Understanding and breaking the intergenerational cycle of abuse in families enrolled in routine mental health services: study protocol for a randomized controlled trial and two non-interventional trials investigating mechanisms of change within the UBICA II consortium.
Parents' mental illness (MI) and parental history of early life maltreatment (ELM) are known to be significant risk factors for poor parenting while poor parenting is a crucial mediator of the intergenerational continuity of child maltreatment. Hence, maltreatment prevention programs for families with an MI parent, which pay particular attention to experiences of ELM in the parent, are urgently needed. Parental mentalizing was previously found to mediate successful parenting. Interventions aimed at improving the parental mentalizing capacity reduced maltreatment risk in parents. The aim of the present study is to investigate the effectiveness of a mentalization-based parenting-counseling in acutely mentally ill parents currently treated at a psychiatric hospital. Mentalization-based parenting-counseling (MB-PC) vs. enhanced standard clinical care (SCC+) will be administered in a cluster-randomized-controlled trial (RCT). Patients treated at psychiatric hospitals with children between 1.5 and 15 years will be included in the trial. MB-PC will be administered as a 12-h combined individual and group program enriched by social counseling (over a course of 5 weeks) as add-on to standard clinical care, while the control condition will be standard clinical care plus a 90-min psychoeducation workshop on positive parenting. Primary efficacy endpoint is self-reported parenting practices at follow-up. Embedded within the RCT will be two sub-studies investigating social cognition and dyadic synchrony as biobehavioral mechanisms of change. The main goal of the present study is to investigate ways to break the intergenerational continuity of maltreatment by assessing the benefits of a prevention program which aims at improving parenting in vulnerable mothers and fathers. MB-PC is a short, low-cost intervention which can be delivered by nurses and social workers and is applicable to MI patients with children with a broad range of diagnoses. If it is shown to be effective, it can be directly implemented into standard psychiatric hospital care thereby providing help to prevent child maltreatment. German Clinical Trials Register DRKS00017398 . Registered on 5 July 2019.


Combined antithrombotic treatment with aspirin and clopidogrel for patients with capsular warning syndrome: a case report.
Capsular warning syndrome is characterized by recurrent transient ischemic attacks and is caused by microthrombosis or hypoperfusion of small-sized vessels. The pathophysiological basis of this syndrome is not well understood and currently a consensus has not been reached on its optimal treatment. In this study, we present 2 cases with favorable clinical outcomes after combined antithrombotic treatment with loading doses of clopidogrel and aspirin.


Change Talk During Brief Motivational Intervention With Young Adult Males: Strength Matters.
Client change talk (CT) during motivational interviewing (MI) has been described as a predictor of change in alcohol use. We examined the predictive validity of different strength levels of CT within a brief MI session for 174 young men from the general population screened as hazardous drinkers. CT was measured using the MI Skill Code (MISC 2.1) and categorized with positive (toward change) and negative (against change) valence and 3 strength levels (1=low, 2=medium, 3=high). Analyses included linear regression models predicting drinking at 3-month follow-up, while controlling for baseline drinking. Frequency of overall negative CT (i.e., sum of -1, -2, -3) significantly predicted poorer drinking outcomes. In a multivariate model entering frequency of CT utterances at each level of strength (i.e. +1, +2, +3, -1, -2, -3), the directionality of negative strength ratings was consistently in the expected direction, but only CT-2 was statistically significant. In contrast, overall CT positive (i.e., sum of +1, +2, +3) was not a significant predictor of less alcohol use, but the multivariate model showed that the presence of CT+3 significantly predicted less drinking at 3-month follow-up. Averaged strength summary score (i.e. on the scale from -3 to +3) was a significant predictor of better outcome, while percent positive CT was not. Moderation analyses showed that young men with lower baseline readiness to change or lower alcohol problem severity had higher follow-up drinking when they expressed more CT+1 or CT+2, while the opposite pattern was observed with those reporting higher baseline readiness to change or higher alcohol problem severity. Mixed findings for varying levels of positive CT strength might explain previous studies showing poor predictive validity of positive client language in MI. Together with other studies in similar settings, these findings suggest the importance of advanced MI techniques to shape client language to soften negative change talk (also known as sustain talk) and elicit positive CT verbalized with high intensity.


Establishment and application of a predictive model for gefitinib-induced severe rash based on pharmacometabolomic profiling and polymorphisms of transporters in non-small cell lung cancer.
Rash is a well-known predictor of survival for patients with gefitinib therapy with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash obtain the more survival benefits from gefitinib is still unknown, and predicted model for severe rash is needed. The relationship between gefitinib-induced rash and progression free survival (PFS) was primarily explored in the retrospective cohort. The association between rash and gefitinib/metabolites concentration and genetic polymorphisms were determined by pharmacometabolomic and pharmacogenomics methods in the exploratory cohort and validated in an external cohort. The survival for patients with rash was significantly higher than that of patients without rash (p = 0.0002, p = 0.0089), but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was found to be associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve analysis (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95% CI = 2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95% CI = 0.958-11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95% CI = 2.067-72.465, p = 0.0087; GG vs CC, OR = 5.103, 95% CI = 1.032-33.938, p = 0.061). This model was confirmed in the validation cohort with an excellent predictive ability (AUC = 0.749, 95% CI = 0.710-0.951). Our finding demonstrated that the incidence, not the severity, of gefitinib-induced rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash.


Acute self-limited colitis associated with Cryptosporidium in an immunocompetent patient.
A case report of acute self-limiting colitis associated with enteric Cryptosporidium infection in an immunocompetent child is presented. This case broadens the spectrum of symptoms and manifestation of Cryptosporidium infection in a normal human host.


Heme oxygenase-1 contributes to the protective effect of resveratrol against endothelial dysfunction in STZ-induced diabetes in rats.
Endothelial dysfunction is a common complication of diabetes that mainly stems from increased reactive oxygen species, which makes antioxidants of great benefit. Resveratrol (RSV) is an antioxidant that shows protective effects in a variety of disease models where the ameliorative effect appears to be mediated, in part, via heme oxygenase-1 (HO-1) induction. However, the pathophysiological relevance of HO-1 in the ameliorative response of RSV in endothelial dysfunction is not clearly defined. The present study was conducted to investigate whether HO-1 plays a role in diabetes-induced vascular dysfunction. Streptozotocin-diabetic rats were treated with RSV (10 mg/kg) in presence or absence of an HO-1 blocker, Zinc protoporphyrin (ZnPP) to assess vascular function and indicators of disease status. We found that RSV treatment significantly abrogated diabetes induced vascular dysfunction. This improvement was associated with the ability of RSV to decrease oxidative stress markers alongside a reduction in the aortic TGF-β expression, elevation of NOS3 expression and aortic nitrite concentration as well as HO activity. These ameliorative effects were diminished when ZnPP was administered prior to RSV. Our results clearly demonstrate the protective effects of RSV in diabetes-associated endothelial dysfunction and verified a causal role of HO-1 in this setting.


Inhibitory effect of activin A on activation of lipopolysaccharide-stimulated mouse macrophage RAW264.7 cells.
Activin A is a member of transforming growth factor beta (TGF-beta) superfamily, which is also named restrictin-P, and can inhibit the secretion of nitric oxide (NO) and interleukin-1beta (IL-1beta) from LPS-activated mouse macrophages. In this study, the regulation effect and possible mechanism of activin A as an anti-inflammatory factor on lipopolysaccharide (LPS)-activated macrophages were investigated in vitro. It was observed that activin A could not only decrease the secretion of IL-1beta and NO, as well as the mRNA expressions of IL-1beta and iNOS, but also suppress the pinocytosis of mouse macrophage cell line RAW264.7 cells induced by LPS. In addition, activin A could obviously reduce the expressions of CD68 and CD14, as well as Toll-like receptor 4 (TLR4) on RAW264.7 cells induced by LPS, but could not influence the proliferation of RAW264.7 cells. These findings suggest that activin A may play an important down-regulation role in inflammatory factor production and phagocytosis of the activated macrophages via suppressing the maturation of LPS-induced macrophages or LPS-TLR4 signal transduction.


Zinc balance in premature infants given the minimal dietary zinc requirement.
A zinc balance study was conducted on low birth weight infants (670 to 2420 g) fed unsupplemented human milk (the mother's or pooled) (group 1, n = 17) or human milk with zinc supplementation (group 2, n = 17). The mean zinc concentrations of the diets in groups 1 and 2 were 2.2 +/- 1.1 mg/L and 8.4 +/- 0.8 mg/L, respectively, and the mean copper concentration of the diets in both groups was 0.45 +/- 0.12 mg/L. The studies were performed 7 to 128 days after birth, which corresponded to 29 to 43 weeks postconceptional age. The turning point of zinc balance from negative to positive appeared to be greatly influenced by the postconceptional age, being approximately 36 weeks in both group 1 and group 2, rather than other factors such as the zinc intake and the postnatal age. The calculated minimal requirement of dietary zinc during the period from 36 to 40 weeks postconceptional age, for an adequate amount of zinc retention in infants (250 micrograms/kg/d), was 0.8 mg/kg/d. Zinc supplementation did not appear to interfere with copper retention.


Artemisinin resistance in P. falciparum: probing the interacting partners of Kelch13 protein in parasite.
Artemisinin (ART) resistance in Plasmodium is threatening the artemisinin combination therapies-the first line of defence against malaria. ART resistance has been established to be mediated by the Plasmodium Kelch13 (PfK13) protein. For the crucial role of PfK13 in multiple pathways of the Plasmodium life cycle and ART resistance, it is imperative that we investigate its interacting partners. We recombinantly expressed PfK13-p (Bric a brac/Poxvirus and zinc finger and propeller domains), generating anti-PfK13-p antibodies to perform co-immunoprecipitation assays and probed PfK13 interacting partners. Surface plasmon resonance and pull-down assays were performed to establish physical interactions of representative proteins with PfK13-p. The co-immunoprecipitation assays identified 17 proteins with distinct functions in the parasite life cycle- protein folding, cellular metabolism, and protein binding and invasion. In addition to the overlap with previously identified proteins, our study identified 10 unique proteins. Fructose-biphosphate aldolase and heat shock protein 70 demonstrated strong biophysical interaction with PfK13-p, with KD values of 6.6 µM and 7.6 µM, respectively. Additionally, Plasmodium merozoite surface protein 1 formed a complex with PfK13-p, which is evident from the pull-down assay. This study adds to our knowledge of the PfK13 protein in mediating ART resistance by identifying new PfK13 interacting partners. Three representative proteins-fructose-biphosphate aldolase, heat shock protein 70, and merozoite surface protein 1-demonstrated clear evidence of biophysical interactions with PfK13-p. However, elucidation of the functional relevance of these physical interactions are crucial in context of PfK13 role in ART resistance.


