival or death were retrieved. Patients with and without cerebral edema were compared. Variables that were significant on univariate analysis were entered in a multiple logistic regression analysis to determine the predictors for cerebral edema. Odds ratio and 95% confidence interval were calculated using SPSS version 15. Mean age of the patients was 5.6 (standard deviation, 3.8) years. Fifty-five (71.4%) patients had new-onset diabetes mellitus. Cerebral edema was seen in 20 patients (26%). Blood glucose, serum osmolality, and CO(2) values at admission and rate of decline in glucose and osmolality during the first 12 hrs were similar in the cerebral edema and noncerebral edema groups. On multiple logistic regression analysis, fluid refractory shock (odds ratio, 7.3; 95% confidence interval, 1.3-41; p = .025) and presence of azotemia (odds ratio, 4.3; 95% confidence interval, 1.1-16; p = .034) at admission were predictors for development of cerebral edema. Mortality in cerebral edema group was 25% as compared to 3% in the noncerebral edema group. Patients with fluid refractory shock and azotemia at admission had higher odds for development of cerebral edema. Initial blood glucose, effective osmolality, or decline in glucose and osmolality had no association with cerebral edema.


Extracellular Vesicles as Potential Biomarkers for Early Detection and Diagnosis of Pancreatic Cancer.
Pancreatic carcinoma (PC) is highly metastatic, and it tends to be detected at advanced stages. Identifying and developing biomarkers for early detection of PC is crucial for a potentially curative treatment. Extracellular vesicles (EVs) are bilayer lipid membrane-structured nanovesicles found in various human bodily fluids, and they play important roles in tumor biogenesis and metastasis. Cancer-derived EVs are enriched with DNA, RNA, protein, and lipid, and they have emerged as attractive diagnostic biomarkers for early detection of PC. In this article, we provided an overview of the cell biology of EVs and their isolation and analysis, and their roles in cancer pathogenesis and progression. Multiplatform analyses of plasma-based exosomes for genomic DNA, micro RNA, mRNA, circular RNA, and protein for diagnosis of PC were critically reviewed. Numerous lines of evidence demonstrate that liquid biopsy with analysis of EV-based biomarkers has variable performance for diagnosis of PC. Future investigation is indicated to optimize the methodology for isolating and analyzing EVs and to identify the combination of EV-based biomarkers and other clinical datasets, with the goal of improving the predictive value, sensitivity, and specificity of screening tests for early detection and diagnosis of PC.


Is irritable bowel syndrome also present in dogs?
Irritable bowel syndrome (IBS) in humans is described as the recurrent presence of gastrointestinal signs, without gross histopathologic evidence of inflammation and of other morphologic lesions; however, it is a syndrome not unanimously defined in veterinary medicine. There is some evidence that dysmotility could be related to stressors in some dogs that present with clinical signs (e.g. chronic idiopathic large-bowel diarrhea) that share overlapping aspects with human IBS. The authors hypothesize that an IBS-like condition, similar to that described in humans, might also be present in dogs. Nevertheless, the diagnostic path for canine IBS needs to be further elucidated and its pathogenesis better defined for a more rational therapeutic approach.


The PML isoform IV is a negative regulator of nuclear EGFR's transcriptional activity in lung cancer.
Epidermal growth factor receptor (EGFR) is a membrane-bound receptor tyrosine kinase, which can transduce intracellular signals responsible for cell proliferation. It is frequently overexpressed and/or constitutively activated in non-small cell lung cancer and thus is considered as a major cause of this disease. Recently, EGFR has been found in the nucleus where the nuclear EGFR (nEGFR) can function as a transcription factor activating the transcription of genes such as cyclin D1 gene (CCND1), which is essential for cell proliferation. Nevertheless, how nEGFR's transcriptional activity is regulated remains unclear. Promyelocytic leukemia protein (PML) is a tumor suppressor, which is lost in various cancers including lung cancer. However, the role of PML in the suppression of lung cancer growth is still unclear. When we investigated the role of PML in the regulation of lung cancer cell growth, we found that PML isoform IV (PMLIV) preferentially represses the growth of lung cancer cells bearing constitutively active EGFR. Besides, when growing in the EGFR activating conditions, the growth of EGFR wild-type bearing A549 cells has been repressed by PMLIV overexpression. We also found that PMLIV can interact physically with nEGFR and represses the transcription of nEGFR target genes. We showed that PMLIV is recruited by nEGFR to the target promoters and reduces the promoter histone acetylation level via HDAC1. Together, our results suggest that PMLIV interacts with nEGFR upon EGFR activation and represses the transcription of nEGFR target genes such as CCND1 and thus leading to inhibition of the lung cancer cell growth.


Radiologic and neuroradiologic findings in the mucopolysaccharidoses.
The mucopolysaccharidoses (MPS) represent a group of inheritable, clinically heterogeneous lysosomal storage disorders, in which progressive accumulation of glycosaminoglycans (GAGs) can affect organs and tissues all over the body. The current paper discusses the skeletal X-ray and neuroimaging findings in MPS patients, and the imaging techniques that can be used for diagnosing and monitoring abnormalities in the skeleton and central nervous system. Most MPS types show a typical radiologic expression, called dysostosis multiplex, which manifests as malformations of the skeletal system involving bones in the skull, thorax, spine, pelvis, long bones, and hands. Abnormalities of the spine and GAG deposits in the meninges surrounding the spinal cord can result in spinal cord compression, which, if untreated, can lead to compressive myelopathy. Magnetic resonance imaging (MRI) is the most powerful imaging technique for detecting spinal cord compression, but also radiography and computed tomography are useful. GAG deposits in the brain and surrounding tissues can result in brain anomalies, i.e. white matter lesions, brain atrophy, and hydrocephalus, which can be detected using MRI. Skeletal X-ray and neuroimaging findings can play an important role in diagnosis, follow-up, surgical or medical planning, and assessment of treatment response in MPS patients. There is a need for standardized procedures in evaluating and monitoring neurologic complications in these patients.


