The protective effects of free wheel-running against cocaine psychomotor sensitization persist after exercise cessation in C57BL/6J mice.
Previous literature suggests that free access to a running wheel can attenuate the behavioral responsiveness to addictive drugs in rodents. In a few studies, wheel-running cessation accentuated drug responsiveness. Here, we tested whether free wheel-running cessation is followed by (1) an accentuation or (2) an attenuation of cocaine psychomotor sensitization, knowing that no cessation of (continuous) wheel-running is associated with an attenuation of cocaine responsiveness. Male C57BL/6J mice, aged 35 days, were housed singly either with (exercising mice) or without (non-exercising mice) a running wheel. At the end of a period of 36 days, half of the exercising mice were deprived of their wheel whereas the other half of exercising mice kept their wheel until the end of experimentation (which lasted 85 days). The non-exercising mice were housed without wheel throughout experimentation. Testing took place 3 days after exercise cessation. After 2 once-daily drug-free test sessions, mice were tested for initiation of psychomotor sensitization over 13 once-daily injections of 8 mg/kg cocaine. Post-sensitization conditioned activation (saline challenge) and long-term expression of sensitization were assessed 2 or 30 days after the last sensitizing injection (same treatments as for initiation of sensitization), respectively. Exercising mice and mice undergoing wheel-running cessation exhibited comparable degrees of attenuation of all cocaine effects in comparison with the continuously non-exercising mice, which showed the greatest effects. Thus, the efficaciousness of wheel-running at attenuating cocaine sensitization not only resisted to exercise cessation but was also unambiguously persistent (an important effect rarely reported in previous literature).


Model of pulmonary extravasation as an effect of neutropenia in endotoxic shock in guinea pigs.
A guinea pig model was developed to document the association of polymorphonuclear neutrophils (PMN) decrease with pulmonary leakage after a sublethal infusion of endotoxin (LPS Escherichia coli 0111:B4, 5 micrograms/min/kg). A control group was prepared in the same manner and given an infusion of vehicle alone. Severe leukopenia developed, mostly expressed in the neutrophil population. There was a decrease in RBC catalase and fibronectin. Plasma leakage in the lung followed the endotoxin infusion, which could indicate endothelial cell damage. The results from the present study suggest an activation of PMN in endotoxin-infused animals, degranulation and release of toxic oxygen species, resulting in pulmonary plasma extravasation.


Prostaglandin F2alpha involves heparan sulphate sugar chains and FGFRs to modulate osteoblast growth and differentiation.
The present investigation extends our previous studies on PGF2alpha-mediated signalling in osteoblast metabolism. In particular, the role of PGF2alpha as modulator of heparan sulphate proteoglycans (HSPGs), fibroblast growth factor 2 (FGF-2) and fibroblast growth factor receptors (FGFRs) was evaluated. We hereby reported the novel observation that PGF2alpha was able to promote the formation of HSPGs/FGF-2/FGFRs complexes. Moreover, our data suggested that PGF2alpha could induce new synthesis of heparan sulphate (HS) chains on osteoblasts by a mechanism involving a modulation of MAPK signalling and that HS is required for the regulation of FGF-2 induced by PGF2alpha. Indeed, a proteolytic cleavage of HSPGs with heparinase III (Hep III) prior to PGF2alpha administration down-regulated the basal expression of phospho-p44/42, likely inhibiting FGFRs tyrosine kinase activity. Interestingly, MAPK signalling influenced syntheses and subcellular localization of FGF-2, its specific receptor and HS. In addition, the proteolytic cleavage by Hep III and the MAPK kinase inhibition by PD-98059 also revealed that PGF2alpha induced cell proliferation is dependent on HSPGs and FGF-2 specific receptor, respectively. Of further relevance of this study, we demonstrated, by using a specific siRNA for FGFR1, that PGF2alpha modulates Runx2 expression by FGFR1 and HS.


Mechanistic study on inhibition of porcine pancreatic α-amylase using the flavonoids from dandelion.
This study was designed to investigate quantitatively the inhibition and molecular mechanism of pancreatic α-amylase exhibited by flavonoids from dandelion to reveal its potential use in relieving postprandial hyperglycemia. The results show that the flavonoids reversibly inhibited the α-amylase in a non-competitive manner with Michaelis-Menten constant (Km) and half-inhibitory concentration (IC50) value of 10.51 and 0.0067 mg/mL, respectively. The flavonoids present a strong ability to quench the intrinsic fluorescence of α-amylase through static quenching by forming a complex. The values of the binding site (n) at different temperatures were found to be approximately the unity, indicating the presence of a single class of molecular binding of the dandelion flavonoids on α-amylase. The positive values of enthalpy and entropy change reveal that the binding was predominately driven by hydrophobic interactions. This study suggests a benefit of incorporating the dandelion flavonoids in making functional foods in managing the diet of the diabetes.


Desmoplastic Reaction, Immune Cell Response, and Prognosis in Colorectal Cancer.
The relationships between tumor stromal features (such as desmoplastic reaction, myxoid stroma, and keloid-like collagen bundles) and immune cells in the colorectal carcinoma microenvironment have not yet been fully characterized. In 908 tumors with available tissue among 4,465 incident colorectal adenocarcinoma cases in two prospective cohort studies, we examined desmoplastic reaction, myxoid stroma, and keloid-like collagen bundles. We conducted multiplex immunofluorescence for T cells [CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3] and for macrophages [CD68, CD86, IRF5, MAF, and MRC1 (CD206)]. We used the inverse probability weighting method and the 4,465 incident cancer cases to adjust for selection bias. Immature desmoplastic reaction was associated with lower densities of intraepithelial CD3+CD8+CD45RO+ cells [multivariable odds ratio (OR) for the highest (vs. lowest) density category, 0.43; 95% confidence interval (CI), 0.29-0.62; Ptrend <0.0001] and stromal M1-like macrophages [the corresponding OR, 0.44; 95% CI, 0.28-0.70; Ptrend = 0.0011]. Similar relations were observed for myxoid stroma [intraepithelial CD3+CD8+CD45RO+ cells (Ptrend <0.0001) and stromal M1-like macrophages (Ptrend = 0.0007)] and for keloid-like collagen bundles (Ptrend <0.0001 for intraepithelial CD3+CD8+CD45RO+ cells). In colorectal cancer-specific survival analyses, multivariable-adjusted hazard ratios (with 95% confidence intervals) were 0.32 (0.23-0.44; Ptrend <0.0001) for mature (vs. immature) desmoplastic reaction, 0.25 (0.16-0.39; Ptrend <0.0001) for absent (vs. marked) myxoid stroma, and 0.12 (0.05-0.28; Ptrend <0.0001) for absent (vs. marked) keloid-like collagen bundles. Immature desmoplastic reaction and myxoid stroma were associated with lower densities of tumor intraepithelial memory cytotoxic T cells and stromal M1-like macrophages, likely reflecting interactions between tumor, immune, and stromal cells in the colorectal tumor microenvironment.


Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis.
Oxidative stress can be defined as the imbalance between cellular oxidant species production and antioxidant capability. Reactive oxygen species (ROS) are involved in a variety of different cellular processes ranging from apoptosis and necrosis to cell proliferation and carcinogenesis. In fact, molecular events, such as induction of cell proliferation, decreased apoptosis, and oxidative DNA damage have been proposed to be critically involved in carcinogenesis. Carcinogenicity and aging are characterized by a set of complex endpoints, which appear as a series of molecular reactions. ROS can modify many intracellular signaling pathways including protein phosphatases, protein kinases, and transcription factors, suggesting that the majority of the effects of ROS are through their actions on signaling pathways rather than via non-specific damage of macromolecules; however, exact mechanisms by which redox status induces cells to proliferate or to die, and how oxidative stress can lead to processes evoking tumor formation are still under investigation.


Relationship between development of post-thrombotic syndrome and serial ultrasound, D-dimer, and factor VIII activity after a first deep venous thrombosis.
The aim of this study was to evaluate the relationship of post-thrombotic syndrome (PTS) with residual vein thrombosis, deep venous reflux (DVT), D-dimer, and factor VIII (FVIII) after a first deep venous thrombosis (DVT). There were 133 participants with objectively confirmed DVT, of whom 114 were observed for 6 months after completion of anticoagulation. Ultrasound, D-dimer, and FVIII evaluations were undertaken at 6 weeks after completion of anticoagulation and at the end of follow-up. PTS was considered present in those with a score of ≥5 on the Villalta scale at either assessment. The cumulative incidence of PTS was 51.8%, with median duration of follow-up of 11 months. Median D-dimer and FVIII in those with PTS were significantly higher at both time points compared with those without. Similarly, residual vein thrombosis and deep venous reflux were more prevalent in those with PTS at both study assessments. On multivariable analysis, only FVIII at end of study remained significantly associated with PTS with an odds ratio of 2.83 (95% confidence interval, 1.09-7.42; P = .034). Ultrasound markers and D-dimer were not significantly associated with PTS after adjustment for age, body mass index, Charlson Index ≥1, and proximal extent of DVT. FVIII activity at end of follow-up was independently associated with PTS, suggesting underlying activation of coagulation.


Sickle cell hematuria controlled by intrarenal oxychlorosene irrigation.
Therapy for prolonged renal bleeding related to sickle cell disease can be challenging. We review the treatment of a woman with a 4-week history of renal bleeding thought to be due to sickle cell trait. The hemorrhage ceased immediately following irrigation of the involved kidney with oxychlorosene. Before radical surgery is performed for this problem this relatively simple approach should be considered. Further documentation of the efficacy and safety is necessary before advocating this modality for routine use.


[Microbial settlement of paint- and building-materials in the sphere of drinking-water. 1. Information: long time observation of a bitumen paint in a drinking-water-reservoir (author's transl)].
In a drinking water reservoir with a freshly applied bituminous coating a microbial settlement was found on the walls. Its development was observed over a period of 23 months. The slime on the walls consisted of bacteria and fungi and was secondarily colonized by protozoa and nematodes. The quantities of the microbial coating decreased during a 12 months time. In the beginning of the time of observation a high number of bacteria was found in the water. The carbon fixed by the microbes came from fossile sources to an amount of 90%.


Estimation of sensitivity and specificity of multiple repeated binary tests without a gold standard.
A model for multiple diagnostic tests, applied repeatedly over time on each subject, is proposed; gold standard data are not required. The model is identifiable with as few as three tests, and correlation among tests at each time point in the diseased and nondiseased populations, as well as across time points, is explicitly included. An efficient Markov chain Monte Carlo scheme allows for straightforward posterior inference; sample R code is available in the Supporting Web Materials for this paper. The proposed model is broadly illustrated via simulations and an analysis of scaphoid fracture data from a prospective study. In addition, omnibus tests constructed from individual tests in parallel and serial are considered.


