Polymorphism and double hexamer structure in the archaeal minichromosome maintenance (MCM) helicase from Methanobacterium thermoautotrophicum.
Methanobacterium thermoautotrophicum minichromosome maintenance complex (mtMCM), a cellular replicative helicase, is a useful model for the more complex eukaryotic MCMs. Biochemical and crystallographic evidence indicates that mtMCM assembles as a double hexamer (dHex), but previous electron microscopy studies reported only the presence of single heptamers or single hexamers (Pape, T., Meka, H., Chen, S., Vicentini, G., Van Heel, M., and Onesti, S. (2003) EMBO Rep. 4, 1079-1083; Yu, X., VanLoock, M. S., Poplawski, A., Kelman, Z., Xiang, T., Tye, B. K., and Egelman, E. H. (2002) EMBO Rep. 3, 792-797). Here we present the first three-dimensional electron microscopy reconstruction of the full-length mtMCM dHex in which two hexamers contact each other via the structurally well defined N-terminal domains. The dHex has obvious side openings that resemble the side channels of LTag (large T antigen). 6-fold and 7-fold rings were observed in the same mtMCM preparation, but we determined that assembly as a double ring favors 6-fold structures. Additionally, open rings were also detected, which suggests a direct mtMCM loading mechanism onto DNA.


Chenodeoxycholic Acid Derivative HS-1200 Inhibits Hepatocarcinogenesis and Improves Liver Function in Diethylnitrosamine-Exposed Rats by Downregulating MTH1.
Aim. To investigate the effects of HS-1200 on liver tumorigenesis and liver function in a diethylnitrosamine- (DEN-) induced hepatocellular carcinoma (HCC) rat model. Methods. Rats were randomly assigned into five groups: control, HS-1200, HCC, HCC + low dose HS-1200, and HCC + high dose HS-1200 groups. Rat HCC model was established by intraperitoneal injection of DEN. And rats were given HS-1200 by daily oral gavage. After 20 weeks, we examined animal body weight, liver weight, liver pathological changes, serum levels of AST, ALT, and AFP, and mutT homologue gene 1 (MTH1) in liver tissue. Results. Oral gavage of HS-1200 significantly increased animal body weight and decreased liver weight as well as liver coefficient in HCC rats (P < 0.05 versus HCC group). Moreover, oral administration of HS-1200 suppressed tumorigenesis, attenuated pathological changes in liver tissues, and decreased serum levels of AST, ALT, and AFP in HCC rats (P < 0.05 versus HCC group). In addition, the mRNA level of MTH1 was upregulated in the liver tissues of HCC rats (P < 0.05 versus control group), which was reversed by HS-1200 treatment in a dose-dependent manner (P < 0.05 versus HCC group). Conclusions. HS-1200 inhibits hepatocarcinogenesis and improves liver function maybe by inducing downregulation of MTH1.


Imaging the essential role of spin fluctuations in high-T(c) superconductivity.
We have used scanning tunneling spectroscopy to investigate short-length electronic correlations in three-layer Bi2Sr2Ca2Cu3O(10+delta) (Bi-2223). We show that the superconducting gap and the energy Omega(dip), defined as the difference between the dip minimum and the gap, are both modulated in space following the lattice superstructure and are locally anticorrelated. Based on fits of our data to a microscopic strong-coupling model, we show that Omega(dip) is an accurate measure of the collective-mode energy in Bi-2223. We conclude that the collective mode responsible for the dip is a local excitation with a doping dependent energy and is most likely the (pi, pi) spin resonance.


Partial characterization of a novel gammaherpesvirus isolated from a European badger (Meles meles).
A herpesvirus causing a cytopathic effect was isolated from pulmonary fibroblast cultures established from a European badger (Meles meles). A study was undertaken to classify and to assess some in-vitro growth characteristics of this virus. From a panel of 27 mammalian cell lines, in-vitro replication of the badger herpesvirus (BadHV) was only demonstrated with a mink lung cell line, suggesting a high degree of host specificity. Using PCR with degenerate primers, three independent fragments of the BadHV genome were sequenced. The largest of these fragments comprised a 6.2 kb segment including the DNA polymerase and glycoprotein B genes. Phylogenetic analysis of these sequences demonstrated that the BadHV is novel and clearly grouped with members of the Gammaherpesvirinae. In view of the oncogenic and immunosuppressive potential of many related herpesviruses, it is possible that BadHV can impact on existing acute or chronic disease in badgers.


The Montreal Cognitive Assessment is superior to the Mini-Mental State Examination in detecting patients at higher risk of dementia.
To examine the discriminant validity of the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) in detecting patients with cognitive impairment at higher risk for dementia at a memory clinic setting. Memory clinic patients were administered the MoCA, MMSE, and a comprehensive formal neuropsychological battery. Mild cognitive impairment (MCI) subtypes were dichotomized into two groups: single domain-MCI (sd-MCI) and multiple domain-MCI (md-MCI). Area under the receiver operating characteristic curve (ROC) analysis was used to compare the discriminatory ability of the MoCA and the MMSE. Two hundred thirty patients were recruited, of which 136 (59.1%) were diagnosed with dementia, 61 (26.5%) with MCI, and 33 (14.3%) with no cognitive impairment (NCI). The majority of MCI patients had md-MCI (n = 36, 59%). The MoCA had significantly larger AUCs than the MMSE in discriminating md-MCI from the lower risk group for incident dementia (NCI and sd-MCI) [MoCA 0.92 (95% CI, 0.86-0.98) vs. MMSE 0.84 (95% CI, 0.75-0.92), p = 0.02). At their optimal cut-off points, the MoCA (19/20) remained superior to the MMSE (23/24) in detecting md-MCI [sensitivity: 0.83 vs. 0.72; specificity: 0.86 vs. 0.83; PPV: 0.79 vs. 0.72; NPV: 0.89 vs. 0.83; correctly classified: 85.1% vs. 78.7%]. The MoCA is superior to the MMSE in the detection of patients with cognitive impairment at higher risk for incident dementia at a memory clinic setting.


Mechanism of active repolarization of inhibitory junction potential in murine colon.
Enteric inhibitory responses in gastrointestinal (GI) smooth muscles involve membrane hyperpolarization that transiently reduce the excitability of GI muscles. We examined the possibility that an active repolarization mechanism participates in the restoration of resting membrane potential after fast inhibitory junction potentials (IJPs) in the murine colon. Previously, we showed these cells express a voltage-dependent nonselective cation conductance (NSCC) that might participate in active repolarization of IJPs. Colonic smooth muscle cells were impaled with micro-electrodes and voltage responses to nerve-evoked IJPs, and locally applied ATP were recorded. Ba2+ (500 muM), a blocker of the NSCC, slowed the rate of repolarization of IJPs. We also tested the effects of Ba2+, Ni2+, and mibefradil, all blockers of the NSCC, on responses to locally applied ATP. Spritzes of ATP caused transient hyperpolarization, and the durations of these responses were significantly increased by the blockers of the NSCC. We considered whether NSCC blockers might affect ATP metabolism and found that Ni2+ decreased ATP breakdown in colonic muscles. Mibefradil had no effect on ATP metabolism. Because both Ni2+ and mibefradil had similar effects on prolonging responses to ATP, it appears that restoration of resting membrane potential after ATP spritzes is not primarily due to ATP metabolism. Neurally released enteric inhibitory transmitter and locally applied ATP resulted in transient hyperpolarizations of murine colonic muscles. Recovery of membrane potential after these responses appears to involve an active repolarization mechanism due to activation of the voltage-dependent NSCC expressed by these cells.


Loneliness and health-related variables in early adolescents: an extension.
The purpose of this study was to extend knowledge about loneliness and health-related variables. In classrooms, 135 early adolescents responded to measures of loneliness, symptom patterns, and perceived health status. Statistically significant correlations were found for loneliness scores with ratings for symptom patterns (.44) and with ratings for perceived health status (-.46).


Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats.
Oxycholesterols (OCs) are produced from cholesterol by oxidation of the steroidal backbone and side-chain. OCs are present in blood and evidence suggests their involvement in disease development and progression. However, limited information is available regarding the absorption mechanisms and relative absorption rates of dietary OCs. Although ezetimibe is known to inhibit intestinal cholesterol absorption via Niemann-Pick C1-Like 1 (NPC1L1), whether it also inhibits dietary OC absorption is unclear. We investigated the effects of ezetimibe on OC absorption in rats fed an OC-rich diet containing 10 different OCs. We collected lymphatic fluid using permanent cannulation of the thoracic duct and quantified OC levels. Ezetimibe treatment significantly reduced the apparent absorption of 5β,6β-epoxycholesterol (5,6β-epoxy) and its levels in the proximal intestinal mucosa in OC-fed rats. Using in silico analyses, the binding energy of NPC1L1 N-terminal domain (NPC1L1-NTD) and 5,6β-epoxy was found to be similar to that of NPC1L1-NTD and cholesterol, suggesting that polar uncharged amino acids located in the steroidal part of 5,6β-epoxy were involved. Our results indicate that ezetimibe-mediated inhibition of dietary OC absorption varies depending on the specific OC, and only the absorption of 5,6β-epoxy is significantly reduced.


The multiple functions of HIV-1 Tat: proliferation versus apoptosis.
The HIV-1 transactivating factor Tat plays critical roles in the pathogenesis of AIDS. Originally discovered as a potent activator of viral replication, Tat has now been found to be involved in the regulation of both viral and cellular gene expression. Due to its structure, Tat protein can be secreted by infected cells, and can penetrate neighboring uninfected cells, altering their function in the absence of viral replication. Indeed, increasing number of reports suggest a multifunctional effect of Tat, which depends on cell type and the degree of cellular maturation. Here, we discuss intracellular activities of Tat in HIV-infected cells, as well as in cells exposed to Tat, and focus on two contradictory aspects of Tat-mediated effects: cell proliferation and cell death.