Polyclonal activation of immunoglobulin secretion without prior DNA synthesis in human B lymphocytes induced by Klebsiella pneumoniae.
The capacity of various cell preparations of Klebsiella pneumoniae K43 (Klebs) to induce [3H]thymidine uptake and immunoglobulin (Ig) secretion by human mononuclear blood cells (MNC) and their lymphocyte subpopulations was investigated. All Klebs preparations were virtually devoid of mitogenic properties, in contrast to control preparations of pokeweed mitogen (PWM) and group A streptococcal cell membranes (A-ScM). Klebs induced differentiation of B cells into Ig-secreting cells. B-cell populations that were sufficiently depleted of T cells to be unresponsive to A-ScM ("highly purified B cells") showed a marked response to Klebs. Similarly, the number of plaque-forming cells (PFC) in Klebs-driven cultures did not change after restitution of T cells, whereas the presence of restituted T cells augmented the B-cell response to PWM and A-ScM. Radical removal of adherent MNC ("monocytes"), however, completely abrogated the PFC response and [3H]thymidine uptake of both MNC activated by Klebs and MNC activated by PWM or A-ScM.


Dawn, diacylglycerol, calcium, and protein kinase C--the retinal wrecking crew. A signal transduction cascade for rhabdom shedding in the Limulus eye.
Vertebrate and invertebrate photoreceptors shed their photosensitive membrane on a daily basis. Although we have detailed knowledge of the morphology of the disc shedding and renewal process in vertebrate photoreceptors, and of the turnover of rhabdom in invertebrate photoreceptors, we know relatively little about the molecular mechanisms whereby these processes are triggered by light and/or by circadian efferent input to the retina. We have used the horseshoe crab, Limulus polyphemus, as a model system to unravel the molecular means by which the trigger light is communicated to the intracellular machinery responsible for the daily breakdown of the photosensitive membrane. Phorbol esters, potent and specific activators of protein kinase C (PKC), induce a robust burst of rhabdom shedding when injected subretinally into the compound lateral eye of Limulus. This occurs in the absence of the light trigger normally required to initiate shedding in the lateral eye at dawn, suggesting that PKC may play a role in the light triggering of rhabdom shedding. Diacylglycerol (DAG) analogs were also found to elicit rhabdom shedding in the lateral eye without a light trigger, but at uncharacteristically high concentrations. However, injecting inositol trisphosphate (InsP3) and DAG analog simultaneously results in a tenfold decrease in the concentration of DAG analog required to initiate a shedding event. Immunohistochemical screening for PKC in the lateral eye shows that two isozymes (PKC beta II and PKC zeta) are co-localized to the retinular cell rhabdom. Taken together, these data suggest that light triggers rhabdom shedding at dawn via a classical Ca(2+)-sensitive PKC, similar to PKC beta II, which is activated synergistically by the light-evoked production of DAG and InsP3.


Computerized automated syndromic and topographical neurologic diagnosis of lesions of the cranial nerves.
A system is described which, by means of a digital computer, computes from a previously automatically recorded objective neurologic finding a syndromic and topographical conclusion. For the present the system is designed and checked for lesions of the cranial nerves, but its principle is appropriate for the whole syndromic and topographical neurologic diagnosis.


Evaluation of phenotypic detection of carbapenemase-producing Pseudomonas spp. from clinical isolates.
Carbapenems are considered last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. Although the main mechanism of carbapenem-resistance in Pseudomonas aeruginosa is the loss of OprD porin, carbapenemases continue to be a problem worldwide. The aim of this study was to evaluate the performance of phenotypic tests (Carba NP, Blue Carba, and mCIM/eCIM) for detection of carbapenemase-producing Pseudomonas spp. in Brazil. One hundred twenty-seven Pseudomonas spp. clinical isolates from different Brazilian states were submitted to phenotypic and molecular carbapenemase detection. A total of 90 carbapenemase-producing P. aeruginosa and 5 Pseudomonas putida (35, blaVIM-2; 17, blaSPM-1; 2, blaIMP-10; 1, blaVIM-24; 1, blaNDM-1; 39, blaKPC-2). The phenotypic Carba NP, Blue Carba, and mCIM/eCIM showed sensitivity of 94.7%, 93.6%, and 93.6%, and specificity of 90.6%, 100%, and 96.8%, respectively. However, only the Carba NP presented the highest sensitivity and showed the ability in differentiating the carbapenemases between class A and class B using EDTA. Blue Carba failed to detect most of the class B carbapenemases, having the worst performance using EDTA. Our results show changes in the epidemiology of the spread of carbapenemases and the importance of their detection by phenotypic and genotypic tests. Such, it is essential to use analytical tools that faithfully detect bacterial resistance in vitro in a simple, sensitive, rapid, and cost-effective way. Much effort must be done to improve the current tests and for the development of new ones.


A Review of Research Progress on Agathis dammara and its Application Prospects for Cardiovascular Diseases and Fatty Liver Disease.
Cardiovascular diseases and fatty liver disease have become the leading causes of death in modern society. However, the currently existing drugs do not solve all issues related to these diseases; thus, it is expected that more potential drugs for clinical use will be developed. Undeniably, natural products have attracted increasing attention. It is of great significance to identify effective active monomer components for drug discovery and disease prevention. As a pure natural product, Agathis dammara (AD) has antioxidant, hypolipidemic, hypoglycemic, antitumor, and anti-inflammatory activities. However, at present, there are few reports regarding the effects of AD on chronic inflammatory cardiovascular diseases, such as aneurysm, atherosclerosis, myocardial ischemia-reperfusion injury, and cardiac hypertrophy and liver diseases such as fatty liver disease. AD and products derived from it have a very broad application prospect for cardiovascular diseases and fatty liver disease.


Microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors.
Macroscopic vascular invasion is known to be a poor prognostic factor in hepatocellular carcinoma (HCC). The aim of this study was to determine the outcomes and predictive factors after hepatic resection for HCC with microvascular invasion (MVI). One hundred ten patients who underwent curative resection for HCC without macroscopic vascular invasion were included in this retrospective study. The risk factors of these patients for recurrence-free and disease-specific survival were investigated, and the clinicopathological factors predicting the presence of MVI were also determined. Of the 110 resected specimens, 49 (45%) had evidence of MVI. By univariate analysis, MVI was found to be statistically significantly associated with greater tumor size, gross classification, histological grade, and intrahepatic micrometastasis. Gross classification proved to be the only independent predictive factor for MVI by multiple logistic regression analysis. By multivariate analysis, cirrhosis and MVI were identified as independent risk factors for recurrence-free survival. The 5-year recurrence-free survival rates for patients with and without MVI were 20.8% and 52.6%, respectively. By multivariate analysis, the number of tumors, presence of MVI, and intrahepatic micrometastasis were identified as independent predictors of disease-specific survival. The 5-year disease-specific survival rates for patients with and without MVI were 59.3% and 92.0%, respectively. The presence of MVI was the most important risk factor affecting recurrence and survival in HCC patients after curative resection. Furthermore, this study showed that gross classification of HCC can be very helpful in predicting the presence of MVI.


IL-37 isoform D acts as an inhibitor of soluble ST2 to boost type 2 immune homeostasis in white adipose tissue.
White adipose tissue (WAT) homeostasis substantiated by type 2 immunity is indispensable to counteract obesity and metabolic disorders. IL-33/suppression of tumorigenicity (ST) 2 signaling promotes type 2 response in WAT, while potential regulators remain to be discovered. We identified human IL-37 isoform D (IL-37D) as an effective trigger for ST2-mediated type 2 immune homeostasis in WAT. IL-37D transgene amplified ST2+ immune cells, promoted M2 macrophage polarization and type 2 cytokine secretion in WAT that mediate beiging and inflammation resolution, thereby increasing energy expenditure, reducing obesity and insulin resistance in high-fat diet (HFD)-fed mice. Mechanistically, either endogenous or exogenous IL-37D inhibited soluble ST2 (sST2) production from WAT challenged with HFD or TNF-α. Recombinant sST2 impaired the beneficial effects of IL-37D transgene in HFD-fed mice, characterized by damaged weight loss, insulin action, and type 2 cytokine secretion from WAT. In adipose-derived stem cells, IL-37D inhibited TNF-α-stimulated sST2 expression through IL-1 receptor 8 (IL-1R8)-dependent NF-κB inactivation. Collectively, human IL-37D suppresses sST2 to boost type 2 immune homeostasis in WAT, which may be a promising therapy target for obesity and metabolic disorders.


Placebo-controlled, double-blind, randomized pilot study of imiquimod 5% cream applied once per week for 6 months for the treatment of actinic keratoses.
Imiquimod 5% cream applied twice weekly for 16 weeks is effective for treating actinic keratoses but may be limited by local side effects. We sought to explore the efficacy and safety of a once weekly for 24 weeks dosing regimen using a left versus right side of head design. Twenty patients were enrolled; 15 completed and 5 discontinued for reasons unrelated to adverse events. At the posttreatment visit (week 28), 7 (46.7%) of 15 patients had marked improvement or better on the imiquimod side versus one (6.7%) of 15 on the placebo side. The average investigator assessment scale score change was +2.20 for imiquimod compared with -0.27 for placebo (P = .0002, Wilcoxon signed rank test). Skin reactions were minimal or nonexistent in most patients. Limitations of the study include a small sample size and a lack of objective measure of local side effects. Imiquimod 5% cream applied once weekly for 24 weeks was convenient for patients and resulted in improvement of actinic keratoses with minimal side effects.


Efficacy and safety of canagliflozin in patients with type 2 diabetes based on history of cardiovascular disease or cardiovascular risk factors: a post hoc analysis of pooled data.
Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors. Analyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports. At week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (-0.95 and -1.07%) versus no history of CV disease (-0.71 and -0.90%), history of hypertension (-0.72 and -0.89%) versus no history of hypertension (-0.73 and -0.95%), baseline statin use (-0.77 and -0.99%) versus no statin use (-0.69 and -0.85%), and 0-1 CV risk factor (-0.72 and -0.87%) versus ≥2 CV risk factors (-0.74 and -1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups. The efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors. Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010.