Disease-associated patterns of acetylation stabilize tau fibril formation.
Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has emerged. Using tau fragments, we identify patterns of acetylation that flank amyloidogenic motifs on the tau fragments that promote rapid fibril assembly. We determined a 3.9 Å cryo-EM amyloid fibril structure assembled from an acetylated tau fragment uncovering how lysine acetylation can mediate gain-of-function interactions. Comparison of the structure to an ex vivo tauopathy fibril reveals regions of structural similarity. Finally, we show that fibrils encoding disease-associated patterns of acetylation are active in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting tau aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct amyloid folds.


Preparation of phosphorylcholine derivatives of bovine serum albumin and their application to the affinity chromatography of C-reactive protein.
A simple method for the preparation of phosphorylcholine derivatives of bovine serum albumin (PC-BSA) by reductive alkylation of the amino groups of bovine serum albumin with choline phosphoryl glycoaldehyde is described. Choline phosphoryl glycoaldehyde was generated by periodate oxidation of glyceryl phosphorylcholine. PC-BSA was immobilized on SH-derivatized Toyopearl HW 65 by reacting the single SH group of PC-BSA with a bismaleimido reagent and then coupling maleimidated PC-BSA to the thiolated gel. The affinity purification of C-reactive protein (CRP), which is based on the Ca2+-dependent affinity of CRP for the phosphorylcholine residue of PC-BSA, was readily accomplished using the PC-BSA Toyopearl HW 65 column. The resulting CRP preparation from serum and pleural fluid was homogeneous as assessed by native polyacrylamide gel electrophoresis. PC-BSA derivatives were also shown to be reactive with Limulus polyphemus CRP.


Occurrence, compositional distribution, and toxicity assessment of pyrethroid insecticides in sediments from the fluvial systems of Chaohu Lake, Eastern China.
Surface sediment-associated synthetic pyrethroid insecticides (SPs) are known to pose high risks to the benthic organisms in Chaohu Lake, a shallow lake of Eastern China. However, the pollution status of the lake's tributaries and estuaries is still unknown. The present study was conducted to investigate the occurrence, compositional distribution, and toxicity of 12 currently used SPs in the surface sediments from four important tributaries, as well as in the sediment cores at their estuaries, using GC-MS for quantification. All SPs selected were detectable, with cypermethrin, es/fenvalerate, and permethrin dominant in both surface and core sediments, suggesting that these compounds were extensively applied. Urban samples contained the highest summed concentrations of the 12 SPs analyzed (Σ12SP) in both surface and core sediments compared with rural samples, suggesting that urban areas near aquatic environments posed high risks for SPs. The mean concentration of Σ12SP in surface sediments of each river was generally higher than that found in core sediments from its corresponding estuary, perhaps implying recent increases in SP usage. Surface sediments were significantly dominated by cypermethrin and permethrin, whereas core sediments were dominated by permethrin and es/fenvalerate. The compositional distributions demonstrated a spatial variation for surface sediments because urban sediments generally contained greater percentages of permethrin and cypermethrin, but rural sediments had significant levels of es/fenvalerate and cypermethrin. In all sediment cores, the percentage of permethrin gradually increased, whereas es/fenvalerate tended to decrease, from the bottom sediments to the top, indicating that the former represented fresh input, whereas the latter represented historical residue. Most urban samples would be expected to be highly toxic to benthic organisms due to the residue of SPs based on a calculation of toxic units (TUs) using toxicity data of the amphipod Hyalella azteca. However, low TU values were found for the samples from rural areas. These results indicate that the bottom sediments were exposed to high risk largely by the residual SPs from urban areas. The summed TUs were mostly attributable to cypermethrin, followed by λ-cyhalothrin and es/fenvalerate. Despite permethrin contributing ∼28.7 % of the Σ12SP concentration, it only represented 6.34 % of the summed TUs. Therefore, our results suggest that high levels of urbanization can increase the accumulation of SPs in aquatic environments.


Incidence trends and risk factors for hyponatremia in epilepsy patients: A large-scale real-world data study.
This study aimed to evaluate the annual incidence and risk factors of hyponatremia in pediatric, adult, and older adult patients with epilepsy. We enrolled 26,179 patients: 8598 pediatric patients (aged 0-15 years), 16,476 adults (aged 16-64 years), and 1105 older adults (aged ≥65 years). Patients were included if their serum sodium levels were measured between January 2006 and December 2020. Moderate-severe hyponatremia was defined as a serum sodium level of less than 130 mEq/L. From 2006 to 2020, 677 patients (2.6%) developed moderate-severe hyponatremia. The incidence of hyponatremia per 1000 person-years was 3.1 in the pediatric group, 19.8 in the adult group, and 50.4 in the older adult group. The incidence increased markedly from 36.8 in 2007 to 58.5 in 2020 in the older adult group but remained unchanged in the adult group and tended to decrease in the pediatric group. In the multiple logistic regression model, use of carbamazepine, valproate, phenytoin, phenobarbital, benzodiazepines, and antipsychotics was found to be a significant risk factor for hyponatremia. In adult patients, carbamazepine, benzodiazepine, and antipsychotics induced hyponatremia in a dose-dependent manner. Concomitant use of zonisamide reduced the risk of hyponatremia. Hyponatremia will become an increasingly important concern in clinical settings because the population of epilepsy patients is aging. Serum sodium levels should be monitored carefully when patients are receiving first-generation antiseizure medications or antipsychotics or combinations of these drugs. Our findings may help to minimize the risk of hyponatremia in epilepsy patients.


Moral barrier to compassion: How perceived badness of sufferers dampens observers' compassionate responses.
Compassion has been theorized as a desirable prosocial emotion due to its potential to transcend arbitrary boundaries (e.g., race, physical distance) and motivate us to alleviate the suffering of all human beings. Our paper nevertheless examines a potential moral barrier to compassion--whether and how moral evaluations of the suffering and the sufferer hinder our compassion and prosocial motivation. In four pre-registered studies (total N = 421, within-participant design), we demonstrated that adult U.S. participants withheld their compassion and willingness to help when they perceived moral badness of the sufferer, even when the perceived moral badness did not directly cause the suffering. The effects were found in terms of diverse types of moral judgments, including the sufferers' immoral intention (e.g., harming another; Study 1), bad moral character (e.g., being a dishonest person; Study 2), and even mere associations with groups perceived as deserving of suffering based on moral status (Studies 3-4). Deservedness judgment--how much the sufferer was viewed as deserving the suffering--mediated the effect between moral judgment and compassionate responses. Importantly, participants judged withholding compassion based on moral deservedness as what should be done and what morally good people would do, suggesting that people hold a normative view of the tendency that might make it difficult to overcome. Our findings thus reveal moral judgment as a barrier that prevents us from alleviating the suffering of all human beings.


The use of attributable fraction in the design and interpretation of epidemiologic studies.
Because of the etiologic heterogeneity present in many diseases and the interaction among causal factors in the development of disease, relative risks relating any one exposure to a disease may be low, especially in the presence of common exposures. Nevertheless, in the design of epidemiologic studies, arbitrary values of relative risks are often used to determine the sample size required to detect an association between a particular exposure and a disease outcome. Such an approach may not yield adequate statistical power to detect an association. In this commentary, the authors point out the value of using the attributable fraction to determine an appropriate value of relative risk to use for sample size calculations. The approach is particularly useful in cluster investigations where the magnitude of the expected attributable fraction can be readily estimated from the observed and expected rates of disease. Specification of an attributable fraction is also useful in the design of case-control studies of etiologically heterogeneous diseases, especially when common exposures are suspected. Finally, the relationship among attributable fraction, relative risk and exposure frequency is valuable in interpreting results of an epidemiologic study and gaining insight into the differences in relative risk estimates found in various studies.


Flow cytometric estimation of the plasma membrane diversity of bone marrow cells in mice treated with WR-2721 and cyclophosphamide.
The effects of S-2-/3-aminopropylamino/ethyl phosphorothioic acid (WR-2721, Amifostine) and cyclophosphamide (CP) on the cell surface exposure of phosphatidylserine (PS) and the plasma membrane impairment of bone marrow cells were assessed by flow cytometry assay with fluoresceinated annexin V (annexin V - FITC) and propidium iodide (PI). During the 96 h-period after treatment of adult male Swiss mice with WR-2721 (400 mg/kg b.wt.) and CP (200 mg/kg b.wt.), bone marrow cells expressing PS on the outer leaflet of the plasma membrane, which bound annexin V, and cells with a compromised cell membrane, which allowed PI to bind to the cellular DNA, were analysed. Temporary changes in the frequency of early apoptotic cells (annexin V - FITC positive/PI negative), late apoptotic and necrotic cells (annexin V - FITC positive/PI positive), and the number of live cells (annexin V - FITC negative/PI negative), were dependent on the drug(s) given. Application of CP distinctly triggered apoptotic and necrotic cell death, and WR-2721 pre-treatment of mice affected cell death induced by CP, causing reduction of the number of apoptotic and necrotic cells. The chemoprotective action of WR-2721 against PS externalisation and the plasma membrane impairment of normal bone marrow cells was shown.


Effectiveness and tolerability of a fixed-dose combination of olmesartan and amlodipine in clinical practice.
To assess the efficacy and tolerability of a fixed-dose combination of olmesartan and amlodipine in an unselected population of patients in primary care and to compare the results with recent randomized controlled trial evidence. A multicenter, noninterventional, noncontrolled observational study with 8241 hypertensive patients seen by 2187 physicians in daily practice. Blood pressure (BP) reduction, comorbid disease, pharmacotherapy, and tolerability were documented over a 12-18-week observational period. Patients had a mean age of 62.8 ± 11.8 years (48.1% female), and 74.8% had at least one comorbid risk factor or condition. In total, 51.3% received olmesartan-amlodipine 20/5 mg, 30.6% received 40/5 mg, and 17.9% received 40/10 mg at baseline, mostly because of lack of efficacy on prior antihypertensive therapy (73.8%). BP at baseline was 161.8 ± 16.6/93.6 ± 10.2 mmHg (39.8% had Grade 2 hypertension), and the observed BP reduction was -29.0 ± 17.1/-13.5 ± 10.9 mmHg (P < 0.0001), with a significant correlation between BP at baseline and BP reduction (Spearman's Rho -0.811 for systolic BP and -0.759 for diastolic BP). BP reduction appeared to be dependent on dose and prior antihypertensive therapy, but not on age, gender, body mass index, duration of hypertension, or the presence of diabetes. At the final visit, 69.4% (4.3% at baseline) were controlled (<140/90 mmHg). Adverse drug reactions were observed in 2.76% of the study population; 94.25% of these adverse drug reactions were judged as nonserious events, and 31.5% of all adverse drug reactions reported were peripheral edema. The fixed-dose olmesartan-amlodipine combination was effective and well tolerated in an unselected population of patients in primary care practice. These results confirm prior randomized controlled trial evidence.