Intraoperative Adjunct Methods for Localization in Primary Hyperparathyroidism.
Primary hyperparathyroidism (pHPT) is a frequently seen endocrine disease, and its main treatment is surgery. In the majority of pHPT, the disease involves only a single gland, and the majority of the pathological glands can be determined by preoperative localization methods.In addition to preoperative localization studies in parathyroidectomy, the use of adjunct methods to improve intraoperative localization in order to increase success of surgery is becoming widespread. These methods include different approaches, mainly intraoperative parathyroid hormone (PTH) measurement, followed by intraoperative gamma probe application, intraoperative ultrasonography, parathyroid imaging with methylene blue, and frozen section examination. Recently, especially promising new imaging methods have been described in the literature with various optical technologies to increase the localization of the parathyroid glands and to evaluate their viability. These methods include parathyroid imaging with autofluorescence, indocyanine green imaging with autofluorescence, autofluorescence imaging with methylene blue, autofluorescence imaging with 5-aminolevulinic acid, optical coherence tomography, laser speckle contrast imaging, dynamic optical contrast imaging, and Raman spectroscopy. Currently, minimally invasive parathyroidectomy has become the standard treatment for selected pHPT patients with the aid of preoperative imaging and intraoperative auxiliary methods . The aim of the present study was to evaluate the routinely used new promising intraoperative adjunct methods in pHPT.


Regulation of vasopressin V1b receptors and stress adaptation.
Vasopressin (VP) regulates pituitary corticotroph function by acting upon plasma membrane G-protein receptors of the V1b subtype (V1bR), coupled to calcium-phospholipid signaling. The number of these receptors in the anterior pituitary varies during stress in direct correlation with corticotroph responsiveness, suggesting that the V1bR plays an important role during adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to stress. The molecular regulation of pituitary V1bR involves transcriptional and translational mechanisms. V1bR gene transcription, which is necessary to maintain V1bR mRNA levels, depends on a number of responsive elements in the promoter region, of which the stretch of GA repeats near the transcription start point (GAGA box) is essential. Although transcriptional activation is necessary to maintain V1bR mRNA levels, the lack of correlation between VP binding and V1bR mRNA suggests that V1bR content is mainly regulated at the translational level. Two potential mechanisms by which the 5' untranslated region (5'UTR) of the V1bR mediates negative and positive regulation of V1bR translation were identified. This includes the repressor effect of small open reading frames (ORF) present upstream of the main V1bR ORF, and an internal ribosome entry site (IRES), which activates V1bR translation. The existence of multiple loci of regulation for the V1bR at transcriptional and translational levels provides a mechanism to facilitate plasticity of regulation of the number of pituitary vasopressin receptors according to physiological demand.


A functional approach to understanding the role of NCKX5 in Xenopus pigmentation.
NCKX5 is an ion exchanger expressed mostly in pigment cells; however, the functional role for this protein in melanogenesis is not clear. A variant allele of SLC24A5, the gene encoding NCKX5, has been shown to correlate with lighter skin pigmentation in humans, indicating a key role for SLC24A5 in determining human skin colour. SLC24A5 expression has been found to be elevated in melanoma. Knockdown analyses have shown SLC24A5 to be important for pigmentation, but to date the function of this ion exchanger in melanogenesis has not been fully established. Our data suggest NCKX5 may have an alternative activity that is key to its role in the regulation of pigmentation. Here Xenopus laevis is employed as an in vivo model system to further investigate the function of NCKX5 in pigmentation. SLC24A5 is expressed in the melanophores as they differentiate from the neural crest and develop in the RPE of the eye. Morpholino knockdown and rescue experiments were designed to elucidate key residues and regions of the NCKX5 protein. Unilateral morpholino injection at the 2 cell stage resulted in a reduction of pigmentation in the eye and epidermis of one lateral side of the tadpole. Xenopus and human SLC24A5 can rescue the morpholino effects. Further rescue experiments including the use of ion exchange inactive SLC24A5 constructs raise the possibility that full ion exchanger function of NCKX5 may not be required for rescue of pigmentation.


Choline and inositol distribution in algae and fungi.
Inositol and choline were present in varying amounts among the species of Rhodophyta, Phaeophyta, Chlorophyta, and Euglenophyta examined. However, in the two members of the order Fucales (division Phaeophyta) examined, no detectable amounts of choline were found. In contrast, the species of Cyanophyta examined contained no detectable amounts of either choline or inositol. All species of the fungal classes Phycomyceteae, Ascomyceteae, and Basidiomyceteae collected contained both inositol and choline in varying amounts. The red, brown, and blue-green algae usually contained much less inositol and choline than do plant and animals sources, but the fungi and the algae Chlorella and Euglena contained amounts comparable to those present in plant sources.


Influences of Sex and Age on the Hematological Profile of the Jundiá (Silver Catfish) Rhamdia quelen.
In this study, sex and age influenced the hematological profiles of Jundiá (Silver Catfish) Rhamdia quelen. Females showed lower levels of hemoglobin, young fish increased lymphocyte counts, and older fish increased hematocrit values. These results indicate that, depending on age and sex, the fish have disparate hematological profiles. For this reason, it is important to consider the sex and age of an R. quelen when examining the impact of environmental and management factors on this species in terms of their hematological profiles. Received May 24, 2015; accepted March 24, 2016.


Alveolar nitric oxide concentration plays an important role in identifying cough variant asthma and assessing asthma control in children.
To study the value of alveolar nitric oxide concentration (CaNO) in the identification and disease control of cough variant asthma. A retrospective study was conducted on cough variant asthma (CVA-Group), nonasthmatic cough (NAC-Group) and healthy control children (C-Group) aged 5-12 years. The exhaled nitric oxide and spirometry test results of the three groups were collected and compared. A total of 410 children were included in this study, including 190 in the CVA-Group, 183 in the NAC-Group, and 37 in the C-Group. The CaNO values of the CVA-Group [11.40 ppb (8.48-14.25)] were significantly higher than those of the NAC-Group and C-Group (all p values <.05). The MMEF %pred values of the CVA-Group [63.65 (56.28-73.58)] were significantly lower than those of the NAC-Group and C-Group (all p values <.05). FeNO50, JawNO and other spirometry indices (FVC %pred, FEV1%pred, FEV1/FVC %pred) showed no significant difference among the three groups. ROC curve analysis showed that the optimal cutoff point value of CaNO was 9.45 ppb, corresponding to 0.816 sensitivity and 0.736 specificity. Spearman correlation analysis showed a significant negative correlation between the CaNO measurement and CVA control score. CaNO can not only help identify CVA early in children aged 5-12 years with chronic cough but is also significantly negatively correlated with the CVA control score.


[The new draft law on care and coercion. Concerning the use and the reduction of antipsychotics without a valid indication in people with intellectual disabilities].
In the Netherlands, many people with an intellectual disability and challenging behavior are still prescribed antipsychotic medication, often for many years and in high doses. According to the new draft law on care and coercion, prescribing antipsychotics, without a valid indication, for people with an intellectual disability, will be regarded as coercion. The effect for clinical practice will be that such antipsychotic medication will have to be re-assessed and, in many cases, reduced and stopped. To comment on the effectiveness, the side effects and futility of prescribing antipsychotics to people with an intellectual disability and challenging behavior in order to arrive at recommendations about the evaluation of antipsychotics and, if possible, about the reduction of antipsychotics for intellectually challenged people who do not really require such medication. Practical recommendations are made based on recent literature and clinical experience. Thorough evaluation and - when possible - the reduction of antipsychotics for people with an intellectual disability requires psychiatrists to invest time and energy in diagnosis and stability of patients, to invest in the patient's environment and to opt for a controlled reduction of antipsychotics. The new draft law on care and coercion highlights the urgent need for guidelines concerning the reduction of antipsychotics for people with an intellectual disability when there is no clear indication that such a step will benefit the patient.


[Distribution and sources of polycyclic aromatic hydrocarbons in sediments from rivers of Pearl River Delta and its nearby South China Sea].
Polycyclic aromatic hydrocarbons (PAHs) are measured in surface sediments from rivers and estuary of Pearl River Delta and its nearby South China Sea. Total PAH concentration varied from 255.9 - 16 670.3 ng/g and a moderate to low level compare to relevant areas worldwide. The order of PAHs concentration in sediments was: rivers of Pearl River Delta > estuary > South China Sea, and the most significant PAH contamination was at Guangzhou channel of Zhujiang river. A decrease trend for PAHs concentration with distance from estuary to open sea can be sees in South China Sea. Coal and biomass combustion is the major source of PAHs in nearshore of South China Sea, and petroleum combustion is the main source of pyrolytic PAHs in rivers and estuary of Pearl River Delta according to PAHs diagnostic ratios. Petroleum PAHs are revealed have a high contribution to PAHs in Xijiang River, estuary and some stations in Zhujiang River. A comparison of data from study in 1997 with data from present study indicates that there is no clear change in the PAH concentration over time but the source of PAHs in Pearl River Delta have been change from a main coal combustion to petroleum combustion and being reflect in the sediments in rivers and estuary of Pearl River Delta where there have high sedimentation rate.


Development and characterization of novel microsatellite markers in Hyptis pectinata (Lamiaceae).
A microsatellite-enriched library was constructed and a set of 19 SSR markers were developed to characterize a germplasm collection of Hyptis pectinata (L.) Poit., maintained at the Universidade Federal de Sergipe (UFS). Fifteen markers of 19 ranged from moderately to highly polymorphic. A total of 113 alleles were identified, with a mean of 7.52 alleles per locus. The mean HO and HE were 0.582 and 0.657, respectively. The primers developed were efficient tools for accessing the genetic diversity of the germplasm collection analyzed and may also be useful for other studies involving this species and other species in the genus Hyptis.


Frequency tunable single photon diode based on giant atom coupling to a waveguide.
The single photon scattering properties in a waveguide coupling to a giant atom with a three-level system are investigated theoretically. One of the transitions of the giant atom couples to the waveguide at two points while the other one is driven by a classical field. Using the analytical expressions of the single photon scattering amplitudes, the conditions for realizing perfect single photon nonreciprocal scattering are discussed in both Markovian regime and non-Markovian regime. In the Markovian regime, the perfect non-reciprocity can be realized by adjusting the external classical field, the energy dissipation of the giant atom, the phase difference between the two coupling strengths and the accumulated phase resulting from the photon propagating between the two coupling points. In the non-Markovian regime, the non-reciprocal scattering phenomenon becomes more abundant due to the time delay. However, the analytical results show that the perfect non-reciprocity can still be achieved. When the incident photon is resonant with the giant atom, the nonreciprocity can be switched by controlling the classical field. For the non-resonant single photon, one can adjust the Rabi frequency of the classical field to obtain the perfect non-reciprocal single photon transmission. Our work provides a manner to realize a frequency tunable single photon diode.