Two Distinct Types of Linear Distribution in Nonmass Enhancement at Breast MR Imaging: Difference in Positive Predictive Value between Linear and Branching Patterns.
To compare positive predictive values (PPVs) of linearly distributed nonmass enhancement (NME) with linear and branching patterns and to identify imaging characteristics of NME that would enable classification as Breast Imaging Reporting and Data System category 3 lesions. The institutional review board approved this retrospective study and waived the requirement to obtain informed consent. Reports of breast magnetic resonance (MR) examinations (n = 9453) that described NME were reviewed from examinations performed at the study institution from January 2008 to December 2011. NME with linear distribution was allocated to one of two subtypes: linear pattern (arrayed in a line) or branching pattern (with branches). The χ(2) test, Fisher exact test, or Student t test was performed for univariate analyses. Factors that showed a significant association with outcome at univariate analyses were assessed with multivariate analyses by using a logistic regression model. Interobserver agreement of the two subtypes between initial interpretation and the interpretation by two additional radiologists who were blinded to any clinical or pathologic information was evaluated with κ analysis. Within the 156 linearly distributed NME lesions, the PPV of the branching pattern (71 of 95 lesions [75%]; 95% confidence interval [CI]: 66%, 84%) was significantly higher than that of the linear pattern (five of 61 lesions [8%]; 95% CI: 1%, 15%) (P < .0001). The PPV of linear pattern lesions smaller than 1 cm was 0% (0 of 30 lesions; 95% CI: 0%, 0%). At multivariate analysis, branching pattern and NME lesion size of 1 cm or greater were significant predictors of malignancy (P < .0001 [odds ratio: 21.6; 95% CI: 7.5, 62.2] and P = .015 [odds ratio: 5.8; 95% CI: 1.4, 24.0], respectively). Substantial interobserver agreement was obtained for differentiating the two subtypes, with κ values of 0.64 (95% CI: 0.51, 0.76), 0.70 (95% CI: 0.59, 0.82), and 0.64 (95% CI: 0.51, 0.76) between the initial interpreter and reviewer 1, the initial interpreter and reviewer 2, and reviewer 1 and reviewer 2, respectively. The branching pattern was a significantly stronger predictor of malignancy than was the linear pattern. NME lesions with a linear pattern that are smaller than 1 cm can be managed with follow-up.


Combined transcervical transmastoid approach to giant parotid pleomorphic adenoma: a case report.
Although rare, giant major salivary gland pleomorphic adenomas are among the most astonishing patient presentations. Patients may ignore these slow-growing, benign lesions until significant functional impairment occurs. Complete tumor excision and facial nerve preservation in these cases are challenging requirements and are greatly aided by combined transcervical and transmastoid approaches to these lesions. In the presented case, facial nerve monitoring accurately identified the collateralization between the upper and lower divisions of the facial nerve and allowed the required sacrifice of the lower division without the need for facial nerve grafting or reconstruction. The patient recovered full function of all branches.


Effect of granulocytic chalone on the growth rate of continuous cell lines propagated in vitro: a new assay system.
The progress of research on granulocytic chalone has been hampered by a lack of reliable assay systems. This paper reports the use of continuous cell lines growing in liquid suspension culture as a new method for assessing the effect of granulocytic chalone on cell proliferation. Partially purified granulocytic chalone (PPGC) was added to cultures of a rat myeloid cell line (W25), a human myeloid cell line (HL60), a human B lymphocytic cell line (8392), and a human T lymphocytic cell line (8402). The growth rate of the target cell populations was directly assessed by serial cell counts. PPGC pretreatment resulted in a significant inhibition of cell proliferation of the 2 myeloid permanent cell lines, while the growth rate of the lymphocytic cell lines was not affected. Moreover, inhibition of cell proliferation was spontaneously reversed when PPGC treatment was discontinued. Since PPGC from ox leucocytes displayed an inhibitory effect on cell proliferation which was specific to the myeloid cells, spontaneously reversible and not species-specific, it appears to have all the essential properties of a granulocytic chalone.


Population Pharmacokinetics of Tobramycin Inhalation Solution in Pediatric Patients With Cystic Fibrosis.
Tobramycin inhalation solution given as a twice daily inhalation of nebulized aerosols of 300 mg is approved for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis patients over 6 years of age. To investigate tobramycin pharmacokinetics (PK) after inhalation of tobramycin in pediatric cystic fibrosis patients below 7 years, a population PK approach was used to evaluate tobramycin PK data in patients 6 months to 44 years of age from 4 clinical studies. The final model used a 2-compartmental, first-order absorption model with effect of body mass index on the apparent central volume of distribution. Relative bioavailability in patients between 6 months and 7 years increased with age by a linear relationship, and was modeled as a ratio to that of patients over 7 years. Simulation showed that steady-state concentrations of tobramycin are lower in pediatric patients 6 months to 6 years than those in patients over 6 years. However, systemic exposure is not predictive of clinical efficacy due to direct dosing at the infection site. P aeruginosa eradication rate and safety profile in patients less than 7 years of age were similar to patients older than 6 years; therefore, no dose adjustment is warranted in the younger pediatric patients.


TIGAR impedes compression-induced intervertebral disc degeneration by suppressing nucleus pulposus cell apoptosis and autophagy.
To investigate whether TP53-induced glycolysis and apoptosis regulator (TIGAR) participates in compression-induced intervertebral disc (IVD) degeneration, and to determine the regulatory effect of TIGAR on nucleus pulposus (NP) cell autophagy and apoptosis following compression-induced injuries. IVD tissues were collected from human patients undergoing surgery (n = 20) and skeletally mature Sprague-Dawley rats (n = 15). Initially, the effect of compression on the expression of TIGAR was evaluated with in vivo and in vitro models. In addition, TIGAR was silenced to investigate the regulatory effect of TIGAR on compression-induced intracellular reactive oxygen species (ROS) levels, autophagy, and apoptosis in rat NP cells. Furthermore, the P53 inhibitor pifithrin-α (PFTα) and SP1 inhibitor mithramycin A were employed to detect expression level changes of TIGAR and autophagy-associated target molecules. TIGAR expression of NP cells increased gradually in human degenerative IVDs and in rat NP cells under compression both in vivo and in vitro. TIGAR knockdown enhanced compression-induced intracellular ROS generation and the NADPH/NADP+ and GSH/GSSG ratios. Moreover, TIGAR knockdown amplified the compression-induced caspase-3 activation and the apoptosis rate of rat NP cells. Likewise, knockdown of TIGAR significantly accelerated LC3B expression and autophagosome formation in rat NP cells during compression-induced injuries. The results also established that mithramycin A could inhibit TIGAR expression and autophagy levels in NP cells under compression conditions, while PFTα had no similar effect. Our data demonstrated that TIGAR acted as an important endogenous negative regulator of ROS levels, which might inhibit compression-induced apoptosis and autophagy through SP1-dependent mechanisms.