Dysanapsis ratio as a predictor for expiratory flow limitation.
To determine the efficacy of the dysanapsis ratio (DR) in predicting expiratory flow limitation during exercise, 146 subjects (73 men, 73 women) performed standard pulmonary function and maximal incremental exercise tests. Tidal flow-volume loops were recorded at maximal exercise with maximal flow-volume loops measured pre- and post-exercise. Men had larger (p<0.05) lung volumes, flow rates, and V˙O2max compared to women, but DR was similar (0.21±0.05 vs. 0.20±0.06, respectively, p>0.05). V˙O2max was not different (p>0.05) between the EFL subjects compared to the non-EFL subjects for both men and women. Men with EFL compared to non-EFL men had smaller FVC (5.16±0.89L vs. 5.67±0.86L, p<0.05) and DR (0.19±0.05 vs. 0.23±0.04, p<0.05). Similarly, women with EFL compared to non-EFL had significantly smaller DR (0.18±0.05 vs. 0.24±0.05), but similar FVC (3.88±0.52 vs. 4.12±0.64, p>0.05). A DR threshold was not determined; however, a DR continuum exists with increasing DR leading to decreased prevalence of EFL. In conclusion, DR is effective in determining the likelihood of EFL at maximal exercise.


Three-dimensional curved beam stress analysis of the human femur.
We discuss an analytical approach to the investigation of the normal, shear, and principal stresses transmitted to the human femur. Two cases are considered: in the first the femur is treated as a three dimensional isotropic curved beam, and in the second as a three dimensional anisotropic composite curved beam, consisting of two different materials, the spongy bone and the cortical bone. The composite beam theory is used to investigate stresses in the femur, in which the spongy bone is surrounded by a cortical bone jacket; compatibility of stresses and strains being introduced at the interface of the two bones in order to derive the stress equations at any point in the cross section. General loading conditions are considered in the analysis, in which the femur is subjected to normal and shear forces, and to biaxial bending and twisting moments.


Furanoterpenoids from Siphonochilus aethiopicus.
Two new furanoterpenoid derivatives, namely 4a alpha H-3,5 alpha,8 alpha beta-trimethyl-4,4a,9-tetrahydro-naphtho[2,3-b]-furan-8-one and 2-hydroxy-4a alpha H-3,5 alpha, 8a beta-trimethyl-4,4a,9-tetrahydronaphtho[2,3-b]-furan-8-one, were isolated from Siphonochilus aethiopicus, a member of the family Zingiberaceae. Their structures were elucidated using high field NMR techniques.


Hyaluronic acid lipoate: synthesis and physicochemical properties.
The synthesis and physicochemical characterisation of mixed lipoic and formic esters of hyaluronan (Lipohyal) are presented in this paper. The synthesis was conducted by activating lipoic acid with 1,1'-carbonyldiimidazole to obtain lipoyl imidazolide, which reacted with hyaluronan (HA) in formamide under basic conditions. This procedure allows researchers to modulate easily the degree of substitution over a range of 0.05-1.8. Radical scavenger properties were analysed by UV-vis spectroscopy, where improved performance was demonstrated for Lipohyal with respect to the HA row material and lipoic acid. The chemical modification also causes HA to show an improved resistance to hyaluronidase digestion. These findings show that Lipohyal is a highly interesting derivative for applications in the tricological and dermo-cosmetic field and as an anti-aging ingredient. Moreover, Lipohyal can be easily crosslinked by UV irradiation, resulting in an innovative hydrogel with distinctive viscoelastic properties that is suitable as both a dermal-filler and as an intra-articular medical device.


New one-pot synthesis of anti-tuberculosis compounds inspired on isoniazid.
A library of thirty N-substituted tosyl N'-acryl-hydrazones was prepared with p-toluenesulfonyl hydrazide, methyl propiolate and different aldehydes in a one-pot synthesis via an aza-Michael reaction. The scope of the reaction was studied, including aliphatic, isoprenylic, aromatic and carbocyclic aldehydes. The prepared collection was tested against Mycobacterium tuberculosis H37Rv. Nine analogs of the collection showed Minimum Inhibitory Concentration ≤10 μM, of which the most active members (MIC of 1.25 μM) were exclusively E isomers. In order to validate the mechanism of action of the most active acrylates, we tested their activity on a M. tuberculosis InhA over-expressing strain obtaining MIC that consistently doubled those obtained on the wild type strain. Additionally, the binding mode of those analogs on M. tuberculosis InhA was investigated by docking simulations. The results displayed a hydrogen bond interaction between the sulfonamide and Ile194 and the carbonyl of the methyl ester with Tyr 158 (both critical residues in the interaction with the fatty acyl chain substrate), where the main differences on the binding mode relays on the hydrophobicity of the nitrogen substituent. Additionally, chemoinformatic analysis was performed to evaluate in silico possible cytotoxicity risk and ADME-Tox profile. Based on their simple preparation and interesting antimycobacterial activity profile, the newly prepared aza-acrylates are promising candidates for antitubercular drug development.


Venom-gland transcriptomics of the Malayan pit viper (Calloselasma rhodostoma) for identification, classification, and characterization of venom proteins.
The Malayan pit viper (Calloselasma rhodostoma) is a hemotoxic snake widely found in Southeast Asia and is responsible for the majority of poisoning cases in this region, including Thailand. However, a comprehensive knowledge of the venom protein profile and classification, as well as novel venom proteins, of this viper is still limited. Recently, the detailed composition of several snake venoms has been discovered through the use of transcriptome analysis. Therefore, the aim of this study was to employ a next-generation sequencing platform and bioinformatics analysis to undertake venom-gland de novo transcriptomics of Malayan pit vipers. Furthermore, 21,272 functional coding genes were identified from 36,577 transcripts, of which 314 transcripts were identified as toxin proteins, accounting for 61.41% of total FPKM, which can be categorized into 22 toxin gene families. The most abundant are snake venom metalloproteinase kistomin (P0CB14) and zinc metalloproteinase/disintegrin (P30403), which account for 60.47% of total toxin FPKM and belong to the SVMP toxin family, followed by snake venom serine protease 1 (O13059) and Snaclec rhodocetin subunit beta (P81398), which account for 6.84% and 5.50% of total toxin FPKM and belong to the snake venom serine protease (SVSP) and Snaclec toxin family, respectively. Amino acid sequences of the aforementioned toxins were compared with those identified in other important medical hemotoxic snakes from Southeast Asia, including the Siamese Russell's viper (Daboia siamensis) and green pit viper (Trimeresurus albolabris), in order to analyze their protein homology. The results demonstrated that ranges of 58%-62%, 31%-60%, and 48%-59% identity was observed among the SVMP, Snaclec, and SVSP toxin families, respectively. Understanding the venom protein profile and classification is essential in interpreting clinical symptoms during human envenomation and developing potential therapeutic applications. Moreover, the variability of toxin families and amino acid sequences among related hemotoxic snakes found in this study suggests the use and development of universal antivenom for the treatment of envenomating patients is still challenging.


Heme oxygenase-1 is an antifibrogenic protein in human hepatic myofibroblasts.
Hepatic myofibroblasts play a key role in the development of liver fibrosis associated with chronic liver diseases. We have shown that oxidative stress is a messenger of 15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2) in human hepatic myofibroblasts. The aim of the present study was to investigate the role of a stress-inducible protein, heme oxygenase-1 (HO-1), in the action of 15-d-PGJ2. Expression of HO-1 was characterized in biopsy specimens of normal human liver and active cirrhosis by immunohistochemistry, and in cultured human hepatic myofibroblasts by Northern and Western blot analysis. Functional studies also were performed in cultured human hepatic myofibroblasts. Immunohistochemistry showed that in biopsy specimens from normal livers, HO-1 protein expression was restricted to Kupffer cells. Biopsy specimens from cirrhotic patients displayed HO-1 protein both in macrophages and in myofibroblasts within fibrotic septa. HO-1 messenger RNA (mRNA) and protein also were detected in cultured human hepatic myofibroblasts and increased in response to 15-d-PGJ2 in a time- and dose-dependent manner. Induction of HO-1 in human hepatic myofibroblasts mediated 2 major antifibrogenic properties of 15-d-PGJ2, namely, inhibition of proliferation and of procollagen I mRNA expression. These effects were ascribed to bilirubin, one of the products of HO-1-mediated heme degradation. This study shows that HO-1 is expressed in human hepatic myofibroblasts and induced during chronic liver injury. Moreover, these data unravel HO-1 as a major antifibrogenic pathway.


Validity of the Draw a Person: A Quantitative Scoring System (DAP:QSS) for Clinically Evaluating Intelligence.
To assess the psychometric properties of the Draw a Person: A Quantitative Scoring System (DAP:QSS), in 2543 children (M = 11.43 ± 3.06 years), correlations between drawings scores and Raven's Matrices scores, age, and academic achievement were examined. Although older children (> 11 years) obtained higher drawing scores than younger ones (p < 0.001), age significantly correlated with DAP:QSS scores only in children younger than 11 years (r = 0.493, p < 0.001), indicating conflictive evidence for construct validity and a possible ceiling effect. No correlations emerged between DAP:QSS scores and grades (r = 0.056, p = 0.097). DAP:QSS scores were significantly associated with Raven's Matrices score, but low correlation coefficients (0.156-0.498), low sensitivity (0.12), and high false negative (87.9%) and positive (82%) rates suggest poor DAP:QSS validity as an intelligence measure. The researchers concluded that DAP:QSS failed to produce a psychometrically sound assessment of children's intellectual functioning.


Metabolomics Applications in Children: A Right Way to Go.
Metabolomics is a new science based on the study of the metabolome, representing the set of all the metabolites of a biological organism, which are the final products of its gene expression. Metabolomics appears to be a promising tool in perinatal studies, such as hypoxic-ischemic encephalopathy (HIE), intrauterine growth restriction (IUGR), congenital infections, genetic diseases, neonatal nutrition.


