Induction of an epitope-specific humoral immune response by lipopeptide-hapten conjugates: enhancement of the anti-melittin response by a synthetic T helper (Th)-cell epitope.
Lipopeptides of bacterial origin constitute potent immunoadjuvants when combined with antigens. After the immunization with lipopeptides covalently coupled to non-immunogenic low-molecular-mass antigens or haptens, a hapten-specific humoral immune response can often be obtained. The response against synthetically prepared melittin fragments was further enhanced by the additional introduction of a T helper (Th)-cell epitope into the lipopeptide-hapten conjugate. The Th-cell epitope applied, which is presented by the MHC class II molecule of the BALB/c (H-2d) haplotype, consisted of a synthetic 16-amino-acid oligopeptide derived from sperm whale myoglobin. The immune-enhancing effect was most pronounced for the melittin-derived peptide fragments [Mel(1-16)] and [Mel(17-26)-CONH2]. Antibodies obtained after 3 immunizations with the conjugates recognized the synthetic as well as the native melittin molecule. Our results show that it is possible to markedly enhance a weak hapten-specific immune response by coupling the haptens to a lipopeptide conjugated to a haplotype-specific T helper-cell epitope. The novel conjugates are well suited for the optimization of immunization procedures, and for the development of novel synthetic vaccines.


[Medical and surgical therapy of familial hypophosphatemic vitamin D resistant rickets with ambulation disorders].
Three children with familial hypophosphatemic rickets showed, in the untreated state, active rickets of the metaphyseal areas of long bones. All were treated with combined phosphate /1-2 g daily by mouth in 4-5 divided doses) and vitamin D2 therapy for 2-5 years. The radiological appearance of the metaphyses became practically normal in two, whereas little change took place in the endosteal bone surface. Bone biopsies demonstrated osteomalacia. Therefore, two subjects were given phospate (1-2 g daily) and 1-alpha-hydroxyvitamin D (0.25-0.50 microgram daily) for 2 years; then phosphate (1 g daily) and 1.25 dihydroxyvitamin D (0.25-0.50 microgram daily) combined therapy for 5 years; the third patient had phosphate (1 g daily) and 1.25 dihydroxyvitamin D (0.25 microgram daily) combined therapy for 2 years. After therapy with low doses of 1.25 dihydroxyvitamin D, X-rays showed a nearly normal bone aspect, without nephrocalcinosis in all patients. All subjects were submitted to osteothomies with positive results.


A flexible AFT model for misclassified clustered interval-censored data.
Motivated by a longitudinal oral health study, we propose a flexible modeling approach for clustered time-to-event data, when the response of interest can only be determined to lie in an interval obtained from a sequence of examination times (interval-censored data) and on top of that, the determination of the occurrence of the event is subject to misclassification. The clustered time-to-event data are modeled using an accelerated failure time model with random effects and by assuming a penalized Gaussian mixture model for the random effects terms to avoid restrictive distributional assumptions concerning the event times. A general misclassification model is discussed in detail, considering the possibility that different examiners were involved in the assessment of the occurrence of the events for a given subject across time. A Bayesian implementation of the proposed model is described in a detailed manner. We additionally provide empirical evidence showing that the model can be used to estimate the underlying time-to-event distribution and the misclassification parameters without any external information about the latter parameters. We also provide results of a simulation study to evaluate the effect of neglecting the presence of misclassification in the analysis of clustered time-to-event data.


Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion.
Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology.


LncRNA PVT1 promotes malignant progression in squamous cell carcinoma of the head and neck.
Long non-coding RNAs (lncRNAs) are potentially critical regulators of cancer malignant behaviours. Aberrant expression and dysfunction of lncRNA PVT1 have been reported in multiple human cancers. However, its role in squamous cell carcinoma of the head and neck (SCCHN) remains largely unknown. Our current study demonstrated that PVT1 expression was increased in SCCHN. High PVT1 expression was positively correlated with SCCHN clinical parameters including T classification, clinical stages and cervical lymph node metastasis. More importantly, high PVT1 expression predicted a poor prognosis in SCCHN patients. Gain-of function and loss-of function studies further indicated that PVT1 promoted the proliferation and invasion of SCCHN both in vitro and in vivo, which was accompanied by epithelial-mesenchymal transition and enhanced cancer stem cell-like properties. Further mechanistic investigation revealed that PVT1 activated Wnt/β-catenin signalling pathway, and inhibition of Wnt/β-catenin signalling reversed the malignant progression caused by PVT1 overexpression. Together, our study reveals that PVT1 accelerates the malignant progression of SCCHN and represents a potential biomarker and therapeutic target in SCCHN.


Effects of wheat-flour and oat mill fractions on jejunal flow, starch degradation and absorption of glucose over an isolated loop of jejunum in pigs.
The effect of cereal-based diets varying in dietary fibre (DF) on gastric emptying and glucose absorption over an isolated loop of jejunum was studied in four pigs fitted with two sets of re-entrant cannulas. The pigs were fed on either a wheat-flour diet or three diets based on oat flour (endosperm), rolled oats or oat bran containing different amounts of soluble DF. Mean transit time (MTT) of liquid estimated from the output from the first jejunal cannula was significantly higher with the two diets having the highest DF content, but MTT of dry matter (DM), starch, xylose and neutral non-starch polysaccharides (nNSP) was not correlated directly to the DF content of the diet. DF had a stimulatory effect on secretion of gastrointestinal juices, but the effect was not linearly correlated with the DF content of the diet. Starch was significantly degraded in digesta collected within 30 min after feeding with malto-oligosaccharides accounting for 140-147 g/kg total starch. The degradation was more extensive with higher DF and lower starch content of the diet. However, taking into account the differences in jejunal flow, the amount of malto-oligosaccharides available for absorption in the first 0.5 h decreased with higher levels of DF in the oat-based diets. The absorption of glucose from the isolated loop was 18-34 g/m intestine over an 8 h period with no significant differences between diets. This corresponded to a non-significant decrease in recovery of starch from 0.91 to 0.82 with increasing levels of DF and decreasing levels of starch in the diet. This suggests that the capacity for absorption of large doses of starch entering the proximal small intestine after ingestion of a carbohydrate-rich cereal-based diet has a major influence on the absorption at this site. Consequently any effect of DF on glucose absorption may be exerted either through the rate of gastric emptying or by impaired rate of absorption more distal in the small intestine and not by displacement of the site for starch absorption.


Hypotonic-hyporesponsive Episodes After Diphtheria, Tetanus and Acellular Pertussis Vaccination.
Hypotonic-hyporesponsive episode (HHE) after whole cell pertussis vaccination is a known adverse event. Less is known about the risk of HHE after administration of acellular pertussis vaccines. Using parental interviews, this study actively surveyed for HHE among infants after doses 1 and 2 of acellular pertussis vaccine. We interviewed the parents of 52,531 infants. HHE was reported at a rate of 22.8 per 100,000 doses (95% CI: 11.8-39.9) of acellular pertussis vaccine, approximately 45 episodes per 100,000 children. These rates are lower than HHE rates reported after whole cell pertussis vaccines and within the range of HHE rates reported in other studies of acellular pertussis vaccines.


Dive-related fatalities among tourist and local divers in the northern Croatian littoral (1980-2010).
The aim of the study was to retrospectively analyze diving fatalities occurring in Primorje-Gorski Kotar County (northern Croatian littoral), Croatia between 1980 and 2010 in order to identify differences between fatally injured tourist and resident divers, as well as temporal changes in the frequency of diver deaths. Medico-legal and police reports of 47 consecutive fatal diving cases were reviewed to determine the frequency of death among divers in relation to year and month of death, age, sex, nationality, organization of diving, diving type, and health condition. The majority of victims were foreign citizens (59.6%) most of whom fell victim to scuba diving (70.4%). It was found that 79% of resident divers succumbed during free-diving. The number of diving fatalities increased significantly in the last three decades, especially among free-divers. Of the victims, 93% were males, usually belonging to younger age groups with tourist divers being significantly older than local divers. And 31.9% of divers, mostly tourists, showed signs of acute, chronic, or congenital pathological conditions. Fatally injured foreign divers differ from resident diver fatalities in diving method and age. Tourists are the group most at risk while scuba diving according to the Croatian sample. Occupational scuba divers and free-divers are the group most at risk among resident divers. This study is an important tool in uncovering the most common victims of diving and the related risk factors. It also highlights the problems present in the legal and medical monitoring of recreational divers and discusses possible pre-event, event, and post-event preventive actions that could lead to reduced mortality rates in divers.


Internalization is essential for the antiapoptotic effects of exogenous thymosin beta-4 on human corneal epithelial cells.
Exogenous thymosin beta-4 (Tbeta(4)) has been shown to inhibit the apoptosis in nontransformed human corneal epithelial cells that is triggered by ethanol. The purpose of this study is to examine whether exogenous Tbeta(4) protects SV40-immortalized human corneal epithelial T (HCE-T) cells against the toxic effects of Fas ligand (FasL) and hydrogen peroxide (H(2)O(2)) and to elucidate its mechanism of action. HCE-T cells were incubated without or with the recombinant histidine-tagged Tbeta(4) produced by Escherichia coli before the addition of FasL or H(2)O(2). Cell viability was determined by MTT or MTS assay, and activation of caspase-8, -9, and -3 was examined by colorimetric and fluorescent substrate cleavage assays. The internalization of exogenous Tbeta(4) in HCE-T cells was analyzed by immunofluorescence staining. Cytochalasin D, an actin depolymerization agent, was added to examine whether the actin cytoskeleton is involved in Tbeta(4) entry and whether the internalization of this peptide is crucial for its cytoprotection. The death of HCE-T cells induced by both FasL and H(2)O(2) was dramatically reduced by the recombinant Tbeta(4) pretreatment. Moreover, FasL-mediated activation of caspases-8 and -3 as well as H(2)O(2)-triggered stimulation of caspases-9 and -3 in these cells was abolished by preincubating them with the exogenous Tbeta(4). Of note, internalization of this G-actin-sequestering peptide into HCE-T cells was found to be essential in cell death prevention, in that disruption of the cellular entry of Tbeta(4) by cytochalasin D abrogated its cytoprotective effects. This is the first report to demonstrate that the internalization of exogenous Tbeta(4) is essential for its antiapoptotic activity in human corneal epithelial cells.


