In vitro stability of nitrate reductase from wheat leaves: I. Stability of highly purified enzyme and its component activities.
NADH-nitrate reductase has been highly purified from leaves of 8-day-old wheat (Triticum aestivum L. cv. Olympic) seedlings by affinity chromatography, using blue dextran-Sepharose 4B. Purification was assessed by polyacrylamide gel electrophoresis. The enzyme was isolated with a specific activity of 23 micromoles nitrite produced per minute per milligram protein at 25 C. At pH 7.5, the optimum pH for stability of NADH-nitrate reductase, this enzyme, and a component enzyme reduced flavin adenine mononucleotide (FMNH(2))-nitrate reductase has a similar stability at both 10 and 25 C. Two other component enzymes-methylviologen-nitrate reductase and NADH-ferricyanide reductase-also have a similar but higher stability. At this pH the Arrhenius plot for decay of NADH-nitrate reductase and methylviologen-nitrate reductase indicates a transition temperature at approximately 30 C above which the energy of activation for denaturation increases. FMNH(2)-nitrate reductase and NADH-ferricyanide reductase do now show this transition. The energy of activation for denaturation (approximately 9 kcal per mole) of each enzyme is similar between 15 and 30 C. The optimum pH for stability of the component enzymes was: NADH-ferricyanide reductase, 6.6; FMNH(2)-nitrate reductase and methylviologen-nitrate reductase, 8.9. All of our studies indicate that the NADH-ferricyanide reductase was the most stable component of the purified nitrate reductase (at pH 6.6, t((1/2)) [25 C] = 704 minutes). Data are presented which suggest that methylviologen and FMNH(2) do not donate electrons to the same site of the nitrate reductase protein.


Leaf water content and hormone effects on ribonuclease activity.
In barley (Hordeum vulgare) leaves in which the water balance was not hampered, kinetin and abscisic acid effected the well documented decrease and increase, respectively, in RNase activity. When the plants were exposed to water shortage, leaf-water saturation deficit increased steadily, with kinetin enhancing and abscisic acid retarding the rise. Under drought, the pattern of hormonal effects was inverted, with kinetin enhancing RNase activity over and above the activity assayed in abscisic acid-treated leaves. A very close relationship between RNase activity and water saturation deficit was found and significantly, it was maintained irrespective of the hormonal treatment, which in itself markedly modified leaf-water saturation deficit. The inverted effects of kinetin and of abscisic acid on RNase activity under conditions of water shortage were interpreted as resulting primarily from the effects of these hormones on leaf-water. It is suggested that under conditions of increased water deficiency in the plant, cell-water supersedes hormonal regulation in effecting RNase activity.


The impact of lead and cadmium on selected motility, prooxidant and antioxidant parameters of bovine seminal plasma and spermatozoa.
The aim of this study was to investigate the effects of lead (Pb) and cadmium (Cd) content on basic motility characteristics (motility-MOT, progressive motility-PROG) as well as selected markers of the prooxidant-antioxidant balance (catalase-CAT, glutathione-GSH, malondialdehyde-MDA) in bovine seminal plasma and spermatozoa. Twenty five semen samples were collected from breeding bulls and used in the study. Motility analysis was carried out using the Computer Assisted Sperm Analysis (CASA) system. The samples were centrifuged, fractions of seminal plasma and spermatozoa were separated, lysates were prepared from the sperm cell fractions. Pb and Cd concentrations were determined by the voltametric method (ASV), antioxidants and MDA were analyzed by UV/Vis spectrophotometry. The analysis showed that the average concentration of Pb in the seminal plasma was 0.23 ± 0.02 μg/mL, while its amount in the sperm cells was significantly higher (0.41 ± 0.07 μg/mL; P < 0.05). The average Cd content in bovine seminal fractions was similar and non-significant: 0.09 ± 0.01 μg/mL in the seminal plasma and 0.11 ± 0.01 μg/mL in spermatozoa (P > 0.05). The correlation analysis revealed that both heavy metals were significantly negatively correlated with MOT and PROG (P < 0.05; P < 0.01; P < 0.001), CAT (P < 0.05; P < 0.01) as well as GSH (P < 0.05; P < 0.01) but significantly positively associated with MDA as the marker of lipid peroxidation (P < 0.05; P < 0.01). Moreover the samples were categorized in three quality groups (Excellent, Good, Moderate) according to their motility values. The lowest Pb, Cd and MDA concentrations but the best antioxidant characteristics were found in samples of the best quality, moderate quality samples exhibited the highest Pb, Cd and MDA content together with the worst antioxidant capacity. This study demonstrates that Pb and Cd are serious toxic elements, which are able to increase the risk of seminal oxidative stress development and a subsequent decrease of male fertility.


Large electric field effect in electrolyte-gated manganites.
We have studied electrostatic field-induced doping in La0.8Ca0.2MnO3 transistors using electrolyte as a gate dielectric. For positive gate bias, electron doping drives a transition from a ferromagnetic metal to an insulating ground state. The thickness of the electrostatically doped layer depends on bias voltage but can extend to 5 nm requiring a field doping of 2x10;{15} charges per cm;{2} equivalent to 2.5 electrons per unit cell area. In contrast, negative gate voltages enhance the metallic conductivity by 30%.


Parallel and Efficient Sensitivity Analysis of Microscopy Image Segmentation Workflows in Hybrid Systems.
We investigate efficient sensitivity analysis (SA) of algorithms that segment and classify image features in a large dataset of high-resolution images. Algorithm SA is the process of evaluating variations of methods and parameter values to quantify differences in the output. A SA can be very compute demanding because it requires re-processing the input dataset several times with different parameters to assess variations in output. In this work, we introduce strategies to efficiently speed up SA via runtime optimizations targeting distributed hybrid systems and reuse of computations from runs with different parameters. We evaluate our approach using a cancer image analysis workflow on a hybrid cluster with 256 nodes, each with an Intel Phi and a dual socket CPU. The SA attained a parallel efficiency of over 90% on 256 nodes. The cooperative execution using the CPUs and the Phi available in each node with smart task assignment strategies resulted in an additional speedup of about 2×. Finally, multi-level computation reuse lead to an additional speedup of up to 2.46× on the parallel version. The level of performance attained with the proposed optimizations will allow the use of SA in large-scale studies.