Extracellular discontinuities in cardiac muscle: evidence for capillary effects on the action potential foot.
It has become of fundamental importance to understand variations in the shape of the upstroke of the action potential in order to identify structural loading effects. One component of this goal is a detailed experimental analysis of the time course of the foot of the cardiac action potential (Vm foot) during propagation in different directions in anisotropic cardiac muscle. To this end, we performed phase-plane analysis of transmembrane action potentials during anisotropic propagation in adult working myocardium. The results showed that during longitudinal propagation there was initial slowing of Vm foot that resulted in deviations from a simple exponential; corollary changes occurred at numerous sites during transverse propagation. We hypothesized that the effect on Vm foot observed in the experimental data was created by the microscopic structure, especially the capillaries. This hypothesis predicts that the phase-plane trajectory of Vm foot will deviate from linearity in the presence of a high density of capillaries, and that a linear trajectory will occur in the absence of capillaries. Comparison of the results of Fast and Kléber (Circ Res. 1993;73:914-925) in a monolayer of neonatal cardiac myocytes, which is devoid of capillaries, and our results in newborn ventricular muscle, which is rich in capillaries, showed drastic differences in Vm foot as predicted. Because this comparison provided experimental support for the capillary hypothesis, we explored the underlying biophysical mechanisms due to interstitial electrical field effects, using a "2-domain" model of myocytes and capillaries separated by interstitial space. The model results show that a propagating interstitial electrical field induces an inward capacitive current in the inactive capillaries that causes a feedback effect on the active membrane (source) that slows the initial rise of its action potential. The results show unexpected mechanisms related to extracellular structural loading that may play a role in selected conduction disturbances, such as in a reperfused ischemic region surrounded by normal myocardium.


Developing a Novel Framework for an Undergraduate Cancer Research Education and Engagement Program for Underrepresented Minority Students: the Florida-California CaRE2 Research Education Core (REC) Training Program.
Lack of substantive research experiences and technical skills mentoring during undergraduate studies leaves many underrepresented minority (URM) students unprepared to apply to competitive graduate programs. As a part of our ongoing effort to increase the pipeline for the development and training of successful URM scientists in biomedical sciences with focus on reducing cancer health disparities, the Florida-California Cancer Research Education and Engagement (CaRE2) Health Equity Center was launched in 2018. Funded through an NIH/NCI U54 grant mechanism, the CaRE2 Center is a triad partnership among Florida Agricultural and Mechanical University (FAMU), a minority-serving institution, University of Florida (UF), and University of Southern California (USC) Cancer Center. One of the objectives of the triad partnership is to promote the coordination and implementation of the training of the next generation of Black and Latinx biomedical scientists in Florida and California. An important component of the CaRE2 program is the Research and Education Core (REC) designed to coordinate the training of URM students and researchers at different levels in their academic and professional developments. The undergraduate cancer research training program under FAMU-CaRE2 Center is a 3-year (2018-2021) project to identify, train, mentor, and provide the URM undergraduate students with the support network they need to flourish in the program and beyond. In its year-1 funding cycle, the program has made significant progress in developing a novel framework for an undergraduate cancer research education and engagement program at FAMU, one of the forefront minority institutions in the nation. The mentored research program is complemented with professional development and engagement activities, including cancer research seminars, workshops, and community outreach activities. The purpose of this paper is to discuss the strategies implemented for an effective partnership, the leadership and mentoring skills, and outcomes from the year-1 experiences. In addition, we present the progress made in advancing the pool of underrepresented minority students with scientific and academic career progression paths focused on cancer health disparities.


Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy.
Catamenial epilepsy is a type of refractory epilepsy characterized by seizure clusters around perimenstrual or periovulatory period. The pathophysiology of catamenial epilepsy still remains unclear, yet there are few animal models to study this gender-specific disorder. The pathophysiology of perimenstrual catamenial epilepsy involves the withdrawal of the progesterone-derived GABAergic neurosteroids due to the decline in progesterone level at the time of menstruation. These manifestations can be faithfully reproduced in rodents by specific neuroendocrine manipulations. Since mice and rats, like humans, have ovarian cycles with circulating hormones, they appear to be suitable animal models for studies of perimenstrual seizures. Recently, we created specific experimental models to mimic perimenstrual seizures. Studies in rat and mouse models of catamenial epilepsy show enhanced susceptibility to seizures or increased seizure exacerbations following neurosteroid withdrawal. During such a seizure exacerbation period, there is a striking decrease in the anticonvulsant effect of commonly prescribed antiepileptics, such as benzodiazepines, but an increase in the anticonvulsant potency of exogenous neurosteroids. We discovered an extrasynaptic molecular mechanism of catamenial epilepsy. In essence, extrasynaptic δGABA-A receptors are upregulated during perimenstrual-like neuroendocrine milieu. Consequently, there is enhanced antiseizure efficacy of neurosteroids in catamenial models because δGABA-A receptors confer neurosteroid sensitivity and greater seizure protection. Molecular mechanisms such as these offer a strong rationale for the clinical development of a neurosteroid replacement therapy for catamenial epilepsy.


Dopaminergic modulation of short-term synaptic plasticity in fast-spiking interneurons of primate dorsolateral prefrontal cortex.
Dopaminergic regulation of primate dorsolateral prefrontal cortex (PFC) activity is essential for cognitive functions such as working memory. However, the cellular mechanisms of dopamine neuromodulation in PFC are not well understood. We have studied the effects of dopamine receptor activation during persistent stimulation of excitatory inputs onto fast-spiking GABAergic interneurons in monkey PFC. Stimulation at 20 Hz induced short-term excitatory postsynaptic potential (EPSP) depression. The D1 receptor agonist SKF81297 (5 microM) significantly reduced the amplitude of the first EPSP but not of subsequent responses in EPSP trains, which still displayed significant depression. Dopamine (DA; 10 microM) effects were similar to those of SKF81297 and were abolished by the D1 antagonist SCH23390 (5 microM), indicating a D1 receptor-mediated effect. DA did not alter miniature excitatory postsynaptic currents, suggesting that its effects were activity dependent and presynaptic action potential dependent. In contrast to previous findings in pyramidal neurons, in fast-spiking cells, contribution of N-methyl-D-aspartate receptors to EPSPs at subthreshold potentials was not significant and fast-spiking cell depolarization decreased EPSP duration. In addition, DA had no significant effects on temporal summation. The selective decrease in the amplitude of the first EPSP in trains delivered every 10 s suggests that in fast-spiking neurons, DA reduces the amplitude of EPSPs evoked at low frequency but not of EPSPs evoked by repetitive stimulation. DA may therefore improve detection of EPSP bursts above background synaptic activity. EPSP bursts displaying short-term depression may transmit spike-timing-dependent temporal codes contained in presynaptic spike trains. Thus DA neuromodulation may increase the signal-to-noise ratio at fast-spiking cell inputs.