Irreversible enzyme-shuttle immunoassay.
The concept of a competitive enzyme immunoassay that utilizes simultaneously the bound and the free analyte-enzyme conjugate (heterobifunctional conjugate) for signal generation in response to varying analyte concentrations in samples has been investigated. Two antigenic sites of the heterobifunctional conjugate are used in the assay for binding to immunoglobulins: the analyte derivative binds to an immobilized antibody, Ab(1), and the enzyme component binds to a spatially separated immobilized antibody, Ab(2). The analytical system is set up such that in the absence of analyte, the conjugate is predominantly bound in the compartment that contains Ab(1). With increasing concentration of native analyte in samples, an increasing concentration of native analyte in samples, an increasing amount of conjugate migrates to the second compartment that contains Ab(2). The enzyme bound in each compartment is used for signal generation. Mathematical models have been developed to determine the optimal conditions and to predict the performance of such dual-antibody systems. The theoretical predictions are supported by experimental results. The dual-antibody system has been compared with a conventional competitive enzyme immunoassay using the same reagents.


Activation of the pheromone-responsive MAP kinase drives haploid cells to undergo ectopic meiosis with normal telomere clustering and sister chromatid segregation in fission yeast.
Meiosis is a process of importance for sexually reproducing eukaryotic organisms. In the fission yeast Schizosaccharomyces pombe, meiosis normally proceeds in a diploid zygote which is produced by conjugation of haploid cells of opposite mating types. We demonstrate that activation of the pheromone-responsive MAPK, Spk1, by the ectopic expression of a constitutively active form of Byr1 (MAPKK for Spk1) induced the cells to undergo meiosis while in the haploid state. Moreover, the induction of meiosis required Mei2 (a key positive regulator of meiosis), but did not require Mei3; Mei3 is normally required to inactivate the Pat1 kinase (a negative regulator of Mei2) thereby allowing Mei2 to drive meiosis. Therefore, expression of a constitutively active form of Byr1 activates Mei2 without the need of Mei3. In cells induced to undergo meiosis by activating the Spk1 MAPK signaling pathway, telomeres clustered at the spindle pole body (SPB) and centromeres detached normally from the SPB during meiotic prophase, and the cells showed the correct segregation of sister chromatids during meiotic divisions. In contrast, in meiosis induced by inactivation of Pat1, sister chromatids segregate precociously during the first meiotic division. Thus, these results suggest that activation of Spk1 drives meiosis in S. pombe.


Predictive Value of UGT1A1*28 Polymorphism In Irinotecan-based Chemotherapy.
The UGT1A1*28 polymorphism was suggested to be significantly connected with irinotecan-induced toxicity and response to chemotherapy. However, the results of previous studies are controversial. Hence we carried out a meta-analysis to investigate the effect of UGT1A1*28 polymorphism on severe diarrhea, neutropenia, and response of patients who had undergone irinotecan-based chemotherapy. The PubMed, Web of Science, Wanfang, and CNKI databases were searched for clinical trials assessing the association of UGT1A1*28 polymorphism with severe diarrhea, neutropenia, and response to irinotecan-based chemotherapy. The combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the relationship under a fixed- or random-effects model. Fifty-eight studies including 6087 patients with cancer were included. Our results showed that patients carrying the TA6/7 and TA7/7 genotypes had a greater prevalence of diarrhea and neutropenia than those with the TA6/6 genotype (TA6/7+TA7/7 vs. TA6/6: diarrhea, OR = 2.18, 95%CI = 1.68-2.83; neutropenia, OR = 2.15, 95%CI = 1.71-2.70), particularly patients with metastatic colorectal cancer. Stratified analysis showed that Asians with the TA6/7 and TA7/7 genotypes were more likely to have diarrhea and neutropenia, and Caucasians with the TA6/7 and TA7/7 genotypes were more likely to have neutropenia than other groups. However, patients with the TA6/7+TA7/7 genotypes showed a higher response than patients with TA6/6 genotype (OR = 1.20, 95%CI = 1.07-1.34), particularly Caucasians (OR = 1.23, 95%CI = 1.06-1.42) and patients with metastatic colorectal cancer (OR = 1.24, 95%CI = 1.05-1.48). Our data showed that the UGT1A1*28 polymorphism had a significant relationship with toxicity and response to irinotecan-based chemotherapy. This polymorphism may be useful as a monitoring index for cancer patients receiving irinotecan-based chemotherapy.


Determination of steroid hormones, hormone conjugates and macrolide antibiotics in influents and effluents of sewage treatment plants utilising high-performance liquid chromatography/tandem mass spectrometry with electrospray and atmospheric pressure chemical ionisation.
In this study we present a high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) method which has been elaborated to analyse steroid hormones, hormone conjugates, oral contraceptives and macrolide antibiotics unchanged in unfiltered influents and effluents of sewage treatment plants (STPs). HPLC separation of the steroid hormones was achieved in 35 min, as well as those of the antibiotics. The analytes were extracted by solid-phase extraction, followed by clean-up using size exclusion chromatography (SEC). For the final quantification HPLC/MS/MS was used. The two ionisation modes, electrospray ionisation (ESI) and atmospheric pressure chemical ionisation (APCI), in HPLC/MS/MS were compared for the analysis of steroid hormones. For quantitative results drastic matrix effects were observed while using ESI. These effects were less pronounced while using APCI. These pitfalls were additionally reduced by clean-up using SEC as well as isotope dilution. Additionally, two multiple reaction monitoring (MRM) transitions per compound were used to prevent false positive results. Recovery experiments with spiked tap water with concentrations varying from 1 to 1000 ng/L gave constant recovery rates: The recovery rates for the hormones and conjugates ranged from 58 to 107%, those of the contraceptives ranged from 83 to 109%. The relative standard deviation was found to be 7 to 24% and the limits of detection were 0.1 to 4.5 ng/L. The recovery rates of the macrolide antibiotics ranged from 76 to 103%, while the relative standard deviation was found to be 7 to 14% and the limits of detection ranged from 0.6 to 1.8 ng/L. The maximum concentrations found in influents of a STP was 470 ng/L for estriol and 1200 ng/L for erythromycin.


Epidemiologic aspects of poliomyelitis eradication.
Mass immunization with oral poliovirus vaccine was begun in the United States in 1963, and the last outbreak of natural poliomyelitis occurred in 1972. In the subsequent 10 years, there has been only one outbreak, in 1979, due to the introduction of wild polio-virus to an underimmunized Amish population. Paradoxically, eradication occurred even though 5%-10% of the population zero to 14 years of age were unimmunized and susceptible. It is suggested that this eradication was due to two factors. First, the marked seasonality of poliovirus infections, imposed on a reduced number of susceptibles , led to wintertime fade-outs of wild poliovirus over sizable areas. Second, although reintroductions into virus-free areas did occur, they did not equal the frequency of fade-outs. This led, in turn, to an annual stepwise reduction in the number of infected states over a 10-year period, culminating in eradication. Measles makes an instructive comparison because it has more stubbornly resisted eradication. Although regional fade-outs of measles have occurred regularly during the seasonal low, measles is more frequently reintroduced because of its greater transmissibility. It is suggested that this difference in reintroduction was a critical determinant of the difference between the eradicability of measles and poliomyelitis.


The assessment of stability and reliability of a virtual reality-based intravenous injection simulator.
The aim of this study was to validate the feasibility of a virtual reality-based (without haptic feedback) intravenous injection system as an effective tool for computer-assisted instruction and training. The stability and reliability of the system were assessed. A personal computer, a needle/catheter device, and a data acquisition interface are included in this system. Using Virtual Reality Modeling Language, an interactive virtual environment was developed. Ten participants, ranging from 20 to 28 years of age, were recruited for this study. The self-learning and training procedures encompassed an intravenous catheterization process. The experimental results showed that after a few trials, the change in task time was not obvious in each trial, and the error frequency decreased slightly with more trials. High intraclass correlation coefficients also were obtained for task time and error frequency by analyzing the test-retest reliability. These results indicated that the system was stable and that the system reliability was acceptable.


Heparin cofactor II modulates the response to vascular injury.
Heparin cofactor II (HCII) has several biochemical properties that distinguish it from other serpins: (1) it specifically inhibits thrombin; (2) the mechanism of inhibition involves binding of an acidic domain in HCII to thrombin exosite I; and (3) the rate of inhibition increases dramatically in the presence of dermatan sulfate molecules having specific structures. Human studies suggest that high plasma HCII levels are protective against in-stent restenosis and atherosclerosis. Studies with HCII knockout mice directly support the hypothesis that HCII interacts with dermatan sulfate in the arterial wall after endothelial injury and thereby exerts an antithrombotic effect. In addition, HCII deficiency appears to promote neointima formation and atherogenesis in mice. These results suggest that HCII plays a unique and important role in vascular homeostasis.


Laurus nobilis: Composition of Essential Oil and Its Biological Activities.
Laurus nobilis is native to the southern Mediterranean region and cultivated mainly in Europe and the USA as an ornamental and medicinal plant. The chemical composition of the essential oil (EO) from leaves of L. nobilis, collected in Southern Italy, was studied by GC and GC-MS. In all, 55 compounds were identified, accounting for 91.6% of the total oil. 1,8-Cineole (31.9%), sabinene (12.2%), and linalool (10.2%) were the main components. Antimicrobial and antifungal activities of EO and 1,8-cineole were determined in vitro. The cytotoxicity of the EO was evaluated against SH-SY5Y cell line, as well as the influence of the EO on the expression of adenylate cyclase 1 (ADCY1), suggesting possible oil effects on the Central Nervous System.