Genomic position effects lead to an inefficient reorganization of nucleosomes in the 5'-regulatory region of the chicken lysozyme locus in transgenic mice.
The chicken lysozyme locus is gradually activated during macrophage development exhibiting a specific chromatin structure with each differentiation state. Its small size and the extensive characterization of its cis-regulatory elements allows us to study even subtle changes in chromatin structure of the entire gene locus during transcriptional activation. Tissue-specific and position independent expression of the lysozyme locus in transgenic mice requires the cooperation of all cis-regulatory elements. In order to elucidate further the molecular basis of locus activation, we have determined nucleosome positions within the complete 5'-regulatory region of the chicken lysozyme locus in chicken myeloid cell lines and transgenic mice. Each cis-regulatory element develops its unique nucleosomal structure and each one remodels chromatin differently. The nucleosomal organization of the endogenous gene in chicken cell lines and the transgene in the mouse turned out to be identical, enabling us to study the influence of cis-regulatory deletions on the development of an active chromatin structure in transgenic mice. Transgenes with a deletion of an important cis-regulatory element show an impediment in nucleosome reorganization as compared with the complete lysozyme locus. We demonstrate that multicopy transgene-clusters in position dependently expressing mouse lines exhibit a heterogeneous chromatin organization.


Copper-catalyzed oxidative cyclization of glycine derivatives toward 2-substituted benzoxazoles.
A novel and straightforward intramolecular cyclization of glycine derivatives to 2-substituted benzoxazoles through copper-catalyzed oxidative C-H/O-H cross-coupling was described. A variety of glycine derivatives involving short peptides underwent cross-dehydrogenative-coupling readily to afford diverse 2-substituted benzoxazoles. The synthetic method has the advantages of simple operation, broad substrate scope and mild reaction conditions, thus providing an alternative effective approach for benzoxazole construction.


Microvirga lupini sp. nov., Microvirga lotononidis sp. nov. and Microvirga zambiensis sp. nov. are alphaproteobacterial root-nodule bacteria that specifically nodulate and fix nitrogen with geographically and taxonomically separate legume hosts.
Strains of Gram-negative, rod-shaped, non-spore-forming bacteria were isolated from nitrogen-fixing nodules of the native legumes Listia angolensis (from Zambia) and Lupinus texensis (from Texas, USA). Phylogenetic analysis of the 16S rRNA gene showed that the novel strains belong to the genus Microvirga, with ≥ 96.1% sequence similarity with type strains of this genus. The closest relative of the representative strains Lut6(T) and WSM3557(T) was Microvirga flocculans TFB(T), with 97.6-98.0% similarity, while WSM3693(T) was most closely related to Microvirga aerilata 5420S-16(T), with 98.8% similarity. Analysis of the concatenated sequences of four housekeeping gene loci (dnaK, gyrB, recA and rpoB) and cellular fatty acid profiles confirmed the placement of Lut6(T), WSM3557(T) and WSM3693(T) within the genus Microvirga. DNA-DNA relatedness values, and physiological and biochemical tests allowed genotypic and phenotypic differentiation of Lut6(T), WSM3557(T) and WSM3693(T) from each other and from other Microvirga species with validly published names. The nodA sequence of Lut6(T) was placed in a clade that contained strains of Rhizobium, Mesorhizobium and Sinorhizobium, while the 100% identical nodA sequences of WSM3557(T) and WSM3693(T) clustered with Bradyrhizobium, Burkholderia and Methylobacterium strains. Concatenated sequences for nifD and nifH show that the sequences of Lut6(T), WSM3557(T) and WSM3693(T) were most closely related to that of Rhizobium etli CFN42(T) nifDH. On the basis of genotypic, phenotypic and DNA relatedness data, three novel species of Microvirga are proposed: Microvirga lupini sp. nov. (type strain Lut6(T) =LMG 26460(T) =HAMBI 3236(T)), Microvirga lotononidis sp. nov. (type strain WSM3557(T) =LMG 26455(T) =HAMBI 3237(T)) and Microvirga zambiensis sp. nov. (type strain WSM3693(T) =LMG 26454(T) =HAMBI 3238(T)).


An all permanent magnet electron cyclotron resonance ion source for heavy ion therapy.
A high charge state all permanent Electron Cyclotron Resonance ion source, Lanzhou All Permanent ECR ion source no. 3-LAPECR3, has been successfully built at IMP in 2012, which will serve as the ion injector of the Heavy Ion Medical Machine (HIMM) project. As a commercial device, LAPECR3 features a compact structure, small size, and low cost. According to HIMM scenario more than 100 eμA of C(5+) ion beam should be extracted from the ion source, and the beam emittance better than 75 π*mm*mrad. In recent commissioning, about 120 eμA of C(5+) ion beam was got when work gas was CH4 while about 262 eμA of C(5+) ion beam was obtained when work gas was C2H2 gas. The design and construction of the ion source and its low-energy transportation beam line, and the preliminary commissioning results will be presented in detail in this paper.


Endosperm cell division in maize kernels cultured at three levels of water potential.
The influence of osmoticum treatments on early kernel development of maize (Zea mays L.) was studied using an in vitro culture method. Kernels with subtending cob sections were placed in culture at 5 days after pollination. Sucrose (0.29, 0.44, or 0.58 molar) and sorbitol (0, 0.15, or 0.29 molar) were used to obtain six media with water potentials of -1.1, -1.6, or -2.0 megapascals. Kernel water potential declined in correspondence with the water potential of the medium; however, fresh weight growth was not significantly inhibited from 5 to 12 days after pollination. In stress treatments with media water potentials of -1.6 or -2.0 megapascals, endosperm tissue accumulated water and solutes from 10 and 12 days after pollination at a rate similar to or greater than that of the control (-1.1 megapascals). In contrast, endosperm cell division was inhibited in all treatments relative to control. At 10 days after pollination, endosperm sucrose concentration was greater in two of the -2.0 megapascal treatments with 0.44 or 0.58 molar media sucrose compared to control kernels cultured in 0.29 molar sucrose at -1.1 megapascals. Significant increases in abscisic acid content per gram of fresh weight were detected in two -2.0 megapascal treatments (0.29 molar sucrose plus 0.29 molar sorbitol and 0.58 molar sucrose) at 10 days after pollination. We conclude that in cultured maize kernels, endosperm cell division was more responsive than fresh weight accumulation to low water potential treatments. Data were consistent with mechanisms involving abscisic acid or lowered tissue water potential, or an interaction of the two factors.