Prenatal and postnatal diagnoses of thalassemias and hemoglobinopathies by HPLC.
The conventional approach to qualitative and quantitative analyses of hemoglobin (Hb) molecules for the diagnoses of hemoglobinopathies requires a combination of tests. We used an automated HPLC (VARIANT) system to study alpha-thalassemia and beta-thalassemia syndromes in Thailand. The beta-thalassemia short program is applicable to the diagnosis of alpha-thalassemia and beta-thalassemia disorders, including Hb H, EA Bart's disease, and EF Bart's disease, in adults, newborns, and fetuses. The system cannot quantify accurately certain Hb molecules, such as Hb H and Hb Bart's. The alpha-thalassemia short program was therefore developed and used to quantify Hb Bart's to detect alpha-thalassemia genotypes in cord blood. This automated HPLC system is an alternative approach to the diagnosis of complicated thalassemia syndromes in Thailand and Southeast Asia.


Reversible estrous cycle suppression in prepubertal female rabbits treated with slow-release deslorelin implants.
The aim of this study was to examine the long-term effect of a 4.7-mg deslorelin GnRH analog implant on ovarian function in the prepubertal female rabbit. Seven female rabbits (group 1) were treated with the implant at the age of 60 days. The implant was inserted subcutaneously in the umbilical region. Two animals (group 2) were not treated and served as a control group. The vulva of all 9 animals was examined for the presence of typical cyclical changes, additionally the occurrence of mounting behavior was recorded. Ovarian function was checked by administration of a short-acting GnRH agonist to induce ovulation and pseudopregnancy (0.8 μg of buserelin per animal intramuscularly). Ten days after each treatment with buserelin, blood was collected for progesterone measurement to confirm pseudopregnancy. After implant insertion, the first blood collection (Day 10) was done without preceding induction of ovulation to screen for implant induced ovulation and pseudopregnancy. The implant was in situ for 273 days, and during this time span, 12 attempts of induction of ovulation were carried out in intervals of 21 days, beginning at the age of 81 days. Afterward, it was removed under local anesthesia and 3 further inductions of ovulation by the same scheme were conducted. The insertion of the implant led to the establishment of a pseudopregnancy in 2 of 7 animals; the remaining 5 animals did not show elevated progesterone values. Attempts to induce ovulation by administration of the short-acting GnRH analog while the slow-release GnRH analog implant was in place were not successful in treated animals, and progesterone concentrations were basal. The effect was reversible as ovulation could be induced in 2 subsequent cycles in all animals by the third induction of ovulation after implant removal. Induction of ovulation in control animals at the age of 110 and 131 days resulted in elevated progesterone levels after 10 days. No adverse side effects could be observed in implant-treated animals. The typical red coloration of the vulva could be seen in group 2 and after implant removal in group 1. The results suggest that in 5 of 7 rabbits, puberty was delayed by the treatment with the 4.7-mg deslorelin slow-release analog until the implant had been removed. In the other animals, the treatment induced an initial flare-up phenomenon. Afterward, the treatment could reversibly suppress ovarian function in all 7 treated animals.


Dispersal at a snail's pace: historical processes affect contemporary genetic structure in the exploited wavy top snail (Megastraea undosa).
We used population genetics to assess historical and modern demography of the exploited wavy top snail, Megastraea undosa, which has a 5-10 day pelagic larval duration. Foot tissue was sampled from an average of 51 individuals at 17 sites across the range of M. undosa. Genetic structure at the mtDNA locus is strikingly high (ΦST of 0.19 across 1000 km), and a major cline occurs in northern Baja California (ΦCT of 0.29 between northern and southern populations). Genetic data indicate that the northern region is highly connected through larval dispersal, whereas the southern region exhibits low genetic structure. However, additional analyses based on patterns of haplotype diversity and relationships among haplotypes indicate that M. undosa has likely recently expanded into the Southern California Bight or expanded from a small refugial population, and analysis using isolation by distance to calculate dispersal distance indicates surprisingly short estimates of dispersal from 30 m to 3 km. This scenario of a northward expansion and limited larval dispersal is supported by coalescent-based simulations of genetic data. The different patterns of genetic variation between northern and southern populations are likely artifacts of evolutionary history rather than differences in larval dispersal and this may have applications to management of this species. Specifically, these data can help to inform the scale at which this species should be managed, and given the potentially very small dispersal distances, this species should be managed at local scales. Consideration of the evolutionary history of target species allows for a more accurate interpretation of genetic data for management.


Fusimotor drive may adjust muscle spindle feedback to task requirements in humans.
The aim of the present study was to investigate whether the fusimotor control of muscle spindle sensitivity may depend on the movement parameter the task is focused on, either the velocity or the final position reached. The unitary activities of 18 muscle spindle afferents were recorded by microneurography at the common peroneal nerve. We compared in two situations the responses of muscle spindle afferents to ankle movements imposed while the subject was instructed not to pay attention to or to pay attention to the movement, both in the absence of visual cues. In the two situations, three ramp-and-hold movements were imposed in random order. In one situation, the three movements differed by their velocity and in the other by the final position reached. The task consisted in ranking the three movements according to the parameter under consideration (for example, slow, fast, and medium). The results showed that paying attention to movement velocity gave rise to a significant increase in the dynamic and static responses of muscle afferents. In contrast, focusing attention on the final position reached made the muscle spindle feedback better discriminate the different positions and depressed its capacity to discriminate movement velocities. Changes are interpreted as reflecting dynamic and static gamma activation, respectively. The present results support the view that the fusimotor drive depends on the parameter the task is focused on, so that the muscle afferent feedback is adjusted to the task requirements.


Structure, Ionic Conductivity, and Dielectric Properties of Li-Rich Garnet-type Li5+2xLa3Ta2-xSmxO12 (0 ≤ x ≤ 0.55) and Their Chemical Stability.
Lithium garnet oxides are considered as very promising solid electrolyte candidates for all-solid-state lithium ion batteries (SSLiBs). In this work, we present a cubic garnet-type Li5+2xLa3Ta2-xSmxO12 (0 ≤ x ≤ 0.55) system as a potential electrolyte for SSLiBs. Powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) were employed to investigate the structural stability of Li5+2xLa3Ta2-xSmxO12. The results from PXRD and SEM suggested structural and morphological transformation as a function of dopant concentration. In addition to Li-ion transport in Li5+2xLa3Ta2-xSmxO12, the dielectric properties were also investigated in the light of electron energy loss functions, which showed some surface energy loss and negligible volume energy loss for the studied garnets. Surface and volume energy loss functions of a mixed conducting LiCoO2 was studied for comparison. The long-term chemical stability of one of members, Li5.3La3Ta1.85Sm0.15O12, was performed on aged sample using PXRD, SEM, and thermogravimetric analysis.


Abatacept Promotes Regulatory B Cell Functions, Enhancing Their Ability to Reduce the Th1 Response in Rheumatoid Arthritis Patients through the Production of IL-10 and TGF-β.
Abatacept mimics natural CD152 and competes with CD28 for binding to CD80/CD86 on APC, such as B cells, thereby preventing T cell activation. However, its potential impact on B cells has not been identified. The aim of this study was to assess whether abatacept can potentiate the immunoregulatory properties of B cells in vitro and in patients with rheumatoid arthritis (RA). T and B cells from healthy controls were purified. The suppressor properties of B cells in the presence of abatacept or control IgG1 were evaluated based on the ability of these cells to inhibit the polyclonal expansion (anti-CD3/CD28 stimulation) of T cells or their differentiation into Th1 or Th17 cells. Similar analyses were also performed with cells from RA patients before and 3 mo after abatacept initiation. Abatacept significantly potentiated regulatory B cell regulatory functions by enhancing their ability to produce IL-10 and TGF-β, resulting in the increased generation of regulatory T cells and limited T cell proliferation and differentiation into Th1 and Th17 cells. Interestingly, B cells isolated from patients that received a 3-mo treatment with abatacept had an increased ability to reduce T cell functions, confirming the above observations. Abatacept binding to CD80/CD86 induces and promotes regulatory B cell functions by enhancing the ability of these cells to produce IL-10 and TGF-β in vitro and in RA patients.


Caenorhabditis elegans: plague bacteria biofilm blocks food intake.
Bubonic plague is transmitted to mammals, including humans, by the bites of fleas whose digestive tracts are blocked by a mass of the bacterium Yersinia pestis. In these fleas, the plague-causing bacteria are surrounded by an extracellular matrix of unknown composition, and the blockage depends on a group of bacterial genes known as the hmsHFRS operon. Here we show that Y. pestis creates an hmsHFRS-dependent extracellular biofilm to inhibit feeding by the nematode Caenorhabditis elegans. Our results suggest that feeding obstruction in fleas is a biofilm-mediated process and that biofilms may be a bacterial defence against predation by invertebrates.


Identification of m6A-related genes and m6A RNA methylation regulators in pancreatic cancer and their association with survival.
N6-methyladenosine (m6A) modification holds an important position in tumorigenesis and metastasis because it can change gene expression and even function in multiple levels including RNA splicing, stability, translocation and translation. In present study, we aim to conducted comprehensive investigation on m6A RNA methylation regulators and m6A-related genes in pancreatic cancer and their association with survival time. Based on Univariate Cox regression analysis, protein-protein interaction analysis, LASSO Cox regression, a risk prognostic model, STRING, Spearman and consensus clustering analysis, data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database was used to analyze 15 m6A RNA methylation regulators that were widely reported and 1,393 m6A-related genes in m6Avar. We found that 283 candidate m6A RNA methylation-related genes and 4 m6A RNA methylation regulatory factors, including RNA binding motif protein 15 (RBM15), methyltransferase like 14 (METTL14), fat mass and obesity-associated protein (FTO), and α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5), differed significantly among different stages of the American Joint Committee on Cancer (AJCC) staging system. Protein-protein interaction analysis indicated epidermal growth factor receptor (EGFR), plectin-1 (PLEC), BLM RecQ like helicase (BLM), and polo like kinase 1 (PLK1) were closely related to other genes and could be considered as hub genes in the network. The results of LASSO Cox regression and the risk prognostic model indicated that AJCC stage, stage T and N, KRAS mutation status and x8q23.3 CNV fragment mutation differed significantly between the high-risk and the low-risk subgroups. The AUCs of 1 to 5 years after surgery were all more than 0.7 and increased year by year. Finally, we found KRAS mutation status and AJCC stage differed significantly among these groups after TCGA samples divided into subgroups with k=7. Moreover, we identified four m6A RNA methylation related genes expressed significantly differently among these seven subgroups, including collagen type VII alpha 1 chain (COL7A1), branched chain amino acid transaminase 1 (BCAT1), zinc finger protein 596 (ZNF596), and PLK1. Our study systematically analyzed the m6A RNA methylation related genes, including expression, protein-protein interaction, potential function, and prognostic value and provides important clues to further research on the function of RNA m6A methylation and its related genes in pancreatic cancer.