Modeling Parkinson's Disease: Not Only Rodents?
Parkinson's disease (PD) is a common chronic progressive multifactorial neurodegenerative disease. In most cases, PD develops as a sporadic idiopathic disease. However, in 10%-15% of all patients, Mendelian inheritance of the disease is observed in an autosomal dominant or autosomal recessive manner. To date, mutations in seven genes have been convincingly confirmed as causative in typical familial forms of PD, i.e., SNCA, LRRK2, VPS35, PRKN, PINK1, GBA, and DJ-1. Family and genome-wide association studies have also identified a number of candidate disease genes and a common genetic variability at 90 loci has been linked to risk for PD. The analysis of the biological function of both proven and candidate genes made it possible to conclude that mitochondrial dysfunction, lysosomal dysfunction, impaired exosomal transport, and immunological processes can play important roles in the development of the pathological process of PD. The mechanisms of initiation of the pathological process and its earliest stages remain unclear. The study of the early stages of the disease (before the first motor symptoms appear) is extremely complicated by the long preclinical period. In addition, at present, the possibility of performing complex biochemical and molecular biological studies familial forms of PD is limited. However, in this case, the analysis of the state of the central nervous system can only be assessed by indirect signs, such as the level of metabolites in the cerebrospinal fluid, peripheral blood, and other biological fluids. One of the potential solutions to this problem is the analysis of disease models, in which it is possible to conduct a detailed in-depth study of all aspects of the pathological process, starting from its earliest stages. Many modeling options are available currently. An analysis of studies published in the 2000s suggests that toxic models in rodents are used in the vast majority of cases. However, interesting and important data for understanding the pathogenesis of PD can be obtained from other in vivo models. Within the framework of this review, we will consider various models of PD that were created using various living organisms, from unicellular yeast (Saccharomyces cerevisiae) and invertebrate (Nematode and Drosophila) forms to various mammalian species.


Structured Pyramidal Neural Networks.
The Pyramidal Neural Networks (PNN) are an example of a successful recently proposed model inspired by the human visual system and deep learning theory. PNNs are applied to computer vision and based on the concept of receptive fields. This paper proposes a variation of PNN, named here as Structured Pyramidal Neural Network (SPNN). SPNN has self-adaptive variable receptive fields, while the original PNNs rely on the same size for the fields of all neurons, which limits the model since it is not possible to put more computing resources in a particular region of the image. Another limitation of the original approach is the need to define values for a reasonable number of parameters, which can turn difficult the application of PNNs in contexts in which the user does not have experience. On the other hand, SPNN has a fewer number of parameters. Its structure is determined using a novel method with Delaunay Triangulation and k-means clustering. SPNN achieved better results than PNNs and similar performance when compared to Convolutional Neural Network (CNN) and Support Vector Machine (SVM), but using lower memory capacity and processing time.


In Vitro Evaluation of Apoptotic Induction of Butyric Acid Derivatives in Colorectal Carcinoma Cells.
Butyric acid, a short chain fatty acid, plays an important role in the prevention of colon cancer. The aim of this study was to analyze the growth inhibitory and apoptotic effect of butyric acid derivatives in colorectal cancer cells. Human colorectal carcinoma HCT116 cells, were treated with the IC50 concentration of sodium butyrate, indole-3-butyric acid, tributyrin and 2-amino-n-butyric acid. Comet assay, caspase-3 assay and cell-cycle analysis were used to analyze apoptosis. Tributyrin and indole-3-butyric acid showed the least IC50 values at 24 h incubation. Butyric acid derivatives significantly activated caspase-3 activity compared with the control. Additionally, indole-3-butyric acid and tributyrin caused G0/G1 and G2/M phase arrest. Butyric acid derivatives effectively induced apoptosis in HCT116 cells.


Magnetic properties and molecular structures of binuclear (2-pyrazinecarboxylate)-bridged complexes containing Re(IV) and M(II) (M = Co, Ni).
Three novel Re(iv) compounds, the mononuclear complex Bu(4)N[ReBr(5)(Hpyzc)] (1) and the heterobimetallic complexes [ReBr(5)(mu-pyzc)M(dmphen)(2)].2CH(3)CN [M = Co (2), Ni (3)] (Hpyzc = 2-pyrazinecarboxylic acid, dmphen = 2,9-dimethyl-1,10-phenanthroline), have been synthesized and their crystal structures determined by single-crystal X-ray diffraction. The structure of 1 consists of [ReBr(5)(Hpyzc)](-) complex anions and tetrabutylammonium cations, Bu(4)N(+). The Re(iv) is surrounded by five bromide anions and a N-donor Hpyzc monodentate ligand, in a distorted octahedral environment. The structures of 2 and 3 consist of dinuclear units [ReBr(5)(mu-pyzc)M(dmphen)(2)], with the metal ions linked by a pyzc bridge ligand, being bidentate toward M(II) and monodentate toward Re(IV). The environment of Re(IV) is the same as in 1, whereas M(II) is six-coordinate, being surrounded by four nitrogen atoms of two bidentate dmphen ligands and one oxygen atom and one nitrogen atom of the pyzc anion. The magnetic properties of 1-3 were investigated in the temperature range 2.0-300 K. 1 shows the expected magnetic behavior for a mononuclear Re(IV) complex with a weak intermolecular antiferromagnetic coupling at low temperatures. The bimetallic complexes exhibit an intramolecular ferromagnetic coupling between Re(IV) and the M(II) ion (Co, Ni).


SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging.
Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.


Identification of transforming genes as hst in DNA samples from two human hepatocellular carcinomas.
In a DNA-mediated transfection assay using NIH3T3 cells, the DNAs from two out of twelve human hepatocellular carcinomas gave transformants. The transforming gene was identified as hst, which was originally found in DNAs from stomach cancers and a noncancerous portion of stomach mucosa, the putative product being a growth factor. Transcripts were not detected in the original HCC 1 and HCC2 upon Northern blot analysis. The possible mechanisms involved in the hst gene activation are discussed.


Contemporary surgical management of rectovaginal fistula in Crohn's disease.
Rectovaginal fistula is a disastrous complication of Crohn's disease (CD) that is exceedingly difficult to treat. It is a disabling condition that negatively impacts a women's quality of life. Successful management is possible only after accurate and complete assessment of the entire gastrointestinal tract has been performed. Current treatment algorithms range from observation to medical management to the need for surgical intervention. A wide variety of success rates have been reported for all management options. The choice of surgical repair methods depends on various fistula and patient characteristics. Before treatment is undertaken, establishing reasonable goals and expectations of therapy is essential for both the patient and surgeon. This article aims to highlight the various surgical techniques and their outcomes for repair of CD associated rectovaginal fistula.


The ontogeny of relational memory and pattern separation.
Episodic memory relies on memory for the relations among multiple elements of an event and the ability to discriminate among similar elements of episodes. The latter phenomenon, termed pattern separation, has been studied mainly in young and older adults with relatively little research on children. Building on prior work with young children, we created an engaging computer-administered relational memory task assessing what-where relations. We also modified the Mnemonic Similarity Task used to assess pattern discrimination in young and older adults for use with preschool children. Results showed that 4-year-olds performed significantly worse than 6-year-olds and adults on both tasks, whereas 6-year-olds and adults performed comparably, even though there were no ceiling effects. However, performance on the two tasks did not correlate, suggesting that two distinct mnemonic processes with different developmental trajectories may contribute to age-related changes in episodic memory.


Autologous stem cell therapy for inherited and acquired retinal disease.
The mammalian retina, derived from neural ectoderm, has little regenerative potential. For conditions where irreversible retinal pigment epithelium or photoreceptor cell loss occurs, advanced techniques are required to restore vision. Inherited retinal dystrophies and some acquired conditions, such as age-related macular degeneration, have a similar end result of photoreceptor cell death leading to debilitating vision loss. These diseases stand to benefit from future regenerative medicine as dietary recommendations and current pharmacologic therapy only seek to prevent further disease progression. Cell-based strategies, such as autologously derived induced pluripotent stem cells, have come a long way in overcoming previous technical and ethical concerns. Clinical trials for such techniques are already underway. These trials and the preceding preclinical studies will be discussed in the context of retinal disease.


How do people with gastro-oesophageal reflux disease perceive their disease? Results of a multinational survey.
To determine how patients with gastro-oesophageal reflux disease (GERD) perceive their condition. Subjects with a formal diagnosis of GERD (n = 929) and those who did not have a formal diagnosis but regularly suffered from symptoms suggestive of GERD (heartburn or acid regurgitation, n = 924) were identified as part of a multinational survey. Symptoms had been present for a mean of 11 years in diagnosed individuals and 8 years in undiagnosed individuals. Over-the-counter (OTC) antacids were used by 78% of undiagnosed individuals. Most patients (68% of undiagnosed and 46% of diagnosed subjects) did not consider themselves to have a serious condition, while 70% of undiagnosed and 58% of diagnosed respondents believed that their condition would not have any long-term health consequences. A key perception driving the decision to seek medical care was the belief that a physician, and prescribed medication, could help. Conversely, the perception that OTC medications work effectively was the greatest barrier to visiting a physician. Diagnosed patients, who, on average, waited 2 years before seeking medical advice, indicated that prescription medication reduced the severity and frequency of their symptoms. There is widespread perception that GERD is a non-serious disease without long-term health consequences, and some patients find that OTC medications are a sufficiently effective treatment option. Educational initiatives should perhaps be targeted at those in greatest medical need, overcoming the barriers that dissuade many of these patients from seeking appropriate medical care.