Assessing the effect of the Expanding Maternal and Neonatal Survival program on improving stabilization and referral for maternal and newborn complications in Indonesia.
To determine if the Expanding Maternal and Neonatal Survival (EMAS) program was associated with improved effectiveness of the referral system in Indonesia to facilitate timely and effective management of complications experienced by women and newborns. Poisson regression using longitudinal monitoring data was used to assess the impact of the EMAS program on stabilization practices prior to referral. Data from a nonrandomized quasi-experimental pre-post evaluation study were used to assess the impact of the EMAS program along the referral pathway using χ2 analysis. Monitoring data demonstrated improvements in intervention areas for stabilization of pre-eclampsia/eclampsia (24% vs 61%, incidence rate ratio [IRR] 2.4; 95% confidence interval [CI], 2.3-2.6) and treatment of newborns with suspected severe infection (30% vs 54%, IRR 2.0; 95% CI, 1.6-2.4) prior to referral. The EMAS program was associated with significantly higher levels of communication, advanced notification, back referral, and hospital emergency readiness and staff preparedness compared with the comparison arm. The EMAS program contributed to improvements in the management of obstetric and newborn complications, including communication, transportation, and preparation of pregnant mothers in need of referral and hospital emergency readiness and staff preparedness.


Members of the Gq alpha subunit gene family activate phospholipase C beta isozymes.
The relative specificities of members of the G alpha q family of GTP-binding proteins were tested for their ability to activate different phosphoinositide-specific phospholipase C (PI-PLC) beta isozymes. Cos-7 cells were transfected with cDNA corresponding to G alpha q, G alpha 11, G alpha 14, and G alpha 16. Most of the recombinant protein was bound to the cell membrane and these membranes were washed to elute endogenous PI-PLC activity. The membrane preparation was reconstituted with purified preparations of the PI-PLC beta isozymes and guanosine 5'-O-thiotriphosphate (GTP gamma S)-stimulated enzyme activity was measured. All four proteins of the G alpha q family were found to stimulate PI-PLC beta 1, with G alpha q and G alpha 11 being most efficient. On the other hand, G alpha 16 was found to most effectively activate PI-PLC beta 2, while G alpha q, G alpha 11, and G alpha 14 showed less stimulation. Specific anti- G alpha 16 antibody blocked the stimulation of both PI-PLC beta 1 and PI-PLC beta 2 in the enriched membrane fraction. We conclude that there is specificity in the interaction of different members of the Gq family with different PI-PLC beta effectors. This specificity may be important in generating tissue- or receptor-specific responses in vivo.


Population pharmacokinetics meta-analysis of plitidepsin (Aplidin) in cancer subjects.
To characterize the population pharmacokinetics of plitidepsin (Aplidin) in cancer patients. A total of 283 patients (552 cycles) receiving intravenous plitidepsin as monotherapy at doses ranging from 0.13 to 8.0 mg/m(2) and given as 1- or 24-h infusions every week; 3- or 24-h infusion biweekly; or 1-h infusion daily for 5 consecutive days every 21 days were included in the analysis. An open three-compartment pharmacokinetic model and a nonlinear binding to red blood cells model were used to describe the plitidepsin pharmacokinetics in plasma and blood, respectively, using NONMEM V software. The effect of selected covariates on plitidepsin pharmacokinetics was investigated. Model evaluation was performed using goodness-of-fit plots, posterior predictive check and bootstrap. Plasma clearance and its between subject variability (%) was 13.6 l/h (71). Volume of distribution at steady-state was calculated to be 4791 l (59). The parameters B (max) and C (50) of the non-linear blood distribution were 471 microg/l (56) and 41.6 microg/l, respectively. Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, creatinine clearance, albumin, total protein, performance status, co-administration of inhibitors or inducers of CYP3A4 and presence of liver metastases were not statistically related to plitidepsin pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of plitidepsin blood and plasma concentrations in cancer patients. The integration of phase I/II pharmacokinetic data demonstrated plitidepsin linear elimination from plasma, dose-proportionality up to 8.0 mg/m(2), and time-independent pharmacokinetics. The distribution to red blood cells can be considered linear at doses lower than 5 mg/m(2) administered as 3-h or longer infusion. No clinically relevant covariates were identified as predictors of plitidepsin pharmacokinetics.


[Immunoreactivity of pulmonary tuberculosis patients to tuberculous antigens purified by affinity columns coupled with monoclonal antibodies directed to Mycobacterium tuberculosis].
Immunoaffinity-purified antigens (MAb-Ags) of Mycobacterium tuberculosis, which has been obtained in a previous study by use of anti-M. tuberculosis monoclonal antibodies and designated MTA 2a (24 kD), MTA 6a (19 kD) and MTA 8a (19 kD), were examined for their antigenicity by determining the responsiveness to these antigens of pulmonary tuberculosis (TB) patients and non-tuberculous controls. Serum anti-MAb-Ags ELISA antibody levels in TB patients were significantly higher than those in non-tuberculosis controls, including patients with atypical mycobacterial infection and Mantoux-test-positive healthy individuals. MAb-Ags stimulated proliferation of peripheral blood lymphocytes (PBL) from TB patients as determined by 3H-thymidine uptake of PBL. MAb-Ags also stimulated PBL from TB patients to increase T4/T8 ratio and Ia-positive T cells. After stimulation with MAb-Ags, increase of IL-2 receptor-positive T cells in PBL from TB patients was not significantly higher than that in PBL from healthy persons. Responses of PBL from non-tuberculosis controls to MAb-Ags varied considerably, and the response was either none or weak, in some cases, or as high as that of PBL from TB patients, in the other cases. In general, MAb-Ags stimulated PBL from TB patients and some of Mantoux test-positive persons to almost the same extent as PPDs did.


Oral surgery related fungal endocarditis: The need for a novel concept in endocarditis prophylaxy.
Current paper aims to hypothesize that, oral surgical interventions such as tooth extractions, endosseous implant placement, subgingival curettage, etc. might result in widespread of fungal species via blood stream and can cause fungal contaminations of the cardiac valves. We hereby suggest that, an additional fungal endocarditis risk assessment and prevention protocol should be created for patients with a possible risk of endocarditis development.


Mutations outside the anisomycin-binding site can make ribosomes drug-resistant.
Eleven mutations that make Haloarcula marismortui resistant to anisomycin, an antibiotic that competes with the amino acid side chains of aminoacyl tRNAs for binding to the A-site cleft of the large ribosomal unit, have been identified in 23S rRNA. The correlation observed between the sensitivity of H. marismortui to anisomycin and the affinity of its large ribosomal subunits for the drug indicates that its response to anisomycin is determined primarily by the binding of the drug to its large ribosomal subunit. The structures of large ribosomal subunits containing resistance mutations show that these mutations can be divided into two classes: (1) those that interfere with specific drug-ribosome interactions and (2) those that stabilize the apo conformation of the A-site cleft of the ribosome relative to its drug-bound conformation. The conformational effects of some mutations of the second kind propagate through the ribosome for considerable distances and are reversed when A-site substrates bind to the ribosome.


Osteoid osteoma of the distal phalanx: a report of four cases and review of the literature.
Four cases of osteoid osteoma of the distal phalanx are described. The difficulty of diagnosis is stressed. Complete removal of the nidus is essential for surgical cure. Other modes of treatment are discussed and our series compared to other similar cases described in the literature.


Optimized Workflow for Whole Genome and Transcriptome Next-Generation Sequencing of Single Cells or Limited Nucleic Acid Samples.
Whole genome and whole transcriptome sequencing require orders of magnitude more of starting nucleic acid than what is found in single cells or other extremely limited samples. High fidelity amplification of this minute amount of nucleic acids is essential to overcome the limitations caused by the low input, degradation and contamination, and to ensure a sufficient amount of DNA for preparation of high complex and high quality next-generation sequencing (NGS) libraries. Recent technical advances in multiple displacement amplification (MDA) enable studies of rare cell types, heterogeneity of body fluids, tissues, environmental samples, and organisms that cannot be cultured. Several strategies for amplification of limiting amounts of nucleic acid have been described, with PCR being popular. However, PCR-based methods result in high error rates, lower library complexity, and lower coverage uniformity. In this article, a HiFi MDA is used to accurately amplify the limited material and to allow library preparation starting from high input, while reducing PCR cycling to achieve sufficient library yields. This article describes a complete workflow from cells and small quantities of DNA or RNA to NGS libraries for Illumina sequencing instruments. © 2023 QIAGEN GmbH. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Whole genome amplification from single cells Support Protocol 1: PicoGreen™ quantification of MDA amplified DNA Support Protocol 2: Purification of amplified DNA after MDA Basic Protocol 2: Whole transcriptome amplification from single cells Alternate Protocol: Whole transcriptome amplification from purified RNA Basic Protocol 3: Enrichment of complete small genomes using target-specific primers in MDA Basic Protocol 4: Complete viral RNA amplification using target-specific primers in MDA Basic Protocol 5: Enzymatic fragmentation and adapter ligation of MDA amplified material Basic Protocol 6: Normalization of library concentration using magnetic beads.


Chronic trifluoperazine treatment does not induce lipid peroxidation in the rat cortex.
Rats received continuous chronic trifluoperazine hydrochloride (4.4-4.9 mg/kg/day) treatment for 15 months via their drinking water. Drug treatment did not alter the content of polyunsaturated fatty acids in the cerebral cortex when compared to age-matched control animals. Similarly, there was no change in basal levels of malondialdehyde (MDA) when measured by a fluorimetric or spectrophotometric technique. Incubation of cortical homogenates in air, or with FeSO4 plus ascorbic acid or H2O2 plus FeSO4, stimulated MDA production to the same extent in tissue from drug-treated and control animals. The chronic administration of trifluoperazine to rats does not appear to promote lipid peroxidation as has been suggested for haloperidol.