Enhanced antitumor activity of irofulven in combination with irinotecan in pediatric solid tumor xenograft models.
Irofulven, a novel chemotherapeutic agent with a broad spectrum of activity, is effective against preclinical models of pediatric tumors. The cytotoxic activity of irofulven is augmented when combined with agents that interact with DNA topoisomerase I; however, none of the reported studies have used the protracted dosing schedule found to be active clinically in treatment of childhood cancers. The objective of this study was to evaluate the antitumor activity of irofulven in combination with irinotecan administered on a protracted schedule in a panel of pediatric solid tumor xenografts. Irofulven and irinotecan were evaluated alone or in combination against eight independent xenografts, which included childhood brain tumors (n=5), neuroblastoma (n=1), and rhabdomyosarcoma (n=2). Irofulven was administered i.v. daily for 5 days with courses repeated every 21 days for a total of three cycles. Doses of irofulven ranged from 1.33 to 4.6 mg/kg. Irinotecan was given i.v. daily for 5 days each week for 2 weeks repeated every 21 days for three cycles at doses between 0.28 and 1.25 mg/kg. Irofulven and irinotecan, given as single agents, induced few responses in pediatric solid tumor xenografts at the selected doses. At the same doses, irofulven in combination with irinotecan demonstrated superior antitumor activity, inducing complete responses in seven of the eight xenograft lines. These studies show that the cytotoxic activity of irofulven is greater when combined with protracted administration of irinotecan. Although the systemic exposure of irofulven required to induce objective responses in this panel of pediatric solid tumors was in excess of that achievable in patients receiving maximally tolerated doses using this schedule of drug administration, the enhanced activity of irofulven in combination with irinotecan supports the pursuit of alternative administration strategies and combinations.


Scope of an Integrative Neurophysiotherapy Approach in Achieving Gross Motor Milestones in a Child with Meningitis: A Case Report.
Meningitis caused by bacteria, which is an inflammation of the meninges affecting the pia, arachnoid, and subarachnoid space, is still one of the leading causes of death and morbidity in infants and young children. Neisseria meningitidis, group B streptococcus (GBS), Haemophilus influenzae type B (Hib), Listeria monocytogenes, and Streptococcus pneumoniae have been found to be the most frequent causative agents. Infants and children can have modest, fluctuating, non-specific, or even absent clinical signs of bacterial meningitis. They may include bulging fontanelles, vomiting, diarrhea, respiratory distress, hypothermia, lethargy, irritability, poor feeding, and fever in babies. In this case report, an 18-month-old child presented to a local hospital with complaints of multiple episodes of high-grade fever. After 10 days, his symptoms worsened and he experienced two episodes of seizures at one-day intervals at night. He was taken to Acharya Vinoba Bhave Rural Hospital for further management. Blood investigations revealed seropositive results for dengue virus infection. On MRI and CT scan, it was diagnosed as an old case of subdural hematoma in the right frontotemporal region of the brain. The patient was on intravenous ceftriaxone and phenytoin. Gross motor developmental milestones in children with meningitis can be improved with early integrative neurophysiotherapy and a goal-oriented therapeutic regimen that includes mobility exercises, proprioceptive neuromuscular facilitation techniques, positioning, oromotor retraining, neurodevelopmental techniques, and balance and coordination retraining. A complex case presents with bacterial meningitis, hydrocephalus, and seizure disorder. The bacterial infection inflames the protective membranes of the brain, causing hydrocephalus. Increased cerebrospinal fluid puts pressure on the brain, leading to seizures. Managing these interconnected conditions requires a multidisciplinary approach making it unique, involving infectious disease, neurology, and neurosurgery expertise.


Exploring the Relationship Among Divergence Time and Coding and Non-coding Elements in the Shaping of Fungal Mitochondrial Genomes.
The order Hypocreales (Ascomycota) is composed of ubiquitous and ecologically diverse fungi such as saprobes, biotrophs, and pathogens. Despite their phylogenetic relationship, these species exhibit high variability in biomolecules production, lifestyle, and fitness. The mitochondria play an important role in the fungal biology, providing energy to the cells and regulating diverse processes, such as immune response. In spite of its importance, the mechanisms that shape fungal mitogenomes are still poorly understood. Herein, we investigated the variability and evolution of mitogenomes and its relationship with the divergence time using the order Hypocreales as a study model. We sequenced and annotated for the first time Trichoderma harzianum mitochondrial genome (mtDNA), which was compared to other 34 mtDNAs species that were publicly available. Comparative analysis revealed a substantial structural and size variation on non-coding mtDNA regions, despite the conservation of copy number, length, and structure of protein-coding elements. Interestingly, we observed a highly significant correlation between mitogenome length, and the number and size of non-coding sequences in mitochondrial genome. Among the non-coding elements, group I and II introns and homing endonucleases genes (HEGs) were the main contributors to discrepancies in mitogenomes structure and length. Several intronic sequences displayed sequence similarity among species, and some of them are conserved even at gene position, and were present in the majority of mitogenomes, indicating its origin in a common ancestor. On the other hand, we also identified species-specific introns that advocate for the origin by different mechanisms. Investigation of mitochondrial gene transfer to the nuclear genome revealed that nuclear copies of the nad5 are the most frequent while atp8, atp9, and cox3 could not be identified in any of the nuclear genomes analyzed. Moreover, we also estimated the divergence time of each species and investigated its relationship with coding and non-coding elements as well as with the length of mitogenomes. Altogether, our results demonstrated that introns and HEGs are key elements on mitogenome shaping and its presence on fast-evolving mtDNAs could be mostly explained by its divergence time, although the intron sharing profile suggests the involvement of other mechanisms on the mitochondrial genome evolution, such as horizontal transference.


High-Precision Thin Wall Bipolar Plates for Fuel Cell Applications via Injection Compression Molding with Dynamic Mold Temperature Control.
In recent years, the demand for polymer compound solutions for the application of bipolar plates in polymer electrolyte membrane fuel cells (PEMFC) has increased continuously due to significant cost and lifetime advantages compared to metallic solutions. The main challenge of the compounds is the high filler content required to ensure sufficient electrical conductivity of the bipolar plates. The associated increase in viscosity and simultaneously increased thermal conductivity limit the conventional injection molding process in terms of achievable flow path length to wall thickness ratios (plate aspect ratio). In order to evaluate the extent to which highly modified electrically conductive polymer material systems can be processed into thin-walled and highly dimensionally stable bipolar plates, an injection compression molding process with dynamic mold temperature control (ICM-DT) has been developed. For this purpose, a compound was prepared from polypropylene (PP) and graphite-flakes. The compound was characterized with respect to the achieved filler content, the electrical conductivity, as well as the pressure- and temperature-dependent solidification range. The ICM-DT experiments were carried out by varying the maximum mold temperature and the compression force. In addition, the process was designed with multiple compression and decompression steps to account for a possible pressure-dependent solidification of the compound. The plates were characterized with respect to the achieved plate aspect ratio and the flow-path-dependent dimensional thickness stability. It was shown that the plate aspect ratio could be increased by up to 125% with the maximum filler content compared to conventional injection molding processes provided in the literature. With the multi-stage ICM-DT process, it was also possible to optimize the thickness dimensional stability with a maximum deviation of 3% over the flow path.