Estimate of the magnitude of risky and protective behaviors associated with road traffic injuries in capitals participating in the Life in Traffic Project of Brazil.
Brazil occupies the fifth position in the ranking of the highest mortality rates due to RTI in the world. With the objective of promoting traffic safety and consequently reducing deaths, Brazil created the Life in Traffic Project (LTP). The main goal of LTP is reducing 50% of RTI deaths, by promoting interventions to tackle risk factors, such as driving under the influence of alcohol and excessive and/or inappropriate speed. Thus, the aim of this study was to estimate the magnitude of risky and protective factors for RTI in capitals participating in the LTP in Brazil. We estimated these factors according to sociodemographic (age group, sex, education, race and, type of road user). A total of 5,922 car drivers and motorcyclists from 14 Brazilian capitals participating in the LTP were interviewed. Data collection was carried out in sobriety checkpoints at night and consisted of the administration of an interview and a breathalyzer test. Risky and protective behaviors associated with RTI were investigated. Covariates of the study were: age, sex, education, race and, type of road user. Poisson multiple regression analysis was used to assess the relationship between variables of interest. The prevalence of individuals with positive blood alcohol concentration (BAC) was 6.3% and who reported driving after drinking alcohol in the last 30 days was 9.1%. The others risky behaviors reported were: driving at excessive speed on roads of 50 km/h, using a cell phone for calls while driving, using a cell phone to send or read calls while driving, running a red light. Use of seatbelts and helmets showed prevalence above 96,0% Use of seatbelts showed prevalence of 98.6% among car drivers, and helmet use was described by 96.6% of motorcycle drivers. Most risky behaviors were more prevalent in younger age groups (except BAC measurement higher in older participants), in males (except for cell phone use), in participants with higher education level and without a driver's license. Excessive speed and driving under the influence of alcohol, defined as priorities within the LTP, need more consistent interventions, as they still have considerable prevalence in the cities investigated. The factors described such as cell phone usage and passing red traffic lights should also need to be prioritized as a focus on promoting traffic safety.


Brain tumor stem cells.
Since the end of the 'no-new-neuron' theory, emerging evidence from multiple studies has supported the existence of stem cells in neurogenic areas of the adult brain. Along with this discovery, neural stem cells became candidate cells being at the origin of brain tumors. In fact, it has been demonstrated that molecular mechanisms controlling self-renewal and differentiation are shared between brain tumor stem cells and neural stem cells and that corruption of genes implicated in these pathways can direct tumor growth. In this regard, future anticancer approaches could be inspired by uncovering such redundancies and setting up treatments leading to exhaustion of the cancer stem cell pool. However, deleterious effects on (normal) neural stem cells should be minimized. Such therapeutic models underline the importance to study the cellular mechanisms implicated in fate decisions of neural stem cells and the oncogenic derivation of adult brain cells. In this review, we discuss the putative origins of brain tumor stem cells and their possible implications on future therapies.


Analysis of impact of nosocomial infections on cost of patient hospitalisation.
The scale of the economic problem of the occurrence of nosocomial infections and the resulting high additional costs of treatment can only be assessed using economic analyses. The aim of the study was to analyse the impact of a nosocomial infection in a patient in the treatment process and the direct costs of patient hospitalisation. The article contributes to a cost analysis, which is a relevant basis for adopting effective solutions and decisions on the introduction of new programmes and measures to reduce nosocomial infections and associated costs. In the first phase of the micro-economic analysis, we analysed the course of hospitalisation of a non-colonised patient treated in an ordinary hospital room. In the second phase, we analysed the process of hospitalisation of a patient who developed a nosocomial infection and was transferred to an isolation room. The difference in cost of both types of treatment allowed us to carry out an economic analysis to estimate the direct costs of nosocomial infection, which are not related to the initial diagnosis of the patient but only to the patient hospitalisation. To calculate the individual types of direct costs of both alternative treatments, we first used the process flow diagram method, which then enabled us to analyse the impact of the occurrence of nosocomial infection on the efficiency and costs of the hospital. The results showed that the total direct cost of hospitalisation of a non-colonised patient was 1,317.58 euro per day, and the direct cost of hospitalisation of a patient with a nosocomial infection was 2,268.14 euro per day of hospitalisation. We found that reducing nosocomial infections would have a significant impact on the savings or reduction in healthcare costs associated with a different work process for patients in isolation. It would save 950.56 euro per patient for each day of hospitalisation for individual treatment of a patient hospitalised in an isolation room as consequence of a nosocomial infection.


With no interaction, knockdown of Apollon and MDR1 reverse the multidrug resistance of human chronic myelogenous leukemia K562/ADM cells.
Chemotherapy is the main treatment method for patients with chronic myeloid leukemia (CML) and has achieved marked results. However, the acquisition of multidrug resistance (MDR) has seriously affected the quality of life and survival rate of patients. The overexpression of the inhibitors of apoptosis proteins (IAPs) and the adenosine triphosphate (ATP)-dependent binding cassette (ABC) transporters are the two main causes of MDR. Apollon and MDR1 are the most important and representative members, respectively, among the IAPs and ABC transporters. In the present study, we investigated the role of Apollon and MDR1 in chemotherapy resistance and their mechanism of interaction. We respectively knocked down the expression of Apollon and MDR1 using short hairpin RNA (shRNA) in adriamycin (ADM) resistant human CML K562 cells and examined the drug sensitivity, the consequences with regard to ADM accumulation and the alterations in the expression of Apollon and MDR1. The expression levels of Apollon and MDR1 mRNA were higher in the K562/ADM cells compared with the parental K562 cells as determined by reverse transcription‑polymerase chain reaction (RT-PCR). The plasmids of Apollon and MDR1 shRNA were respectively stably transfected into K562/ADM cells using Lipofectamine 2000. The transfection efficiency was detected by fluorescence microscopy. Cell Counting Kit-8 (CCK-8) assay revealed that Apollon or MDR1 knockdown significantly increased the chemosensitivity of the K562/ADM cells to ADM. Flow cytometric assay revealed that K562/ADM/shMDR1 cells exhibited a significantly increased intracellular accumulation of ADM, and that changes were not found in the K562/ADM/shApollon cells. Compared with the parental K562/ADM cells, a significantly decreased expression of Apollon mRNA and protein was determined in the K562/ADM/shApollon cells without affecting the expression of MDR1 as determined by RT-PCR and western blotting. Likewise, the expression levels of MDR1 mRNA and protein also markedly downregulated in the K562/ADM/shMDR1 cells had no effect on Apollon expression. Collectively, our findings demonstrated, for the first time, that downregulation of Apollon or MDR1 through stable transfection with the Apollon- or MDR1-targeting shRNA induced MDR reversal through respective inhibition of Apollon or MDR1 expression and function. However, the reversal mechanism of Apollon and MDR1 revealed no direct interaction with each other.


Short-term discontinuation of HAART regimens more common in vulnerable patient populations.
The durability of HAART regimens is often limited by antiretroviral toxicity and nonadherence, which lead to virologic failure. We sought to determine sociodemographic and psychosocial patient factors predictive of short-term discontinuation of HAART regimens overall and stratified by the reason for discontinuation. A retrospective cohort study of the UAB 1917 Clinic Cohort evaluated short-term HAART regimen discontinuation (within 12 months of regimen initiation) between 1/1995 and 8/2004 classified as (1) gastrointestinal (GI) toxicity, (2) non-GI toxicity, (3) virologic failure or nonadherence (VF/NA), (4) loss to follow-up, and (5) other. Multivariable multinomial logistic regression models accounting for dependent observations were fit to assess the relationship between patient factors and type-specific regimen discontinuation. Among the 738 study participants, 1026 of 1852 HAART regimens (55%) were discontinued within 12 months of initiation. In multivariable analysis, discontinuation for GI toxicity was more common in patients lacking private health insurance and those with a history of intravenous (IV) drug use, whereas non-GI toxicity was more common in younger patients and females. African-American patients and those with a history of IV drug use were more likely to stop a regimen due to VF/NA. Loss to follow-up was more common in younger patients, individuals who were uninsured, and those with a history of IV drug use. Short-term discontinuation of HAART regimens is more common in vulnerable populations that bear a disproportionate burden of the U.S. HIV/AIDS epidemic. More vigilant monitoring of patient populations at higher risk of toxicity and virologic failure may allow for improved HAART regimen durability.


Damage to the optic chiasm in myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis mice.
Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG)-experimental autoimmune encephalomyelitis (EAE) mice were characterized using magnetic resonance imaging (MRI) and validated using electron microscopy (EM). MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin-stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T2-weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T2-weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis.


The role of color flow Doppler ultrasound in dialysis access.
Color flow Doppler provides accurate imaging and access flow volume measurement of the hemodialysis vascular access. It can readily identify subsets of patients at high risk for future thrombosis. It is noninvasive, mobile, and allows convenient clinical evaluation at the dialysis facility. In Europe, Doppler ultrasound has become the standard of care for evaluation of arteriovenous (AV) fistula dysfunction and is essential in the preoperative evaluation for access placement. It also can diagnose the arterial inflow disease that has become more prevalent in our aging, diabetic, end-stage renal disease (ESRD) population. Access management programs based on Doppler ultrasound have been highly successful and have produced outcome data as good or better than provided with other techniques. In light of its proven clinical efficacy, reimbursement and regulatory agencies should allow its appropriate inclusion into integrated access management programs. In conclusion, Doppler ultrasound should be included as a part of an integrated vascular access management program. This is supported by clinical outcome data and direct comparisons with other modalities.


Recombinant human erythropoietin-induced erythropoiesis regulates hepcidin expression over iron status in the rat.
The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600IU/kgbody weight/week), 3 times per week, during 3weeks. Hematological and iron data were evaluated. The expression of several genes involved in iron metabolism was analyzed by qPCR. Liver hepcidin protein was evaluated by Western Blot. The rHuEPO treatment induced erythropoiesis and increased transferrin saturation (TSAT) in a dose dependent manner. Tf receptor 2 (TfR2), hemojuvelin (HJV) and bone morphogenetic protein 6 (BMP6) were up-regulated in rHuEPO200 group. Matriptase-2 was down-regulated in rHuEPO200 group, and up-regulated in the other rHuEPO-treated groups. Hepcidin synthesis was increased in rHuEPO200 group, and repressed in the rHuEPO400 and rHuEPO600 groups. Our study showed that when a high erythropoietic stimulus occurs, hepcidin synthesis is mainly regulated by TSAT; however, when the erythropoiesis rate reaches a specific threshold, extramedullary hematopoiesis is triggered, and the control of hepcidin synthesis is switched to matriptase-2, thus inhibiting hepcidin synthesis.