How do side chains orient globally in protein structures?
An angle Omega is defined to serve as a metric for global side-chain orientations, which reflects the orientation of the side chain relative to the radial vector from the center of the protein to an amino acid. The side-chain orientations of buried residues exhibit characteristically different orientations than do exposed residues, in both monomeric and dimeric structures. Overall, buried side chains point mostly inward, whereas surface side chains tend to point outward from the surface. This difference in behavior also correlates well with the residue hydrophobicity; so a global side-chain orientation can be viewed as a direct structural manifestation of hydrophobicity. When various solvent-accessible layers are considered, the behavior is relatively continuous between centrally located and exposed residues. In the case of interfacial residues between subunits, there are statistically significant differences between exposed residues and interface residues for ALA, ARG, ASN, ASP, GLU, HIS, LYS, THR, VAL, MET, PRO, and overall the interface residues have an increased tendency to point inward. Presumably, these substantial differences in orientations of side chains may be a manifestation of hydrophobic forces.


A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: enoxaparin versus unfractionated heparin in non-ST-segment elevation acute coronary syndromes.
The purpose of this study was to compare the effect of receiving pretreatment with antithrombin before randomization as well as overall efficacy and safety of enoxaparin versus unfractionated heparin (UFH) in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial. The SYNERGY trial results demonstrated noninferiority in outcomes with enoxaparin compared with UFH. Randomized treatment was independent of prerandomization treatment. Analyses were first performed on the 4 prerandomization subgroups: patients who received no antithrombin therapy and those who were treated with enoxaparin or UFH or both. Then, we focused on the subgroup of patients who received no pretreatment or were pretreated with and randomized to the same drug. Of the 9,978 patients, 2,440 did not receive prerandomization therapy and 6,138 received consistent therapy through randomization. The primary end point was the composite of death and nonfatal myocardial infarction (MI) at 30 days. After adjustment for differences among the subgroups, no significant difference in the association between the 4 pretreatment groups and death or MI remained (p = 0.171). The randomized treatment effect on 30-day death or MI tended to vary with pretreatment (p = 0.055 for interaction test after adjustment). Patients who received consistent therapy with enoxaparin had significantly less death or MI than patients randomized to UFH (adjusted p = 0.041) with a trend toward increased bleeding. Treatment with antithrombin therapy before randomization had potential impact on comparison of study drug effects. After adjustment for differences in baseline characteristics between subgroups, consistent therapy with enoxaparin might be superior to UFH in reducing death or nonfatal MI, with a modest excess in bleeding.


Helicobacter pylori infection and lactose intolerance increase expiratory hydrogen.
Infection with Helicobacter pylori (H.pylori) may cause dyspepsia and/or unexplained functional nonspecific, gastrointestinal complaints of the irritable bowel syndrome (IBS) spectrum. Hitherto, in H. pylori infected patients with symptoms of the IBS spectrum the occurrence of additional food intolerance/malabsorption is not evaluated. We used a retrospective analysis of charts from 548 patients who presented with gastrointestinal complaints of the irritable bowel syndrome spectrum. An enzyme-linked IgA immunosorbent assay or histologic evaluation of gastric mucosa were used to detect H. pylori infection. A hydrogen breath (H2) test was performed to evaluate fructose malabsorption (FM) and lactose intolerance (LIT). Serum diamine oxidase value of <10 U/ml and a response to a histamine-reduced diet was used to identify histamine intolerance (HIT). We found 293 patients infected with H. pylori, within these were 58 H. pylori patients with LIT, 23 H. pylori LIT patients with FM and 46 H. pylori LIT patients with HIT. Additionally, 13 H. pylori, lactose- and histamine intolerance patients also had FM. The Kruskal Wallis test and pairwise comparison were used to analyze differences of the area under the curve of expiratory hydrogen. In lactose H2 breath tests compared with LIT-only patients, LIT with H. pylori, LIT and H. pylori with HIT, LIT and H. pylori with FM showed significantly higher exhaled H2 levels (p=0.022). Pairwise comparison demonstrated H. pylori infected patients with LIT exhaled more H2 compared to LIT-only (p=0.029). H. pylori with lactose- and histamine intolerance, and H. pylori with lactose-, histamine intolerance and FM compared to H. pylori-only patients indicated a significantly higher occurrence of stomach pain during lactose H2 breath tests (p=0.012 and p=0.005, respectively). We demonstrate that LIT patients with high expiratory H2 levels in lactose breath tests may have H. pylori infection and possibly additional food intolerance/malabsorption. Subsequently, besides H. pylori eradication, a dietician is necessary for an individually tailored reduction- or exclusion diet of symptom triggering food components.


Orofacial pain evaluation in children.
Pain evaluation in children and its diagnosis are problems not always easy to solve. Children, because of their immaturity, are not always able to well communicate or to describe the clear characteristics of the disease by which they are affected. Moreover, they are often unable to report the real intensity of the pain they experience. These problems are related to their immature, not fully evolved psyche. Such problems can create difficulties to the physician who is called to examine and evaluate the origin of orofacial pain, as well as hesitation regarding when it could be necessary to start a drug therapy. Aim of this work is to propose the basic tools for the evaluation and measurement of pain that are better suitable for children, as these instruments can be used together with an accurate anamnesis and a meticulous examination, in order to formulate a precise differential diagnosis among the pathologies that affect the head and neck. A list of the most common painful diseases affecting this area is also presented. A systematic literature review about the methods for evaluation and measurement of pain in children was conducted. The commonly used scales of measurement were examined: VAS, VSN, CAS, FPS and the Oucher SCALE. The different pathologies of head and neck and their characteristics are described and the possible causes of orofacial pain have been divided into extracranial and intracranial, in order to easily direct diagnosis. Orofacial pain in children is an issue of great interest in consideration of its high frequency in paediatric dentistry. Its measurement and evaluation is possible despite the small compliance of paediatric patients. Thanks to the modern technique and knowledge this evaluation can be realistic and reproducible. Evaluation scales of pain are suitable at any age and skill of the child and, together with a careful anamnesis and a proper clinical examination, allow the clinician to conduct a precise differential diagnosis of the pain so as to set the ideal therapy for the little patient.


Effects of aminophylline and salbutamol on diaphragmatic force during compensated metabolic acidosis.
We investigated the effects of aminophylline and salbutamol on tetanic force generated by the diaphragm during compensated metabolic acidosis in dogs. Anesthetized, mechanically ventilated animals were prepared with an open thorax. A cast was placed around the abdomen to maintain length and geometry of the diaphragm during contractions. A thin-walled latex balloon was positioned beneath the diaphragm to measure transdiaphragmatic pressure (Pdi). Pdi served as the index of diaphragmatic force of contraction. We measured Pdi during supramaximal phrenic stimulation at low and high frequencies and also during spontaneous inspiratory efforts for a constant diaphragmatic EMG activity. Compensated metabolic acidosis significantly reduced Pdi at all stimulation frequencies (p less than 0.05). The mean percent decrease at low frequencies was greater than at high (p less than 0.05). Pdi was decreased during spontaneous contractions as well (p less than 0.05). Administration of aminophylline significantly improved Pdi at all frequencies of phrenic stimulation (p less than 0.05) and during spontaneous inspiratory efforts (p less than 0.05). Infusion of salbutamol did not have a significant effect on Pdi at any frequency of stimulation but did produce a small potentiating effect during spontaneous contractions (p less than 0.05). We also recorded and analyzed the Pdi response to a single supramaximal impulse to the phrenic nerve, referred to as a twitch, to gain insight into possible cellular mechanisms underlying alterations in tetanic force of contraction. Compensated metabolic acidosis led to a significant reduction in peak twitch tension (PTT) (p less than 0.05) and half relaxation time (1/2RT) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Neuroblastoma screening in infants postponed after the sixth month of age: a trial to reduce "overdiagnosis" and to detect cases with "unfavorable" biologic features.
Encouraged by Japanese reports of the benefits of screening 6 month-old infants for neuroblastoma, a neuroblastoma screening program was introduced in Austria in 1991. However, because of concerns related to "overdiagnosis" by screening at this age, the screening test was performed at a later age. From March 1991 to February 1995 neuroblastoma screening was performed on filter paper urine specimens in 100,043 Austrian infants (median age 8.5 months). Primary analysis of urine catecholamines (vanillylmandelic acid and homovanillic acid was performed by use of an E1A method. Questionable or positive results were confirmed by high performance liquid chromatography (HPLC). A double retest was requested following a positive HPLC result. Twenty-one infants were admitted to a hospital following repeatedly elevated values of vanillymandelic acid (VMA) and/or homovanillic acid (HVA). Eleven infants were found to have neuroblastoma (three stage 1, four stage 2B, four stage 3). Treatment consisted of surgery alone with total or subtotal resection in eight cases, surgery and chemotherapy in two cases, and chemotherapy alone in one case. Biologic features were assessed in all tumors excluding ploidy in one case. The majority of the tumors analyzed were near-triploid (9/10), however, two tumors revealed N-myc amplification. Our results demonstrate that stage distribution and biologic features of neuroblastomas diagnosed by screening at 8.5 months are different from the results of screening at 6 months. Furthermore, the detection of one neuroblastoma among 9,100 screened infants is significantly lower than the incidence of the Japanese screening program. Our results suggest that screening at an age of 7 to 10 months reduces overdiagnosis and may be of more benefit than earlier screening.