[Coronary artery surgery in diabetic patients].
Currently, 15% to 30% of the patients that undergo coronary artery surgery are diabetics. As a group, they have less favorable anatomic and clinical characteristics than the general population. Specifically, diabetics have more extensive coronary disease, more vessels involved, and more diffuse stenosis, so they need a higher number of distal anastomoses to achieve complete revascularization. In spite of these drawbacks, they can undergo coronary artery bypass procedures with an operative mortality similar to that of non-diabetic patients. However, some postoperative complications are significantly more prevalent among diabetics, mainly renal failure, neurological accidents, sternal dehiscence, and infection. In early studies of the late results of surgical revascularization, mainly based on venous grafts, late survival and clinical improvement were less satisfactory in diabetics than in non-diabetics. However, in recent experiences, in which the internal mammary artery has been used extensively, the clinical outcome of diabetics has been similar to that of non-diabetics, confirming this procedure as the preferred one in revascularizing the coronary arteries of diabetics with multivessel disease. Off-pump surgery and extensive use of arterial grafts are becoming established strategies for reducing operative risk and improving long-term clinical results. However, continuous, strict medical management of hyperglycemia and other known coronary risk factors, especially lipid levels, is essential.


R&D and productivity: measurement issues and econometric results.
The direct successes of space, defense, and health research are not reflected in the national productivity accounts. Nor are many of the improvements in technologically complex new products. Econometric studies underestimate, therefore, the full contribution of R&D, especially since it is difficult to trace its spillover effects. Nevertheless, a recent study finds a significant contribution of R&D to productivity growth in the largest U.S. manufacturing corporations, with no evidence of a major decline in it, and a larger role for basic research and a smaller one for federally financed R&D expenditures than is implied by their relative importance in total R&D expenditures.


Anthropogenic refugia ameliorate the severe climate-related decline of a montane mammal along its trailing edge.
We conducted detailed resurveys of a montane mammal, Urocitellus beldingi, to examine the effects of climate change on persistence along the trailing edge of its range. Of 74 California sites where U. beldingi were historically recorded (1902-1966), 42 per cent were extirpated, with no evidence for colonization of previously unoccupied sites. Increases in both precipitation and temperature predicted site extirpations, potentially owing to snowcover loss. Surprisingly, human land-use change buffered climate change impacts, leading to increased persistence and abundance. Excluding human-modified sites, U. beldingi has shown an upslope range retraction of 255 m. Generalized additive models of past distribution were predictive of modern range contractions (AUC = 0.76) and projected extreme reductions (52% and 99%, respectively) of U. beldingi's southwestern range to 2080 climates (Hadley and CCCMA A2). Our study suggests the strong impacts of climate change on montane species at their trailing edge and how anthropogenic refugia may mitigate these effects.


Portraiture and excavations.
In a footnote to the review of M. M. Gerasimov's The Face Finder [173, 712 (1971)], the misspelling of Julius Koliman's name is erroneously attributed to a bibliography (1962) by W. M. Krogman. The error occurs in a different authority's work. Kollmann established methods (1898) for building on a skull a face recognizably correct.


Comparative Evaluation of Various Temperature Changes on Stress Distribution in Class II Mesial-occlusal-distal Preparation restored with Different Restorative Materials: A Finite Element Analysis.
The principal goal of dentistry is to maintain and improve the quality of life of the dental patients. As many of these objectives require the replacement or alterations of the existing tooth structure, the main challenge for centuries has been the development and selection of biocompatible materials that can withstand the unique conditions of the oral environment.Finite element analysis (FEA) is a modern technique of numerical stress analysis that has become a solution to the task of predicting failure due to unknown stresses by showing problem areas in a material and allowing designers to see all of theoretical stresses within. To evaluate and compare the effect of various temperature changes on the stress distribution, in class II mesial-occlusal-distal (MOD) cavity when restored with different restorative materials, using the finite element method (FEM). Using FEA, various thermal stresses generated in class II MOD lesion using different restorative materials were studied. The computer-generated models of intact tooth and teeth restored with the different restorative materials were designed, and thermal stress at different temperatures was observed when subjected to the thermal loads of 5°C, 20°C, 36°C, and 55°C. From the results of the study, it can be concluded that glass ionomer cement (GIC) performed best, followed by intact tooth, composite resin, silver amalgam, and zinc oxide eugenol cement. Restoration of class II MOD lesions with materials of lower modulus of elasticity and lower coefficient of thermal expansion will enable better stress distribution.How to cite this article: Srivastava B, Devi NN, Gupta N, Singh R. Comparative Evaluation of Various Temperature Changes on Stress Distribution in Class II Mesial-occlusal-distal Preparation restored with Different Restorative Materials: A Finite Element Analysis. Int J Clin Pediatr Dent 2018;11(3):167-170.


X-ray-free protocol for pectus deformities based on magnetic resonance imaging and a low-cost portable three-dimensional scanning device: a preliminary study.
To compare a standard protocol using chest computed tomography (CT) to a non-irradiant protocol involving a low-cost portable 3D scanner and magnetic resonance imaging (MRI) for all pectus deformities based on the Haller index (HI). From April 2019 to March 2020, all children treated for pectus excavatum or carinatum at our institution were evaluated by chest CT, 3D scanning (iPad with Structure Sensor and Captevia-Rodin4D) and MRI. The main objectives were to compare the HI determined by CT or MRI to a derived index evaluated with 3D scanning, the external Haller index (EHI). The secondary objectives were to assess the inter-rater variability and the concordance between CT and MRI for the HI and the correction index. Eleven patients were evaluated. We identified a strong correlation between the HI with MRI and the EHI (Pearson correlation coefficient = 0.900; P < 0.001), with a strong concordance between a radiologist and a non-radiologist using intra-class correlation for the HI with MRI (intra-class correlation coefficient = 0.995; [0.983; 0.999]) and the EHI (intra-class correlation coefficient = 0.978; [0.823; 0.995]). We also identified a marked correlation between the HI with CT and the EHI (Pearson coefficient = 0.855; P = 0.002), with a strong inter-rater concordance (intra-class correlation coefficient = 0.975; [0.901; 0.993]), a reliable concordance between CT and MRI for the HI and the correction index (Pearson coefficient = 0.886; P = 0.033). Non-irradiant pectus deformity assessment is possible in clinical practice, replacing CT with MRI and 3D scanning as a possible readily-accessible monitoring tool.