Identification of regions on the hemagglutinin-neuraminidase protein of human parainfluenza virus type 2 important for promoting cell fusion.
The hemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins of two paramyxoviruses, human parainfluenza virus type 2 (PIV2) and simian virus 41 (SV41), were expressed in HeLa cells by transfecting with recombinant plasmid harboring each glycoprotein gene. Expressed F proteins could not induce cell fusion by themselves, but evoked prominent cell fusion when coexpressed with homologous HN proteins. It was also proved that PIV2 HN protein could weakly promote SV41 F-mediated cell fusion. By analyzing the fusion-promoting function of chimeric HN proteins of PIV2 and SV41, it was revealed that the N-terminal region (about 16% of total amino acids) of either PIV2 HN or SV41 HN protein could define the type-specific fusion-promoting function for homologous F protein. Analyses of additional chimeras indicated that the N-terminal region in PIV2 HN protein (designated region I, consisting of 94 amino acids) could be reduced to a 58-amino-acid region (region I') which was located at the membrane-proximal end of the ectodomain. Furthermore, PIV2 HN protein proved to promote cell fusion mediated by PIV4A F protein. Unexpectedly, analyses of another set of chimeras revealed that the promoting function of PIV2 HN protein for PIV4A F-mediated cell fusion was not merely carried by its region I but also by another region ranging from residue 148 to 209 (region II). Finally, it was indicated that regions I' (in the presumed stalk domain) and II (in the globular head) in PIV2 HN protein might play important roles in promoting cell fusion mediated by the F proteins.


Pharmacokinetics and brain dispositions of tacrine and its major bioactive monohydroxylated metabolites in rats.
The current study aims to investigate the pharmacokinetics and brain disposition of tacrine and its three major bioactive monohydroxylated metabolites (1-hydroxytacrine, 2-hydroxytacrine and 4-hydroxytacrine). An assay for simultaneous quantification of tacrine and three above metabolites in rat plasma and brain tissue was developed. Four analytes together with internal standard were extracted from rat plasma or brain tissue homogenate by liquid-liquid extraction using ethyl acetate. Baseline separation of the four studied compounds was achieved by a Thermo Hypersil BDS C(18) column with gradient elution using acetonitrile and ammonium formate-triethylamine (pH 4.0) under fluorescence detection. Extraction recoveries of all analytes ranged from 82.1% to 93.2% in both rat plasma and brain tissue. The intra- and inter-day precision and accuracy of each analyte at lower limit of quantification (LLOQ) and three quality control (QC) concentrations (low, middle and high) was within 12% RSD and within 11% bias in both biological matrices. The LLOQ for tacrine, 1-hydroxytacrine, 2-hydroxytacrine and 4-hydroxytacrine were found to be 2.5, 6.7, 2.1 and 2.1 ng/ml in plasma, and 12.3, 33.5, 10.6 and 10.5 ng/g in brain tissue, respectively. All four analytes were stable during analysis. The developed method provides a simple, sensitive and reproducible procedure for pharmacokinetics and brain disposition study of tacrine and its three major metabolites in rats after oral administration of tacrine. Pharmacokinetic study demonstrated that tacrine could be quickly absorbed and extensively metabolized to its monohydroxylated metabolites in vivo. In addition, rat brain disposition study showed that tacrine and its monohydroxylated metabolites were evenly distributed in different brain regions except for a slight lower concentration of tacrine in olfactory region. Moreover, tacrine and 4-hydroxytacrine exhibited a much higher brain-to-plasma ratio than that of 1-hydroxytacrine and 2-hydroxytacrine.


Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet.
Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17β-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression.


Molecular Diversity and Plasmid Analysis of KPC-Producing Escherichia coli.
The emergence and spread of Klebsiella pneumoniae carbapenemase (KPC) among Enterobacteriaceae presents a major public health threat to the world. Although not as common as in K. pneumoniae, KPC is also found in Escherichia coli strains. Here, we genetically characterized 9 carbapenem-resistant E. coli strains isolated from six hospitals in the United States and completely sequenced their blaKPC-harboring plasmids. The nine strains were isolated from different geographical locations and belonged to 8 different E. coli sequence types. Seven blaKPC-harboring plasmids belonged to four different known incompatibility groups (IncN, -FIA, -FIIK2, and -FIIK1) and ranged in size from ∼16 kb to ∼241 kb. In this analysis, we also identified two plasmids that have novel replicons: (i) pBK28610, which is similar to p34978-3 with an insertion of Tn4401b, and (ii) pBK31611, which does not have an apparent homologue in the GenBank database. Moreover, we report the emergence of a pKP048-like plasmid, pBK34397, in E. coli in the United States. Meanwhile, we also found examples of interspecies spread of blaKPC plasmids, as pBK34592 is identical to pBK30683, isolated from K. pneumoniae In addition, we discovered examples of acquisition (pBK32602 acquired an ∼46-kb fragment including a novel replication gene, along with Tn4401b and other resistance genes) and/or loss (pKpQIL-Ec has a 14.5-kb deletion compared to pKpQIL-10 and pBK33689) of DNA, demonstrating the plasticity of these plasmids and their rapid evolution in the clinic. Overall, our study shows that the spread of blaKPC-producing E. coli is largely due to horizontal transfer of blaKPC-harboring plasmids and related mobile elements into diverse genetic backgrounds.


[Economic evaluation of health technologies: theory and practice].
Health care systems are committed to maintain and improve the health of their citizens in an effective, fair and accessible way. New medical technologies that offer improvement upon existing alternatives are progressing at a rapid pace. These new sophisticated health technologies are high priced and have been viewed as a significant factor in increasing the cost of healthcare expenditures. The abundance of new medical alternatives, combined with scarcity of resources, has led to the need for priority setting in a way that maximizes the health benefit of those insured. Economic evaluation of medical technologies is the analysis which compares the costs and consequences of alternative healthcare interventions. Economic evaluation of medical technologies can be used by policy makers as a tool to aid in resource allocation decisions. The inclusion of an economic perspective in the evaluation of health and health care has become an increasingly accepted component of health policy and planning. The health care system in Israel has come to acknowledge the advantages of this method. There is still a need for more suitable and structured guidelines to conducting economic evaluation in order to make this emergent and welcome process and its products useable.


Prevalence of Listeria monocytogenes in ready-to-eat foods sampled from the point of sale in Wales, United Kingdom.
A survey of Listeria in ready-to-eat food took place in Wales, United Kingdom, between February 2008 and January 2009. In total, 5,840 samples were taken and examined for the presence of Listeria species, including L. monocytogenes. Samples were tested using detection and enumeration methods, and the results were compared with current United Kingdom guidelines for the microbiological quality of ready-to-eat foods. The majority of samples were negative for Listeria by both direct plating and enriched culture. Seventeen samples (0.29%) had countable levels of Listeria species (other than L. monocytogenes), and another 11 samples (0.19%) had countable levels of L. monocytogenes. Nine samples (0.15%) were unsatisfactory or potentially hazardous when compared with United Kingdom guideline limits; six (0.10%) were in the unsatisfactory category (>100 CFU/g) for Listeria species (other than L. monocytogenes), and three (0.05%) were in the unacceptable or potentially hazardous category (>100 CFU/g) for L. monocytogenes. All three of these samples were from sandwiches (two chicken sandwiches and one ham-and-cheese sandwich). The most commonly isolated serotype of L. monocytogenes was 1/2a. This survey was used to determine the current prevalence of Listeria species and L. monocytogenes in ready-to-eat foods sampled from the point of sale in Wales.