Metalens-array-based high-dimensional and multiphoton quantum source.
The development of two-dimensional metasurfaces has shown great potential in quantum-optical technologies because of the excellent flexibility in light-field manipulation. By integrating a metalens array with a nonlinear crystal, we demonstrate a 100-path spontaneous parametric down-conversion photon-pair source in a 10 × 10 array, which shows promise for high-dimensional entanglement and multiphoton-state generation. We demonstrate two-, three- and four-dimensional two-photon path entanglement with different phases encoded by metalenses with fidelities of 98.4, 96.6, and 95.0%, respectively. Furthermore, four-photon and six-photon generation is observed with high indistinguishability of photons generated from different metalenses. Our metalens-array-based quantum photon source is compact, stable, and controllable, indicating a new platform for integrated quantum devices.


Attitudes of anesthesiology residents and faculty members towards pain management.
There is a large armamentarium of pain-reducing interventions and analgesic choices available to anesthesiologists, but oligoanalgesia continues to be a large problem. We studied the attitudes of residents and faculty members of anesthesiology towards different domains of pain medicine. anonymous questionnaires were mailed to 68 professionals containing demographic and personal data plus 40 items in 10 domains: control, emotion, disability, solicitude, cure, opioids, harm, practice settings, training, and barriers. Internal consistency was 0.70 and the test-retest reliability was 0.80. With 81% response rate, we observed desirable beliefs towards all domains except moderately undesirable beliefs towards the domain solicitude. Scores of residents and faculties were not significantly different. Continuing education programs on both the international guidelines, routine professional education, are needed to improve attitudes towards pain control.


Glycopeptidolipid glycosylation controls surface properties and pathogenicity in Mycobacterium abscessus.
Mycobacterium abscessus is an emerging and difficult-to-manage mycobacterial species that exhibits smooth (S) or rough (R) morphotypes. Disruption of glycopeptidolipid (GPL) production results in transition from S to R and severe lung disease. A structure-activity relationship study was undertaken to decipher the role of GPL glycosylation in morphotype transition and pathogenesis. Deletion of gtf3 uncovered the prominent role of the extra rhamnose in enhancing mannose receptor-mediated internalization of M. abscessus by macrophages. In contrast, the absence of the 6-deoxy-talose and the first rhamnose in mutants lacking gtf1 and gtf2, respectively, affected M abscessus phagocytosis but also resulted in the S-to-R transition. Strikingly, gtf1 and gtf2 mutants displayed a strong propensity to form cords and abscesses in zebrafish, leading to robust and lethal infection. Together, these results underscore the importance and differential contribution of GPL monosaccharides in promoting virulence and infection outcomes.


[A case presenting with Raeder's syndrome-like symptoms due to vertebral artery aneurysm].
A 50-year-old man complained of headache around his left orbit, left frontal pain and paresthesia associated with left incomplete Horner syndrome. MRI demonstrated a mass at the level of medulla oblongata. Left vertebral angiogram revealed an aneurysm of left vertebral artery. Following the removal of the aneurysm, these Raeder's syndrome-like symptoms improved. Therefore, they were probably caused by a compression of the spinal tract of the trigeminal nerve and the central sympathetic tract by the aneurysm. This is the first report of Reader's syndrome-like symptoms caused by vertebral artery aneurysm, thus indicating that MRI and cerebral angiogram are necessary for differential diagnosis of this syndrome.


Key elements in the quality assessment of a type 3 medication review.
Background: Medication reviews are a structured evaluation of a patient's pharmacotherapy with the aim of optimizing medicines use and improving health outcomes. This entails detecting drug related problems and recommending interventions. A high level of quality is essential for the successful implementation of this service in community pharmacies but currently there is no instrument or tool to assess that overall quality. Aim: This study investigated the development of quality criteria of type 3 medication reviews (MR3s). Methods: After surveying the literature, an electronic questionnaire was developed to gather information about quality criteria for MR3. This survey, in Dutch, was distributed electronically. Four groups were queried: 1) pharmacists, mainly working in the Netherlands, involved in practice research and contacted through the PRISMA (Practice Research In Collaboration With Pharmacists) foundation, 2) Belgian pharmacy academics and pharmacists active in professional associations (APA), 3) Belgian pharmacists trained in medication review (MR) by the Royal Pharmacists Association of Antwerp (KAVA) and 4) Belgian pharmacy students. The survey included 57 criteria, divided into eight domains, which were ranked according to their importance by the participants. The results were analyzed statistically using the nonparametric Kruskal-Wallis test. Results: The survey was completed by 95 participants, including 42 PRISMA pharmacists, 19 APA pharmacists, 18 KAVA pharmacists and 16 pharmacy students. Opinions from participants from the different groups overlapped significantly. The use of simple and understandable language in the conversation with the patient was considered essential by the majority. Discussing the usefulness and purpose of a MR3 with the patient was also rated highly by all groups. Differences of opinion were present in aspects about laboratory values, the use of specific tools, and reporting to and consultation with the treating physician. The participants themselves formulated a limited number of additional assessment criteria. Conclusion: There was widespread agreement on the hierarchy of the quality assessment criteria for MR3s. Minor differences were related to the experience of the participants. With these results and a small number of suggested extra criteria, a quality assessment instrument for MR3 can be created.


Thoracoscopic Clockwise Lobectomy May Be a Stylized Procedure for Treating Children with Congenital Lung Malformations.
Background: Thoracoscopic lobectomy is a challenging procedure in children with congenital lung malformations (CLMs). This study aims to evaluate the safety and efficacy of thoracoscopic clockwise lobectomy (TCL) in CLMs in children and its potential to be a stylized procedure. Methods: All patients with CLMs who received TCL from 2015 to 2019 in our hospital were retrospectively reviewed. Clinical information was extracted from medical records, including patient demographics, operative details, and outcomes. Results: A total of 184 patients with a median age of 6.8 months (range, 3-156) and a median weight of 9 kg (range, 6-45) received TCL. Lesions were all located in the lower lobe and included congenital pulmonary airway malformation (n = 133), intralobar sequestration (n = 44), bronchiectasis (n = 4), and congenital lobar emphysema (n = 3). The mean (±standard deviation [SD]) operating time was 46 ± 7.5 minutes (range, 35-113). The mean (±SD) blood loss was 3.5 ± 0.8 mL (range, 1-60). Three patients converted to thoracotomy, and 162 patients did not have a chest tube placed. The postoperative course was uneventful in all patients except 2 patients who developed air leaks and 23 patients who developed a mild fever. The median length of postoperative hospital stay was 2 days. A total of 163 patients were followed up for more than 1 year without any complications. Conclusion: TCL is suitable for lower lobectomy and is safe and effective in standard and complicated thoracoscopic lobectomy. It could be recommended as a stylized procedure in treating children with CLMs.


How does dementia affect driving in older patients?
Driving is a complex activity that always becomes impaired at some point in older adults with degenerative dementia. Over time, disruption of the visual processing circuits of the brain that link the occipital and prefrontal regions, particularly in the right hemisphere, leads to increasing degrees of driving impairment that ultimately preclude safe driving. Neuropsychological tests of visuospatial ability, executive function and attention that tap into the integrity of these brain regions provide the clinician with important information regarding the need for a formal determination of driving competence. Enhancement of cognitive function in these domains through anti-dementia therapy and exercise may partially mitigate risk; however, all drivers with dementia must ultimately retire from driving when dementia becomes moderately severe, and often in earlier stages of the illness. Future efforts to improve screening tests for hazardous driving and to develop interventions to help prolong the time that drivers with mild dementia can continue to drive safely are needed for our increasingly aged and mobile population.


A large uterine leiomyoma leading to non-puerperal uterine inversion: A case report.
Although leiomyomas are the most common gynecologic disorders, non-puerperal uterine inversion due to leiomyoma is considered as a rare clinical problem. This condition can occur as a complication of a large sub-mucous leiomyoma that leads to dilate cervix and protrude into vagina. The patient may have several symptoms such as heavy vaginal bleeding, pelvic pain and intermittent acute urinary retention. We presented a 32-year-old nulliparous woman with 17 years of unexplained infertility and diagnosis of a large vaginal prolapsed non-pedunculated leiomyoma. Haultain's procedure was used to reposition uterine inversion and remove leiomyoma through a posterior incision, using laparotomy.


Rubinstein-Taybi syndrome: clinical and molecular cytogenetic studies.
The Rubinstein-Taybi syndrome (RTS) is a rare but well-defined condition characterized by growth and mental retardation, broad thumb-hallux, and distinctive facial features. Ten unrelated Taiwanese children (6 boys and 4 girls) with clinical features suggestive of RTS were evaluated. The associated anomalies included cryptochidism (6/6 males), microcephaly (9/10), congenital heart diseases (8/10), pectus excavatum (5/10), low IGF-I level (4/10), strabismus/nystagmus (4/10), epilepsy (3/10), glaucoma (2/10), cleft palate (2/10), web neck (2/10), limb hypoplasia (2/10), sleep apnea (1/10), and vesico-ureteral reflux (1/10). All of them had normal thyroid function. High-resolution chromosome studies by both G- and R-banding were applied to detect any microscopic chromosomal deletion, particularly over the 16p13 region (responsible for RTS locus). A panel of five cosmids spanning the human cyclic AMP-responsive element binding (CREB) binding protein (CREBBP or CBP) gene in terms of RT100, RT102, RT191, RT203 and RT166 (Leiden, the Netherlands) were used for fluorescence in situ hybridization on the metaphases of those patients. Three cases showed whole or partial deletion of one copy of the CBP gene. Thus, the rate for detecting interstitial submicroscopic deletion of this region by FISH was about 30% in these RTS patients. The disease severity seemed to be correlated with size of the deletion.


Ab initio exploration of rearrangement reactions: intramolecular hydrogen scrambling processes in acetone.
The recently developed metadynamics method is applied to the intramolecular hydrogen migration reactions of acetone in the gas phase. Comparison of different sets of collective coordinates allows efficient description of the underlying free energy surface. The simulations yielded numerous reactions: the enol-oxo tautomerism, the decomposition of acetone to various products, and rearrangement reactions. On the basis of the calculated activation barriers it is concluded that the enol-oxo tautomerism is the most frequent intramolecular proton-exchange process the acetone undergoes in the gas phase.