Assessment of prophylactic effect of Senna auriculata (L.) Roxb. leaves on alcohol-induced pancreatitis in rat model.
Aqueous leaf extract of Senna auriculata (L.) Roxb. syn. Cassia auriculata (SLEx) is known to possess potential antidiabetic and antioxidant properties. Based on the known correlation between exocrine pancreatic function and endocrine secretary capacity, here, we studied the prophylactic effect of the SLEx on alcohol induced pancreatitis in rats. To induce chronic pancreatitis, the rats were fed with unsaturated fat i.e. corn oil (2.5 mL/kg) along with high dose of ethanol (10.2 g/kg) for 4 wk, and was increased 0.6 g/kg after every 2 days for 1 wk and then 0.6 g/kg after every 4 days for a period of 4 wk. SLEx was orally administered to rats at dose of 400 mg/kg/day for 4 wk. At the end of 4th wk, pancreatic enzymes i.e., α-amylase, lipase, serum and pancreatic MDA levels were estimated. Pancreatic histopathological studies were also performed. The SLEx significantly reduced the serum levels of α-amylase and lipase along with significant suppression in serum and pancreatic tissue lipid peroxidation. Histomorphological studies did not show any fatty vacoules in acinar cells of SLEx-treated rats. However, vacoulation was seen in acini of pathogenic control rats. With the results, we conclude that Senna auriculata aqueous leaf extract has potential to reduce the ethanol-induced pathogenecity, and it possesses prophylactic effect on alcohol-induced pancreatitis. However, a long term trial is needed to ascertain its therapeutic potential for pancreatitis.


Insight into the Earthquake Risk Information Seeking Behavior of the Victims: Evidence from Songyuan, China.
Efficient risk communication is a vital way to reduce the vulnerability of individuals when facing emergency risks, especially regarding earthquakes. Efficient risk communication aims at improving the supply of risk information and fulfilling the need for risk information by individuals. Therefore, an investigation into individual-level information seeking behavior within earthquake risk contexts is very important for improved earthquake risk communication. However, at present there are very few studies that have explored the behavior of individuals seeking earthquake risk information. Under the guidance of the Risk Information Seeking and Processing model as well as relevant practical findings using the structural equation model, this study attempts to explore the main determinants of an individual's earthquake risk information seeking behavior, and to validate the mediator effect of information need during the seeking process. A questionnaire-based survey of 918 valid respondents in Songyuan, China, who had been hit by a small earthquake swarm, was used to provide practical evidence for this study. Results indicated that information need played a noteworthy role in the earthquake risk information seeking process, and was detected both as an immediate predictor and as a mediator. Informational subjective norms drive the seeking behavior on earthquake risk information through both direct and indirect approaches. Perceived information gathering capacity, negative affective responses and risk perception have an indirect effect on earthquake risk information seeking behavior via information need. The implications for theory and practice regarding risk communication are discussed and concluded.


A Method for Automated Classification of Parkinson's Disease Diagnosis Using an Ensemble Average Propagator Template Brain Map Estimated from Diffusion MRI.
Parkinson's disease (PD) is a common and debilitating neurodegenerative disorder that affects patients in all countries and of all nationalities. Magnetic resonance imaging (MRI) is currently one of the most widely used diagnostic imaging techniques utilized for detection of neurologic diseases. Changes in structural biomarkers will likely play an important future role in assessing progression of many neurological diseases inclusive of PD. In this paper, we derived structural biomarkers from diffusion MRI (dMRI), a structural modality that allows for non-invasive inference of neuronal fiber connectivity patterns. The structural biomarker we use is the ensemble average propagator (EAP), a probability density function fully characterizing the diffusion locally at a voxel level. To assess changes with respect to a normal anatomy, we construct an unbiased template brain map from the EAP fields of a control population. Use of an EAP captures both orientation and shape information of the diffusion process at each voxel in the dMRI data, and this feature can be a powerful representation to achieve enhanced PD brain mapping. This template brain map construction method is applicable to small animal models as well as to human brains. The differences between the control template brain map and novel patient data can then be assessed via a nonrigid warping algorithm that transforms the novel data into correspondence with the template brain map, thereby capturing the amount of elastic deformation needed to achieve this correspondence. We present the use of a manifold-valued feature called the Cauchy deformation tensor (CDT), which facilitates morphometric analysis and automated classification of a PD versus a control population. Finally, we present preliminary results of automated discrimination between a group of 22 controls and 46 PD patients using CDT. This method may be possibly applied to larger population sizes and other parkinsonian syndromes in the near future.


A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.
A systematic review was undertaken and an economic model constructed to evaluate the clinical effectiveness and cost-effectiveness of docetaxel (Taxotere, Sanofi-Aventis) in combination with prednisone/prednisolone for the treatment of metastatic hormone-refractory prostate cancer (mHRPC). The main comparators considered were other established chemotherapy regimens and best supportive care. Twenty-one resources (including MEDLINE, EMBASE and the Cochrane Library) were searched to April 2005. Two reviewers independently assessed studies for inclusion. Data from included studies were extracted and quality assessed. Where appropriate, outcomes were synthesised using formal analytic approaches. A new economic model was developed in order to establish the cost-effectiveness of docetaxel compared with a range of potential comparators. A separate review was undertaken to identify sources of utility data required to estimate quality-adjusted life-years (QALYs). Sensitivity analyses were also undertaken to explore the robustness of the main analysis to alternative assumptions related to quality of life. Monte Carlo simulation was used to propagate uncertainty in input parameters through the model in such a way that the results of the analysis could be presented with their uncertainty. The impact of uncertainty surrounding the decision was established using value of information and implementation approaches. Seven randomised controlled trials were identified that met the inclusion criteria. A direct comparison of docetaxel plus prednisone versus mitoxantrone plus prednisone in an open-label randomised trial showed improved outcomes for docetaxel plus prednisone in terms of overall survival, quality of life, pain and prostate-specific antigen decline. Two other chemotherapy regimens that included docetaxel: docetaxel plus estramustine and docetaxel plus prednisone plus estramustine, also showed improved outcomes in comparison with mitoxantrone plus prednisone. Indirect comparison suggested that docetaxel plus prednisone seems to be superior to corticosteroids alone in terms of overall survival. Conclusions on cost-effectiveness were primarily informed by the results of the in-house model. This indicated that mitoxantrone plus a corticosteroid is probably cheaper and more effective than corticosteroid alone. Compared with mitoxantrone plus prednisone/prednisolone, the use of docetaxel plus prednisone/prednisolone (3-weekly) appears cost-effective only if the NHS is prepared to pay 33,000 pounds per QALY. The incremental cost-effectiveness ratio associated with docetaxel plus prednisone (3-weekly) remained fairly robust to these variations with estimates ranging from 28,000 pounds to 33,000 pounds per QALY. Value of information analysis revealed that further research is potentially valuable. Given a maximum acceptable ratio of 30,000 pounds per QALY, the expected value of information was estimated to be approximately 13 million pounds. This systematic review of the research suggests that docetaxel plus prednisone seems to be the most effective treatment for men with mHRPC. The economic model suggests that treatment with docetaxel plus prednisone/prednisolone is cost-effective in patients with mHRPC provided the NHS is prepared to pay 33,000 pounds per additional QALY. Future research should include the direct assessment of quality of life and utility gain associated with different treatments, including the effect of adverse events of treatment, using generic instruments, which are suitable for the purposes of cost-effectiveness analyses.


[Severe pneumococcal meningitis and ceftriaxone allergy].
We report the case of a 51-year-old man with an allergy to amoxicillin/acid clavulanique who presented with Streptococcus pneumoniae meningitis. Initial treatment consisted of an association of antibiotics including ceftriaxone. Six days after treatment was initiated the patient developed skin reaction and the diagnosis of allergy to ceftriaxone was established by the dosage of specific IgE. Typically Streptococcus pneumoniae meningitis is treated with vancomycin and a third-generation cephalosporin. This association had to be modified because cross allergy to cephalosporins could have developed in this patient who had previously reacted to penicillins.


Assessment of the Safety and Efficiency of a Preperitoneal Continuous Infusion Using Bupivacaine after Abdominal Laparotomy in Digestive Carcinology.
The purpose of this paper is to evaluate the safety and efficacy of continuous preperitoneal wound infiltration using bupivacaine after abdominal laparotomy in relation to plasma bupivacaine concentration and visual analog scale. Our study was performed on 60 adult patients with digestive cancer, operated at laparotomy, and randomized into two groups: bupivacaine and saline groups. The wound infiltration was through a multiperforated catheter along the scar. For the bupivacaine group, 0.25% bupivacaine was used; however, for the saline group, only saline (0.9%) was infiltrated. The pain was assessed by using the visual analog scale (VAS) in both groups. Plasma bupivacaine concentration was measured by high-performance liquid chromatography. The bupivacaine group had significantly lower postoperative morphine consumption and lower postoperative pain than the saline group (P < 0.0001). The majority of patients in the bupivacaine group had significant relief with the VAS scores of less than 3/10 cm at rest and 6/10 cm on mobilization. However, for the saline group, the VAS scores were higher than 6/10 cm either at rest or with mobilization. There was no clinical sign of toxicity and no technical complications for the bupivacaine group. Only eleven patients required morphine in this group, but the majority of patients received morphine at different doses in the saline group. Plasma bupivacaine was at very low concentrations. Overall, the current study has confirmed that continuous preperitoneal wound infiltration as postoperative analgesia is a simple, effective, and safe technique. It allows decreasing of morphine consumption and subsequently canceling their side effects.


Systemic Amyloid A Amyloidosis in Island Foxes (Urocyon littoralis): Severity and Risk Factors.
Systemic amyloid A (AA) amyloidosis is highly prevalent (34%) in endangered island foxes (Urocyon littoralis) and poses a risk to species recovery. Although elevated serum AA (SAA) from prolonged or recurrent inflammation predisposes to AA amyloidosis, additional risk factors are poorly understood. Here we define the severity of glomerular and medullary renal amyloid and identify risk factors for AA amyloidosis in 321 island foxes necropsied from 1987 through 2010. In affected kidneys, amyloid more commonly accumulated in the medullary interstitium than in the glomeruli (98% [n= 78 of 80] vs 56% [n= 45], respectively;P< .0001), and medullary deposition was more commonly severe (19% [n= 20 of 105]) as compared with glomeruli (7% [n= 7];P= .01). Univariate odds ratios (ORs) of severe renal AA amyloidosis were greater for short- and long-term captive foxes as compared with free-ranging foxes (ORs = 3.2, 3.7, respectively; overall P= .05) and for females as compared with males (OR = 2.9;P= .05). Multivariable logistic regression revealed that independent risk factors for amyloid development were increasing age class (OR = 3.8;P< .0001), San Clemente Island subspecies versus San Nicolas Island subspecies (OR = 5.3;P= .0003), captivity (OR = 5.1;P= .0001), and nephritis (OR = 2.3;P= .01). The increased risk associated with the San Clemente subspecies or captivity suggests roles for genetic as well as exogenous risk factors in the development of AA amyloidosis.