[Isolation and identification of Rhodopseudomonas viridis and Rhodopseudomonas sulfoviridis].
Under selective culture conditions, two pure cultures (strain G and strain SG) of the purple nonsulfur photosynthetic bacteria containing bacteriochlorophyll b were isolated from pulp effluent and sludge of sewage treatment plant by means of agar shake dilution. Although the cells of strain G and strain SG contained bacteriochlorophyll b and carotenoids, intra-cytoplasmic membranes were of lamellar type parallel to cytoplasmic membrane, the two strains differ in using various organic carbon sources, depending on reduced sulfur compounds and assimilate sulfate. According to Bergey's Manual of Systematic Bacteriology Volume 3, strain G was identified to be Rhodopseudomonas viridis,, strain SG was identified to be Rhodopseudomonas sulfoviridis.


Polysubstance Use Patterns Among High Dose Benzodiazepine Users: A Latent Class Analysis and Differences Between Male and Female Use.
Benzodiazepines (BZDs) represent one of the most widely used groups of pharmaceuticals, but if used for long periods of time they are associated with dependence and an increased risk of harmful effects. High-dose (HD) BZD dependence is a specific substance use disorder associated with a poor quality of life. It is especially important to pinpoint differences in HD BZD addict subgroups in order to tailor treatment to the individual's specific needs, also considering possible comorbidities with other substance use disorders. We conducted a study to evaluate HD BZD dependence (converted doses to diazepam equivalents, mg) in an Italian sample of 1,354 participants. We also investigated if and to which extent participants co-used other substances (alcohol, tobacco, cannabis/cannabinoids, cocaine, and heroin). We then performed latent class analysis (LCA) to identify the use patterns of these substances, finding three classes: participants in Class 1 (4.3% of the sample) had the highest probability of also using cocaine and alcohol (Polysubstance BZD users); Class 2 comprised subjects with the highest probability of being former heroin, cocaine, THC, and alcohol users (Former polysubstance BZD users); Class 3 represented mono-dependence BZD users (78.5% of the sample) and was the most prevalent among women, while young men were most prevalent in Class 1. The present study underlines different characteristics in HD BZD users both concerning other addictions and sex, and also highlights the need for a stricter control of BZD use, ranging from prescriptions to sales.


Chemoembolotherapy for recurrent hepatocellular carcinoma in the residual liver after hepatectomy.
The efficacy of transcatheter arterial chemoembolization using Lipiodol (TACE) to treat recurrent hepatocellular carcinoma (r-HCC) in the residual liver after radical hepatic resection was evaluated. During the last 8 years, TACE was performed in 68 patients with r-HCC for an aggregate total of 150 times. Of the 68 patients, 4 had a massive type r-HCC with tumor thrombus in the main portal vein (PVTT) at the time of the first TACE. Among the remaining 64 patients without PVTT, multiple r-HCCs were revealed in 46, and a single r-HCC in 18 by angiography and/or follow-up CT scans after the initial TACE. In 26 of the 68 patients (38.2%), at least one or more r-HCCs were fed not only by the hepatic arteries, but also by the extrahepatic collateral arteries, such as branches of the right inferior phrenic artery. The cumulative survival rates of these patients after hepatectomy and after the initial TACE for r-HCC were 98.6% and 87.1% for one year, 89.7% and 62.9% for 2 years, 74.0% and 34.3% for 3 years, 53.1% and 20.0% for 4 years and 40.3% and 0% for 5 years (mean survival duration: 1,647 days and 947 days), respectively. These results indicate that repeat TACE against r-HCC can help obtain long-term survival in patients with r-HCC. However, during TACE, we must give consideration to the newly developed collateral feeding artery to the r-HCC.


Pulmonary complications of systemic vasculitides.
The pulmonary vasculitides are a heterogeneous group of diseases that often occur as a component of systemic vasculitic diseases. Most frequently, pulmonary vasculitis is observed in vasculitic syndromes that preferentially affect small vessels. Pulmonary involvement may develop because the lung has an extensive vascular and microvascular network. Sensitising antigens can easily reach the lung, and there are large numbers of vasoactive and activated immune cells in the lung. A diagnosis often can be made on the basis of clinical presentation and serologic studies, but biopsy of skin, nose, kidney, or lung may be necessary to ascertain the precise syndrome.


[Diagnosis, treatment and prognosis of neuroendocrine carcinoma of the colorectum].
To investigate the diagnosis, treatment and prognosis of colorectal neuroendocrine carcinoma. Clinical data of 39 patients with colorectal neuroendocrine carcinoma from Jan 1995 to Jan 2010 were analyzed retrospectively and the related literatures were reviewed. There were 27 males and 12 females. No patients presented endocrinal dysfunction symptoms. Fourteen patients were diagnosed as neuroendocrine cancer by preoperative pathological examination. All the patients received postoperative adjuvant chemotherapy including cis-platinum and etoposide. Twenty-two patients underwent curative resection, while 14 underwent palliative resection and 3 underwent biopsy alone. Of the 36 surgical resection specimens, vascular invasion was found in 27 patients (75.0%) and regional lymph node metastasis was found in 29 patients (80.6%). Length of follow-up ranged from 4 to 67 months. The 1-year, 3-year and 5-year survival rates were 48.2%, 16.5% and 6.8%, respectively. Statistically significant differences in survival were observed and associated with tumor staging, vascular invasion and surgery type (P<0.05), but not related to gender, age, tumor location, or diameter (P>0.05). Clinical symptoms and signs of colorectal neuroendocrine carcinoma are nonspecific with poor prognosis. Tumor staging, vascular invasion and surgical type have potential impact on survival.


Consumption of fish: benefits and perceived risk.
Fish, a useful source of protein, may be polluted by microbes, natural toxins, and/or synthetic chemicals. However, based on a review of the U.S. General Accounting Office, "There does not appear to be a compelling case to implement a mandatory comprehensive federal seafood inspection program." Although earlier studies showed higher body burdens of polychlorinated biphenyls (PCBs) in populations who consumed a lot of fish from polluted waterways, a recent study refutes these observations. No information is available in the United States on the levels of polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) in anglers who consume a great deal of fish presumed to be contaminated by these chemicals.