The molecular basis of craniofacial placode development.
The sensory organs of the vertebrate head originate from simple ectodermal structures known as cranial placodes. All cranial placodes derive from a common domain adjacent to the neural plate, the preplacodal region, which is induced at the border of neural and non-neural ectoderm during gastrulation. Induction and specification of the preplacodal region is regulated by the fibroblast growth factor, bone morphogenetic protein, WNT, and retinoic acid signaling pathways, and characterized by expression of the EYA and SIX family of transcriptional regulators. Once the preplacodal region is specified, different combinations of local signaling molecules and placode-specific transcription factors, including competence factors, promote the induction of individual cranial placodes along the neural axis of the head region. In this review, we summarize the steps of cranial placode development and discuss the roles of the main signaling molecules and transcription factors that regulate these steps during placode induction, specification, and development. For further resources related to this article, please visit the WIREs website.


Diaphragmatic hernia in a female newborn with focal dermal hypoplasia and marked asymmetric malformations (Goltz-Gorlin syndrome).
We report a female newborn with focal dermal hypoplasia (Goltz-Gorlin Syndrome) and marked asymmetric malformations on the right side of the body. Diaphragmatic hernia on the same side, which has not been reported in this syndrome, led to perinatal complications.


Combined Fluorescence-Guided Resection and Intracavitary Thermotherapy with Superparamagnetic Iron-Oxide Nanoparticles for Recurrent High-Grade Glioma: Case Series with Emphasis on Complication Management.
Concepts improving local tumor control in high-grade glioma (HGG) are desperately needed. The aim of this study is to report an extended series of cases treated with a combination of 5-ALA-fluorescence-guided resection (FGR) and intracavitary thermotherapy with superparamagnetic iron oxide nanoparticles (SPION). We conducted a single-center retrospective review of all recurrent HGG treated with FGR and intracavitary thermotherapy (n = 18). Patients underwent six hyperthermia sessions in an alternating magnetic field and received additional adjuvant therapies on a case-by-case basis. Nine patients were treated for first tumor recurrence; all other patients had suffered at least two recurrences. Nine patients received combined radiotherapy and thermotherapy. The median progression-free survival was 5.5 (95% CI: 4.67-6.13) months and median overall survival was 9.5 (95% CI: 7.12-11.79) months. No major side effects were observed during active treatment. Thirteen patients (72%) developed cerebral edema and more clinical symptoms during follow-up and were initially treated with dexamethasone. Six (33%) of these patients underwent surgical removal of nanoparticles due to refractory edema. The combination of FGR and intracavitary thermotherapy with SPION provides a new treatment option for improving local tumor control in recurrent HGG. The development of cerebral edema is a major issue requiring further refinements of the treatment protocol.


Mechanisms transducing the aldosterone secretagogue signal of endothelins in the human adrenal cortex.
Evidence has been provided that the 21-amino acid hypertensive peptide endothelin (ET)-1 exerts a potent secretagogue effect on human adrenocortical zona glomerulosa (ZG), acting through two receptor subtypes, called ET(A) and ET(B), the signaling mechanism(s) of which has (have) not yet been investigated. Collagenase dispersed human ZG cells were obtained from normal adrenals of patients undergoing nephrectomy/adrenalectomy for renal cancer. The selective ET(A)- and ET(B)-receptor activation was obtained by exposing dispersed cells to ET-1 plus the ET(B)-receptor antagonist BQ-788 and to the ET(B)-receptor agonist BQ-3020, respectively. The phospholipase (PL) C inhibitor U-73122 abolished ET(A) receptor-mediated secretory response, but only partially prevented the ET(B) receptor-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin, the calmodulin inhibitor W-7 and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes. When added together, calphostin-C and wortmannin or W-7 abolished ET(A)-mediated secretory response, but only decreased ET(B)-mediated one. The ET(B) receptor-, but not the ET(A) receptor-mediated aldosterone response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. ET(A)-receptor activation raised inositol triphosphate (IP(3)) production from dispersed ZG cells, while ET(B)-receptor stimulation enhanced both IP(3) and prostaglandin-E(2) production. Collectively, our findings indicate that ETs stimulate aldosterone secretion from human ZG cells, acting through ET(A) receptors exclusively coupled to PLC/PKC-dependent pathway and ET(B) receptors coupled to both PLC/PKC- and COX-dependent cascades.


Use of total lymphocyte count and hemoglobin concentration for monitoring progression of HIV infection.
Prognostic markers for HIV monitoring are needed for resource-limited regions. Prior research has demonstrated rapid declines in total lymphocyte count (TLC) and hemoglobin levels before AIDS, but the prognostic accuracy of these declines has not been examined prospectively. Longitudinal TLC and hemoglobin data from men in the Multicenter AIDS Cohort Study (MACS) before the introduction of potent HIV therapy were used to identify the first time when the TLC was <or=1200 cells/mm, TLC declined by >33% per year, and hemoglobin declined by >11.6% per year. The prognostic value of these declines for AIDS was evaluated by Cox regression models and Kaplan-Meier survival curves. Rapid declines in TLC or hemoglobin were associated with progression to AIDS (relative hazard [RH]=4.70, 95% confidence interval [CI]: 3.23-6.86 for TLC; RH=5.55, 95% CI: 3.69-8.36 for hemoglobin). The World Health Organization criterion for initiating therapy, a TLC<or=1200 cells/mm, was also predictive of progression to AIDS (RH=6.14, 95% CI: 4.33-8.71). Even among those with a TLC>1200 cells/mm, a rapid decline in TLC or hemoglobin was strongly associated with progression to AIDS (RH=2.53, 95% CI: 1.56-4.10 for TLC; RH=5.28, 95% CI: 3.11-8.97 for hemoglobin). In the MACS, rapid declines in TLC or hemoglobin concentration indicated an increased likelihood of progression of HIV infection to AIDS. These results support the potential utility of these markers for monitoring HIV-infected people in resource-limited regions, but critical levels and rates of decline of markers for such regions remain to be defined.


Association of has_circ_0001944 upregulations with prognosis and cancer progression in patients with colorectal cancer.
CircRNAs are functional in cancer-related processes and are promising candidates for cancer prognostic biomarkers. The study aimed to evaluate the functional and clinical significance of has_circ_0001944 in colorectal cancer (CRC), including predictive value for overall survival (OS) and recurrence-free survival (RFS), and its effect on cell growth and metastasis. This retrospective study included 133 patients with CRC. The expression of has_circ_0001944 in tissues and cells was quantified by real-time quantitative reverse transcription PCR. Receiver operating characteristics and Kaplan-Meier survival analysis were used to assess the significance of has_circ_0001944 as a prognostic marker, and its reliability was validated using multivariate regression analysis. Subsequently, XTT, transwell migration, and modified-transwell invasion assays were used to determine the behavior of the CRC cells in response to has_circ_0001944 inhibition. Results of the qRT-PCR showed upregulation of has_circ_0001944 in the CRC samples compared to the normal samples. High has_circ_0001944 expression indicated shorter OS and RFS, comes down to poor prognosis. Multivariate regression analysis showed that elevated has_circ_0001944 increased the risk of death or recurrence and is a valuable prognostic factor. Following the has_circ_0001944 inhibition, the proliferation, migration and invasion of the CRC cells were reduced. miR-548b-3p was target miRNA of has_circ_0001944. Up-regulation of has_circ_0001944 is associated with a poor prognosis of CRC. has_circ_0001944 downregulation can slow the progression of CRC partly by targeting miR-548b-3p.


Predicting the hyperglycemic crisis death (PHD) score: a new decision rule for emergency and critical care.
We investigated independent mortality predictors of hyperglycemic crises and developed a prediction rule for emergency and critical care physicians to classify patients into mortality risk and disposition groups. This study was done in a university-affiliated medical center. Consecutive adult patients (> 18 years old) visiting the emergency department (ED) between January 2004 and December 2010 were enrolled when they met the criteria of a hyperglycemic crisis. Data were separated into derivation and validation sets-the former were used to predict the latter. December 31, 2008, was the cutoff date. Thirty-day mortality was the primary endpoint. We enrolled 295 patients who made 330 visits to the ED: derivation set = 235 visits (25 deaths: 10.6%), validation set = 95 visits (10 deaths: 10.5%). We found 6 independent mortality predictors: Absent tachycardia, Hypotension, Anemia, Severe coma, Cancer history, and Infection (AHA.SCI). After assigning weights to each predictor, we developed a Predicting Hyperglycemic crisis Death (PHD) score that stratifies patients into mortality-risk and disposition groups: low (0%) (95% CI, 0-0.02%): treatment in a general ward or the ED; intermediate (24.5%) (95% CI, 14.8-39.9%): the intensive care unit or a general ward; and high (59.5%) (95% CI, 42.2-74.8%): the intensive care unit. The area under the curve for the rule was 0.946 in the derivation set and 0.925 in the validation set. The PHD score is a simple and rapid rule for predicting 30-day mortality and classifying mortality risk and disposition in adult patients with hyperglycemic crises.


Ethical considerations relating to writing a medical scientific paper for publication.
Unethical practices are not unusual in medical scientific articles, but they are not always recognized as being unethical. The author discusses both obvious unethical behavior, such as fraud, plagiarism, and conflict of interest, and a number of other practices, such as errors in citations, misuse of statistics, and wasteful publication, which are more widespread and generally accepted, but which may be considered unethical. Increased awareness of these issues could reduce the extent of these practices.


Sensitivity and uncertainty analysis for Abreu & Johnson numerical vapor intrusion model.
This study conducted one-at-a-time (OAT) sensitivity and uncertainty analysis for a numerical vapor intrusion model for nine input parameters, including soil porosity, soil moisture, soil air permeability, aerobic biodegradation rate, building depressurization, crack width, floor thickness, building volume, and indoor air exchange rate. Simulations were performed for three soil types (clay, silt, and sand), two source depths (3 and 8m), and two source concentrations (1 and 400 g/m(3)). Model sensitivity and uncertainty for shallow and high-concentration vapor sources (3m and 400 g/m(3)) are much smaller than for deep and low-concentration sources (8m and 1g/m(3)). For high-concentration sources, soil air permeability, indoor air exchange rate, and building depressurization (for high permeable soil like sand) are key contributors to model output uncertainty. For low-concentration sources, soil porosity, soil moisture, aerobic biodegradation rate and soil gas permeability are key contributors to model output uncertainty. Another important finding is that impacts of aerobic biodegradation on vapor intrusion potential of petroleum hydrocarbons are negligible when vapor source concentration is high, because of insufficient oxygen supply that limits aerobic biodegradation activities.


Stereoselective synthesis of sugar-fused (or 1,2-annulated) isochromans and isochromanones by using oxa-Pictet-Spengler reaction.
A highly efficient stereoselective synthesis of sugar fused 1,2-annulated isochromans is reported by utilizing the oxa-Pictet-Spengler cyclization reaction. The process is found to be very general as both glucal and galactal derived C2-hydroxy-α-C-aryl glycosides lead to the target molecules in good yields. The utility of this strategy was extended to the synthesis of sugar fused isochromanones, which are bergenin type molecules.