Experimental transcerebral fistula. Perineural olfactory CSF flow in the normal, hydrocephalic, and postoperative hydrocephalic dog shown by radionuclide ventriculography.
Cerebrospinal fluid dynamics were studied in eight dogs during normal, hydrocephalic, and postoperative phases. Radionuclide-labeled substances introduced into the normal ventricular system flow out of the exits from the fourth ventricle to the convexity subarachnoid spaces superiorly to be absorbed in the sagittal sinus, and basorostrally to the exits from the perineural olfactory sheath into the nose to produce physiological cerebrospinal fluid (CSF) rhinorrhea. Serial radionuclide ventriculography of the head following intraventricular isotope injection of labeled proteins and chelate into the kaolin-induced hydrocephalic system shows a high degree of ventricular stasis with no perineural olfactory nerve flow (rhinorrhea). An operative transcerebral fistula, fashioned from a dilated lateral ventricle to the convexity subarachnoid space, reestablishes perineural olfactory flow of CSF into the nose, as demonstrated by the radionuclide ventriculography studies. This suggests a potential method for treatment of hydrocephalus. Serial imaging studies in this surgically modified system clearly demonstrate radionuclide flow through the patent fistula to distal absorption sites, thereby bypassing the basal obstruction. Moreover, augmented CSF pressures associated with obstructive hydrocephalus can be controlled by such treatment. The application of this method in treating clinical hydrocephalus is discussed with emphasis on fistula arachnoid closure to assure fistula patency.


PARALLEL EVOLUTION OF LAKE-STREAM PAIRS OF THREESPINE STICKLEBACKS (GASTEROSTEUS) INFERRED FROM MITOCHONDRIAL DNA VARIATION.
Three drainage systems in British Columbia, Canada, contain divergent parapatric lake-stream pairs of threespine sticklebacks (Gasterosteus aculeatus): Drizzle and Mayer Lakes on Graham Island, Queen Charlotte Islands, and Misty Lake on northeastern Vancouver Island. Ecological and morphological differences between members of all three lake-stream pairs are strikingly similar; lake fish are melanistic and slim bodied with smaller mouths and more gill rakers than the mottled-brown and robust-bodied stream sticklebacks. We estimated the level of genetic divergence between lake and stream fish in Misty Lake and tested hypotheses of single versus multiple origins of the pairs by assaying mitochondrial DNA (mtDNA) restriction site variation in samples from the three lake systems. MtDNA analysis revealed the existence of two highly divergent lineages differing by 2.7% in sequence. One lineage predominated in Misty stream fish (73%), whereas the other lineage predominated in Misty Lake samples (96%). Comparable forms (lake or stream) in the different lakes did not cluster together in terms of mtDNA nucleotide divergence, suggesting that the pairs have had independent origins. We concluded that: (1) divergent mtDNA lineages in North Pacific sticklebacks stem from historical isolation in the two major glacial refugia proposed for the North Pacific (Beringia and Cascadia); (2) the stream and lake pair in Misty Lake are distinct gene pools; (3) the divergence between parapatric lake and stream Gasterosteus represents parallel evolution having occurred at least twice in the North Pacific; and (4) different scales of evolutionary divergence exist in North Pacific Gasterosteus, that is, a relatively ancient divergence of mtDNA clades as well as recent (i.e., postglacial) divergence of ecotypes within major clades.


Paleoproterozoic sterol biosynthesis and the rise of oxygen.
Natural products preserved in the geological record can function as 'molecular fossils', providing insight into organisms and physiologies that existed in the deep past. One important group of molecular fossils is the steroidal hydrocarbons (steranes), which are the diagenetic remains of sterol lipids. Complex sterols with modified side chains are unique to eukaryotes, although simpler sterols can also be synthesized by a few bacteria. Sterol biosynthesis is an oxygen-intensive process; thus, the presence of complex steranes in ancient rocks not only signals the presence of eukaryotes, but also aerobic metabolic processes. In 1999, steranes were reported in 2.7 billion year (Gyr)-old rocks from the Pilbara Craton in Australia, suggesting a long delay between photosynthetic oxygen production and its accumulation in the atmosphere (also known as the Great Oxidation Event) 2.45-2.32 Gyr ago. However, the recent reappraisal and rejection of these steranes as contaminants pushes the oldest reported steranes forward to around 1.64 Gyr ago (ref. 6). Here we use a molecular clock approach to improve constraints on the evolution of sterol biosynthesis. We infer that stem eukaryotes shared functionally modern sterol biosynthesis genes with bacteria via horizontal gene transfer. Comparing multiple molecular clock analyses, we find that the maximum marginal probability for the divergence time of bacterial and eukaryal sterol biosynthesis genes is around 2.31 Gyr ago, concurrent with the most recent geochemical evidence for the Great Oxidation Event. Our results therefore indicate that simple sterol biosynthesis existed well before the diversification of living eukaryotes, substantially predating the oldest detected sterane biomarkers (approximately 1.64 Gyr ago), and furthermore, that the evolutionary history of sterol biosynthesis is tied to the first widespread availability of molecular oxygen in the ocean-atmosphere system.


Why DID they have children? Rural midlife women who are childfree.
There remain strong social pressures and attitudes in the United States about feminine identity, especially the expectation of conforming to the role of mother. Ideal femininity and being a mother are often intrinsically linked. Childfree women, those women who choose not to become mothers, face limited understanding, appreciation or acceptance to remain in a non-parenting role and are often presumed as less feminine or caring. This qualitative exploratory study of 10 childfree midlife women in a predominantly rural area of a Midwest state examines how reactions and attitudes of others affected self-esteem and feminine identity through a retrospective lens. Primary themes identified: Motherhood, as underscored by social and societal expectations and stigma; Personal Choice; and Feminine Self-Esteem are addressed. The influence of rural settings is also considered in the discussion. Recommendations for practice with older childfree women are provided.


The effects of an educational program for premenstrual syndrome of women of Korean industrial districts.
The purpose of this study is to find an intervention that will help alleviate women's signs and discomforts associated with premenstrual syndrome (PMS). As the social activities of women increase, eliminating PMS becomes increasingly important for many Korean women. A possible health care countermeasure for PMS is to assess PMS at an early stage; clarify the premenstrual signs, symptoms, and tensions; and afterward alleviate the premenstrual signs and discomforts. Related educational programs have been found to be effective interventions. Studies in Korea until now generally have focused on premenstrual signs and discomforts. This study, in contrast, was carried out in order to find women who have physical, mental, emotional, and behavioral discomforts due to PMS, then to provide them with an educational program, and eventually to establish an intervention that would help alleviate their premenstrual signs and discomforts.


High Expression of RhoF Predicts Worse Overall Survival: A Potential Therapeutic Target for non-M3 Acute Myeloid Leukemia.
Rho GTPases are involved in multiple human malignancies and diverse biological functions. However, the patterns and prognostic significance of the expression of RhoD subfamily in acute myeloid leukemia (AML) remain unknown. Here, we detected the expressions of RhoD subfamily genes in AML on the basis of several published datasets and analyzed the survival of RhoD subfamily across the TCGA profiles and in a GEO series. We found that the expression of RhoF, but not RhoD, increased in AML patients in TCGA and GEO (all P<0.001); the survival analysis of two independent cohorts demonstrated that higher RhoF expression was significantly associated with poorer overall survival (OS) (P<0.001), whereas RhoD expression had no significant effect on OS in patients with AML (P>0.05); the subgroup analysis showed that high RhoF expression was correlated with poor 1-, 3-, and 5-year OS (P<0.05 for all); upregulated RhoF expression had a more significant prognostic value for OS in the younger patients (age<60), the intensive chemotherapy group, and wild-type groups (IDH1, NRAS, and TP53) (P<0.05 for all). Multivariate analysis indicated high RhoF expression as a strongly independent unfavorable prognostic factor for OS in patients without transplantation (P<0.05). Furthermore, a higher RhoF expression was closely associated with an older age, intermediate-/poor-risk cytogenetics and mutations in IDH1, NRAS, and TP53. RhoF expression was negatively correlated with BM blasts (P=0.020) and WBC (P=0.003). These findings suggest that high RhoF expression is associated with worsening OS in AML patients and is a potential therapeutic target for the treatment of AML.


Vitamin K status in patients with Crohn's disease and relationship to bone turnover.
There is a high prevalence of osteopenia among patients with Crohn's disease (CD). There is some evidence that a deficiency of certain bone-active nutrients (including vitamins K and D) may have a partial role in this bone loss. To compare the intake and the status of vitamin K in CD patients, currently in remission, with age- and sex-matched controls, and furthermore to investigate the relationship between vitamin K status and bone turnover in these patients. CD patients (n = 44; mean age: 36.9 yr) and matched controls (n = 44) were recruited from the Cork University Hospital and Cork City area, respectively. Bloods were analyzed for the total and undercarboxylated (Glu)-osteocalcin and urine analyzed for cross-linked N-telopeptides of type I collagen (NTx). Vitamin K(1) intake was estimated by food frequency questionnaire. Vitamin K(1) intake in CD patients tended to be lower than that of controls (mean (SD), 117 (82) vs 148 (80) mug/d, respectively; p= 0.059). Glu and NTx concentrations in CD patients were higher than controls (mean (SD), 5.1 (3.1) vs 3.9 (2.1) ng/ml, respectively; p= 0.03 for Glu; and 49 (41) vs 25.8 (19.5) nM BCE/mM creatinine, respectively; p= 0.001 for NTx). In CD patients, Glu was significantly correlated with NTx (r= 0.488; p < 0.001), even after controlling for age, gender, vitamin D status, calcium intake, and corticosteroid use. Vitamin K status of CD patients was lower than that of the healthy controls. Furthermore, the rate of bone resorption in the CD was inversely correlated with vitamin K status, suggesting that it might be another etiological factor for CD-related osteopenia.