The innate natural killer cells in transplant rejection and tolerance induction.
The roles of adaptive immune cells in transplant models have been extensively studied, but very little is known about the role of innate immune cells in the allograft response, especially in tolerance induction. In this review, we summarized the latest developments in the study of the role of natural killer cells in mediating graft rejection and tolerance induction. Natural killer cells are potent cytolytic cells; they also induce tissue inflammation by producing powerful proinflammatory cytokines. Thus, natural killer cells can act as effector cells in transplant rejection. Recent studies, however, have demonstrated additional roles for natural killer cells in the induction of transplant tolerance. We found that natural killer cells control survival of graft-derived donor cells and killing of donor dendritic cells by host natural killer cells inhibits direct priming of alloreactive T cells. Natural killer cells are also shown directly to suppress the activation of T cells. In other models, natural killer cells are found to regulate the induction of regulatory T cells. These new findings may have important clinical implications in tolerance induction. Natural killer cells are involved in both graft rejection and tolerance induction; such opposing effects may be mediated by differences in the activation status of natural killer cells. We believe that natural killer cells can be therapeutically modified for the induction of transplant tolerance.


Use of measures of disproportionality in pharmacovigilance: three Dutch examples.
Spontaneous reporting systems for suspected adverse drug reactions (ADRs) remain a cornerstone of pharmacovigilance. In The Netherlands 'the Netherlands Pharmacovigilance Foundation Lareb' maintains such a system. A primary aim in pharmacovigilance is the timely detection of either new ADRs or a change of the frequency of ADRs that are already known to be associated with the drugs involved, i.e. signal detection. Adequate signal detection solely based on the human intellect (case by case analysis or qualitative signal detection) is becoming time consuming given the increasingly large number of data, as well as less effective, especially in more complex associations such as drug-drug interactions, syndromes and when various covariates are involved. In quantitative signal detection measures that express the extent in which combinations of drug(s) and clinical event(s) are disproportionately present in the database of reported suspected ADRs are used to reveal associations of interest. Although the rationale and the methodology of the various quantitative approaches differ, they all share the characteristic that they express to what extent the number of observed cases differs from the number of expected cases. In this paper three Dutch examples are described in which a measure of disproportionality is used in quantitative signal detection in pharmacovigilance: (i) the association between antidepressant drugs and the occurrence of non-puerpural lactation as an example of an association between a single drug and a single event; (ii) the onset or worsening of congestive heart failure associated with the combined use of nonsteroidal anti-inflammatory drugs and diuretics as an example of an association between two drugs and a single event (drug-drug interaction); and the (iii) (co)-occurrence of fever, urticaria and arthralgia and the use of terbinafine as an example of an association between a single drug and multiple events (syndrome). We conclude that the use of quantitative measures in addition to qualitative analysis is a step forward in signal detection in pharmacovigilance. More research is necessary into the performance of these approaches, especially its predictive value, its robustness as well as into further extensions of the methodology.


Prediction errors of the Oklahoma Premorbid Intelligence Estimate-3 (OPIE-3) stratified by 13 age groups.
The Oklahoma Premorbid Intelligence Estimate-3 (OPIE-3) combines Wechsler Adult Intelligence Scale-3rd edition (WAIS-III) subtest raw scores (vocabulary, information, matrix reasoning, and picture completion) and demographic data (i.e., age, education, gender, ethnicity, and region) to predict FSIQ scores. Differences between OPIE-3 estimated FSIQ scores and actual FSIQ scores were compared across 13 age groups in a random sample (N=1201) of the WAIS-III standardization sample. There were mean differences in estimated FSIQ between age groups (P<.01). There was a trend that the OPIE-3 algorithms underestimated FSIQ for individuals 16-17 (2.7 points) and 80-89 years old (3.5 points). However, the differences in estimation errors were small and the percentage of individuals misclassified by more than 10 FSIQ points by age group was similar across groups. The OPIE-3(2ST), OPIE-3MR, and OPIE-3VOC yielded robust estimates of FSIQ across age groups in a neurologically intact sample. Limitations, particularly with individuals aged 16-17 and 85-89 years, are discussed.


Effect of continuous deep sedation on survival in the last days of life of cancer patients: A multicenter prospective cohort study.
Continuous deep sedation is ethically controversial with respect to whether it shortens a patient's life. To examine whether continuous deep sedation shortens patient survival from the day of Palliative Performance Scale decline to 20 (PPS20). A part of a multicenter prospective cohort study (EASED study). We recruited consecutive adult patients with advanced cancer admitted to 23 participating palliative care units in 2017 in Japan. We compared survival from PPS20 between those who did and did not receive continuous deep sedation. Continuous deep sedation was defined as the continuous administration of sedative medication with the intention to keep a patient continuously unconscious to alleviate otherwise uncontrollable symptoms, but the dose of sedatives was adjusted to achieve adequate symptom relief for each patient. The propensity score-weighting method was used to control for potential confounders, and five sensitivity analyses were performed. A total of 1926 patients were enrolled. Patients discharged alive were excluded, and we analyzed 1625 patients of whom 156 (9.6%) received continuous deep sedation. Median survival from PPS20 of 1625 patients was 81 h (95% CI: 77-88). The RASS scores decreased to ⩽-4 was 66% at 24 h. Continuous deep sedation was not associated with a significant survival risk (adjusted hazard ratio: 1.06, 95% CI: 0.85-1.33). All sensitivity analyses, including continuous deep sedation defined as the RASS score was ⩽-4 achieved the essentially the same results. Continuous deep sedation with careful dose adjustment was not associated with shorter survival in the last days of life in patients with advanced cancer.


Absence of Short-Term Variability of CTA 102.
Short-time variations in intensity of about 40 percent, with a period of the order of 100 days, have been reported for the quasistellar radio source CTA 102 at 32.5-centimeter wavelength. We have observed CTA 102 at 25.5-centimeter wavelength over a 67-day, period and have detected no significant variations of intensity.


The Role of Immunonutrition in Patients Undergoing Pancreaticoduodenectomy.
Pancreaticoduodenectomy (PD) is one of the most difficult and complex surgical procedures in abdominal surgery. Malnutrition and immune dysfunction in patients with pancreatic cancer (PC) may lead to a higher risk of postoperative infectious complications. Although immunonutrition (IN) is recommended for enhanced recovery after surgery (ERAS) in patients undergoing PD for 5-7 days perioperatively, its role in patients undergoing pancreatectomy is still unclear and controversial. It is known that the proper surgical technique is very important in order to reduce a risk of postoperative complications, such as a pancreatic fistula, and to improve disease-free survival in patients following PD. However, it has been proven that IN decreases the risk of infectious complications, and shortens hospital stays in patients undergoing PD. This is a result of the impact on altered inflammatory responses in patients with cancer. Both enteral and parenteral, as well as preoperative and postoperative IN, using various nutrients, such as glutamine, arginine, omega-3 fatty acids and nucleotides, is administered. The most frequently used preoperative oral supplementation is recommended. The aim of this paper is to present the indications and benefits of IN in patients undergoing PD.