Identification of genes from Aspergillus oryzae that are preferentially expressed in membrane-surface liquid culture.
We identified 22 genes from Aspergillus oryzae that are preferentially expressed in membrane-surface liquid culture (MSLC), among which Ser/Thr protein kinase (aopk1) and phosphatase (aoppt) genes were cloned. We also revealed that aopk1 encodes a protein with an N-terminal sequence 150 amino acid residues longer than that predicted from the registered sequence in GenBank.


Radiation databases and archives - examples and comparisons.
Studies of ionizing radiation effects through the archiving of data began with standardizing medical treatments in the early 1900s shortly after the discovery of X-rays. Once the breadth of the delayed effects of ionizing radiation was recognized, the need for long-term follow up became apparent. There are now many human archives of data from nuclear disasters and accidents, occupational exposures, and medical procedures. Planned animal irradiation experiments began around the time of the Cold War and included a variety of doses, fractions, dose rates, and types of ionizing radiation. The goal of most of these studies was to supplement information coming from human data through carefully planned experimental conditions and immediate and uninterrupted data collection. This review aims to highlight major archives and databases that have shaped the field of radiation biology and provide a broad range of the types of datasets currently available. By preserving all of these data and tissue sets, radiation biologists can combine databases and conduct large-scale analyses of detailed existing data and perform new assays with cutting edge scientific approaches.


Computer--based drug design, synthesis and biological evaluation of new pyrimidinone derivatives linked to arylpiperazine and 2'-carbethoxy-biphenylylmethyl moeities as alpha1-adrenoceptor antagonists and angiotensin II AT1 receptor antagonists.
Two new series of pyrimidinone derivatives linked to arylpiperazine moieties and 2'-carbethoxy-biphenylmethyl moieties were designed, synthesized and biologically evaluated for their in vivo hypotensive activities. The design of arylpiperazine analogues (IIa-f, IIIa-c, VIIa.b, IX) was based upon structural modification of the newly discovered selective alpha1-AR antagonist drug; Urapidil. Compare/fit studies of these molecules with the previously generated and validated alpha1-AR antagonist hypothesis showed that these molecules have comparable affinities for the alpha1-AR antagonist hypothesis while compound IIIc had the highest fitting value. The in vivo biological evaluation of these compounds for their effects on blood pressure of normotensive cats in comparison to the lead compound prazosin, was consistent with the results of molecular modeling fit values. As expected, compound IIIc exhibited the highest hypotensive activity among the test set compounds. Meanwhile, the design of 2'-carbethoxy-biphenylylmethyl analogues (XIa,b) was based upon the molecular modeling simulation fitting of their carboxylic acid bioprecursors with the previously generated and validated Ang II receptor antagonist hypothesis. Such compare/fit studies predicted that the designed compounds (XIa,b) showed comparable fitting affinities between their de-esterified analogues and the Ang II antagonist pharmacophore. In vivo biological evaluation of these compounds for their effects on blood pressure of normotensive cats showed that compound Xla exhibited hypotensive activity more or less similar to losartan.


Development of a subcritical water extraction approach for trace analysis of chloramphenicol, thiamphenicol, florfenicol, and florfenicol amine in poultry tissues.
Subcritical water extraction was investigated as a novel and alternative technology for the separation of trace amounts of chloramphenicol, thiamphenicol, florfenicol and its major metabolite florfenicol amine from poultry tissues and its results were compared with those of conventional shaking extraction, ultrasonic extraction, and pressurized liquid extraction. Decreasing the polarity of water by successively increasing the extraction temperature from 50°C to 200°C at the moderate pressure enabled selective, highly effective extractions to be performed. Rapid quantification of the target compounds was carried out by ultra-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS). The critical parameters of subcritical water extraction such as solvent modifier, temperature, pressure, extraction time, and static cycles were varied with control. The optimized extraction procedures using subcritical water as extraction solvent, were carried out on a pressurized liquid extractor operated at 150°C and 100bar, applying two static cycles for 3min. Average recoveries of the four analytes from fortified samples ranged between 86.8% and 101.5%, with relative standard deviations (RSDs) lower than 7.7%. The limits of detection (LODs) and quantification (LOQs) for the target compounds were in the ranges of 0.03-0.5μgkg(-1) and 0.1-2.0μgkg(-1), respectively. The proposed method is fast, sensitive, water-based thus more environmental acceptable, making it a suitable replacement for conventional organic solvent extraction in veterinary drug residue analysis.


Chemopreventive potential of 3-[2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino]-2-thioxoimidazolidin-4-one on 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis.
In the present work, a new bis heterocyclic compound comprising both the piperidone and thiohydantoin nuclei namely 3-[2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino]-2-thioxoimidazolidin-4-one was synthesised and characterised with the help of mp, elemental analysis, FT-IR, MS and one-dimensional NMR ((1)H and (13)C) spectra. The inhibitory effect of 3-[2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino]-2-thioxoimidazolidin-4-one on 7,12-dimethylbenz[a]anthracene (DMBA) induced buccal pouch carcinogenesis was investigated in Syrian male hamsters. All the hamsters that were painted with DMBA on their buccal pouches for 14 weeks developed squamous cell carcinoma. Administration of 3-[2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino]-2-thioxoimidazolidin-4-one effectively suppressed the oral carcinogenesis initiated with the DMBA as revealed by a reduced incidence of neoplasms. Lipid peroxidation, glutathione (GSH) content and the activities of glutathione peroxidase (GPx), glutathione S-transferase (GST) were used to biomonitor the chemopreventive potential of 3-[2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino]-2-thioxoimidazolidin-4-one. Lipid peroxidation was found to be significantly decreased, whereas GSH, GPx, GST and GGT were elevated in the oral mucosa of tumour bearing animals. Our data suggest that 3-[2,6-bis(4-fluorophenyl)-3-methylpiperidin-4-ylideneamino]-2-thioxoimidazolidin-4-one may exert its chemopreventive effects in the oral mucosa by modulation of lipid peroxidation, antioxidants and detoxification systems.


Relationship of sulfamethazine disposition kinetics to acetylator phenotype in man. A preliminary study.
The relationship between sulfamethazine disposition kinetics and acetylation phenotype was studied in man. Sulfamethazine pharmacokinetic parameters were determined after the administration of the drug as an oral suspension. When the half-life, acetylation rate constant, or per cent available dose excreted in the urine as acetylsulfamethazine of each subject was plotted on frequency distribution histograms, bimodal distribution patterns were observed. However, when acetylation clearance values were plotted in the same manner, an apparent trimodal pattern was seen. The failure to identify the presumed homozygous rapid acetylator using the commonly employed indices of drug metabolism, i.e., half-life, metabolic rate constant, or per cent of the dose metabolized, was attributed to a significant increase in the apparent volume of distribution of this genotype, as well as the low renal clearance of sulfamethazine found in all genotypes. This preliminary study points out the value of using metabolic clearance as an index of drug metabolizing capacity and suggests its application to further pharmacogenetic studies.


Medical research ethics in Thailand: what should be the most appropriate approach? An analysis based on Western ethical principles.
An approach to the ethical consideration of medical research in Thailand is presented in terms of Western principles. It is argued that at the present time the principle of therapeutic beneficence is to be considered a priority over respect for autonomy, expressed as informed consent. This approach is especially recommended for therapeutic research in an inpatient hospital setting in Thailand. Only when valid and effective informed consent processes have been developed should respect for autonomy be given more weight in research ethics considerations. The discussion is presented within the context of recent developments in the field of bioethics and in light of some recent findings in informed consent research both in and outside of Thailand.


A beta-coupled gauche kink description of the lipid bilayer phase transition.
A statistical-mechanical model for a lipid bilayer was built around the assumption that beta-coupled gauche kinks are the only nonstraight hydrocarbon chain configurations allowed. Packing of these chains was considered and expressions for the energy and entropy are developed based on those considerations. A solution was obtained which was not exact but was still accurate enough to be useful. In addition, an intermolecular potential was formulated which includes the attractive and repulsive forces between the hydrocarbon chains, the polar group repulsions, and hydrophobic forces. Combining the solution to the kinking model and the intermolecular potential, we obtain the total free energy of the lipid bilayer, which exhibits a first-order phase transition at a characteristic temperature. The theoretical heat of transition indicates that kinks alone can provide enough disorder for the transition to occur. Other physical quantities can be calculated, including order parameters. The order parameters calculated here give a picture of chains which are rigid near the polar group and more fluid near the methyl group.


Cationic cryptand complexes of tin(II).
A series of cationic cryptand complexes of tin(II), [Cryptand[2.2.2]SnX][SnX(3)] (10, X = Cl; 11, X = Br; 12, X = I) and [Cryptand[2.2.2]Sn][OTf](2) (13), were synthesized by the addition of cryptand[2.2.2] to a solution of either tin(II) chloride, iodide, or trifluoromethanesulfonate. The complexes could also be synthesized by the addition of the appropriate trimethylsilyl halide (or pseudohalide) reagent to a solution of tin(II) chloride and cryptand[2.2.2]. The complexes were characterized using a variety of techniques including NMR, Raman, and temperature-dependent Mössbauer spectroscopy, mass spectrometry, and X-ray diffraction.


The oxidase activity of vascular adhesion protein-1 (VAP-1) is essential for function.
Vascular adhesion protein-1 (VAP-1) has been implicated in the pathogenesis of inflammatory diseases and is suggested to play a role in immune cell trafficking. It is not clear whether this effect is mediated by the oxidase activity or by other features of the protein such as direct adhesion. In order to study the role of VAP-1 oxidase activity in vivo, we have generated mice carrying an oxidase activity-null VAP-1 protein. We demonstrate that the VAP-1 oxidase null mutant mice have a phenotype similar to the VAP-1 null mice in animal models of sterile peritonitis and antibody induced arthritis suggesting that the oxidase activity is responsible for the inflammatory function of VAP-1.