Waggawagga: comparative visualization of coiled-coil predictions and detection of stable single α-helices (SAH domains).
Waggawagga is a web-based tool for the comparative visualization of coiled-coil predictions and the detection of stable single α-helices (SAH domains). Overview schemes show the predicted coiled-coil regions found in the query sequence and provide sliders, which can be used to select segments for detailed helical wheel and helical net views. A window-based score has been developed to predict SAH domains. Export to several bitmap and vector graphics formats is supported. http://waggawagga.motorprotein.de


Alcohol consumption and risk of cardiovascular disease among hypertensive women.
This study investigated the relation between alcohol consumption and the risk of cardiovascular disease (CVD) among 10 530-hypertensive women from the EPIC-NL cohort. Alcohol consumption was assessed using a validated food-frequency questionnaire and participants were followed for occurrence of CVD. During 9.4 years follow-up, we documented 580 coronary heart disease (CHD) events and 254 strokes, 165 of which were ischemic. An inverse association (Ptrend=0.009) between alcohol consumption and risk of CHD was observed with a multivariate-adjusted hazard ratio of 0.72 (95% confidence interval: 0.52-1.01) for those consuming 70-139.9 g alcohol/week compared to lifetime abstainers. Of different beverages, only red wine consumption was associated with a reduced risk of CHD. A U-shaped relation (P=0.08) was observed for total stroke with a hazard ratio of 0.65 (0.44-0.95) for consuming 5-69.9 g alcohol/week compared with lifetime abstainers. Similar results were observed for ischemic stroke with a hazard ratio of 0.56 (0.35-0.89) for consuming of 5-69.9 g alcohol/week. We conclude that moderate alcohol consumption is associated with a reduced risk of CHD among hypertensive women. Light alcohol consumption tended to be related to a lower risk of stroke. Current guidelines for alcohol consumption in the general population also apply to hypertensive women.


Towards a theoretically informed policy against a rakghoul plague outbreak.
A long time ago in a galaxy far, far away, the Sith Lord Karness Muur engineered the rakghoul plague, a disease that transformed infected humans into near-mindless predatory rakghouls. At its peak, the disease infected millions of individuals, giving rise to armies of rakghouls on a number of planets. Whether rakghoul populations have persisted until this day is not known, making a rakghoul invasion on Earth not completely improbable. Further, a strategy for defence against an outbreak of the disease on Earth has not yet been proposed. To fill this glaring gap, we developed the first mathematical model of the population dynamics of humans and rakghouls during a rakghoul plague outbreak. Using New South Wales as a model site, we then obtained ensembles of model predictions for the outcome of the rakghoul plague in two different disease control strategy scenarios (population evacuation and military intervention), and in the absence thereof. Finally, based on these predictions, we propose a set of policy guidelines for successfully controlling and eliminating outbreaks of the rakghoul plague in Australian states.


The risk of breast cancer linked to menopausal hormone therapy.
The Norwegian "Women and cancer" study has shown that when combination hormone replacement products were used for more than five years the relative risk of breast cancer was almost tripled. The population attributable risk was 27 %. In a nested case-control study we have updated the risk estimates for hormone replacement therapy in post-menopausal women since 2002. We selected an age-matched control for each of the 589 women (aged 46-63) who were found in the period 2004-8 to have invasive breast cancer or cancer in situ. These women responded in 2003-6 to a questionnaire on menstruation and the use of hormone replacement therapy. The data from this and earlier questionnaires were compared and analysed using logistical regression. 226 (26 %) of the women were using hormone replacement at the time of the survey. The average time of use was ten years. Current users had a higher risk of breast cancer than never-users: adjusted OR 2.1 (95 % CI 1.5-3.0). The use of combination therapy for more than five years resulted in the highest risk: OR 3.0 (95 % CI 1.9-4.7). Earlier use of oestrogen products did not result in a higher risk. Neither oestradiol nor tibolon caused a statistically significant increase in risk. 232 cases of breast cancer (17 %) in women aged 45-64 could be attributed to the use of hormones. Long-term use of combination products increases the risk of breast cancer. Relative risk estimates have undergone little change since the previous study, but population attributable risk has fallen along with the decline in new users.


C-undecylcalix[4]resorcinarene Langmuir-Blodgett/Porous Reduced Graphene Oxide Composite Film as a Electrochemical Sensor for the Determination of Tryptophan.
In this study, a composite film was developed for the electrochemical sensing of tryptophan (Trp). Porous reduced graphene oxide (PrGO) was utilized as the electron transfer layer, and a C-undecylcalix[4]resorcinarene Langmuir-Blodgett (CUCR-LB) film served as the molecular recognition layer. Atomic force microscopy (AFM), transmission electron microscopy (TEM), Raman spectroscopy, scanning electron microscopy (SEM), and electrochemical experiments were employed to analyze the characteristics of the CUCR-LB/PrGO composite film. The electrochemical behavior of Trp on the CUCR-LB/PrGO composite film was investigated, revealing a Trp linear response range of 1.0 × 10-7 to 3.0 × 10-5 mol L-1 and a detection limit of 3.0 × 10-8 mol L-1. Furthermore, the developed electroanalytical method successfully determined Trp content in an amino acid injection sample. This study not only introduces a rapid and reliable electrochemical method for the determination of Trp but also presents a new strategy for constructing high-performance electrochemical sensing platforms.


Impact of gender difference in hospital outcomes following percutaneous coronary intervention. Results of the Belgian Working Group on Interventional Cardiology (BWGIC) registry.
To determine whether there are gender-based differences in in-hospital outcomes among patients undergoing percutaneous coronary intervention (PCI). We studied a large cohort using clinical data from a registry of 130,985 PCI procedures in Belgium, from January 2006 to February 2011. Compared to males, females were significantly older (70.3 vs. 64.8 years), and were more frequently diabetic or hypertensive. Men smoked more and more frequently had previous myocardial infarction (MI), previous PCI or previous coronary artery bypass graft (CABG) surgery. Coronary artery disease (CAD) was less severe in women, and PCI to the left anterior descending artery was more common in female patients. Unadjusted in-hospital mortality rates were higher in females versus males (2.5% for women and 1.6% for men, p<0.0001). After multivariable analysis, female gender remained an independent predictor of mortality (odds ratio 1.35, 95% CI: 1.22-1.49, p<0.0001). Gender-based differences in hospital mortality rates after PCI were observed in this large registry. Female sex remained an independent predictor of mortality after multivariable adjustment.