[End-of-stem pain in hip and knee arthroplasty].
End-of-stem pain after knee and hip arthroplasty with diaphyseal supportive stems is a frequently overlooked and potentially underestimated complication. A commonly recurring clinical phenome is the symptom-free interval after surgery of weeks to months, with new onset of symptoms under stress only later. The patient is often again reliant on walking sticks. End-of-stem pain is a diagnosis of exclusion. Pain is projected into the tip of the stem, and if differential diagnoses such as loosening are excluded, then the patient might be treated with a "bending-plate". Since bone cement has a similar elastic modulus to human cortical bone, a change of method to a cemented implant can also be expedient. In the primary situation, in addition to cemented stems, the use of "split-stems" could be useful. After revision surgery of any kind, a timely cessation of pain confirms the diagnosis.


Quality of Life Implications After Transoral Robotic Surgery for Oropharyngeal Cancers.
Oropharyngeal cancers and their treatment can exquisitely affect a patient's quality of life and functional outcome. Transoral robotic surgery offers a minimally invasive surgical approach that mitigates injury from traditional open surgical approaches and offers a treatment more likely to have short-term side effects compared with nonsurgical treatment. Feeding tube dependence, oral intake, and swallowing questionnaires, in addition to swallowing evaluations provide a snapshot of a patient's current swallowing function. Investigation of patient-reported quality-of-life outcomes allows for understanding of their symptomatology and the comparison of different treatment strategies.


The role of Cushing's reflex and the vasopressin-mediated oligoanuric response to intracranial hypertension in patients with abdominal compartment syndrome.
We examined the link between increased intra-abdominal pressure, intracranial pressure, and vasopressin release as a potential mechanism. Intra-abdominal pressure, produced by abdominal-cavity insufflation with carbon dioxide (CO2) during laparoscopic abdominal procedures to facilitate visualization, is associated with various complications, including arterial hypertension and oliguria. Mean arterial pressure, optic nerve sheath diameter, measured as a proxy for intracranial pressure, plasma vasopressin, serum and urine osmolarity, and urine output were measured 4 times during laparoscopic sleeve gastrectomy in 42 patients: before insufflation with CO2 (T0); after insufflation to 15 cm water (H2O) pressure, with 5 cm H2O positive end-expiratory pressure (T1); after positive end-expiratory pressure was raised to 10 cm H2O (T2); and after a return to the baseline state (T3). Mean values at T0 to T3 and the directional consistency of changes (increase/decrease/ unchanged) were compared among the 4 data-collection points. Statistically significant elevations (all P ≤ .001) were noted from T0 to T1 and from T0 to T2 in mean arterial pressure, optic nerve sheath diameter, and vasopressin, followed by decreases at T3. For optic nerve sheath diameter and vasopressin, the increases at T1 and T2 occurred in 98% and 100% of patients, ultimately exceeding normal levels in 88 and 97%, respectively. Conversely, urine output fell from T0 to T1 and T2 by 60.9 and 73.4%, decreasing in 88.1% of patients (all P < .001). Patients with class II obesity exhibited statistically greater increases in optic nerve sheath diameter and vasopressin, but statistically less impact on urine output, than patients with class III obesity. Increased mean arterial pressure, intracranial pressure, and vasopressin release appear to be intermediary steps between increased intra-abdominal pressure and oliguria. Further research is necessary to determine any causative links between these physiological changes.


HDAC1 Expression, Histone Deacetylation, and Protective Role of Sodium Valproate in the Rat Dorsal Root Ganglia After Sciatic Nerve Transection.
Nerve injury is an important reason of human disability and death. We studied the role of histone deacetylation in the response of the dorsal root ganglion (DRG) cells to sciatic nerve transection. Sciatic nerve transection in the rat thigh induced overexpression of histone deacetylase 1 (HDAC1) in the ipsilateral DRG at 1-4 h after axotomy. In the DRG neurons, HDAC1 initially upregulated at 1 h but then redistributed from the nuclei to the cytoplasm at 4 h after axotomy. Histone H3 was deacetylated at 24 h after axotomy. Deacetylation of histone H4, accumulation of amyloid precursor protein, a nerve injury marker, and GAP-43, an axon regeneration marker, were observed in the axotomized DRG on day 7. Neuronal injury occurred on day 7 after axotomy along with apoptosis of DRG cells, which were mostly the satellite glial cells remote from the site of sciatic nerve transection. Administration of sodium valproate significantly reduced apoptosis not only in the injured ipsilateral DRG but also in the contralateral ganglion. It also reduced the deacetylation of histones H3 and H4, prevented axotomy-induced accumulation of amyloid precursor protein, which indicated nerve injury, and overexpressed GAP-43, a nerve regeneration marker, in the axotomized DRG. Therefore, HDAC1 was involved in the axotomy-induced injury of DRG neurons and glial cells. HDAC inhibitor sodium valproate demonstrated the neuroprotective activity in the axotomized DRG.


Designing and understanding light-harvesting devices with machine learning.
Understanding the fundamental processes of light-harvesting is crucial to the development of clean energy materials and devices. Biological organisms have evolved complex metabolic mechanisms to efficiently convert sunlight into chemical energy. Unraveling the secrets of this conversion has inspired the design of clean energy technologies, including solar cells and photocatalytic water splitting. Describing the emergence of macroscopic properties from microscopic processes poses the challenge to bridge length and time scales of several orders of magnitude. Machine learning experiences increased popularity as a tool to bridge the gap between multi-level theoretical models and Edisonian trial-and-error approaches. Machine learning offers opportunities to gain detailed scientific insights into the underlying principles governing light-harvesting phenomena and can accelerate the fabrication of light-harvesting devices.


Health and the social status of blacks in the United States.
Inequalities in health status among various racial and ethnic groups form a prominent chapter in the history of public health in the United States. Inequalities are observed for a wide range of specific conditions, and evolve over time. Little evidence is available to support the contention that any sizable proportion of this overall inequality is caused by genetic factors operating at the population level. On the other hand, social status, as measured by proxy variables like income and education, does provide important information about the black-white differential in health status when used in standard epidemiologic analyses. What is often neglected in these analyses, however, is an attempt to define underlying pathogenic mechanisms that incorporate social processes. Causal explanations based on the broader observation that inequality determined by the structure of social relations is associated with health differentials in all populations offer a plausible theoretic framework. At the same time, the unique character of the experience of specific ethnic subpopulations must be accounted for. Any attempt to account for the impact of race with greater precision will require an attempt to define this demographic variable within the context of social class relations.


Microfluidic integrated acoustic waving for manipulation of cells and molecules.
Acoustophoresis with its simple and low-cost fabrication, rapid and localized fluid actuation, compatibility with microfluidic components, and biocompatibility for cellular studies, has been extensively integrated into microfluidics to provide on-chip microdevices for a variety of applications in biology, bioengineering and chemistry. Among different applications, noninvasive manipulation of cells and biomolecules are significantly important, which are addressed by acoustic-based microfluidics. Here in this paper, we briefly explain the principles and different configurations of acoustic wave and acoustic streaming for the manipulation of cells and molecules and overview its applications for single cell isolation, cell focusing and sorting, cell washing and patterning, cell-cell fusion and communication, and tissue engineering. We further discuss the application of acoustic-based microfluidic systems for the mixing and transport of liquids, manipulation of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) molecules, followed by explanation on the present challenges of acoustic-based microfluidics for the handling of cells and molecules, and highlighting the future directions.


Protein identification assisted by the prediction of retention time in liquid chromatography/tandem mass spectrometry.
Two-dimensional liquid chromatography (2D-LC) coupled on-line with electrospray ionization tandem mass spectrometry (2D-LC-ESI-MS/MS) is a new platform for analysis and identification of proteome. Peptides are separated by 2D-LC and then performed MS/MS analysis by tandem MS/MS. The MS/MS data are searched against database for protein identification. In one 2D-LC-ESI-MS/MS run, we obtained not only the structural information of peptides directly from MS/MS, but also the retention time of peptides eluted from LC. Information on the chromatographic behavior of peptides can assist protein identification in the new platform for proteomics. The retention time of the matching peptides of the identified protein was predicted by the hydrophobic contribute of each amino acid on reversed-phase liquid chromatography (RPLC). By using this strategy proteins were identified by four types of information: peptide mass fingerprinting (PMF), sequence query, and MS/MS ions searched and the predicted retention time. This additional information obtained from LC could assist protein identification with no extra experimental cost.


Imaging of post-synaptic membrane trafficking in neuronal dendrites: progress, limitations, and new developments.
Membrane trafficking of post-synaptic cargo is a key determinant of synaptic transmission and synaptic plasticity. We describe here the latest developments in visualizing individual exocytosis and endocytosis events in neurons using pH-sensitive tags. We show how these tools help decipher the spatial and temporal regulation of membrane trafficking steps during synaptic plasticity.


Near-Complete Genome Sequence of White Spot Syndrome Virus Infecting Cultivated Shrimp (Penaeus vannamei) in Peru.
White spot syndrome virus (WSSV) infects a broad range of aquatic animals, including the shrimp Penaeus vannamei. In this study, we report one genome sequence of WSSV present in shrimp on the north coast of Peru.


Proof-of-Concept and Feasibility Study to Evaluate the Effect of β-Glucan on Protective Qi Deficiency in Adults.
To preliminarily explore the potential effect of β-glucan on Chinese medicine (CM) concept protective qi deficiency (PQD), and the methodology for future definitive studies. To have a standardized assessment of PQD, a list of 13 potentially PQD-relevant parameters were firstly created, each with defined quantitative or categorial scales. Using the data from 37 participants with (21 cases) or without (16 cases) PQD, multivariate logistic modeling was conducted to create a preliminary diagnostic PQD risk score. Subsequently, 21 participants diagnosed with PQD were treated with β-glucan in a dose of 200 mg/day for 8 weeks. Data were collected for trial acceptability measures (rate of recruitment, withdrawal, and compliance), and the participants were assessed for PQD status at baseline and every 2 weeks thereafter. The preliminary logistic model consisted of 3 parameters (low voice and apathy, aversion to wind and cold, and Cun pulse). The resulting risk score demonstrated a degree of PQD-predicting accuracy that, as evaluated by statistical (discrimination and classification) methods, was higher than those obtained from any of the individual candidate parameters. The 21 PQD participants treated with β-glucan demonstrated good receptibility and a time-dependent improvement in PQD status as evidenced by the decrease of PQD participant to 9.5% at the end of study. This study demonstrated the effect of proof-of-concept of β-glucan on improving PQD and the proof-of-concept of a multivariate-model-derived diagnostic PQD risk score. It also indicated feasibility for future definitive studies. Studies like this embody an innovative approach that uses therapies derived from the mainstream biomedicine to enrich therapeutics guided by CM principle. (Trial registration No. NCT03829228).