Age and hearing loss and the use of acoustic cues in fricative categorization.
This study examined the use of fricative noise information and coarticulatory cues for categorization of word-final fricatives [s] and [f] by younger and older Dutch listeners alike. Particularly, the effect of information loss in the higher frequencies on the use of these two cues for fricative categorization was investigated. If information in the higher frequencies is less strongly available, fricative identification may be impaired or listeners may learn to focus more on coarticulatory information. The present study investigates this second possibility. Phonetic categorization results showed that both younger and older Dutch listeners use the primary cue fricative noise and the secondary cue coarticulatory information to distinguish word-final [f] from [s]. Individual hearing sensitivity in the older listeners modified the use of fricative noise information, but did not modify the use of coarticulatory information. When high-frequency information was filtered out from the speech signal, fricative noise could no longer be used by the younger and older adults. Crucially, they also did not learn to rely more on coarticulatory information as a compensatory cue for fricative categorization. This suggests that listeners do not readily show compensatory use of this secondary cue to fricative identity when fricative categorization becomes difficult.


Ability of pediatric emergency medicine physicians to identify anatomic landmarks with the assistance of ultrasound prior to lumbar puncture in a simulated obese model.
Lumbar punctures (LPs) are typically performed using anatomical surface landmarks. However, as body mass index increases, identifying surface landmarks becomes more difficult. Ultrasound has been proposed as a tool for identifying these landmarks prior to LP. This study evaluates the effectiveness of a brief training program in ultrasound identification of anatomical landmarks in a simulated obese model prior to completing an LP. Pediatric emergency medicine physicians completed a pretest questionnaire on ultrasound familiarity prior to an educational session. Participants utilized ultrasonography without the assistance of palpation on a simulation LP model saving images for review. Participants attempted LP on phantom models with simulated body mass indices of 35 and 40 kg/m. Time to image acquisition and successful aspiration of cerebrospinal fluid from the model were recorded. Two expert sonologists independently reviewed all images for correct landmark identification. Seven of the 19 participants had previous familiarity with ultrasound. The mean time to lumbar image acquisition significantly improved for all individuals from 176 seconds to 100 seconds (P = 0.003). Comfort level with ultrasound improved (P < 0.001) as well as comfort level in performing a lumbar ultrasound (P < 0.001). Adequate images were obtained in 96% of the attempts (55/57). The success rate at performing LP was 95% (54/57). After a brief education intervention, pediatric emergency medicine physicians with little to no previous training in ultrasound can obtain adequate lumbar anatomic images and successfully perform LP in a simulated obese model. Comfort level with ultrasound significantly improves with a short course in ultrasound fundamentals.


Radiomics and Qualitative Features From Multiparametric MRI Predict Molecular Subtypes in Patients With Lower-Grade Glioma.
Isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion status have been identified as significant markers for therapy and prognosis in lower-grade glioma (LGG). The current study aimed to construct a combined machine learning-based model for predicting the molecular subtypes of LGG, including (1) IDH wild-type astrocytoma (IDHwt), (2) IDH mutant and 1p19q non-codeleted astrocytoma (IDHmut-noncodel), and (3) IDH-mutant and 1p19q codeleted oligodendroglioma (IDHmut-codel), based on multiparametric magnetic resonance imaging (MRI) radiomics, qualitative features, and clinical factors. A total of 335 patients with LGG (WHO grade II/III) were retrospectively enrolled. The sum of 5,929 radiomics features were extracted from multiparametric MRI. Selected robust, non-redundant, and relevant features were used to construct a random forest model based on a training cohort (n = 269) and evaluated on a testing cohort (n = 66). Meanwhile, preoperative MRIs of all patients were scored in accordance with Visually Accessible Rembrandt Images (VASARI) annotations and T2-fluid attenuated inversion recovery (T2-FLAIR) mismatch sign. By combining radiomics features, qualitative features (VASARI annotations and T2-FLAIR mismatch signs), and clinical factors, a combined prediction model for the molecular subtypes of LGG was built. The 17-feature radiomics model achieved area under the curve (AUC) values of 0.6557, 0.6830, and 0.7579 for IDHwt, IDHmut-noncodel, and IDHmut-codel, respectively, in the testing cohort. Incorporating qualitative features and clinical factors into the radiomics model resulted in improved AUCs of 0.8623, 0.8056, and 0.8036 for IDHwt, IDHmut-noncodel, and IDHmut-codel, with balanced accuracies of 0.8924, 0.8066, and 0.8095, respectively. The combined machine learning algorithm can provide a method to non-invasively predict the molecular subtypes of LGG preoperatively with excellent predictive performance.


Failure of polycythemia-induced increase in arterial oxygen content to suppress the anorexic effect of simulated high altitude in the adult rat.
The anorexic effect of exposure to high altitude may be related to the reduction in the arterial oxygen content (Ca(O2)) induced by hypoxemia and possibly the associated decreased convective oxygen transport (COT). This study was then performed to evaluate the effects of either transfusion-induced polycythemia or previous acclimation to hypobaria with endogenously induced polycythemia on the anorexic effect of simulated high altitude (SHA) in adult female rats. Food consumption, expressed in g/d/100 g body weight, was reduced by 40% in rats exposed to 506 mbar for 4 d, as compared to control rats maintained in room air. Transfusion polycythemia, which significantly increased hematocrit, hemoglobin concentration, Ca(O2), and COT, did not change the anorexic response to the exposure to hypobaric air. Depression of food intake during exposure to SHA also occurred in rats fasted during 31 h before exposure and allowed to eat ad libitum for 2 h during exposure. Body mass loss was similar in 48-h fasted rats that were either hypoxic or normoxic. Body mass loss was similar in normoxic and hypoxic rats, the former eating the amount of food freely eaten by the latter. Hypoxia-acclimated rats with endogenously induced polycythemia taken to SHA again had diminished food intake and lost body mass at rates that were very close to those found in nonacclimated ones. Exposure to SHA also led to a decrease in food consumption, body weight, and plasma leptin in adult female mice. Analysis of data suggest that body mass loss that accompanies SHA-induced hypoxia is due to hypophagia and that experimental manipulation of the blood oxygen transport capacity cannot ameliorate it. Leptin does not appear to be an inducer of the anorexic response to hypoxia, at least in mice and rats.


Anchoring device between Sertoli cells and late spermatids in rat seminiferous tubules.
Near the end of spermiogensis, the late spermatids remain attached to the superficial layer of the seminiferous epithelium for an appreciable period of time (i.e., 3 to 4 days). Ths sickle-shaped heads of the spermatids are embedded in an apical process of Sertoli cell cytoplasm which is connected to the rest of the cell by a narrow stalk. In the concavity of the head several long (2-3 mum) and very narrow (50 nm) tubular projections of the spermatid's plasma membrane invaginate the Sertoli cell cytoplasm. These tubular processes terminate by a bulbous swelling which may measure up to 1 mum in diameter. Along the process the plasma membrane of the Sertoli cell is closely apposed to the spermatid's membrane, the intracellular space being only 6-8 nm wide. In the Sertoli cytoplasm immediately surrounding the tubular portion of the structure there is an accumulation of filamentous material, while next to the bulbous extremity there are, at a shrot distance, smooth surfaced cisternae of endoplasmic reticulum. The whole structure was referred to as a tubulobulbar complex. These complexes, of which there are up to 24 per spermatid, appear as these cells complete their migration toward the apex of the Sertoli cells. They disappear just before the release of the spermatids in the lumen of the seminiferous tubule as a result of the fragmentation of the spermatid's plasma membrane followed by a resorption of the Sertoli plasma membrane. Morphological evidence suggests that the Tubulobulbar complexes serve as anchoring devices that retain the spermatids at the surface of the seminiferous epithelium while their dissolution contributes in part to the process of spermiation. Similar tubulobulbar complexes were also formed by the plasma membranes of two adjacent Sertoli cells close to the Sertoli-Sertoli tight junctions near the tubular limiting membrane.


Experimental study and artificial neural network modeling of tartrazine removal by photocatalytic process under solar light.
This research focuses on the application of an artificial neural network (ANN) to predict the removal efficiency of tartrazine from simulated wastewater using a photocatalytic process under solar illumination. A program is developed in Matlab software to optimize the neural network architecture and select the suitable combination of training algorithm, activation function and hidden neurons number. The experimental results of a batch reactor operated under different conditions of pH, TiO2 concentration, initial organic pollutant concentration and solar radiation intensity are used to train, validate and test the networks. While negligible mineralization is demonstrated, the experimental results show that under sunlight irradiation, 85% of tartrazine is removed after 300 min using only 0.3 g/L of TiO2 powder. Therefore, irradiation time is prolonged and almost 66% of total organic carbon is reduced after 15 hours. ANN 5-8-1 with Bayesian regulation back-propagation algorithm and hyperbolic tangent sigmoid transfer function is found to be able to predict the response with high accuracy. In addition, the connection weights approach is used to assess the importance contribution of each input variable on the ANN model response. Among the five experimental parameters, the irradiation time has the greatest effect on the removal efficiency of tartrazine.


Recurrent abdominal pain and irritable bowel syndrome in children.
Recurrent abdominal pain continues to be one of the most ubiquitous conditions faced by the healthcare team, and has a significant emotional and economic impact. We have moved from considering it a psychological condition to recognizing the physiological and environmental contributions, and considering the condition in the framework of a biopsychosocial model where biology, psychology and social environment interact. Here, we review current studies addressing etiologies, diagnostic techniques and treatment options for recurrent abdominal pain in children. Studies continue to highlight the role of visceral hypersensitivity in recurrent abdominal pain. The psychological state of the child and the parent (most often the mother) in terms of their anxiety, somatization and coping skills can, however, modulate the expression of symptoms. Diagnosis still is made by history and physical examination. Newer treatment options include relaxation and distraction therapies as well as medications. The role of probiotics in children remains to be defined. The approach to the child with recurrent abdominal pain must include the recognition of the physiological contributions, and this information must be relayed to the child and parents. Acknowledgement also must be paid to the role of psychological state in the parent as well as in the child in modulating the severity of symptoms.