Alternative Considerations for Surgical Training and Funding.
Since the late 1880s surgical residency programs have existed in forms that are similar to our current models. Many important variations have been introduced over time. On aggregate this system has worked remarkably well; though as economic, demographic, and cultural changes continue to evolve, one must wonder if we were to change our models how might we do that and what reasoning could we use. This article's focus is to take a stratospheric view of what could be done, particularly in the United States, rather than characterize what happens in other countries with other health economic systems.


Rediscovery of Ixodes confusus in Australia with the first description of the male from Australia, a redescription of the female and the mitochondrial (mt) genomes of five species of Ixodes.
We: (i) report the rediscovery of Ixodes (Sternalixodes) confusus Roberts, 1960 in Australia; (ii) redescribe the male and female of I. confusus; (iii) describe the mitochondrial (mt) genome of I. confusus from five ticks from four localities in Far North Queensland; and (iv) present the first substantial phylogeny of the subgenera of the Ixodes. The mt genomes of I. confusus, I. cornuatus, I. hirsti, I. myrmecobii and I. trichosuri are presented here for the first time. In our phylogeny from entire mt genomes (ca. 15 kb), the subgenus Endopalpiger was the sister-group to subgenera Sternalixodes plus Ceratixodes plus Exopalpiger whereas Exopalpiger was the sister to Sternalixodes plus Ceratixodes. [i.e. ((Endopalpiger) (Sternalixodes, Ceratixodes and Exopalpiger))]. Finally, we show that Ixodes anatis, the kiwi tick, may be closely related to the ticks of marsupials of Australia and Papua New Guinea.


TFEB is a central regulator of the aging process and age-related diseases.
Old age is associated with a greater burden of disease, including neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, as well as other chronic diseases. Coincidentally, popular lifestyle interventions, such as caloric restriction, intermittent fasting, and regular exercise, in addition to pharmacological interventions intended to protect against age-related diseases, induce transcription factor EB (TFEB) and autophagy. In this review, we summarize emerging discoveries that point to TFEB activity affecting the hallmarks of aging, including inhibiting DNA damage and epigenetic modifications, inducing autophagy and cell clearance to promote proteostasis, regulating mitochondrial quality control, linking nutrient-sensing to energy metabolism, regulating pro- and anti-inflammatory pathways, inhibiting senescence and promoting cell regenerative capacity. Furthermore, the therapeutic impact of TFEB activation on normal aging and tissue-specific disease development is assessed in the contexts of neurodegeneration and neuroplasticity, stem cell differentiation, immune responses, muscle energy adaptation, adipose tissue browning, hepatic functions, bone remodeling, and cancer. Safe and effective strategies of activating TFEB hold promise as a therapeutic strategy for multiple age-associated diseases and for extending lifespan.


Radiographic techniques and interpretation of abnormal swallowing in adult and elderly patients.
The radiologic evaluation of oropharyngeal dysfunction requires interpretation of observed morphodynamics and bolus movements. This can be facilitated if a simplified biomechanical approach is used to understand basic physiology. Oral stage activity can be described as a lingual delivery pump and pharyngeal stage activity as a glossopharyngeal propulsion pump. Bolus misdirection into the airway is more often due to oral rather than pharyngeal abnormalities and is frequently inconsistent with regard to timing and degree. The video-deglutition examination is still a relatively new diagnostic study and its purpose, indications, and criteria for patient selection should be clearly understood.


Influence of switching rule on motor learning.
Humans and animals can flexibly switch rules to generate the appropriate response to the same sensory stimulus, e.g., we kick a soccer ball toward a friend on our team, but we kick the ball away from a friend who is traded to an opposing team. Most motor learning experiments have relied on a fixed rule; therefore, the effects of switching rules on motor learning are unclear. Here, we study the availability of motor learning effects when a rule in the training phase is different from a rule in the probe phase. Our results suggest that switching a rule causes partial rather than perfect availability. To understand the neural mechanisms inherent in our results, we verify that a computational model can explain our experimental results when each neural unit has different activities, but the total population activity is the same in the same planned movement with different rules. Thus, we conclude that switching rules causes modulations in individual neural activities under the same population activity, resulting in a partial transfer of learning effects for the same planned movements. Our results indicate that sports training and rehabilitation should include various situations even when the same motions are required.


Antianginal drug therapy for silent myocardial ischemia.
Many of the available nitrate preparations, beta-adrenergic blockers, and calcium antagonists appear to be useful in patients with painful and silent ischemic episodes detected on the ECG (Table 1). More controlled studies need to be done using standardized methodologies for assessing silent myocardial ischemia, to evaluate and compare the different antianginal medications. It is fortunate, however, that the nitrates, beta-blockers, and calcium antagonists, used alone and in combination, appear to have favorable effects not only on painful ischemic episodes but also on those ischemic episodes not associated with pain.


Decoupling analysis between economic growth and resources environment in Central Plains Urban Agglomeration.
Once, the fast-growing economy has dependence on resources and environment, especially in Central Plains Urban Agglomeration (CPUA). Assessing the relationship between economic growth and resources and environment can be helpful in planning future region development. As there were fewer researches on the decoupling analysis in CPUA, therefore, according to the decoupling index designed by Tapio, this paper connected the resources and the environment to describe the comprehensive decoupling state of economic growth and resources environment as a whole with the latest available data in 2004-2015. The results showed that: (1) The change of environmental decoupling index had a greater impact on the comprehensive decoupling index. Economic growth has been less dependent on resources consumption and environment pollution since 2011, and the relationship between economic growth and resources environment reached strong decoupling in 2015. (2) The decoupling state was towards the direction of strong decoupling in Luoyang, Pingdingshan, Jiaozuo, Xuchang, Nanyang, and Xinyang. The economic growth was less dependent on resources consumption and the environment pollution. (3) Economic growth depended strongly on resources consumption and environment pollution in Changzhi, Jincheng, Heze, and Anyang. They had not yet achieved the strong decoupling state among economic growth, resources and the environment. Thus, the policy implementations were put forward to realize strong decoupling in CPUA.


The effects of a low dose of caffeine on cognitive performance.
There is little evidence concerning the effects of caffeine in doses typical of one cup of tea. The present study investigated the effect of 60 mg caffeine, consumed in either tea or hot water, on performance on a subset of the CANTAB test battery. Eight males participated in a practice session and four test sessions. In each test session, the participant consumed a different hot beverage and then, over approximately 90 min, completed nine tests from the CANTAB battery. The four beverages were created by crossing beverage identity (tea or hot water) and caffeine dose (0 or 60 mg). Significant speeding of reaction time by caffeine consumption was found in pattern recognition, delayed match to sample, and match to sample visual search. The effect on reaction time of 60 mg caffeine can be detected, and may be evident within minutes of consumption. Objective reports of immediate beneficial effects of consumption, most research has postponed measurement to coincide with peak plasma caffeine levels (Blanchard and Sawers 1983). The intention of the present study was to investigate the effects of consuming a single cup of tea on a variety of cognitive tests. Testing began immediately after consumption and lasted approximately 80 min.


Enabling long-cycling aqueous sodium-ion batteries via Mn dissolution inhibition using sodium ferrocyanide electrolyte additive.
Aqueous sodium-ion batteries (AIBs) are promising candidates for large-scale energy storage due to their safe operational properties and low cost. However, AIBs have low specific energy (i.e., <80 Wh kg-1) and limited lifespans (e.g., hundreds of cycles). Mn-Fe Prussian blue analogues are considered ideal positive electrode materials for AIBs, but they show rapid capacity decay due to Jahn-Teller distortions. To circumvent these issues, here, we propose a cation-trapping method that involves the introduction of sodium ferrocyanide (Na4Fe(CN)6) as a supporting salt in a highly concentrated NaClO4-based aqueous electrolyte solution to fill the surface Mn vacancies formed in Fe-substituted Prussian blue Na1.58Fe0.07Mn0.97Fe(CN)6 · 2.65H2O (NaFeMnF) positive electrode materials during cycling. When the engineered aqueous electrolyte solution and the NaFeMnF-based positive electrode are tested in combination with a 3, 4, 9, 10-perylenetetracarboxylic diimide-based negative electrode in a coin cell configuration, a specific energy of 94 Wh kg-1 at 0.5 A g-1 (specific energy based on the active material mass of both electrodes) and a specific discharge capacity retention of 73.4% after 15000 cycles at 2 A g-1 are achieved.


Correction to: Association among dispositional mindfulness, self-compassion, and leukocyte telomere length in Chinese adults.
An amendment to this paper has been published and can be accessed via the original article.


Platelet aggregation and fibrinogen binding in human, rhesus monkey, guinea-pig, hamster and rat blood: activation by ADP and a thrombin receptor peptide and inhibition by glycoprotein IIb/IIIa antagonists.
Platelet aggregation and fibrinogen binding in whole blood, induced either by ADP or by a 14 amino acid peptide mimicking an N-terminal region of the platelet thrombin receptor (TRP, thrombin receptor activating peptide), have been studied with blood from different species. Aggregation was assessed by counting the number of single platelets in blood before und after addition of the agonist with an automated cell counter. Both ADP (0.02-0.5 microM) and TRP (1-10 microM) were found to be potent agonists of platelet aggregation in human, rhesus monkey and guinea-pig blood, causing a near-maximal aggregatory response within 2 min of agonist addition. In contrast, hamster and rat platelets were much less responsive to both ADP and TRP in terms of the whole blood aggregation. Echistatin, RGDW and a synthetic glycoprotein (GP) IIb/IIIa antagonist, Ro 43-8857, inhibited fibrinogen binding to purified immobilized human GP-IIb/IIIa with IC50's of 1.6, 88 and 11.4 nM, respectively. In whole human blood, the respective IC50's (as determined by flow cytometric analysis of platelet fibrinogen binding) were 4.4, 1700 and 29.5 nM. The affinities of these three compounds for inhibiting fibrinogen binding in whole blood from rhesus monkeys and guinea-pigs were similar to the affinities for human platelets, but with rat blood echistatin, RGDW and Ro 43-8857 were all around 100-fold less potent. Ro 43-8857 was a potent inhibitor of ADP- or TRP-induced platelet aggregation in human, rhesus monkey and guinea-pig whole blood (IC50 of 69-320 nM) but was much less active in hamster blood.(ABSTRACT TRUNCATED AT 250 WORDS)


Treatment of 1,4-dioxane and trichloroethene co-contamination by an activated binary persulfate-peroxide oxidation process.
The efficacy of a binary oxidant system, hydrogen peroxide (H2O2) and persulfate, was investigated for treatment of 1,4-dioxane (dioxane) and trichloroethene (TCE) co-contamination. Batch experiments were conducted to examine the catalytic efficiency of Fe2+ and NaOH-based activation, oxidant decomposition rates, contaminant degradation effectiveness, and competitive degradation effects. For NaOH activation, the oxidant decomposition rate was moderate and sustained during the entire test period of 96 h. However, dioxane degradation was limited (~ 33%). Conversely, the oxidants were depleted within 24 h for the Fe2+-activated system, and dioxane degradation was complete within 4 h. The activation and radical generation processes were different between Fe2+ and NaOH activation. Both dioxane and TCE underwent complete degradation in the co-contaminant experiment. The results of this study indicate that the Fe2+-catalyzed binary hydrogen peroxide-persulfate oxidant system is effective for oxidation of the tested contaminants separately and as co-contaminants.