Psychological distress and health behaviours among Cambodian Americans at risk for developing diabetes.
This paper reports secondary data analysis of associations between psychological distress and health behaviours among Cambodian Americans. Data are from baseline assessments from a diabetes prevention trial. All participants met stucriteria for depression and were free of diabetes. Participants (n = 191) completed surveys, a food frequency assessment, and wore sleep and physical activity actigraphy devices for 7 days. A factor analysis of symptoms of post-traumatic stress, baksbat (a Cambodian culture-bound syndrome), depression, and anxiety yielded a single factor named 'psychological distress'. Multivariate models controlling for psychotropic medications were run for the following outcomes: sleep actigraphy, self-reported sleep, physical activity actigraphy, self-reported physical activity, nutrition, and substance use. For actigraphy, higher distress was associated with lower moderate/vigorous physical activity and higher mean variability of 24 h total sleep time. Higher distress was also associated with worse self-reported sleep quality as indicated by standard, and culturally-specific, sleep indicators. Higher distress was also associated with lower use of food labels, lower carbohydrate consumption, and higher alcohol consumption as a coping mechanism. Interventions to mitigate diabetes risk in high-distress populations may benefit from strategies to decrease psychological distress. The sequelae of complex trauma may transcend discrete psychiatric diagnoses.


Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis.
Studies in animals showed that the hippocampus, a brain area involved in learning and memory, is sensitive to stress. Although several MRI studies showed smaller hippocampal volume in adults with chronic PTSD, others did not show significant differences from controls. These studies are typified by small sample sizes which may limit the ability to show significant differences. We therefore performed a meta-analytic study of all of these studies to clarify the role of hippocampal structural changes in subjects with PTSD. Nine studies with a total of 133 adult subjects with chronic PTSD, 148 healthy controls, and 53 traumatized controls were included in the meta-analysis. There was significantly smaller volume in both right and left hippocampi in adult subjects with chronic PTSD in comparison with both healthy controls and traumatized controls. These findings are consistent with smaller hippocampal volume in adult subjects with chronic PTSD.


Mast cells in food allergy: Inducing immediate reactions and shaping long-term immunity.
Mast cells are distributed throughout the gastrointestinal tract and function as the main effector cells of IgE-mediated allergic reactions to foods. Allergen-induced cross-linking of IgE antibodies bound to high-affinity IgE receptors, FcεRI, on the surface of mast cells triggers their activation, resulting in the release of mediators of immediate hypersensitivity. These mediators rapidly induce both local gastrointestinal and systemic physiological responses including anaphylaxis. Emerging evidence has revealed that, in addition to inciting immediate reactions, mast cells are key regulators of adaptive immunity to foods. In the gastrointestinal mucosa they provide the priming cytokines that initiate and, over time, consolidate adaptive TH2 responses to ingested allergens as well as TNF and chemokines that orchestrate the recruitment of tissue-infiltrating leukocytes that drive type 2 tissue inflammation. Patients with atopic dermatitis have increased intestinal mast cell numbers and are at a greater risk for food allergy. Recent studies have uncovered a skin-gut axis in which epicutaneous allergen exposure drives intestinal mast cell expansion. The activating effects of IgE antibodies in mast cells are countered by food-specific IgG antibodies that signal via the inhibitory IgG receptor, FcγR2b, suppressing both immediate allergic reactions to foods and the type 2 immune adjuvant activity of mast cells.


Development and Rasch Validation of an Observational Assessment Tool of Upper Limb Functional Impairment in Stroke Survivors: Functional Assessment Test for Upper Limb.
To develop and validate a quick observational clinical tool, the Functional ASsessment Test for Upper Limb (FAST-UL), for the evaluation of upper limb impairment in goal-directed functional-oriented motor tasks after stroke. Observational, cross-sectional, psychometric study. Inpatient and outpatient rehabilitation clinic. A total of 188 post-stroke survivors (mean age 65.2±17.7 years, 61% men, 48% with ischemic stroke and 66% in the sub-acute phase; N=188). Not applicable. Principal component analysis and Rasch analysis through a Partial Credit Model were used to assess the structure and psychometric properties of the 5 items of the FAST-UL (Hand to Mouth [HtM], Reach to Target, Prono-Supination, Grasp and Release, and Pinch and Release [PaR]). The Cronbach's α equal to 0.96 was indicative of an acceptable internal consistency; the reliability, as measured through the Person Separation Reliability equal to 0.87, was good. The FAST-UL tool was unidimensional. All the FAST-UL items were found to fit well the Rasch measurement model. The easiest to perform FAST-UL item was the HtM movement while the most difficult was the PaR movement. The FAST-UL is a quick, easy-to-administer observational assessment tool of upper limb motor impairment in post-stroke survivors with good item-level psychometric properties.


The effect of digitoxose on insulin release, glucose oxidation and oxygen consumption by islets of lean and genetically obese diabetic (ob/ob) mice.
Digitoxose specifically and competitively inhibited glucose stimulated insulin release from islets of both lean and obese mice without affecting either the rate of glucose oxidation or the rate of glucose stimulated oxygen consumption. Obese mouse islets were marginally more resistant to the inhibitory effect of digitoxose than lean mouse islets. Digitoxose provides a means for dissociating glucose stimulated insulin release by isolated islets from their metabolism of glucose confirming that glucose metabolism per se is not a necessary prerequisite for the initiation of insulin release but is required to fuel the insulin secretory process.


[Fasting - a potent modern therapy].
Therapeutic fasting has found its way into modern medicine in the last decade through a multitude of experimental work and animal studies as well as increasing clinical research. It is a procedure with a tradition dating back thousands of years and thus comes with a variety of different practices. What they all have in common, is the reduction of daily food intake for a limited period of time. This has a variety of effects on metabolism, cells and organ systems, which can make it a potent tool in medical practice.


The variability of electric pulp response threshold in premolars: a clinical study.
This study was designed to determine the variability of the electric pulp response threshold in premolars and the relationship between the response threshold and age. Ninety-seven volunteers were recruited, ranging from 20-72 years old. The volunteers were categorized into 6 age groups: group 1, 20-29 years; group 2, 30-39 years; group 3, 40-49 years; group 4, 50-59 years; group 5, 60-69 years; and group 6, 70-79 years. All intact premolars present in each dental arch were tested. Three sites (the tip of the buccal cusp, the center of the middle, and cervical third of the buccal surface) on each tooth crown were tested. In total, 1965 measurements were done. A progressive increase of mean threshold value was observed from groups 1 to 6. The response threshold value showed significant differences among the 6 age groups. The effect of age was more intense in mandibular premolars. In first and second mandibular premolars the cusp tip required the lowest current to evoke a response. In maxillary premolars no significant differences among the sites were found. Also, the mean threshold value of the mandibular premolars was lower than that of the maxillary premolars in subjects of the same age, and the mean threshold value of the first premolars was lower than that of the second premolars. The buccal cusp tip of the first mandibular premolars responded more quickly than any other tested site. Age is related with higher response threshold values. The optimum site for testing the lower premolars is the buccal cusp tip.


Massive subcutaneous emphysema and pneumomediastineum after finger subtotal amputation with barotrauma.
Advancement of pressurized air through subcutaneous tissue after barotraumas involving skin laceration has been documented in the literature. The type and anatomic location of injury, amount of pressure, and time elapsed all play a role in determining the destination of the air advancing through tissues. To report a case demonstrating the vascular system as the anatomic pathway for subcutaneous pressurized air resulting from an industrial accident. We present the case of a 28-year-old laborer wounded by an air valve blast. An enormous accumulation of air was released through a subtotal fingertip amputation. The clinical appearance of massive subcutaneous emphysema around the upper extremity, neck, and chest suggested chest trauma to the clinicians, despite the absence of signs of respiratory distress. X-ray studies revealed pneumomediastinum. After confirmation that the respiratory system was undamaged, microsurgical repair of the injured finger was performed. Resolution of subcutaneous emphysema and pneumomediastinum was complete at the end of follow-up. Compressed air injuries constitute a well-known form of industrial accident. Although most result in localized subcutaneous emphysema, the risk of pneumomediastinum should not be overlooked due to the anatomic structure of the vascular system. The clinician should consider the pressure of compressed air, and must be alert for potential complications.


Always enough but never too much: the how and why of downregulating tissue oxygenation.
Cardiovascular regulation of tissue oxygenation is generally viewed as an anti-drop process that prevents tissue oxygen concentration from falling below some minimum. I propose that cardiovascular regulation is predominately an anti-rise process designed to downregulate oxygen delivery. This maintains an evolutionarily conserved, reduced intracellular environment to prevent oxidation of redox-sensitive regulatory protein thiols. A number of points support this hypothesis. First, oxygen is the only nutrient with a positive, fourfold diffusion gradient from the environment to systemic tissues, minimizing the likelihood that oxygen delivery is limited. Second, hemoglobin (Hb) retains oxygen unless offloading is absolutely necessary. The allosteric properties of Hb keep oxygen tightly bound until absolutely needed, and the Bohr shift, which favors offloading, is only transient and lost when metabolism is restored. Third, a myoglobin-like Hb (xHb) would offload all of its oxygen and could easily have evolved, but it did not. Fourth, oxygen-sensitive vasoconstrictors and hyperoxic-rarefaction prevent acute and chronic over perfusion. Fifth, Fåhraeus and Fåhraeus-Lindqvist effects reduce capillary hematocrit to minimize microcirculatory oxygen content. Sixth, venous blood remains 75% saturated, wasting 75% of cardiac output were an oxygen reserve not needed. Finally, xHb-containing red blood cells could be considerably smaller and thereby decrease Fåhraeus and Fåhraeus-Lindqvist effects and cardiac load. In summary, the capacity of the cardiovascular system to deliver oxygen to the tissues generally exceeds demand, and although maintenance of an oxygen delivery reserve is important, it is more important to prevent excess oxygen delivery.