Endothelin-3 stimulates luteinizing hormone-releasing hormone (LHRH) secretion from LHRH neurons by a prostaglandin-dependent mechanism.
Endothelin (ET) peptides have recently been recognized as putative regulators of the endocrine system. Particularly in the gonadal system, ET-3 stimulates LH secretion from anterior pituitary cells cultured in vitro. In these studies, we evaluate the actions of ET-3, the most abundant species of the ET family in the central nervous system, on LHRH release from arcuate nucleus-median eminence (AN-ME) fragments and an LHRH-secreting neuronal cell line (GT1 cells) in vitro. ET-3 exhibited a stimulatory effect on LHRH secretion from AN-ME fragments and GT1 cells incubated in a static system as well as in a dynamic perifusion paradigm. In all the systems used, the effects of ET-3 on LHRH secretion showed a dose dependency. The increase in LHRH secretion induced by ET-3 was accompanied by an increased secretion of prostaglandin E2 (PGE2), not only in the AN-ME incubations, but also in the GT1 incubation and perifusion systems. Blockade of arachidonic acid and/or PG synthesis significantly reduced the ET-3-induced LHRH and concomitant PGE2 release from both AN-ME fragments and GT1 cells incubated in vitro. In AN-ME incubations, ET-3 effects were enhanced by potassium-induced depolarization. This suggests that activation of other transmitter system(s) may be needed for obtaining a physiological activation of the LHRH neuronal system. In summary, in these studies we provide evidence for a direct action of ET-3 on the LHRH neuronal system. This action is exerted directly on LHRH neurons either at the level of the nerve terminals, the perikaryon, or both. In addition, the effects of ET-3 on LHRH release require a functional arachidonic acid metabolic pathway, particularly involving PG synthesis, in order to obtain stimulation, indicating that PGs are involved in the intracellular events leading to ET-3-evoked LHRH secretion.


Relationship between Resistance to Ethambutol and Rifampin and Clinical Outcomes in Mycobacterium avium Complex Pulmonary Disease.
We evaluated the associations between the in vitro activities of ethambutol and rifampin and clinical outcomes of Mycobacterium avium complex (MAC) pulmonary disease (PD). Among 158 patients with MAC-PD, there was no relationship between high MICs for ethambutol and/or rifampin and treatment failure for MAC-PD. Ethambutol and rifampin resistance was common among MAC isolates (rates of 87% and 59%, respectively), but mutations in embB, rpoB, and rpoC were rare, with detection in only 4% of the drug-resistant MAC isolates.


Common variants in FKBP5 gene and major depressive disorder (MDD) susceptibility: a comprehensive meta-analysis.
Previous studies have investigated the association between common variants in FKBP5 and MDD; however, the results remain inconsistent. In order to conduct a comprehensive meta-analysis of the association between FKBP5 variants and MDD risk, seven studies involving 26582 subjects, including 12491 cases with MDD and 14091 controls, were enrolled totally. Four common SNPs (rs1360780, rs4713916, rs3800373 and rs755658) with complete data from two or more studies were analyzed. In the total sample, there was no evidence of a significant association between MDD and any of the four SNPs using a random-effects model. However, after removing one heterogeneous German study, as indicated by sensitivity analysis, both the rs1360780 T-allele (Z = 2.95, P = 0.003, OR = 1.06, 95% CI = 1.02-1.11) and the rs3800373 C-allele (Z = 3.05, P = 0.002, OR = 1.07, 95% CI 1.02-1.12) were significantly associated with MDD in a fixed-effect model. Our study thus provides support for an association between specific FKBP5 genetic variants and MDD risk. Rs4713916 was not significantly associated with MDD; However, this analysis had limited statistical power and larger sample sizes are required to further validate this result. Future research should also investigate possible gender- and ethnicity-specific differences in the association between FKBP5 and MDD.


Structures and Antibacterial Properties of Isorugosins H-J, Oligomeric Ellagitannins from Liquidambar formosana with Characteristic Bridging Groups between Sugar Moieties.
Three new ellagitannin oligomers, isorugosins H (1), I (2), and J (3), together with 11 known hydrolyzable tannins were isolated from an aqueous acetone extract of the fresh leaves of Liquidambar formosana. Their chemical structures were elucidated based on spectroscopic data and chemical conversion into known hydrolyzable tannins. The bridging mode of the valoneoyl groups between their sugar moieties has been identified only in this plant species. Additionally, the effects of the isorugosins isolated from this species on drug-resistant bacteria were evaluated and showed that isorugosin A (4) exhibited the most potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The isorugosins also had a suppressing effect on pigment formation in Pseudomonas aeruginosa. The isorugosin-protein complexes were analyzed using size-exclusion chromatography and polyacrylamide gel electrophoresis to clarify the relationship of their antibacterial properties with their protein interaction potency as hydrolyzable tannins. The results suggested that the antibacterial properties of hydrolyzable tannins are not simply a result of their binding activity to proteins, but are due to other factors such as the accessibility of polyphenolic acyl groups to bacterial membranes.


Relationship between density and ultrasonic velocity in Brazilian tropical woods.
In this study, the effect of density on the velocity of an ultrasonic wave in wood is investigated. The aim of the present study was to analyze the influence of density on the longitudinal velocity of an ultrasonic wave, propagated in the longitudinal direction. Experiments were conducted on 5cm x 5cm x 5cm wood specimens selected from the following species: pinus caribea (Pinus caribea var. caribea), eucalyptus citriodora (Eucalyptus citriodora), eucalyptus grandis (Eucalyptus grandis), cupiúba (Goupia glabra) and jatobá (Hymenaea sp.). The relationship between density and velocity was analyzed in two different manners: between and within species. The results obtained between species indicated that ultrasonic velocity tends to increase with increasing density. The results obtained within species also showed an increasing trend in ultrasonic velocity as density increased, but the relationship was not as significant as it was for between species.


Breast health promotion: behaviors of midlife women.
The breast is one of the leading sites of invasive cancer. The purpose of this study is to examine the relationships between health locus of control, perceived self-efficacy, demographic health characteristics, and the degree to which they explain the current and future practice of breast self-exam and mammography screening. Data were collected during 1992. Eighty-six women participating in a clinical breast exam and mammography screening program at an ambulatory women's center in a large metropolitan teaching hospital in the Midwest voluntarily completed four questionnaires. Hierarchical regression and discriminant analysis demonstrated that perceived self-efficacy was a significant predictor of health-promotion behavior, and health-promoting lifestyle and locus of control were the most influential predictors of intent for breast self-examination and ongoing mammography.