Non-coding RNAs, guardians of the p53 galaxy.
The TP53 gene is arguably the most important tumor suppressor gene known, contributing multifaceted roles to the process of tumor development. Its protein product p53, is a crucial sequence-specific transcription factor which regulates the expression of a large network of protein-coding genes, as well as thousands of noncoding RNAs (ncRNAs), notably microRNAs and long ncRNAs (lncRNAs). Through a variety of direct and indirect mechanisms, ncRNAs in turn modulate p53 levels and activity. Here the numbers of studies are steadily building which link the contributions of dysregulated ncRNAs to tumorigenesis via their participation throughout the p53 regulatory network. In this review, we will examine how the principal forms of ncRNAs, namely microRNAs, lncRNAs and circular RNAs (circRNAs) function as either effectors or regulators amongst the diversity of p53's cellular responses. We first discuss the more recently discovered connections between miRNAs and p53 signaling before focusing on the remarkable diversity of crosstalk evident between lncRNAs and p53, and subsequently, developing reports linking circRNAs to p53. Highlighted throughout the review are the mechanistic impacts of dysregulated ncRNAs on p53 functions as well as the possible prognostic implications of these interactions. We also describe the emerging connections between ncRNAs and the often-perplexing functions of mutant p53. Finally, in the context of p53 therapeutic approaches, we describe some of the challenges in ncRNA research and their potential for translation.


The physiological (EEG) nature of drowsiness and its relation to performance deficits in narcoleptics.
Ten narcoleptics off medication were compared to matched controls to determine the pattern and level of electroencephalographic (EEG) vigilance, and its relation to performance ability on the 1 h Wilkinson auditory vigilance task. The narcoleptics performed significantly more poorly and spent significantly less time in wakefulness than controls. The EEG of the patients revealed continual fluctuations between wakefulness, stage 1A (slowed and diffusing alpha) and stage 1B (theta activity). Stage 2 sleep only occurred briefly in 4 patients. Stages 3, 4 and REM sleep were never encountered. Controls were continually awake aside from very brief appearances of stage 1A in 5 subjects. Narcoleptic performance during stages 1B and 2 was characterized by lapses (response omissions). Patients also demonstrated significantly more lapses as well as false positive responses than controls during wakefulness and stage 1A. Poorer performance even during wakefulness was demonstrated to be related to inability to sustain wakefulness over time. The results clarify the temporal pattern of physiological vigilance during performance in narcoleptics and also demonstrate the insufficiency of the lapse-microsleep formulation in explaining performance deterioration in these patients.


Exercise Frequency and Fracture Risk in Older Adults-How Often Is Enough?
Due to older people's low sports participation rates, exercise frequency may be the most critical component for designing exercise protocols that address fracture risk. The aims of the present article were to review and summarize the independent effect of exercise frequency (ExFreq) on the main determinants of fracture prevention, i.e., bone strength, fall frequency, and fall impact in older adults. Evidence collected last year suggests that there is a critical dose of ExFreq that just affects bone (i.e., BMD). Corresponding data for fall-related fracture risk are still sparse and inconsistent, however. The minimum effective dose (MED) of ExFreq that just favorably affects BMD at the lumbar spine and femoral neck has been found to vary between 2.1 and 2.5 sessions/week. Although this MED cannot necessarily be generalized to other cohorts, we speculate that this "critical exercise frequency" might not significantly vary among adult cohorts.


Endolysosomal transport of newly-synthesized cathepsin D in a sucrose model of lysosomal storage.
Newly-synthesized soluble lysosomal enzymes are transported from the trans-Golgi network to lysosomes by a mannose 6-phosphate receptor-mediated pathway. Lysosomal storage of indigestible material has been reported to perturb the biosynthesis and the fate of lysosomal hydrolases. In this study, we have focused our attention on the last steps in the transport of newly-synthesized cathepsin D to lysosomes in sucrose-treated WI-38 fibroblasts. Pulse-chase experiments indicate that, in sucrose-treated cells, cathepsin D maturation is delayed by 2 to 4 h. By subcellular fractionation, we show that newly-synthesized cathepsin D precursors transit through organelles endowed with a high sedimentation coefficient. These organelles are recovered in the dense region of a self-forming Percoll density gradient while the bulk of hydrolytic activities is redistributed to the low density region. Only later, are the precursors delivered to organelles containing the bulk of active hydrolases. There, procathepsin D is proteolytically processed into its 31 kDa-mature form. Our results suggest that when sucrose is present, the delayed maturation of procathepsin D is related to the delivery of the polypeptides into an organelle behaving in centrifugation like lysosomes but which is poorly efficient in proteolytic processing of procathepsin D. This low proteolytic activity of this organelle could be due to its poor ability to interact with hydrolase-containing structures.


New antibiotic, isohematinic acid. I. Taxonomy of producing organism, fermentation and isolation.
New antibiotic, isohematinic acid, was found in the culture broth of an actinomycete strain SANK 61681, which was identified as a strain of Actinoplanes philippinesis. Fermentation of isohematinic acid was performed by conventional submerged culture in a 600-liter fermentor. Isolation of isohematinic acid was performed by adsorption of the antibiotic from the culture filtrate on a column of Diaion HP-20 followed by elution with aqueous acetone and extraction with ethyl acetate. Isohematinic acid was finally crystallized from hot methanol.


Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis.
Sclerosing pancreatitis is associated with raised concentrations of IgG4. We treated 22 patients with sclerosing pancreatitis, and identified and followed-up three with concomitant hydronephrosis caused by ureteral mass, later diagnosed as retroperitoneal fibrosis. We histologically examined the ureteral and pancreatic lesions of these patients and noted abundant infiltration of IgG4-bearing plasma cells in both tissues. Treatment with corticosteroids lowered serum concentrations of IgG4. IgG4 might also have a pathological role in a systemic fibrosing process that includes pancreatic and retroperitoneal lesions.


Fufang Zhenzhu Tiaozhi capsule ameliorates hyperuricemic nephropathy by inhibition of PI3K/AKT/NF-κB pathway.
Excessive serum uric acid (SUA) causes hyperuricemic nephropathy (HN), characterized by inflammatory infiltration and tubulointerstitial fibrosis. Most recently, we demonstrated that Fufang Zhenzhu Tiaozhi (FTZ) capsule attenuated diabetic nephropathy through inhibition of renal inflammation and fibrosis. However, whether FTZ ameliorates HN is still unclear. To determine the protective roles and mechanism of FTZ in mouse renal injury and fibrosis under hyperuricemic condition. HN mice, induced by potassium oxonate and hypoxanthine, were administrated with 600 and 1200 mg/kg FTZ (intragastrically) daily for three weeks. SUA levels, renal functions and histological changes were analyzed. Western blotting, quantitative real-time PCR (q-PCR) and RNA sequencing were used to identify the roles and underlying mechanism of FTZ in HN mice. We demonstrated that FTZ treatment mitigated renal injury in mice, as evidenced by the decrease in SUA, serum creatinine (SCr) and cystatin C (Cys C) levels, as well as improved renal histology. FTZ markedly attenuates inflammasome activation, collagen deposition and the imbalance of uric acid transporters. RNA-sequencing revealed a key mechanism involved in the protective effects on HN mice was related to PI3K/AKT/NF-κB pathway. Western blot also confirmed that FTZ diminished the phosphorylation of AKT and p65 in HN mice. FTZ prevents renal injury, inflammation and fibrosis in HN mice via promoting uric acid excretion and inhibiting PI3K/AKT/NF-κB signaling pathway.


Baseline long-term potentiation-like cortical plasticity is associated with longitudinal cortical thinning in healthy adults and in adults with bipolar disorder type II.
The precise neurobiological processes underlying cerebral cortical thinning in aging and psychiatric illnesses remain undetermined, yet aging- and synaptic dysfunction-related loss of synapses are potentially important mechanisms. We used long-term potentiation-like plasticity of the visual evoked potential as an index of synaptic function in the cortex and hypothesized that plasticity at baseline would be negatively associated with future cortical thinning in healthy adults and in adults with bipolar disorder type II. Thirty-two healthy adults and 15 adults with bipolar disorder type II underwent electroencephalography-based measurement of visual evoked potential plasticity and 3T magnetic resonance imaging of the brain at baseline and a follow-up brain scan on average 2.3 years later. The relationships between visual evoked potential plasticity at baseline and longitudinal cortical thickness changes were examined using Freesurfer and the Permutation Analysis of Linear Models tool. The analyses showed a negative association between the plasticity of the N1 visual evoked potential amplitude at baseline and thinning rate in the medial and lateral parietal and medial occipital cortices in healthy adults and in the right medial occipital cortex in the total sample of healthy adults and adults with bipolar disorder type II, indicating greater thinning over time in subjects with less N1 plasticity (pFWER < .05). Although preliminary, the results indicate an association between visual evoked potential plasticity and the future rate of cortical thinning in healthy adults and in bipolar disorder type II, supporting the hypothesis that cortical thinning might be related to synaptic dysfunction.


Elucidating the Role of Interfacial Hydrogen Bonds on Glass Transition Temperature Change in a Poly(Vinyl Alcohol)/SiO2 Polymer-Nanocomposite by Noncovalent Interaction Characterization and Atomistic Molecular Dynamics Simulations.
A thorough experimental investigation of polymer-glass transition temperature (Tg ) is performed on poly(vinyl alcohol) (PVA) and fumed silica nanoparticle (SiNP) composite. This is done together with atomistic molecular dynamics simulations of PVA systems in contact with bare and fully hydroxylated silica. Experimentally, PVA-SiNP composites are prepared by simple solution casting from aqueous solutions followed by its characterization using Fourier-transform infrared spectroscopy (FTIR), dynamic mechanical analysis (DMA), and dynamic scanning calorimetry (DSC). Both theoretical and experimentally deduced Tg are correlated with the presence of hydrogen bonding interactions involving OH functionality present on the surface of SiNP and along PVA polymer backbone. Further deconvolution of FTIR data show that inter-molecular hydrogen bonding present between PVA and SiNP surface is directly responsible for the increase in Tg . SiNP filler and PVA matrix ratio is also optimized for a desired Tg increase. An optimal loading of SiNP exists, in order to yield the maximum Tg increase arising from the competition between hydrogen bonding and crowding effect of SiNP.