Automated age-at-death estimation from 3D surface scans of the facies auricularis of the pelvic bone.
This work presents an automated data-mining model for age-at-death estimation based on 3D scans of the auricular surface of the pelvic bone. The study is based on a multi-population sample of 688 individuals (males and females) originating from one Asian and five European identified osteological collections. Our method requires no expert knowledge and achieves similar accuracy compared to traditional subjective methods. Apart from data acquisition, the whole procedure of pre-processing, feature extraction and age estimation is fully automated and implemented as a computer program. This program is a part of a freely available web-based software tool called CoxAGE3D. This software tool is available at https://coxage3d.fit.cvut.cz/ Our age-at-death estimation method is suitable for use on individuals with known/unknown population affinity and provides moderate correlation between the estimated age and actual age (Pearson's correlation coefficient is 0.56), and a mean absolute error of 12.4 years.


Neurobehavioral outcomes of infants exposed to MDMA (Ecstasy) and other recreational drugs during pregnancy.
3,4-methylenedioxymethamphetamine (MDMA) or "Ecstasy" is one of the most widely used illicit recreational drugs among young adults. MDMA is an indirect monoaminergic agonist and reuptake inhibitor that primarily affects the serotonin system. Preclinical studies in animals have found prenatal exposure related to neonatal tremors and long-term learning and memory impairments. To date, there are no prospective studies of the sequelae of prenatal exposure to MDMA in humans, despite concerns about its potential for harmful effects to the fetus. The present study is the first to prospectively identify MDMA-using women during pregnancy and to document patterns and correlates of use with neonatal and early infancy outcomes of offspring. All mothers and infants were prospectively recruited through the Case Western Reserve University (CWRU) and University of East London (UEL) Drugs and Infancy Study (DAISY) that focused on recreational drug use in pregnant women. Women were interviewed about substance use prior to and during pregnancy and infants were seen at 1 and 4 months using standardized, normative assessments of neonatal behavior, and cognitive and motor development, including the NICU Network Neurobehavioral Scale (NNNS), the Bayley Mental and Motor Development Scales (MDI, PDI), and the Alberta Infant Motor Scales (AIMS). The sample was primarily middle class with some university education and in stable partner relationships. The majority of women recruited had taken a number of illicit drugs prior to or during pregnancy. Group differences between those polydrug using women who had specifically used MDMA during pregnancy (n=28) and those who had not (n=68) were assessed using chi-square and t-tests. MDMA and other drug effects were assessed through multiple regression analyses controlling for confounding variables. Women who used MDMA during pregnancy had fewer prior births and more negative sequelae associated with their drug use, including more health, work, and social problems. MDMA exposed infants differed in sex ratio (more male births) and had poorer motor quality and lower milestone attainment at 4 months, with a dose-response relationship to amount of MDMA exposure. These findings suggest risk to the developing infant related to MDMA exposure and warrant continued follow-up to determine whether early motor delays persist or resolve.


Double blind controlled randomized study on azathioprine efficacy in multiple sclerosis. Preliminary results.
The preliminary results of a double blind controlled prospective randomized trial of Azathioprine for therapeutic efficacy in 38 patients with Multiple Sclerosis are reported. Progression of the disease is significantly reduced in Azathioprine-treated group in comparison to Placebo-treated patients, but this effect is reached only after 3 years of treatment (P less than 0.025) regardless of the clinical course and without affecting relapse rate.


Molecular analysis of the site for 2-arachidonylglycerol (2-AG) on the β₂ subunit of GABA(A) receptors.
2-arachidonyl glycerol (2-AG) allosterically potentiates GABA(A) receptors via a binding site located in transmembrane segment M4 of the β₂ subunit. Two amino acid residues have been described that are essential for this effect. With the aim to further describe this potential drug target, we performed a cysteine scanning of the entire M4 and part of M3. All four residues in M4 affecting the potentiation here and the two already identified residues locate to the same side of the α-helix. This side is exposed to M3, where further residues were identified. From the fact that the important residues span > 18 Å, we conclude that the hydrophobic tail of the bound 2-AG molecule must be near linear and that the site mainly locates to the inner leaflet but stretches far into the membrane. The influence of the structure of the head group of the ligand molecule on the activity of the molecule was also investigated. We present a model of 2-AG docked to the GABA(A) receptor.


Development and external validation of a clinical-radiomics nomogram for preoperative prediction of LVSI status in patients with endometrial carcinoma.
To develop and validate a model that incorporates radiomics based on MRI scans and clinical characteristics to predict lymphovascular invasion (LVSI) in endometrial cancer (EC) patients. There were 332 patients with EC enrolled retrospectively in this multicenter study. Radiomics score (Radscore) were computed using the valuable radiomics features. The independent predictors of LVSI were identified by univariate logistic analysis. Multivariate logistic regression was used to develop a clinical-radiomics predictive model. Based on the model, a nomogram was developed and validated internally and externally. The nomogram was evaluated with discrimination, calibration, decision curve analysis (DCA), and clinical impact curves (CIC). Three predictive models were constructed based on clinicopathological features, radiomic factors and a combination of them, and that the clinic-radiomic model performed best among the three models. Four independent factors comprised the clinical-radiomics model: dynamic contrast enhancement rate of late arterial phase (DCE2), deep myometrium invasion (DMI), lymph node metastasis (LNM), and Radscore. Clinical-radiomics model performance was 0.901 (95% CI 0.84-0.96) in the training cohort, 0.80 (95% CI 0.68-0.92) in the internal validation cohort, and 0.81 (95% CI 0.73-0.9) in the external validation cohort for identifying patients with LVSI, respectively. The model is used to develop a nomogram for clinical use. The MRI-based radiomics nomogram could serve as a noninvasive tool to predict LVSI in EC patients.


Epidermis-dermis junction as a novel location for bone marrow-derived cells to reside in response to ionizing radiation.
Bone marrow-derived cells (BMDCs) can migrate into the various organs in the mice irradiated by ionizing radiation (IR). However, it may not be the case in the skin. While IR is used for bone marrow (BM) transplantation, studying with the epidermal sheets demonstrated that the BMDC recruitment is extraordinarily rare in epidermis in the mouse. Herein, using the chimera mice with BM from green fluorescent protein (GFP) transgenic mice, we simply examined if BMDCs migrate into any layers in the total skin, as opposed to the epidermal sheets, in response to IR. Interestingly, we identified the presence of GFP-positive (GFP(+)) cells in the epidermis-dermis junction in the total skin sections although the epidermal cell sheets failed to have any GFP cells. To examine a possibility that the cells in the junction could be mechanically dissociated during separating epidermal sheets, we then salvaged such dissociated cells and examined its characteristics. Surprisingly, some GFP(+) cells were found in the salvaged cells, indicating that these cells could be derived from BM. In addition, such BMDCs were also associated with inflammation in the junction. In conclusion, BMDCs can migrate to and reside in the epidermis-dermis junction after IR.


Giant diverticula of the colon.
A case of a gas-filled intra-abdominal abscess cavity is reported. The literature is reviewed for similar cases and with reference to the cause and differential diagnosis of abdominal air cysts.


Rethinking emotion as a natural kind: Correctives from Spinoza and hierarchical homology.
It is commonly claimed that the folk category of emotion does not constitute a natural kind, due to the significant compositional differences between its members, especially basic and complex emotions. Arguably, however, this conclusion stems from the dualistic philosophical anthropology underlying the discussion, which presupposes a metaphysical "split" between mind and body. This is the case irrespective of whether a traditional or biological (homology-based) approach to natural kinds is adopted. Since the origins of this increasingly disputed anthropology can ultimately be traced to Descartes' substance dualism, its adverse effects can likewise be addressed using a contemporary theory of emotion developed from Spinoza, one of Descartes' earliest critics on this issue. Furthermore, a Spinozistic view of emotion accords with the recent shift to a hierarchical approach to homology, which recognises that the evolutionary lineage of complex biological units should be traced via relational qualities rather than physical characteristics. Both the Spinozistic approach to emotion and the hierarchical approach to homology show that the compositional variation in the folk category of emotion does not necessarily preclude it from constituting a natural kind.


Effect of copper sulphate on the rate of afferent discharge in the gastric branch of the vagus nerve in the rat.
The afferent nerve activity was recorded from a nerve filament isolated from the peripheral cut end of the gastric branch of the vagus nerve. The gastric perfusion of 4 ml of two different concentrations (0.04% and 0.08%) of CuSO4 solution provoked an increase in afferent activity. The stimulating effect of the 0.08% solution was stronger than that of the 0.04% solution, and lasted for a longer period of time. The observations suggest a possible mechanism by which CuSO4 elicits emesis.


Lipid accumulation in arterial smooth muscle cells. Influence of phenotype.
Isolated smooth muscle cells from the adult pig and rabbit aorta in primary culture undergo a spontaneous change in phenotype from a contractile to a synthetic state over 6-8 days, losing their capacity to contract and gaining the capacity to divide. The change in smooth muscle phenotype to the synthetic state is accompanied by distinct changes in the cells' ability to metabolize LDL, with the rate of degradation of 125I-labelled LDL decreasing to about one fifth of the level in contractile state cells. This does not appear to be due to changes in the number or affinity of LDL receptors since saturable binding of LDL is unaltered. The specific activities of the lysosomal enzymes acid phosphatase and N-acetyl-beta-glucosaminidase increase with change to the synthetic state as do cytochrome c oxidase (mitochondria) and NADPH-dependent cytochrome c reductase (endoplasmic reticulum). In contrast there is a slight but not significant decrease in the specific activity of the lysosomal enzyme acid cholesteryl esterase of rabbit smooth muscle cells and a significant decrease in the activity of pig cells with change in phenotype to the synthetic state. Significantly more [3H]cholesteryl oleate is recovered in synthetic state than in contractile state cells following incubation with 20 micrograms/ml unlabelled LDL and [3H]sodium oleate. Morphologically there is no difference in the number of lipid droplets in contractile and synthetic state cells after incubation in 5% normolipemic serum, but in cells grown in 10% hyperlipemic serum for 4 days synthetic state cells become almost completely filled with lipid droplets while contractile state cells are unaffected. Lipid accumulation also occurs selectively in vivo in synthetic as compared with contractile state smooth muscle cells within intimal fibromuscular thickenings induced by de-endothelialization of the carotid artery of cholesterol-fed rabbits. We suggest that accumulation of lipid in smooth muscle cells of atherosclerotic plaques is related to reduced catabolism of LDL following smooth muscle phenotypic change from the contractile to synthetic state.