Is the measurement of serum formate concentration useful in the diagnostics of acute methanol poisoning? A prospective study of 38 patients.
The aim of this article was to study the role of serum formate (S-formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 - median age 51 [interquartile range (IQR) 37-62] years with confirmed methanol poisoning. S-formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S-formate. Asymptomatic patients had median S-formate of 1.9 (IQR 1.5-2.4) mmol/L. The median S-formate was 15.2 (IQR 13.9-17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1-18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8-18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p > 0.05). Patients with long-term visual sequelae of poisoning had median S-formate of 16.1 (IQR 14.3-19.9) mmol/L; with central nervous system (CNS) sequelae, patients had 15.9 (IQR 14.2-19.5) mmol/L. In lethal cases, the median S-formate was 15.2 (IQR 13.8-15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S-formate ≥17.5 mmol/L, S-lactate ≥7.0 mmol/L and/or pH <6.87. The ROC analysis showed that the corresponding areas under the curve (AUC) were 0.64 (0.44-0.85 CI 95%) for S-formate, 0.75 (0.56-0.93 CI 95%) for 'S-formate+S-lactate' and only 0.54 (0.38-0.69 CI 95%) for serum methanol, which is lower than for S-formate (p < 0.05). The measurement of S-formate is an important tool in the laboratory diagnostics and clinical management of acute methanol poisoning. S-formate ≥3.7 mmol/L can lead to the first clinical signs of visual toxicity, indicating haemodialysis. S-formate ≥11-12 mmol/L is associated with visual/CNS sequelae and a lethal outcome.


Duodeno-jejunal adenocarcinoma as a first presentation of coeliac disease.
Long standing coeliac disease is associated with an increased risk of malignancy, not only of intestinal lymphoma but also small intestinal adenocarcinoma. Two patients whose initial presentation was adenocarcinoma of the small bowel, but who were subsequently found to have coeliac disease after Whipple's resection, are described. The diagnosis was made early in the postoperative period in the first patient after close histological examination of the tumour-free mucosal margins. This patient was placed on a gluten-free diet and had an uncomplicated postoperative recovery with rapid weight gain. Diagnosis and dietary intervention in the second patient was very delayed and resulted in the development of severe malabsorption and weight loss. This illustrates the importance of ruling out coeliac disease prior to surgery in patients with small intestinal malignancies.


Cryptococcosis in solid-organ, hematopoietic stem cell, and tissue transplant recipients: evidence-based evolving trends.
The impact of current transplantation practices on the characteristics of cryptococcosis in solid-organ transplant recipients is not well defined. The incidence of cryptococcal disease among solid-organ transplant recipients has remained unchanged; however, patients are less likely to present with central nervous system or disseminated disease and are more likely to have cryptococcosis limited to the lungs. Additionally, lipid formulations of amphotericin B are now used more frequently, whereas their use in combination with flucytosine has decreased. The overall mortality of cryptococcosis has significantly improved in the current era. Renal failure remains associated with poor outcome, whereas use of lipid formulations of amphotericin B is associated with a higher survival rate. Despite rare infectious complication, certain peculiar attributes of cryptococcal disease in hematopoietic stem cell recipients and tissue transplant recipients warrant recognition.


Vascular endothelial growth factor concentrations from platelets correlate with tumor angiogenesis and grading in a spontaneous canine non-Hodgkin lymphoma model.
Published data strongly suggest that tumor progression and malignancy are associated with increased angiogenesis. However, no data have been published concerning the relationship between microvascular density (MVD), tumor cytosol, and blood vascular endothelial growth factor (VEGF) concentrations in canine non-Hodgkin lymphoma (C-NHL), a neoplasm that shares biological and clinical characteristics with human NHL. We have evaluated MVD and tumor cytosol, serum (S), platelet-poor plasma (P-PP), plasma-activated platelet rich (P-APR) VEGF concentration in a series of 63 B-cells C-NHL by means of immunohistochemistry and enzyme-linked immuno-sorbent assay (ELISA) detection of VEGF. We found that MVD, VEGF from cytosol, and VEGF from P-APR are significantly correlated (p ranging from 0.001 to 0.003) and that these parameters paralleled with the malignancy degree of NHL. Accordingly, spontaneous C-NHL seems to be an interesting model to study the role of angiogenesis as interspecies pathway of tumor malignancy and we suggest that VEGF from P-APR might be a novel useful circulating bio-marker of tumor angiogenesis.


Glycemic index and glycemic load in the Opuntia ficus-indica fruit
There is evidence that support the clinical usage of glycemic index (GI) and glycemic load (GL) in the prevention of chronic disease. To determine the GI and GL of the Opuntia ficus-indica fruit. An analytic, transversal study was made involving 25 healthy volunteers accepted by an informed consent with a normal body mass index, glucose, glycoside hemoglobin, cholesterol and serum triglycerides. The homogeneity of the population was evaluated with anthropometrical and biochemical data using principal component analysis (PCA). The equivalent of 50 g of carbohydrates test food (tuna) and 50 g of dextrose as food standard was provided for the measure of the glucose curve. The GI was determined by calculating the area under the curve by the triangulation method. The CG was reported as the product of IG by carbohydrate loading provided. The IG of the tuna was 48.01 ± 17.4, classified as low, while the CG was 24.0 ± 8.7 rated as high. The chemometric analysis by PCA showed that the selection of the normal population for determining the IG, it is important to consider the values of cholesterol and triglycerides.


A hollow sphere secondary structure of LiFePO4 nanoparticles.
We report on the evolution of a hollow sphere secondary structure of spherical nanoparticles by a solubilization-reprecipitation mechanism based on the difference of solubility products (K(sp)) of two different precipitates. Carbon-coated nanoparticles of olivine structure LiFePO(4) served as the primary nano-blocks to build the secondary nano-architecture.


Synthesis and biological evaluation of cycloalkylidene carboxylic acids as novel effectors of Ras/Raf interaction.
The protooncogenes Ras and Raf play important roles in signal transduction pathways regulated by mitogen-activated protein kinases. Mutations of Ras that arrest the protein in its active state are frequently implicated in tumor formation. We used Ras and Raf proteins in the yeast two-hybrid system to search for natural or synthesized substances capable of modulating Ras/Raf interaction by specifically binding to one of the interacting partners. We found that cycloalkylidene carboxylic acids enhanced Ras/Raf interaction by acting on the cysteine-rich domain of Raf. Several analogues of the active substance 2-cyclohexylidene propanoic acid were synthesized and the importance of the semicyclic double bond in the stabilization of Ras/Raf interaction was demonstrated. Variation of the size and the substituents of the cyclic system as well as the length of the carboxylic acid resulted in enhanced Ras/Raf interaction.