Water-fat MRI in a hibernator reveals seasonal growth of white and brown adipose tissue without cold exposure.
Obligate hibernators, such as ground squirrels, display circannual patterns which persist even under constant laboratory conditions, suggesting that they are regulated by endogenous rhythms. Brown adipose tissue (BAT) is important for thermogenesis during periodic arousals from hibernation when core body temperature rises spontaneously from 5 to 37 °C. In most small eutherians BAT growth requires several weeks of cold exposure. We hypothesized that in the thirteen-lined ground squirrel (Ictidomys tridecemlineatus), a hibernator, BAT growth is regulated, in part, by an endogenous rhythm and we predicted that this growth would precede the hibernation season without cold exposure. We tested this prediction using repeated water-fat magnetic resonance imaging over a year, including the hibernation season. Thoracic BAT depots increased in volume from spring through autumn even though animals were housed at ~22 °C. Subsequent cold exposure (5 °C) enlarged the thoracic BAT further. The fat fraction of this tissue fell significantly during the period of peak growth, indicating relative increases in non-triglyceride components, perhaps mitochondria or vasculature. We also found that the proportion of the body consisting of white adipose tissue (WAT) increased steadily from spring through autumn, and fell throughout hibernation, mirroring changes in body mass. Unlike BAT, WAT fat fractions remained constant (near 90%) throughout the year. Future studies will evaluate the significance of photoperiod and cold exposure on the growth of these tissues. We also found tissue with a fat fraction characteristic of BAT in the head near the eyes, a potentially novel discovery that requires further confirmation.


Grass pea and neurolathyrism: farmers' perception on its consumption and protective measure in North Shewa, Ethiopia.
Neurolathyrism in Ethiopia is caused by food dependency on grass pea (Lathyrus sativus L.). In the study area, a large proportion of the farmers are growing grass pea since it can withstand harsh environments. Socio-economic factors (poverty; lack of money to buy other food legumes) and environmental problems (such as water logging and frost hazards) influence consumption of grass pea. Most of the respondents have the idea that some chemical contained in grass pea causes a health problem. Different processing and preparation methods are used to prepare grass pea into different food forms. The major processing methods include washing and soaking, as the farmers apply these methods mainly because they assume that the chemical that causes lathyrism, scientifically known as β-ODAP (β-N-oxalyl-L-α,β-diaminopropionic acid) is reduced through washing and soaking. The farmers adopt different strategies to avoid the problem of lathyrism such as avoiding consumption of grass pea in the form that they suspect to cause the problem, blending/mixing with other crops, applying different processing/detoxification methods. Since grass pea is consumed with a fear of lathyrism, future research should concentrate either on developing grass pea varieties with safe level of β-ODAP content or improving the traditional/indigenous processing methods.


Maltol prevents the progression of osteoarthritis by targeting PI3K/Akt/NF-κB pathway: In vitro and in vivo studies.
Osteoarthritis (OA), a prevalent degenerative arthritis disease, principle characterized by the destruction of cartilage and associated with the inflammatory response. Maltol, a product formed during the processing of red ginseng (Panax ginseng, CA Meyer), has been reported to have the potential effect of anti-inflammatory. However, its specific mechanisms are not demonstrated. We investigated the protective effect of maltol in the progression of OA both in vitro and in vivo experiments. Human chondrocytes were pre-treated with maltol (0, 20, 40, 60 μM, 24 hours) and incubated with IL-1β (10 ng/mL, 24 hours) in vitro. Expression of PGE2, TNF-α and NO was measured by the ELISA and Griess reaction. The expression of iNOs, COX-2, aggrecan, ADAMTS-5, MMP-13, IκB-α, p65, P-AKT, AKT, PI3K and P-PI3K was analysed by Western blotting. The expression of collagen II and p65-active protein was detected by immunofluorescence. Moreover, the serious level of OA was evaluated by histological analysis in vivo. We identified that maltol could suppress the IL-1β-stimulated generation of PGE2 and NO. Besides, maltol not only suppressed the production of COX-2, iNOs, TNF-α, IL-6, ADAMTS-5, MMP-13, but also attenuated the degradation of collagen II and aggrecan. Furthermore, maltol remarkably suppressed the phosphorylation of PI3K/AKT and NF-κB induced by IL-1β in human OA chondrocytes. Moreover, maltol could block the cartilage destroy in OA mice in vivo. To date, all data indicate maltol is a potential therapeutic agent by inhibiting inflammatory response via the regulation of NF-κB signalling for OA.


Highly Concentrated Multifunctional Silver Nanoparticle Fabrication through Green Reduction of Silver Ions in Terms of Mechanics and Therapeutic Potentials.
Green synthesis of silver nanoparticles (AgNPs) is limited to produce AgNPs with only relatively low concentrations, and is unsuitable for large-scale productions. The use of Myrtus communis (MC) leaf methanolic extract (rich in hydrolyzable tannins) has been recommended to resolve the issues related to the aggregation of nanoparticles at high concentrations of silver ions with added facet of antioxidant properties. The produced highly concentrated MC-AgNPs were characterized by using imaging and spectroscopic methods. Subsequently, antioxidant, anticancer and antifungal activities of the nanoparticles were evaluated. The thermogravimetric analysis and energy dispersive spectroscopy quantitative results suggested that the nanoparticles are biphasic in nature (bio-molecule + Ag0) and layered in structure, suggesting the formation of nanoparticles through a different mechanism than those described in the literature. MC-AgNPs showed greater scavenging activity of nitric oxide and iron (II) chelating ability than the extract. It also showed good reducing power compared to the standard antioxidant. Remarkable anticancer activity of MC-AgNPs (IC50 = 5.99µg/mL) was found against HCT-116 (human colon carcinoma) cell lines after 24h exposure with a therapeutic index value 2-fold higher than the therapeutic index of standard doxorubicin. Furthermore, distinct antifungal activity (MIC = 4µg/mL) was found against Candida krusei. The current method outperforms the existing methods because it produces a large amount of multifunctional nanoscale hybrid materials more efficiently using natural sources; thus, it may be used for diverse biomedical applications.


Toxic effects of perinatal arsenic exposure on the brain of developing rats and the beneficial role of natural antioxidants.
The aim of this study was to determine what changes in biochemical parameters and in the antioxidant capacity occur in the brain of arsenic-exposed rats (50mg As/L in drinking water) and investigate the protective effect of antioxidants as Zn, vitamin C and vitamin E during pregnancy and lactation. After arsenic-exposure, alkaline phosphatase (ALP) activity was enhanced in arsenic group, returning to normal levels in the arsenic+antioxidants one. A significant increase of acetylcholinesterase (AChE) activity was noted in both arsenic groups. Metalloide exposure caused a significant increase in lipid peroxidation (TBARS), whereas antioxidant administration reversed it. Catalase (CAT) activity in arsenic groups was increased, but no changes were found in the other groups. No significant effect of arsenic in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and reduced glutathione concentration (GSH) was noted. This study provides evidence of the deleterious effect of arsenic exposure during gestation and lactation and the beneficial role of antioxidants.


Distinct roles of osteopontin fragments in the development of the pulmonary involvement in sarcoidosis.
Osteopontin (OPN) is a secreted glycoprotein with cell adhesive and chemoattractive functions and is expressed in granulomas of sarcoidosis. It is well documented that full-length OPN (F-OPN) is susceptible to proteolytic fragmentation resulting in carboxyl-terminal OPN (C-OPN). We have previously revealed that C-OPN suppresses cell adhesion mediated by F-OPN. However, the implication of F-OPN and C-OPN in the progression of pulmonary involvement in sarcoidosis has not yet been elucidated. In this study, we demonstrated that (l) OPN was expressed in granulomas of sarcoidosis, (2) plasma F-OPN level in patients with sarcoidosis, especially in stage II patients, was significantly elevated compared with those of the controls, (3) plasma C-OPN levels in patients of stages 0, I, and III were significantly higher than those of the controls, and (4) in vitro recombinant F-OPN induces macrophage migration and that C-OPN inhibits cell migration mediated by F-OPN. These results suggest that F-OPN may promote granuloma formation in sarcoidosis, while C-OPN may suppress it. Thus, OPN and its fragment may play distinct roles in the development of sarcoidosis.


Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil.
To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).


Adenovirus deoxyribonucleic acid replication. II. Synthesis of viral deoxyribonucleic acid in vitro by a nuclear membrane fraction from infected KB cells.
A cell-free system for the study of viral DNA replications was developed by the isolation of a nuclear membrane fraction "DNA replication complex" from adenovirus 2-infected human KB cells late after infection. This complex which possesses both DNA polymerase activity and a virus-specific endonuclease synthesizes exclusively virus-specific DNA sequences in vitro by a semiconservative mechanism. Analysis by rate zonal sedimentation in alkaline sucrose gradients showed that the products of the reaction are small DNA chains approximately 6 to 9 S, presumably "Okazaki intermediates," that are not sealed under our in vitro conditions. Analysis by rate zonal sedimentation in neutral sucrose gradients showed that labeled viral DNA fragments are hydrogen bonded to viral 18 S DNA segments, 0.25 the size of the linear, viral 31 S DNA genome. The 18 S DNA is probably a specific cleavage product of the viral endonuclease found in the replication complex and could represent intermediates in viral DNA replication or degradation products.


Hair analysis: another approach for the assessment of human exposure to selected persistent organochlorine pollutants.
Hair analysis was used for the assessment of exposure to organochlorine pollutants in specimens from Greece, Romania and Belgium. A simple method (using 3 N HCI as incubation reagent, liquid-liquid extraction with hexane/ dichloromethane (DCM), alumina/acid silica clean-up and GC-ECD/GC-MS analysis) was used for screening of specimens. The highest organochlorine load (up to 148 ng/g hair for the sum of PCB, DDT and hexachlorocyclohexane (HCH) isomers) was found in samples from a group of Greek women with past occupational exposure to pesticides. DDTs were the main organochlorine pollutants in Greek samples (up to 70%), while in Belgian hair samples their contribution was reduced to 40%. PCB mean concentration was higher in Belgian specimens (up to 14 ng/g hair). Lindane (y-HCH) was the main HCH isomer found in the samples (up to 82% in the Greek samples). Contribution of p,p'-DDT to the sum of DDTs was higher in Greek samples and indicates recent exposure to technical DDT. Similar PCB 153/sum PCBs ratios were found for each of the three countries suggesting similar sources of pollution with PCBs (mainly dietary). Artificially coloured hair samples were found to have lower, but not statistically significant concentrations of organochlorine pollutants than the non-coloured hair.