Engineered cystine-knot miniproteins for diagnostic applications.
Owing to their extraordinary thermal and biological stability, cystine-knot miniproteins provide an attractive scaffold for the development of peptide-based diagnostics. One of the major advantages of this scaffold lies in the fact that the disulfide-constrained structural core can be functionalized by decoration with bioactive-loop residues. Methods have been developed to generate miniproteins with prescribed binding characteristics to a broad spectrum of different target proteins. They combine structural, biophysical and functional features that are beneficial for applications in molecular diagnostics in vivo (i.e., high affinity and selectivity, small size, high biological stability and fast renal clearance). Promising candidates for tumor imaging have been generated recently and evaluated in animal models, and more applications are expected in the near future.


Isradipine in the treatment of mild-to-moderate hypertension in geriatric patients.
A number of studies have shown the benefit of hypertensive treatment even though the most common forms of the disease are mild-to-moderate in severity. Considering the overall aging of the world's population, it is of particular interest to study hypertension and its treatment in geriatric patients. A short-term study of isradipine was conducted to assess its effectiveness and tolerability in patients with mild-to-moderate hypertension. The study was carried out by general practitioners and involved 3343 patients, aged > or = 18 years, with diastolic blood pressures (DBPs) ranging from 95 to 114 mm Hg. A 4-week wash-out and placebo run-in phase was followed by a 12-week active treatment period with isradipine at 1.25 or 2.5 mg/day, depending on the blood pressure response. Posttreatment results in a subgroup of 1092 patients (444 men and 648 women), aged > or = 60 years, showed decreases in systolic blood pressure (SBP) from 173.1 to 149.2 mm Hg (mean decrease, 20.9 mm Hg) and, in DBP, from 102.0 to 85.0 mm Hg (mean decrease, 16.9 mm Hg). The majority (84.6%) of these patients showed DBP reductions of > 10 mm Hg, and 82.3% achieved normalization (DBP < 90 mm Hg) at the end of treatment. The mean dosage was 1.74 +/- 0.69 mg twice daily, and 37% of patients doubled their initial 1.25 mg twice daily dosages. There were no significant changes in either heart rate or major metabolic parameters. Adverse events were reported by 3.1% of the patients, and 90% of both patients and physicians expressed satisfaction with the therapy. There were no differences between men and women with regard to adverse events or efficacy, nor were the results in patients > or = 60 years different from those in younger patients. Thus, isradipine was effective and well tolerated in these geriatric patients.


Glucagon-like petide-2 acts on colon cancer myofibroblasts to stimulate proliferation, migration and invasion of both myofibroblasts and cancer cells via the IGF pathway.
Glucagon-like peptide (GLP)-2 stimulates intestinal epithelial proliferation by acting, in part, via IGF release from sub-epithelial myofibroblasts. The response of myofibroblasts to GLP-2 remains incompletely understood. We studied the action of GLP-2 on myofibroblasts from colon cancer and adjacent tissue, and the effects of conditioned medium from these cells on epithelial cell proliferation, migration and invasion. GLP-2 stimulated proliferation, migration and invasion of myofibroblasts and the proliferative and invasive responses of cancer-associated myofibroblasts were greater than those of myofibroblasts from adjacent tissue. The responses were inhibited by an IGF receptor inhibitor, AG1024. Conditioned medium from GLP-2 treated myofibroblasts increased proliferation, migration and invasion of SW480, HT29, LoVo epithelial cells and these responses were inhibited by AG1024; GLP-2 alone had no effect on these cells. In addition, when myofibroblasts and epithelial cells were co-cultured in Ibidi chambers there was mutual stimulation of migration in response to GLP-2. The latter increased both IGF-1 and IGF-2 transcript abundance in myofibroblasts. Moreover, a number of IGF binding proteins (IGFBP-4, -5, -7) were identified in myofibroblast medium; in the presence of GLP-2 there was increased abundance of the cleavage products of IGBBP-4 and IGFBP-5 suggesting activation of a degradation mechanism that might increase IGF bioavailability. The data suggest that GLP-2 stimulates cancer myofibroblast proliferation, migration and invasion; GLP-2 acts indirectly on epithelial cells partly via increased IGF expression in myofibroblasts and partly, perhaps, by increased bioavailability through degradation of IGFBPs.


Glucose induces increases in levels of the transcriptional repressor Id2 via the hexosamine pathway.
Changes in glucose levels are known to directly alter gene expression. A number of previous studies have found that these effects are in part mediated by modulating the levels and the activity of transcription factors. We have investigated an alternative mechanism by which glucose might regulate gene expression by modulating levels of a transcriptional repressor. We have focused on Id2, which is a protein that indirectly regulates gene expression by sequestering certain transcription factors and preventing them from forming functional dimers. Id2 targets include the class A basic helix-loop-helix transcription factors and the sterol regulatory element-binding protein (SREBP)-1. We demonstrate that increases in glucose levels cause a rapid increase in levels of Id2 in J774.2 macrophages, and a number of lines of evidence indicate that this is via the hexosamine pathway because 1) the effect of glucose requires glutamine; 2) the effect of glucose is mimicked by low levels of glucosamine; 3) the effect of glucose is inhibited by azaserine, an inhibitor of glutamine:fructose-6-phosphate amidotransferase (GFAT); and 4) adenoviral mediated overexpression of GFAT increases levels of Id2. We go on to show that increases in Id2 can have functional effects on metabolic genes, because Id2 blocked the SREBP-1-induced induction of hormone-sensitive lipase (HSL) promoter activity, whereas Id2 alone does not modulate activity of the HSL promoter. In summary, these studies define a new mechanism by which glucose uses the hexosamine pathway to regulate gene expression by increasing levels of a transcriptional repressor.


Forgetting rate for the familiarity and recollection components of recognition in amnestic mild cognitive impairment: A longitudinal study.
Here we aimed to investigate the rate of forgetting of the familiarity and recollection components of recognition in patients at the onset of medial temporal lobe (MTL) pathology and destined to convert to Alzheimer's disease (AD). For this purpose, we conducted a longitudinal study of 13 patients who were diagnosed with amnestic mild cognitive impairment (a-MCI) at the first assessment and followed-up for 3 years. During this time, five patients converted to AD and eight remained in a stable condition of cognitive impairment. A group of 15 healthy subjects were enrolled as the control group (HC). In order to separately quantify the contribution of recollection and familiarity to recognition memory performance, the experimental sample was submitted to a modified version of Huppert and Piercy's procedure that included a Remember/Know paradigm. Data demonstrated that both stable and converter a-MCI patients forgot memory traces relative to the familiarity components of recognition at the same rate as HC. Conversely, converter a-MCI patients showed accelerated long-term forgetting specifically for the recollection component of recognition compared to stable a-MCI and HC. This is the first empirical demonstration that familiarity and recollection components of declarative memory are subject to different rates of forgetting in a-MCI patients as a function of their longitudinal clinical outcome. Our finding of accelerated long-term forgetting of the recollection component of recognition disclosed by converter a-MCI patients suggests that atrophy in the MTL not only interferes with the storage aspects but also disrupts the consolidation of memory traces.


Characterization of the interaction between Escherichia coli topoisomerase IV E subunit and an ATP competitive inhibitor.
Bacterial topoisomerase IV (ParE) is essential for DNA replication and serves as an attractive target for antibacterial drug development. The X-ray structure of the N-terminal 24 kDa ParE, responsible for ATP binding has been solved. Due to the accessibility of structural information of ParE, many potent ParE inhibitors have been discovered. In this study, a pyridylurea lead molecule against ParE of Escherichia coli (eParE) was characterized with a series of biochemical and biophysical techniques. More importantly, solution NMR analysis of compound binding to eParE provides better understanding of the molecular interactions between the inhibitor and eParE.


[A case of hyponatremia associated with combination therapy of systemic chemotherapy and paroxetine].
A 65-year-old woman with relapsed non small cell lung cancer, who had no prior chemotherapy, was admitted to our hospital. She was initially treated with paroxetine, a selective serotonin-reuptake inhibitor antidepressant, and received cisplatin-based chemotherapy three days after the initiation of the paroxetine. She developed hyponatremia on day 5 after the start of chemotherapy. Based on the laboratory examinations, the syndrome of inappropriate secretion of antiduretic hormone was suggested. Her plasma sodium concentration returned to normal after paroxetine withdrawal and appropriate fluid restriction. Cisplatin-based chemotherapies were subsequently continued without paroxetine and there were no further episodes of electrolyte disturbance. Paroxetine has been used widely for treatment of depressed patients with malignancies. However, careful monitoring of plasma sodium is needed following cisplatin-based chemotherapy in patients taking paroxetine.


The effect of caponization on bone homeostasis of crossbred roosters. I. Analysis of tibia bone mineralization, densitometric, osteometric, geometric and biomechanical properties.
The presented study focuses on assessing the effect of caponization on the densitometric, osteometric, geometric and biomechanical parameters of tibial bones in crossbred chickens. The study was carried out on 96 hybrids between Yellowleg Partridge hens (Ż-33) and Rhode Island Red cockerels (R-11) aged 16 weeks, 20 weeks and 24 weeks. Birds were randomly assigned to 2 groups-the control group (n = 48; which consisted of intact roosters) and the experimental group (n = 48, which consisted of individuals subjected to caponization at the age of 8 weeks). The caponization had no effect on the densitometric, osteometric and geometric parameters (except the horizontal internal diameter of 16-week-old individuals) of tibia bone, as well as the content of calcium (Ca), phosphorus (P) and the Ca/P ratio in the bone mineral fraction in all analyzed age groups of animals. However, it contributes to a lower percentage of ash in the bones of capons at 20 and 24 weeks of age compared to cockerels. On the contrary, some mechanical and material parameters show the negative effect of caponization. Ultimate load and bending moment decreased in capons in all of the analyzed age groups of animals and yield load, stiffness and ultimate stress also decreased but only in the group of 20-week-old and 24-week-old individuals. This can contribute to the weakening of the capon bones, and in the perspective of prolonged maintenance to their deformation and even fracture.