Hydroxyapatite reduces potential Cadmium risk by amendment of sludge compost to turf-grass grown soil in a consecutive two-year study.
Recycling of sludge compost to soil as conditioner is generally regarded as the best means of disposal. However, concerns regarding heavy metal residues and sludge toxicity have recently received increasing public attention. Cadmium (Cd) is a mobile metal commonly found in sludge; therefore, the risk posed by Cd contaminated sludge should be carefully assessed. In this report, the effects of addition of hydroxyapatite (HAP) with sludge compost amendment on potential Cd risk were investigated. The results of consecutive two years showed that exchangeable Cd content in treatment of sludge compost with 1.5% HAP decreased by 6.0% compared with single sludge compost treatment, and residual Cd increased by 7.6%. Compared with single sludge compost, the incremental rate of exchangeable Cd dropped by 38.3% and the reductive rate of residual Cd increased by 37.7% in response to 1.5% HAP addition, indicating that HAP played a role of decreasing Cd phytoavailability. The HAP reduced the amount of Cd uptaken by turf-grass in both root and leaf. Moreover, HAP remarkably improved the quality of turf grass grown in amended soil, including leaf greenness, green maintainable period and root strength. However, HAP did not attenuate the downward mobility of Cd. Taken these together, these findings indicated that HAP can be used as a potential candidate to control surface Cd risk of sludge compost amended soil rather than that from leachate.


Disclosure in therapy by clients with eating difficulties: a Q-Methodology study.
Disclosure by those with eating difficulties is of considerable importance to clinicians and researchers. The aim of the present study was to explore variability in factors considered likely to influence the decision to disclose during psychological therapy by people who experience such difficulties. Thirty-seven participants recruited through a UK-based eating disorder charity completed a Q-sort task. This invited them to sort 47 statements onto a grid reflecting what would make them more or less likely to disclose in therapy. The thirty-seven Q-sorts were analysed using PQ method software. This resulted in the extraction of three factors explaining 41 percent of the variance. Participants loading on the first factor considered maintaining an eating disorder identity as most influential whilst participants loading on the second factor considered the therapeutic relationship as most influential. Those loading on the third factor considered personal readiness and feelings of security as most influential. This study suggests that clinicians need to assess influences on the decision to disclose for individual clients and to modify the early stages of intervention accordingly. Future research could assess the utility of using the Q-sort process and materials in this study as a way to elicit influences on disclosure decisions.


Three-dimensional laser scanning as a reliable and reproducible diagnostic tool in breast cancer related lymphedema rehabilitation: a proof-of-principle study.
In this study, we aimed to assess the reproducibility and reliability of a three-dimensional laser scanner (3DLS) in measuring the upper limb volume of BRCL women undergoing a 2-week complete decongestive therapy (CDT). 3DLS and CM were used to measure the upper limb volume in a cohort of BCRL women before (T0) and after (T1) a 2-week CDT. We evaluated: a) correlation between 3DLS and CM at both time points; b) level of agreement and the consistency of the different measurements at both time points; c) correlation between the inter-rater operator analysis in terms of total limb volume differences before and after rehabilitative treatment of both circumferential method and laser scanning 3D in breast cancer related lymphedema patients. Taken together, 43 BCRL women (age 51.1 ± 5.4 years) were included. Both 3DLS and CM showed a significant inter and intra-operator correlation in the arm volume measurement at both time-points (T0: r2=0.99, p<0.0001; T1: r2=0.99, p<0.0001). 3DLS showed a strong correlation with CM (r2=0.99, p<0.0001) in terms of volume measurement and provided greater intra-operator correlation (r2=0.92 vs. 0.62) in detecting volume variations after the treatment (T1-T0). 3DLS confirmed to be highly sensitive, cheap and easy-to-use in the evaluation of the upper limb volume in BCRL women before and after a rehabilitative treatment. These findings suggest that augmented reality technologies might be very useful in oncological rehabilitation.


Analysis of polymorphism of 18S rRNA gene in Wuchereria bancrofti microfilariae.
The polymorphism of the 18S rRNA gene in Wuchereria bancrofti microfilariae (mf) collected from three different zones in India was analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The RFLPs of the amplified products obtained after digestion with restriction enzymes Ssp I, Msp I and Hha I showed no difference in the banding patterns among the mf isolates from different endemic zones. Further the sequencing of PCR products did not show any difference in the nucleotide sequence either. The phylogenetic analysis of the sequences of W. bancrofti mf isolates from different endemic zones has shown branching with the earlier reported sequences of W. bancrofti and its close relative Brugia malayi.


Global approaches for telling time: omics and the Arabidopsis circadian clock.
The circadian clock is an endogenous timer that anticipates and synchronizes biological processes to the environment. Traditional genetic approaches identified the underlying principles and genetic components, but new discoveries have been greatly impeded by the embedded redundancies that confer necessary robustness to the clock architecture. To overcome this, global (omic) techniques have provided a new depth of information about the Arabidopsis clock. Our understanding of the factors, regulation, and mechanistic connectivity between clock genes and with output processes has substantially broadened through genomic (cDNA libraries, yeast one-hybrid, protein binding microarrays, and ChIP-seq), transcriptomic (microarrays, RNA-seq), proteomic (mass spectrometry and chemical libraries), and metabolomic (mass spectrometry) approaches. This evolution in research will undoubtedly enhance our understanding of how the circadian clock optimizes growth and fitness.


Autoimmune and immunogenetic profile of patients with optic neuritis in a population-based cohort.
Optic neuritis (ON) is an inflammatory optic neuropathy, where the genetic and autoimmune dependency remains poorly characterized. To investigate autoimmune and immunogenetic aspects of ON. In a prospective population-based cohort 51 patients with ON were included. At follow up 20 patients had progressed to multiple sclerosis (MS-ON). All patients were screened for neuronal and systemic autoantibodies. HLA genotypes and allele and genotype frequencies of the PTPN22 C1858T and the PD-1.3 single-nucleotide polymorphisms (SNPs) were determined and compared to a cohort of Danish blood donors, acting as healthy controls. Median follow-up was 366 days (301-430) for MS-ON patients and 375 (range 50-436) for isolated ON (ION). Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), were positive in two patients, no patients had anti-aquaporin-4 antibodies. Coexisting neural autoantibodies were detected in two patients and in 12 patients other systemic autoantibodies were found. Four (8%) had other autoimmune disorders. A family history of autoimmunity was observed in 12 (24%) and of demyelinating disease in six patients (12%). In MS-ON patients the frequencies of HLA-DQB1*06:02 and HLA-DRB1*15:01 tended to be higher compared to controls (p = 0.08). Stratification of patients with presence of oligoclonal bands (OCB) showed an association to the HLA-DQB1*06:02-HLA-DRB1*15:01 haplotype in ION (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)), and in MS-ON patients (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)). No significant associations to PTPN22 1858C/T or PD-1.3 G/A were found in any group comparison. ON patients had a general susceptibility to autoimmunity and two were MOG-IgG positive. HLA-DQB1*06:02 and HLA-DRB1*15:01 were associated with the presence of OCB in ON patients.


Light emission from dye-doped cholesteric liquid crystals at oblique angles: Simulation and experiment.
Dye-doped cholesteric liquid crystals with a helical pitch of the order of a wavelength have a strong effect on the fluorescence properties of dye molecules. This is a promising system for realizing tunable lasers at low cost. We apply a plane wave model to simulate the spontaneous emission from a layer of cholesteric liquid crystal. We simulate the spectral and angle dependence and the polarization of the emitted light as a function of the order parameter of the dye in the liquid crystal. Measurements of the angle dependent emission spectra and polarization are in good agreement with the simulations.


Data-driven load frequency cooperative control for multi-area power system integrated with VSCs and EV aggregators under cyber-attacks.
This paper proposes a cooperative load frequency control (LFC) strategy based on a multi-agent deep reinforcement learning (MADRL) framework for the multi-area power system in the presence of voltage source converters (VSCs) and electric vehicle (EV) aggregators under cyber-attacks. Different from the existing LFC model, a novel transfer function of VSCs is first improved by the space-vector technique and integrated with EV aggregators to develop a multi-area training environment. By installing the agent in different control areas and interacting state transition information between agents and the new environment, the MADRL-based control strategy is achieved for centralized training and decentralized execution. Thus, the proposed MADRL method can coordinate thermal turbines, VSCs, as well as EV aggregators in the different control areas. Furthermore, a suitable cyber-attack model that can circumvent bad data detection (BDD) is reconstructed according to the perspective of adversaries for the LFC system. Then the double critic networks and parameter updating policy are designed to eliminate and mitigate the fluctuations caused by cyber-attacks. The comparative simulation with other control strategies on a three-area test power system demonstrates the superior performance of the proposed MADRL-based approach.


Temperature Dependence of Mechanical, Electrical Properties and Crystal Structure of Polyethylene Blends for Cable Insulation.
There is a long-standing puzzle concerning whether polyethylene blends are a suitable substitution for cable-insulation-used crosslinking polyethylene (XLPE) especially at elevated temperatures. In this paper, we investigate temperature dependence of mechanical, electrical properties of blends with 70 wt % linear low density polyethylene (LLDPE) and 30 wt % high density polyethylene (HDPE) (abbreviated as 70 L-30 H). Our results show that the dielectric loss of 70 L-30 H is about an order of magnitude lower than XLPE, and the AC breakdown strength is 22% higher than XLPE at 90 °C. Moreover, the dynamic mechanical thermal analysis (DMA) measurement and hot set tests suggest that the blends shows optimal mechanical properties especially at high temperature with considerable temperature stability. Further scanning electron microscope (SEM) observation and X-ray diffraction (XRD) analysis uncover the reason for the excellent high temperature performance and temperature stability, which can be ascribed to the uniform fine-spherulite structure in 70 L-30 H blends with high crystallinity sustaining at high temperature. Therefore, our findings may enable the potential application of the blends as cable insulation material with higher thermal-endurance ability.