Better late than never: information retrieval from black holes.
We show that, in order to preserve the equivalence principle until late times in unitarily evaporating black holes, the thermodynamic entropy of a black hole must be primarily entropy of entanglement across the event horizon. For such black holes, we show that the information entering a black hole becomes encoded in correlations within a tripartite quantum state, the quantum analogue of a one-time pad, and is only decoded into the outgoing radiation very late in the evaporation. This behavior generically describes the unitary evaporation of highly entangled black holes and requires no specially designed evolution. Our work suggests the existence of a matter-field sum rule for any fundamental theory.


TRPM2-AS Promotes Bladder Cancer by Targeting miR-22-3p and Regulating GINS2 mRNA Expression.
Bladder cancer (BLCA) refers to the malignancy growth that spreads from the bladder linings to the bladder muscles. However, the impact of miR-22-3p and lncRNA TRPM2-AS on this tumor has generated divergent views in the literature. This research aimed to study the effects of lncRNA TRPM2-AS on BLCA and its interaction with miR-22-3p and GINS2 mRNA. qRT-PCR was employed to measure the expression of TRPM2-AS, miR-22-3p and GINS2 mRNA in bladder tissues and cells. The subcellular localization of TRPM2-AS in T24 and 5637 cell lines was identified using a cell fractionation system. Luciferase assay, RIP assay and RNA pull-down assay were later performed to validate the direct binding relationship between TRPM2-AS, miR-22-3p and GINS2 mRNA. Several experiments were conducted to determine the viability, proliferation, colony formation and apoptosis of the cell lines. Findings indicated that TRPM2-AS was significantly upregulated in BLCA tissues and cell lines. Apart from that, it was observed that TRPM2-AS knockdown significantly inhibited the viability, proliferation and colony formation of BCLA cells, but it promoted the apoptosis of the BCLA cells. A significant downstream target of TRPM2-AS, miR-22-3p was found to show a lower expression level in BLCA tissues and cell lines. However, the inhibition of miR-22-3p considerably enhanced BLCA cell phenotypes. As well as discovering that GINS2 mRNA was a downstream target of miR-22-3p and was significantly upregulated in BLCA, experimental results also indicated that the knockdown of GINS2 suppressed BLCA cell phenotypes. This research confirmed that TRPM2-AS could promote BCLA by binding to miR-22-3p to increase GINS2 expression. This novel interactome in BLCA cell lines might provide more insights into BLCA therapy.


TrophicCS: Spatialized trophic data of the Celtic Sea continental shelf food web.
Understanding the dynamics of species interactions for food (prey-predator, competition for resources) and the functioning of trophic networks (dependence on trophic pathways, food chain flows, etc.) has become a thriving ecological research field in recent decades. This empirical knowledge is then used to develop population and ecosystem modeling approaches to support ecosystem-based management. The TrophicCS data set offers spatialized trophic information on a large spatial scale (the entire Celtic Sea continental shelf and upper slope) for a wide range of species. It combines ingested prey (gut content analysis) and a more integrated indicator of food sources (stable isotope analysis). A total of 1337 samples of large epifaunal invertebrates (bivalve mollusks and decapod crustaceans), zooplankton, fish, and cephalopods, corresponding to 111 taxa (94% determined at the species level), were collected and analyzed for stable isotope analysis of their carbon and nitrogen content. Samples were collected between 2014 and 2016, mostly during the month of November and between 57 and 516 m depth. Sample size varied between taxa (from 1 to 52), with 98 taxa having at least three samples. The gut contents of 1027 fish belonging to 10 commercially important species: black anglerfish (Lophius budegassa), white anglerfish (Lophius piscatorius), blue whiting (Micromesistius poutassou), cod (Gadus morhua), haddock (Melanogrammus aeglefinus), hake (Merluccius merluccius), megrim (Lepidorhombus whiffiagonis), plaice (Pleuronectes platessa), sole (Solea solea), and whiting (Merlangius merlangus) were analyzed. Sampling occurred in November 2014 and 2015. The gut content data set contains the occurrence of prey in gut, identified to the lowest taxonomic level possible. No prey were assigned for 274 empty gut contents. To consider potential ontogenetic diet changes, a large size range was sampled for each species. The TrophicCS data set was used to improve understanding of trophic relationships and ecosystem functioning in the Celtic Sea. Data are released under a CC-BY-NC-SA license, and please cite this paper when reusing the data.


Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR(2) ) is involved in vascular function.
Proteinase-activated receptors (PARs) and toll-like receptors (TLRs) are involved in innate immune responses. The aim of this study was to evaluate the possible cross-talk between PAR(2) and TLR4 in vessels in physiological condition and how it varies following stimulation of TLR4 by using in vivo and ex vivo models. Thoracic aortas were harvested from both naïve and endotoxaemic rats for in vitro studies. Arterial blood pressure was monitored in anaesthetized rats in vivo. LPS was used as a TLR4 agonist while PAR(2) activating peptide (AP) was used as a PAR(2) agonist. Aortas harvested from TLR4(-/-) mice were also used to characterize the PAR(2) response. PAR(2) , but not TLR4, expression was enhanced in aortas of endotoxaemic rats. PAR(2) AP-induced vasorelaxation was increased in aortic rings of LPS-treated rats. TLR4 inhibitors, curcumine and resveratrol, reduced PAR(2) AP-induced vasorelaxation and PAR(2) AP-induced hypotension in both naïve and endotoxaemic rats. Finally, in aortic rings from TLR4(-/-) mice, the expression of PAR(2) was reduced and the PAR(2) AP-induced vasodilatation impaired compared with those from wild-type mice and both resveratrol and curcumine were ineffective. Cross-talk between PAR(2) and TLR4 contributes to vascular homeostasis.