Synthesis of 3-farnesyl salicylic acid, a novel antimicrobial from Piper multiplinervium.
Both 3-farnesyl salicylic acid and 3-geranyl salicylic acid were synthesized from 2,6-dibromophenol and showed low levels of antimicrobial activity against E. coli strains.


Persistence of taste buds in denervated fungiform papillae.
Taste buds in hamster fungiform papillae persist in an atrophic state for as long as 330 days after chorda tympani denervation or 50 days after combined chorda tympani-lingual nerve resection. Although taste bud structure depends on innervation, there is no absolute neural requirement for taste bud survival.


Isolation and characterization of betaA3-crystallin associated proteinase from alpha-crystallin fraction of human lenses.
The purpose was to characterize the properties of a proteinase activity associated with betaA3-crystallin, which was isolated from the alpha-crystallin fraction of human lenses. An inactive, Arg-bond hydrolyzing proteinase in the alpha-crystallin fraction, which was isolated from the water soluble (WS) protein fraction of 60- to 70-year-old human lenses, was activated by sodium deoxycholate treatment. The activated enzyme was purified by a three-step procedure that included a size-exclusion Agarose A1.5 m chromatography, non-denaturing preparative gel-electrophoresis, and size-exclusion HPLC. The purified proteinase was characterized for the proteinase type, proteolysis of bovine recombinant gammaB-, gammaC-, and gammaD-crystallins, and its presence in three different protein fractions of human lenses (i.e., alpha-crystallin, beta(H)-crystallin, and membrane fractions). An inactive, Arg-bond hydrolyzing proteinase present in the alpha-crystallin fraction showed activity on treatment with detergents such as sodium deoxycholate, Triton X-100, octyl beta-D-glucopyranoside, and CHAPS (3-[(3-cholamido propyl) dimethylammonio]-1-propanesulfonate). The sodium deoxycholate-activated enzyme was released from the alpha-crystallin fraction since it eluted at a lower molecular weight species than alpha-crystallin during size-exclusion Agarose A1.5 m chromatography. Following a three-step purification procedure, the enzyme showed three species between 22 kDa and 25 kDa during sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The three protein bands were identified as betaA3-, betaB1-, and betaB2-crystallin by the matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) and tandem mass spectrometric (ES-MS/MS) methods. Inhibitor studies revealed that the enzyme was a serine-type proteinase. Among the recombinant betaA3-, betaB1-, or betaB2-crystallins, only the betaA3-crystallin exhibited the proteinase activity following detergent treatment and size-exclusion chromatography. The proteinase also exhibited proteolysis of gammaC- and gammaD- crystallins, and the cleavage of gammaD-crystallin at M(1)-G(2), Q(54)-Y(55), M(70)-G(71), and Q(103)-M(104) bonds. Further, the enzyme was also present in three fractions of human lenses (alpha-crystallin, beta(H)-crystallin, and membrane fractions). A serine-type betaA3-crystallin proteinase existed in an inactive state in the alpha-crystallin fraction and was activated by detergents. The enzyme proteolyzed alphaA-, alphaB-, gammaC-, and gammaD-crystallins and was present in three fractions (alpha-crystallin, beta(H)-crystallin, and membrane-fractions) of 60 to 70-year-old human lenses.


Frozen section examination of the endocervical margin of cervical conization specimens.
We conducted this retrospective study to determine accuracy of frozen section examination of endocervical margin during cold knife conization. Between June 1993 and June 2001, 310 consecutive patients underwent cervical conization for squamous intraepithelial lesion or stage IA1 cervical cancer. Before 1997, the surgical specimens of 149 patients were processed following a standard pathological procedure (historical group). After 1997, a frozen section of the upper endocervical margin was processed during surgery for 161 patients. If the upper endocervical margin was involved with intraepithelial neoplasia, the surgeon performed a second resection if possible. Results of the frozen section examination were compared with the final diagnoses to determine sensitivity, specificity, and positive and negative predictive values. The usefulness of this procedure was evaluated by comparison of positive margin status rate with the one of the historical control group. For the diagnosis of intraepithelial neoplasia involving the endocervical margin, the sensitivity, specificity, and positive and negative predictive values of frozen section were 91%, 100%, 100%, and 98%, respectively. Eleven patients had definitive positive endocervical margin in the frozen section group (three false negatives, six patients without additional resection, and two patients with intraepithelial neoplasia involving the upper margin of the additional resection) and 17 patients in the historical group (P =.16). Frozen section examination of the endocervical margin of cervical specimen obtained during cold knife conization is highly accurate. Its clinical relevance has to be demonstrated in a multicenter study.


Low-density magnetofluid dispersive liquid-liquid microextraction for the fast determination of organochlorine pesticides in water samples by GC-ECD.
A new micro-extraction technique named low-density magnetofluid dispersive liquid-liquid microextraction (LMF-DMMLE) has been developed, which permits a wider range of solvents and can be combined with various detection methods. Comparing with the existing low density solvents micro-extraction methods, no special devices and complicated operations were required during the whole extraction process. Dispersion of the low-density magnetofluid into the aqueous sample is achieved by using vortex mixing, so disperser solvent was unnecessary. The extraction solvent was collected conveniently with an external magnetic field placed outside the extraction container after dispersing. Then, the magnetic nanoparticles were easily removed by adding precipitation reagent under the magnetic field. In order to evaluate the validity of this method, ten organochlorine pesticides (OCPs) were chosen as the analytes. Parameters influencing the extraction efficiency such as extraction solvents, volume of extraction solvents, extraction time, and ionic strength were investigated and optimized. Under the optimized conditions, this method showed high extraction efficiency with low limits of detection of 1.8-8.4 ng L(-1), good linearity in the range of 0.05-10.00 μg L(-1) and the precisions were in the range of 1.3-9.6% (RSD, n=5). Finally, this method was successfully applied in the determination of OCPs in real water samples.


Relationship of inspired anesthetic concentration to plasma concentration and urinary excretion of sevoflurane metabolites in rats.
In patients, plasma concentrations of sevoflurane metabolites may be independent of inspired sevoflurane concentration over a defined dose range. In contrast, studies using rabbits have found that plasma concentrations and urinary excretion of fluoride ion are dose-dependent up to 3% inspired sevoflurane. We measured sevoflurane metabolite concentrations in adult male Sprague-Dawley rats and related them to inspired sevoflurane concentrations. When plasma concentrations and urinary excretion of metabolites were measured in vivo, they were dependent on inspired anesthetic concentration at concentrations less than 1.25%, but became less dose-dependent at higher anesthetic concentrations. Sevoflurane metabolism by precision-cut liver slices in vitro became dose-independent at more than 10-30 microM sevoflurane. No evidence of substrate inhibition was observed. These data provide evidence that sevoflurane metabolite concentrations are almost independent of inspired anesthetic concentration over at least part of the clinically used concentration range.


Does a 55-year-old Male with Lower Urinary Tract Symptoms and a 50-ml Gland Have To Decide Between Ejaculation and Voiding Function?
Treatment of lower urinary tract symptoms secondary to benign prostatic obstruction may affect ejaculatory function. However, preservation of ejaculation via minimally invasive surgical therapies might impair the long-term durability of voiding improvement.


(Z)-3-(3,4-Di-meth-oxy-benz-yl)-1,5-benzo-thia-zepin-4(5H)-one.
In the title compound, C18H17NO3S, the thia-zepine ring adopts a slightly distorted twist-boat conformation. The dihedral angle between the mean plane of the benzo-thia-zepin ring system and the benzene ring is 60.3 (1)°. In the crystal, mol-ecules are linked by two pairs of inversion-related N-H⋯O and C-H⋯O hydrogen bonds, generating alternating R 2 (2)(8) and R 2 (2)(6) ring motifs, respectively, in a zigzag supra-molecular chain that runs along the c axis. These chains stack along the a axis via S⋯C [3.424 (2) Å] contacts. A three-dimensional supra-molecular network is consolidated by C-H⋯π and π-π inter-actions [inter-centroid distance between di-meth-oxy-benzene rings = 3.815 (1) Å]. The crystal studied was a non-merohedral twin, with a refined value of the minor twin fraction of 0.2477 (6) .


Clinical assessment of Mycoplasma pneumoniae-associated hemophagocytic lymphohistiocytosis.
Mycoplasma pneumoniae has been reported to be an etiologic pathogen of infection-associated hemophagocytic lymphohistiocytosis (HLH), but few case reports have been available to date. The clinical features of four childhood cases of M. pneumoniae-associated hemophagocytic lymphohistiocytosis (Mp-HLH) were retrospectively assessed to obtain data that might be useful for early diagnosis and effective management. The previous English-language literature pertaining to Mp-HLH was also reviewed. The patients were two boys and two girls, aged between 1 and 11 years of age. One patient was demonstrated to have concurrent infection with rubella. All the patients had typical radiographic features of M. pneumoniae pneumonia, and one patient also had encephalopathy as a complication. All the children underwent bone marrow examination because of antibiotic-refractory fever, mild hepatosplenomegaly, cytopenia, hyperferritinemia and elevated levels of urine beta2-microglobulin. Cytopenia and hepatosplenomegaly in the present patients were relatively mild as compared to those in cases of other infection-associated HLH such as Epstein-Barr virus infection-associated HLH. Treatment with corticosteroids resulted in prompt and complete resolution in two cases, and i.v. high-dose gammaglobulin therapy achieved a complete response in another child. Spontaneous resolution under treatment with antibiotics alone was observed in one case. Although Mp-HLH is a rare complication of M. pneumoniae infection, it should always be considered in patients with antibiotic-refractory M. pneumoniae infections with cytopenia. Mp-HLH might be effectively treated by corticosteroids or high-dose gammaglobulin. To clarify the diverse clinical manifestations of M. pneumoniae infections, immunological interactions between M. pneumoniae and the host immune system should be further investigated.


The effect of prostaglandin synthetase inhibitors on human preovulatory follicular fluid prostaglandin, thromboxane, and leukotriene concentrations.
This study evaluates the eicosanoid concentration in luteinized unruptured follicles (LUFs) on the ovaries of patients who had been treated with inhibitors of prostaglandin synthetase. Indomethacin, bromfenac, or azapropazone (or a placebo) was administered orally to 41 women during the periovulatory period. Follicular development was monitored by serial ultrasound examinations, and the onset of ovulation was regulated by an injection of hCG. Follicular fluid was aspirated during sterilization by minilaparotomy, which was performed just before the expected time of ovulation. Prostaglandin E2 and PGF2 alpha levels in the fluid were significantly reduced by indomethacin and bromfenac compared to those after placebo treatment. Bromfenac also reduced the follicular fluid leukotriene B4 level. Therefore, the development of luteinized unruptured follicles after treatment with nonsteroidal antiinflammatory drugs appears to be associated with a significant decrease in the synthesis of ovarian eicosanoids.