Effects of nitrendipine (BAY e 5009), nifedipine, verapamil, phentolamine, papaverine, and minoxidil on contractions of isolated rabbit aortic smooth muscle.
The effects of nitrendipine, a new antihypertensive agent, have been examined using the isolated rabbit aortic strip stimulated with either noradrenaline (1.7 X 10(-8) - 1.7 X 10(-5) mol/L) or potassium (22.7-52.7 mmol/L). Nifedipine, verapamil, phentolamine, papaverine, and minoxidil were used as reference compounds. Nitrendipine and nifedipine had little effect on the contractions of the aortic strip induced by noradrenaline, but concentration-dependently inhibited contractions induced by potassium depolarisation (IC50) (3.1 X 10(-9) and 8.1 X 10(-9) mol/L, respectively). Verapamil had little effect on contractions induced by the highest concentration of noradrenaline (1.7 X 10(-5) mol/L) but inhibited contractions induced by lower concentrations of noradrenaline. Potassium-induced contractions were inhibited with an IC50 of 1.4 X 10(-7) mol/L. Phentolamine competitively inhibited noradrenaline-induced contractions, but had no effect on those induced by potassium. Papaverine inhibited both noradrenaline- and potassium-induced contractions with an IC50 of 2.5 X 10(-5) and 3 X 10(-5) mol/L, respectively. Minoxidil also inhibited both types of contractions, but only at very high concentrations (IC50 1.3 X 10(-3) and 1.8 X 10(-3) mol/L). I conclude that nitrendipine, like nifedipine, acts by inhibiting the depolarisation-induced influx of calcium ions into the vascular smooth muscle. There is no evidence for alpha-adrenoceptor-blocking activity, nor for papaverine-like vasodilator activity. Verapamil also appears to act by a calcium antagonistic action; but may, in addition, possess some alpha-adrenoceptor-blocking activity.


Human papillomavirus DNA in cervix. In-situ hybridization with biotinylated probes on Bouin's fixed paraffin embedded specimens.
We examined retrospectively a series of 65 Bouin's fixed, paraffin-embedded tissue specimens from 8 condylomatous lesions, 16 condylomas associated with cervical intraepithelial neoplasia (CIN), and 12 neoplasia without condylomatous signs, for histological characteristics, the detection of viral structural antigen, the presence and typing of HPV DNA by molecular in situ hybridization with biotinylated probes types 6, 11, 16 and 18 under stringent conditions (Tm - 12 degrees C). HPV DNA was present in 34/65 (52%) specimens. Detection of viral structural antigen was positive in only 14% (3/22) specimens. HPV DNA were identified in 9/9 (100%) condylomatous lesions (with HPV type 6, 11, 18). Three condylomas were coinfected with both HPV type 6 or 11 and type 18; viral antigen was found in two specimens. HPV DNA were detected in 18/31 (58%) low grade and advanced CIN associated with condylomatous changes (type 6 = 5 specimens, type 11 = 3 specimens, type 16 = 4 specimens, type 18 = 6 specimens). Four of these cases were coinfected with both HPV type 6/11 and HPV type 16/18. Viral antigen was negative in all specimens. HPV DNA were detected in 7/25 (28%) advanced intra-cervical neoplasia (CIN III) without anatomopathological condylomatous changes (type 6 = 1 specimen, type 16 = 3 specimens, type 18 = 3 specimens). One of these specimens contained both HPV types 6 and 18. Viral antigen was found in one case. Our data confirm the association of HPV types 6 and 11 with condyloma and low grade neoplasia; HPV types 16 and 18 were associated with advanced cervical neoplasia.(ABSTRACT TRUNCATED AT 250 WORDS)


Pressure distribution on the wall of experimental aneurysms.
Since it is known that turbulent flow exists in aneurysms, we have investigated whether pressure might be distributed unevenly on the aneurysmal wall, and whether it varies with the shape and size of the aneurysm and its orifice diameter as well as with the direction of blood flow in the parent vessel. It was found that in some instances, such as with aneurysms having narrow necks and situated at 90 degrees to the parent vessel blood flow, aneurysmal pressure is relatively low.


Cardiorespiratory response during exercise in patients with cyanotic congenital heart disease with and without a Fontan operation and in patients with congestive heart failure.
To clarify the different cardiorespiratory response to exercise in patients with congenital heart disease and patients with chronic congestive heart failure, we investigated the effect of a progressive exercise test in 30 patients aged 10 to 24 years, including 9 patients with cyanotic congenital heart disease (group A), 13 patients who had undergone a Fontan operation (group B), and 8 patients with reduced left ventricular function (group C), and 18 healthy controls (group D). There was no difference in peak oxygen uptake among patient groups and all group A, B, and C values were lower than those in group D (P<0.001). Although peak heart rate was lower in patient groups than in group D, heart rate at a given exercise intensity was highest in group C. The oxygen pulse (oxygen uptake divided by heart rate=stroke volume x arterial venous oxygen difference), as an indicator of stroke volume, was lower in patients groups, especially in group C, than in group D. There was no difference in tidal volume between groups A and D, but the respiratory rates at any given exercise intensity were higher in group A than in the other patient groups, thus minute ventilation and the ventilatory equivalent were highest in group A. The increased respiratory rate and low tidal volume in group C resulted in rapid and shallow respiration. There was no difference in exertional symptoms at peak exercise among the groups. In addition to impaired responses of stroke volume during exercise in patients with reduced exercise capacity, there was little limitation of increase in ventilation in group B and excessive ventilation in group A. The present results suggest that relationship between ventilatory and cardiac responses during exercise in patients with cyanotic congenital heart disease with and without a Fontan operation is different from the relationship in patients with chronic congestive heart failure; however, these pathological differences did not influence exertional symptoms.


Picosecond and microsecond pulse laser studies of exciton quenching and exciton distribution in spinach chloroplasts at low temperatures.
Studies of the fluorescence quantum yield and decay times, determined at the emission maxima of 685 and 735 nm, using picosecond laser pulses for excitation, indicate that the pigments which are responsible for the 735 nm emission derive their energy by transfer of singlet excitons from the light-harvesting pigments and not by direct absorption of photons. Microsecond pulse laser studies of the fluorescence quantum yields at these two fluorescence wavelengths indicate that long lived quenchers (most probably triplet states), which quench singlet excitions, accumulate preferentially within the long wavelength pigment system which gives rise to the 735 nm emission band.


Human conjunctivitis caused by the bird parasite Philophthalmus.
We removed a trematode of the species Philophthalmus from under the left upper eyelid of a 66-year-old man who had follicular conjunctivitis for three weeks. After removal of the parasite, the conjunctivitis resolved.


Selective NLRP3 Inflammasome Inhibitor MCC950 Suppresses Inflammation and Facilitates Healing in Vascular Materials.
Minimally invasive interventions using drug-eluting stents or balloons are a first-line treatment for certain occlusive cardiovascular diseases, but the major long-term cause of failure is neointimal hyperplasia (NIH). The drugs eluted from these devices are non-specific anti-proliferative drugs, such as paclitaxel (PTX) or sirolimus (SMS), which do not address the underlying inflammation. MCC950 is a selective inhibitor of the NLRP3-inflammasome, which drives sterile inflammation commonly observed in NIH. Additionally, in contrast to broad-spectrum anti-inflammatory drugs, MCC950 does not compromise global immune function due this selective activity. In this study, MCC950 is found to not impact the viability, integrity, or function of human coronary endothelial cells, in contrast to the non-specific anti-proliferative effects of PTX and SMS. Using an in vitro model of NLRP3-mediated inflammation in murine macrophages, MCC950 reduced IL-1β expression, which is a key driver of NIH. In an in vivo mouse model of NIH in vascular grafts, MCC950 significantly enhanced re-endothelialization and reduced NIH compared to PTX or SMS. These findings show the effectiveness of a targeted anti-inflammatory drug-elution strategy with significant implications for cardiovascular device intervention.


The beneficial effect of Radix Dipsaci total saponins on bone metabolism in vitro and in vivo and the possible mechanisms of action.
The purpose of this study is to investigate the anti-osteoporotic effects of Radix Dipsaci total saponins (RTS). We showed that RTS was able to improve bone properties by either an increase of osteoblastic activity or a decrease in osteoclastic activity. Radix Dipsaci has long been used as an anti-osteoporotic drug. The present study investigates the anti-osteoporotic effects of RTS. Three-month-old female rats were randomly assigned into a sham-operated group (sham) and five ovariectomy (OVX) subgroups, namely, OVX with vehicle (OVX), OVX with 17β-ethinylestradiol (E(2)), and OVX with graded doses of RTS (50, 100, or 200 mg/kg/d). RTS and E(2) were administered orally, daily from 1 week after OVX treatment for 4 months. Bone mass, turnover, and strength were evaluated by dual-energy X-ray absorptiometry, biochemical markers, and the three-point bending test. The trabecular bone microarchitecture was assessed by microCT. In vitro experiments were performed to determine the potential molecular mechanisms of the anti-osteoporotic effect of RTS. RTS prevented the loss of bone mass induced by OVX. The preventive effect on bone loss was primarily indicated by decreasing levels of bone turnover markers and confirmed by the changes in urinary calcium and phosphorus excretion. The treatment also enhanced the biomechanical strength of bone and prevented the deterioration of trabecular bone microarchitecture. RTS induced MC3T3-E1 and primary osteoblastic cell maturation and differentiation and increased bone formation by increasing BMP-2 synthesis. In addition, RTS inhibited osteoclastogenesis through an increase in osteoprotegrin and a decrease in NF-kB ligand expression in vitro. RTS treatment can effectively suppress the loss of bone mass induced by OVX and in vitro evidence suggests this could be through actions on both osteoblasts and osteoclasts.


Modulation of an inhibitory reflex in single motor units in human masseter at different joint angles.
The inhibitory reflex evoked in single units in human masseter by lip stimulation was recorded at several joint angles. The pre-stimulus firing frequency of the unit was kept constant. Some modulation of the inhibitory response at different vertical jaw positions (i.e. temporomandibular joint angle) was observed in most masseter units, with the majority of the modulated units being inhibited less when the teeth were closer together.