Dissecting the molecular basis for the modulation of neurotransmitter GPCR signaling by GINIP.
It is well-established that activation of heterotrimeric G-proteins (Gαβγ) by G-protein-coupled receptors (GPCRs) stimulated by neurotransmitters is a key mechanism underlying neuromodulation. Much less is known about how G-protein regulation after receptor-mediated activation contributes to neuromodulation. Recent evidence indicates that the neuronal protein GINIP shapes GPCR inhibitory neuromodulation via a unique mechanism of G-protein regulation that controls neurological processes like pain and seizure susceptibility. However, the molecular basis of this mechanism remains ill-defined because the structural determinants of GINIP responsible for binding Gαi subunits and regulating G-protein signaling are not known. Here, we combined hydrogen-deuterium exchange mass-spectrometry, protein folding predictions, bioluminescence resonance energy transfer assays, and biochemical experiments to identify the first loop of the PHD domain of GINIP as an obligatory requirement for Gαi binding. Surprisingly, our results support a model in which GINIP undergoes a long-range conformational change to accommodate Gαi binding to this loop. Using cell-based assays, we demonstrate that specific amino acids in the first loop of the PHD domain are essential for the regulation of Gαi-GTP and free Gβγ signaling upon neurotransmitter GPCR stimulation. In summary, these findings shed light onto the molecular basis for a post-receptor mechanism of G-protein regulation that fine-tunes inhibitory neuromodulation.


Do patients need to earn total knee arthroplasty?
Traditional orthopaedic thinking dictates that performing total knee arthroplasty (TKA) in patients with relatively early stages of osteoarthritis (OA) will lead to a poor outcome. Our goal was to test this perception, using radiologic parameters as a marker of the degree of OA. Our study involved 130 consecutive patients who underwent TKA for OA. The radiographs of each patient were graded according to the Ahlback classification. Outcome was measured prospectively using the Oxford Knee Score (OKS), which was recorded both preoperatively and 1 year after surgery. The degree of radiologic OA changes preoperatively was not found to influence the outcome of surgery at 1 year, with all patient groups improving to a similar extent. In addition, as has been seen in previous studies, no correlation was found between symptoms of OA and radiologic appearances. The results of this study would support a re-evaluation of traditional orthopaedic practice. This conclusion coincides with other recent work that suggests that TKA is underused and is performed too late in the natural history of OA of the knee.


Allostery without conformation change: modelling protein dynamics at multiple scales.
The original ideas of Cooper and Dryden, that allosteric signalling can be induced between distant binding sites on proteins without any change in mean structural conformation, has proved to be a remarkably prescient insight into the rich structure of protein dynamics. It represents an alternative to the celebrated Monod-Wyman-Changeux mechanism and proposes that modulation of the amplitude of thermal fluctuations around a mean structure, rather than shifts in the structure itself, give rise to allostery in ligand binding. In a complementary approach to experiments on real proteins, here we take a theoretical route to identify the necessary structural components of this mechanism. By reviewing and extending an approach that moves from very coarse-grained to more detailed models, we show that, a fundamental requirement for a body supporting fluctuation-induced allostery is a strongly inhomogeneous elastic modulus. This requirement is reflected in many real proteins, where a good approximation of the elastic structure maps strongly coherent domains onto rigid blocks connected by more flexible interface regions.


The determinants of small-area variation in hospital utilization. The evidence from hospital discharge abstracts.
Small-area differences in hospital use were examined using hospital discharge abstract data for the populations of seven small service areas in Iowa that exhibited substantial variation in admission rates during 1980. The results indicate a marked difference in the age composition of the patient populations with older patients being more common among residents of high-use areas, higher age- and sex-adjusted discharge rates per 1000 in the high-use areas across many diagnostic categories, frequently higher average lengths of stay in high-use areas, a lack of conformity between discharge patterns for selected surgical procedures and diagnoses, and more readmissions to the same hospital during a 12-month period for residents of high-use areas. This data set comprises one part of a study of small-area differences that also employed household surveys, physician surveys, and other existing data sets. The findings illustrate the potential and limitations of hospital discharge abstracts as a data base for evaluating hospital discharge abstracts as a data base for evaluating hospital utilization differentials.


Mild C-H functionalization of alkanes catalyzed by bioinspired copper(ii) cores.
Three new copper(ii) coordination compounds formulated as [Cu(H1.5bdea)2](hba)·2H2O (1), [Cu2(μ-Hbdea)2(aca)2]·4H2O (2), and [Cu2(μ-Hbdea)2(μ-bdca)]n (3) were generated by aqueous medium self-assembly synthesis from Cu(NO3)2, N-butyldiethanolamine (H2bdea) as a main N,O-chelating building block and different carboxylic acids [4-hydroxybenzoic (Hhba), 9-anthracenecarboxylic (Haca), or 4,4'-biphenyldicarboxylic (H2bdca) acid] as supporting carboxylate ligands. The structures of products range from discrete mono- (1) or dicopper(ii) (2) cores to a 1D coordination polymer (3), and widen a family of copper(ii) coordination compounds derived from H2bdea. The obtained compounds were applied as bioinspired homogeneous catalysts for the mild C-H functionalization of saturated hydrocarbons (cyclic and linear C5-C8 alkanes). Two model catalytic reactions were explored, namely the oxidation of hydrocarbons with H2O2 to a mixture of alcohols and ketones, and the carboxylation of alkanes with CO/S2O82- to carboxylic acids. Both processes proceed under mild conditions with a high efficiency and the effects of different parameters (e.g., reaction time and presence of acid promoter, amount of catalyst and solvent composition, substrate scope and selectivity features) were studied and discussed in detail. In particular, an interesting promoting effect of water was unveiled in the oxidation of cyclohexane that is especially remarkable in the reaction catalyzed by 3, thus allowing a potential use of diluted, in situ generated solutions of hydrogen peroxide. Moreover, the obtained values of product yields (up to 41% based on alkane substrate) are very high when dealing with the C-H functionalization of saturated hydrocarbons and the mild conditions of these catalytic reactions (50-60 °C, H2O/CH3CN medium). This study thus contributes to an important field of alkane functionalization and provides a notable example of new Cu-based catalytic systems that can be easily generated by self-assembly from simple and low-cost chemicals.


The Sox17-mCherry fusion mouse line allows visualization of endoderm and vascular endothelial development.
Sox17 is a HMG-box transcription factor that has been shown to play important roles in both cardio-vascular development and endoderm formation. To analyze these processes in greater detail, we have generated a Sox17-mCherry fusion (SCF) protein by gene targeting in ES cells. SCF reporter mice are homozygous viable and faithfully reflect the endogenous Sox17 protein localization. We report that SCF positive cells constitute a subpopulation in the visceral endoderm before gastrulation and time-lapse imaging reveals that SCF monitors the nascent definitive endoderm during epithelialization. After gastrulation, SCF marks the mid- and hindgut endoderm and vascular endothelial network, which can be imaged during establishment in allantois explant cultures. The SCF reporter is downregulated in the endoderm epithelium and upregulated in endothelial cells of the intestine, lung, and pancreas during organogenesis. In summary, the generation of the Sox17-mCherry reporter mouse line allows direct visualization of endoderm and vascular development in culture and the mouse embryo.