A novel cluster of mariner-like elements belonging to mellifera subfamily from spiders and insects: implications of recent horizontal transfer on the South-West Islands of Japan.
Mariner-like elements (MLEs) have been isolated from various eukaryotic genomes and they are divided into 15 subfamilies, including main five subfamilies: mauritiana, cecropia, mellifera/capitata, irritans, and elegans/briggsae. In the present study, MLEs belonging to mellifera subfamily were isolated from various spiders and insects (Hymenoptera and Lepidoptera) inhabiting the South-West Islands of Japan and neighboring regions. MLEs isolated from 15 different species formed a distinct novel cluster in mellifera subfamily. MLEs obtained from three different species [i.e., the bee Amegilla senahai subflavescens (Amsmar1), the wasp Campsomeris sp. (Casmar1), and the swallowtail butterfly Pachliopta aristolochiae (Paamar1)] contained an intact open reading frame that encoded a putative transposase. These transposases exhibited high similarity of 97.9% among themselves. In case of Casmar1, the presence of an intact ORF was found in high frequencies (i.e., 11 out of 12 clones). In addition, these transposases also showed the presence of a terminal inverted repeat-binding motif, DD(34)D and two highly conserved amino acid motifs, (W/L)(I/L)PHQL and YSP(D/N)L(A/S)P. These two motifs differed from previously known motifs, WVPHEL and YSPDLAP. MLEs isolated from these three different species may have been inserted into their genomes by horizontal transfer. Furthermore, the presence of an intact ORF suggests that they are still active in habitats along these isolated islands.


Identifying Migration Routes of Wild Asian Elephants in China Based on Ecological Networks Constructed by Circuit Theory Model.
Humans overlap with Asian elephants, resulting in frequent costly human-elephant conflicts, which disturb and even threaten local residents. In this study, we treat provincial and national nature reserves where Asian elephants still exist and other alternative habitats suitable for Asian elephants in southern Yunnan, China, as ecological patches. By using this approach, we can treat the terrain and surface state factors that hinder the migration of Asian elephants as a form of ecological resistance surface. We can then use a circuit theory model and remote sensing data to construct an ecological network, which allows us to identify ecological corridors and ecological pinch points. Herein, the possible migration routes of wild Asian elephants were identified. The main results are as follows: (1) In the study area, dense forests with steep slopes and high altitudes, cultivated land, and building land have greater migration resistance, while the gently undulating shrubs, bamboo forests, and grasslands far away from the city have less migration resistance. (2) There are three ecological corridor groups in the study area, mainly composed of shrub and grassland. The ecological corridors identified in this paper are the most likely migration routes of wild Asian elephants in China, and areas with higher simulated current densities reflect a higher probability of Asian elephants passing through. (3) According to the analysis, the ecological pinch points in the study area are 602 km2 in total, and woodland and grassland account for 89.2% of the total ecological pinch area. The areas where the pinch points are located have a high probability of Asian elephants passing through and a narrow space. Our findings can provide suggestions and solutions for the current conservation of wild Asian elephant species, alleviate human-elephant conflicts, promote the harmonious coexistence between humans and nature, and provide reference for biological protection and biological reserve planning.


Substrate specificity of cerebral cathepsin D and high-Mr aspartic endopeptidase.
The specificity of action of bovine brain cortex cathepsin D (EC 126.96.36.199) and high-Mr aspartic endopeptidase (EC 3.4.23.-) was studied with the vasoactive peptides renin substrate tetradecapeptide (RSTP), substance P (SP), and angiotensins I and II, and with model peptides--Lys-Pro-Ala-Glu-Phe-Phe (NO2)-Ala-Leu (I), Gly-Gly-His-Phe (NO2)-Phe-Ala-Leu-NH2 (II), and Abz-Ala-Ala-Phe-Phe-pNA (III). Cerebral aspartic peptidases show identical substrate specificity, cleaving the Leu10-Leu bond in RSTP and Phe-Phe in SP and peptide I-III, and not splitting angiotensins I and II. Because of the higher catalytic efficiency of cathepsin D (Kcat value), the specificity constants (Kcat/Km) for cathepsin D-catalyzed hydrolysis of substrates 1-111 are much higher than those for the high-Mr enzyme. High-Mr aspartic peptidase shares a number of properties with cathepsin D (sensitivity to pepstatin, substrate specificity, pH activity profile) and shows partial immunological identity; however, high-Mr aspartic peptidase has a specific activity 7-10 times lower than that of cathepsin D. The kinetic parameters of proteolysis of model peptides presented indicate that the high-Mr enzyme may be a complex of a single-chain cathepsin D with another polypeptide, although the possibility that it is an independent aspartic peptidase cannot be excluded.


Endogenous reductions in N-methyl-d-aspartate receptor activity inhibit nitric oxide production in the anoxic freshwater turtle cortex.
Increased nitric oxide (NO) production from hypoxic mammalian neurons increases cerebral blood flow (CBF) but also glutamatergic excitotoxicity and DNA fragmentation. Anoxia-tolerant freshwater turtles have evolved NO-independent mechanisms to increase CBF; however, the mechanism(s) of NO regulation are not understood. In turtle cortex, anoxia or NMDAR blockade depressed NO production by 27+/-3% and 41+/-5%, respectively. NMDAR antagonists also reduced the subsequent anoxic decrease in NO by 74+/-6%, suggesting the majority of the anoxic decrease is due to endogenous suppression of NMDAR activity. Prevention of NO-mediated damage during the transition to and from anoxia may be incidental to natural reductions of NMDAR activity in the anoxic turtle cortex.


Vardenafil protects isolated rat hearts at reperfusion dependent on GC and PKG.
The type-5 PDE inhibitor vardenafil reduces myocardial infarct size in situ, following ischemia/reperfusion, when applied at reperfusion in animal models. Little is known about the underlying protective signaling. Here, we test whether vardenafil is protective in rat isolated hearts and in a cell model of calcium stress. Infarct size in rat isolated hearts was measured after a 30 min regional ischemia and 120 min reperfusion. Vardenafil (1 nM-1 microM) was infused during reperfusion. HL-1 cardiomyocytes were loaded with tetramethylrhodamine ethyl ester (TMRE), a fluorescent marker of mitochondrial membrane potential (psi m). Vardenafil at reperfusion reduced infarct size as percentage of the ischemic zone from 45.8+/-2.0% in control hearts to 26.2+/-2.7% (P<0.001) only at 10 nM, whereas higher or lower dosages failed to protect. This protective effect was blocked by co-administration of either the GC inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or the PKG inhibitor, KT-5823. HL-1 cardiomyocytes, loaded with TMRE, were treated for 80 min with the calcium ionophore, calcimycin, to induce calcium stress. This reduced the mean cell fluorescence to 63.3 +/- 3.8% of baseline values and vardenafil protected against this fall (78.6 +/- 3.6%, P<0.01). The vardenafil-induced protection of HL-1 cells was blocked by ODQ, KT-5823 or the PKG-inhibiting peptides DT-2 and DT-3, confirming a role for GC and PKG. These results further support the hypothesis that PDE-5 inhibitors are protective in ischemic hearts, in addition to their known clinical effects in the treatment of erectile dysfunction in men.


Fabrication of CdLa2S4@La(OH)3@Co3S4 Z-scheme heterojunctions with dense La, S-dual defects for robust photothermal assisted photocatalytic performance.
Optimize the separation and transport mechanism of photogenerated carriers in heterojunction composites, and make full use of the active sites of each material are key factors to enhance photocatalytic activity. Herein, we successfully synthesize defective CdLa2S4@La(OH)3@Co3S4 (CLS@LOH@CS) Z-scheme heterojunction photocatalysts through a facile solvothermal method, which show broad-spectrum absorption and excellent photocatalytic activity. La(OH)3 nanosheets not only greatly increase the specific surface area of photocatalyst, but also can be coupled with CdLa2S4 (CLS) and form Z-scheme heterojunction by converting irradiation light. In addition, Co3S4 with photothermal properties is obtained by in-situ sulfurization method, which can release heat to improve the mobility of photogenerated carriers, and also be used as a cocatalyst for hydrogen production. Most importantly, the formation of Co3S4 leads to a large number of sulfur vacancy defects in CLS, and thus improving the separation efficiency of photogenerated electrons and holes, and increasing the catalytic active sites. Consequently, the maximum hydrogen production rate of CLS@LOH@CS heterojunctions can reach 26.4 mmol g-1h-1, which is 293 times than pristine CLS (0.09 mmol g-1h-1). This work will provide a new horizon for synthesizing high efficiency heterojunction photocatalysts through switching the separation and transport modes of photogenerated carrier.


Targeting lipid metabolism for ferroptotic cancer therapy.
It has been 10 years since the concept of ferroptosis was put forward and research focusing on ferroptosis has been increasing continuously. Ferroptosis is driven by iron-dependent lipid peroxidation, which can be antagonized by glutathione peroxidase 4 (GPX4), ferroptosis inhibitory protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH) and Fas-associated factor 1 (FAF1). Various cellular metabolic events, including lipid metabolism, can modulate ferroptosis sensitivity. It is worth noting that the reprogramming of lipid metabolism in cancer cells can promote the occurrence and development of tumors. The metabolic flexibility of cancer cells opens the possibility for the coordinated targeting of multiple lipid metabolic pathways to trigger cancer cells ferroptosis. In addition, cancer cells must obtain immortality, escape from programmed cell death including ferroptosis, to promote cancer progression, which provides new perspectives for improving cancer therapy. Targeting the vulnerability of ferroptosis has received attention as one of the significant possible strategies to treat cancer given its role in regulating tumor cell survival. We review the impact of iron and lipid metabolism on ferroptosis and the potential role of the crosstalk of lipid metabolism reprogramming and ferroptosis in antitumor immunity and sum up agents targeting lipid metabolism and ferroptosis for cancer therapy.