4a-Hy-droxy-3,3,6,6-tetra-methyl-9-[6-(3,3,6,6-tetra-methyl-1,8-dioxo-2,3,4,5,6,7,8,9-octa-hydro-1H-xanthen-9-yl)pyridin-2-yl]-2,3,4,4a,5,6,7,8,9,9a-deca-hydro-1H-xanthene-1,8-dione ethanol hemisolvate hemihydrate.
The pyridine ring in the title compound, C(39)H(47)NO(7)·0.5C(2)H(5)OH·0.5 H(2)O, is connected to one 3,3,6,6-tetra-methyl-1,8-dioxoxanthenyl and one 4a-hy-droxy-3,3,6,6-tetra-methyl-1,8-dioxodeca-hydroxanthenyl substituent in the 2- and 6-positions of the ring. In the former substituent, the six-membered xanthenyl ring adopts a flattened envelope conformation (with the methine C atom as the flap) while in the latter, the six-membered xanthenyl ring adopts a twisted envelope conformation (with the C atom bearing the hy-droxy group representing the flap). The hy-droxy H atom forms an intra-molecular hydrogen bond to the pyridyl N atom. An ethanol solvent mol-ecule is disordered with respect to a water mol-ecule in a 1:1 ratio. The water mol-ecule itself is disordered over two positions of equal occupancy.


Modelling a Compensation Standard for a Regional Forest Ecosystem: A Case Study in Yanqing District, Beijing, China.
The assessment of forest ecosystem services can quantify the impact of these services on human life and is the main basis for formulating a standard of compensation for these services. Moreover, the calculation of the indirect value of forest ecosystem services should not be ignored, as has been the case in some previous publications. A low compensation standard and the lack of a dynamic coordination mechanism are the main problems existing in compensation implementation. Using comparison and analysis, this paper employed accounting for both the costs and benefits of various alternatives. The analytic hierarchy process (AHP) method and the Pearl growth-curve method were used to adjust the results. This research analyzed the contribution of each service value from the aspects of forest produce services, ecology services, and society services. We also conducted separate accounting for cost and benefit, made a comparison of accounting and evaluation methods, and estimated the implementation period of the compensation standard. The main conclusions of this research include the fact that any compensation standard should be determined from the points of view of both benefit and cost in a region. The results presented here allow the range between the benefit and cost compensation to be laid out more reasonably. The practical implications of this research include the proposal that regional decision-makers should consider a dynamic compensation method to meet with the local economic level by using diversified ways to raise the compensation standard, and that compensation channels should offer a mixed mode involving both the market and government.


Behavior genetics and eating disorders.
Behavior genetics is concerned with the genetic and environmental influences on individual differences in the vulnerability to eating disorders. We should be skeptical about simple genetic explanations for disorders whose development, maintenance, and possible remission involve the interaction of individual behaviors and environmental circumstances. Twin, family, and adoption studies can help to delineate which phenotypes are most heritable, and which are most responsive to family circumstances or individual environments. Subsequent searches for individual genetic and environmental risk factors can be guided by these results. Although there is consistent evidence of genetic factors influencing vulnerability to eating disorders, the details are far from clear, and additional studies will be useful. The further development of dimensional indices of vulnerability will improve population-based and developmental genetic research, as well as facilitating the search for individual genes.


Kinetics and metabolism of theobromine in male rats.
On the basis of general pharmacological information (blood cells/plasma partition, plasma protein binding) and using HPLC as the principal analytical method, we investigated the kinetics and metabolism of theobromine (a caffeine metabolite) in male rats after a single dose and after a 2 week chronic application. Doses in both conditions varied between 1 and 100 mg/kg. In in vitro and in vivo the fraction of theobromine unbound to plasma proteins averaged 0.90 over a wide range of concentrations. No significant difference was found in the pharmacokinetic profile of the drug after acute or chronic treatment at different doses except for a reduction in the absorption rate constant as the dose increased. AUC values increased in proportion to the dose. The 2 treatment schedules were also similar as regards metabolism, at least 50% of the administered dose of theobromine being excreted unchanged, and 25% as 6-amino-5-[N-methyl- formylamino ]1-methyluracil. Only at the highest doses was there a tendency for theobromine to accumulate at the expense of its major metabolite (a uracil compound).


Nanofiber supported thin-film composite membrane for pressure-retarded osmosis.
Sustainable energy can be harnessed from fluids of differing salinity using a process known as pressure-retarded osmosis (PRO). We address one of the critical challenges of advance PRO by introducing a novel electrospun nanofiber-supported thin-film composite PRO membrane platform. The support was tiered with layers of nanofibers of different diameters to better withstand hydraulic pressure. The membranes successfully withstood an applied hydraulic pressure of 11.5 bar and exhibited performance that would produce an equivalent peak power density near 8.0 W/m(2) under real conditions (using 0.5 M NaCl and deionized water as the draw and feed solutions, respectively). This result shows the immense promise of nanofiber supported thin-film composite membranes for use in PRO.


The diverse roles of histone 2B monoubiquitination in the life of plants.
Covalent modification of histones is an important tool for gene transcriptional control in eukaryotes, which coordinates growth, development, and adaptation to environmental changes. In recent years, an important role for monoubiquitination of histone 2B (H2B) has emerged in plants, where it is associated with transcriptional activation. In this review, we discuss the dynamics of the H2B monoubiquitination system in plants and its role in regulating developmental processes including flowering, circadian rhythm, photomorphogenesis, and the response to abiotic and biotic stress including drought, salinity, and fungal, bacterial, and viral pathogens. Furthermore, we highlight the crosstalk between H2B monoubiquitination and other histone modifications which fine-tunes transcription and ensures developmental plasticity. Finally, we put into perspective how this versatile regulatory mechanism can be developed as a useful tool for crop improvement.


Polydopamine Nanosphere with In-Situ Loaded Gentamicin and Its Antimicrobial Activity.
The mussel inspired polydopamine has acquired great relevance in the field of nanomedicines, owing to its incredible physicochemical properties. Polydopamine nanoparticles (PDA NPs) due to their low cytotoxicity, high biocompatibility and ready biodegradation have already been widely investigated in various drug delivery, chemotherapeutic, and diagnostic applications. In addition, owing to its highly reactive nature, it possesses a very high capability for loading drugs and chemotherapeutics. Therefore, the loading efficiency of PDA NPs for an antibiotic i.e., gentamicin (G) has been investigated in this work. For this purpose, an in-situ polymerization method was studied to load the drug into PDA NPs using variable drug: monomer ratios. Scanning electron microscope (SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) confirmed the successful loading of drug within PDA NPs, mainly via hydrogen bonding between the amine groups of gentamicin and the hydroxyl groups of PDA. The loading amount was quantified by liquid chromatography-mass spectrometry (LC-MS) and the highest percentage loading capacity was achieved for G-PDA prepared with drug to monomer ratio of 1:1. Moreover, the gentamicin loaded PDA NPs were tested in a preliminary antibacterial evaluation using the broth microdilution method against both Gram-(+) Staphylococcus aureus and Gram-(-) Pseudomonas aeruginosa microorganisms. The highest loaded G-PDA sample exhibited the lowest minimum inhibitory concentration and minimum bactericidal concentration values. The developed gentamicin loaded PDA is very promising for long term drug release and treating various microbial infections.


Mononuclear Nonheme High-Spin (S=2) versus Intermediate-Spin (S=1) Iron(IV)-Oxo Complexes in Oxidation Reactions.
Mononuclear nonheme high-spin (S=2) iron(IV)-oxo species have been identified as the key intermediates responsible for the C-H bond activation of organic substrates in nonheme iron enzymatic reactions. Herein we report that the C-H bond activation of hydrocarbons by a synthetic mononuclear nonheme high-spin (S=2) iron(IV)-oxo complex occurs through an oxygen non-rebound mechanism, as previously demonstrated in the C-H bond activation by nonheme intermediate (S=1) iron(IV)-oxo complexes. We also report that C-H bond activation is preferred over C=C epoxidation in the oxidation of cyclohexene by the nonheme high-spin (HS) and intermediate-spin (IS) iron(IV)-oxo complexes, whereas the C=C double bond epoxidation becomes a preferred pathway in the oxidation of deuterated cyclohexene by the nonheme HS and IS iron(IV)-oxo complexes. In the epoxidation of styrene derivatives, the HS and IS iron(IV) oxo complexes are found to have similar electrophilic characters.


Perfluoroctylbromide as a blood pool contrast agent for liver, spleen, and vascular imaging in computed tomography.
Perfluoroctylbromide (PFOB) in emulsion form was tested as a blood pool imaging agent for computed tomography (CT) in five animals (three dogs and two pigs). Computed tomography of the kidneys, liver, spleen, and mediastinum was performed in the control state and at various time intervals after the end of PFOB infusion. The attenuation coefficient of the vascular space increased by 117 Hounsfield units (HU) (range 105-128 HU), the liver by 54 HU (range 43-70 HU), and the spleen by 77 HU (range 69-86 HU) 30 to 50 min after the end of PFOB infusion, 5 ml/kg. The vascular space enhanced by 25 HU for every g of PFOB/100 ml of blood and remained at almost a constant level for hours after the end of infusion. In conclusion, PFOB emulsion, in addition to hepatosplenic enhancement, produces prolonged and substantial opacification of the vascular space, allowing CT imaging of the heart and vascular structures minutes to hours after the end of infusion.


Combined chitosan-thyme treatments with modified atmosphere packaging on a ready-to-cook poultry product.
In the present study, natural antimicrobials chitosan and thyme, and their combination, were evaluated for their effect on the shelf life of a ready-to-cook (RTC) chicken-pepper kebab (skewer) stored under modified atmosphere packaging (MAP) conditions at 4 +/- 0.5 degrees C for 14 days. The following treatments were examined: control samples stored under aerobic packaging (A), samples stored under MAP (M), samples treated with 1.5% chitosan (vol/wt) and stored under MAP (M-CH), samples treated with 0.2% thyme essential oil (vol/wt) (M-T), and samples treated with 1.5% chitosan (vol/wt) and 0.2% thyme essential oil (vol/wt) and stored under MAP (M-CH-T). Treatment M-CH-T significantly affected aerobic plate counts and counts of lactic acid bacteria, Pseudomonas spp., Brochothrix thermosphacta, Enterobacteriaceae, and yeasts and molds during the entire storage period. Similarly, lipid oxidation of the RTC product was retarded (M-CH-T treatment) during storage, whereas redness was maintained in M-T, M-CH, and M-CH-T samples. Based primarily on sensory data (taste attribute), M-CH and M-T treatments extended RTC product shelf life by 6 days, whereas M-CH-T treatment resulted in a product with a shelf life of 14 days that maintained acceptable sensory characteristics (shelf life of the control was 6 days).