Anomalous systemic arterial supply of pulmonary sequestration in adult patients.
This study described the characteristics of the systemic arterial supply of pulmonary sequestration (PS) in an attempt to better distinguish PS from other acquired lesions. We identified 25 patients hospitalized at the Peking Union Medical College Hospital during January 2013 to December 2015 with the assistance of medical catalogers. Twenty-three patients with a definite diagnosis of "pulmonary sequestration" clinically or pathologically were included in the study. The medical records, imaging information, and pathological data were reviewed retrospectively. The general characteristics of the patients and the features of the anomalous arteries were summarized. Aberrant arterial supply of PS was found in all 23 (100%) cases. Among them, twenty patients received surgery, including 14 (70%) with aberrant arterial supply found before surgery, and the other 6 (30%) found during surgery. Nineteen (82.6%) patients had a single systematic arterial supply, with a median diameter of 8 mm. More than one arterial supplies were found in four (17.4%) cases. In 21 (91.3%) cases, the anomalous systemic artery originated from the descending thoracic aorta just adjacent to the sequestrated lung which it supplied, without the presence of accompanying bronchi. In twenty (87.0%) patients who received the surgical intervention, samples of 12 (85.7%) were proved to have elastic vessel walls, out of the 14 samples in which the anomalous systemic arteries were available for analysis. There are no certain pathology diagnostic criteria for the diagnosis of PS. The detecting of the aberrant systematic artery and distinguishing it from the bronchial arteries corresponded to certain lung abnormalities are the keys to the accurate diagnosis of pulmonary sequestration in adult patients. We propose that the characteristic features of the anomalous arteries include: Originating from aorta and its main branches, adjacent to the sequestrated area, directly running into the sequestrated mass without accompanying bronchus branch, being large in diameter, and having elastic vessel wall.


Predicting Hepatocellular Carcinoma Recurrence and Survival.
Beta blockers can inhibit tumor growth and metastases, while necroinflammation can enhance these tumor properties. The aim of this study was to determine whether beta blockers and necroinflammatory disease predict tumor recurrence and/or overall survival following potentially curative therapeutic interventions for patients with hepatocellular carcinoma (HCC). The medical records of 36 adults with non-metastatic HCC who had undergone surgical resections and/or radiofrequency ablation (RFA) were retrospectively reviewed. In addition to post-intervention beta blocker usage and serum alanine aminotransferase levels greater than 2xULN, other variables commonly associated with recurrences such as number and size of tumors, state of differentiation and vascular invasion were included in univariate and multivariate analyses for recurrence and survival. Vascular invasion (OR 29.3, 95% CI 2.6-33.6) and surgical resection (OR 0.19, 95% CI 0.04-0.90) emerged from univariate (p = 0.003 and 0.03 respectively) and multivariate (p = 0.005 and 0.048 respectively) regression as predictors of tumor recurrence whereas beta blocker usage (OR 0.03, 95% CL 0.04-0.9, p = 0.03) and tumor recurrence (OR 6.7, 95% CI 1.6-28.1, p = 0.026) correlated with overall mortality. Neither beta blocker usage nor serum ALT levels predict HCC recurrences, but beta blocker usage is associated with improved overall survival following potentially curative therapeutic interventions for HCC in adults.


Vincristine-Induced Neuropathy Presenting as Ptosis and Ophthalmoplegia in a 2-Year-Old Boy.
Vincristine is used in the treatment of leukemias, solid tumors, and lymphomas. A case of a 2-year-old boy undergoing treatment for leukemia who developed sudden onset bilateral ptosis and ophthalmoplegia along with generalized neuropathy due to vincristine's neurotoxic effects is presented. He was successfully treated with pyridoxine and pyridostigmine. The possible mechanisms of action and the treatment for vincristine-induced neuropathy are discussed. Prompt treatment and close follow-up is needed, especially in children because prolonged ptosis and motility restriction may have a profound effect on a child's visual function.


Treatment of lumbar lytic spondylolisthesis using osteoperiosteal transplants in young patients.
A series of 40 young patients with lumbar spondylolisthesis is presented. The patients were treated surgically using osteoperiosteal transplants as the fusion material. In 29 patients, the fusion was posterior and in 11 patients posterolateral. The loose posterior element was removed in eight patients in connection with fusion. The degree of slipping on admission was less than 30% in 18 patients (45%), 30 to 50% in 5 patients (12.5%), and more than half of the olisthetic vertebral body in 17 patients (42.5%). A good clinical result was obtained in 24 patients (60%), satisfactory in 11 (27.5%), and poor in 5 (12.5%). Solid union was obtained in 29 patients (72.5%), nonunion in 7 cases (17.5%), and in 4 patients (10%) the union was considered uncertain. One patient was reoperated on. The best results were obtained using posterior fusion, while the rate of nonunion was higher in the posterolateral group. The periosteum was taken from the anteromedial aspect of the tibia using a sharp chisel. The method gives clinical and radiological results comparable with those obtained using bone transplants.


Carboxymethylated polyethylenimine modified magnetic nanoparticles specifically for purification of His-tagged protein.
Employing immobilized metal-ion affinity chromatography and magnetic separation could ideally provide a useful analytical strategy for purifying His-tagged protein. In the current study, a facile route was designed to prepare CMPEI-Ni2+ @SiO2 @Fe3 O4 (CMPEI=carboxymethylated polyethyleneimine) magnetic nanoparticles composed of a strong magnetic core of Fe3 O4 and a Ni2+ -immobilized carboxymethylated polyethyleneimine coated outside shell, which was formed by electrostatic interactions between polyanionic electrolyte of carboxymethylated polyethyleneimine and positively charged surface of 3-(trimethoxysilyl)propylamin modified SiO2 @Fe3 O4 . The resulting CMPEI-Ni2+ @SiO2 @Fe3 O4 composite nanoparticles displayed well-uniform structure and high magnetic responsiveness. Hexa His-tagged peptides and purified His-tagged recombinant retinoid X receptor alpha were chosen as the model samples to evaluate the adsorption, capacity, and reusability of the composite nanoparticles. The results demonstrated the CMPEI-Ni2+ @SiO2 @Fe3 O4 nanoparticles possessed rapid adsorption, large capacity, and good recyclability. The obtained nanoparticles were further used to purify His-tagged protein in practical environment. It was found that the nanoparticles could selectively capture His-tagged recombinant retinoid X receptor protein from complex cell lysate. Owing to its easy synthesis, large binding capacity, and good reusability, the prepared CMPEI-Ni2+ @SiO2 @Fe3 O4 magnetic nanoparticles have great potential for application in biotechnological fields.


[Comparative study of the detection of serum folate with improved microbial assay and electrochemiluminescence method].
To compare the result of serum folate determined by improved microbial assay and electrochemiluminescence method, and to look for the relationship between them, so as to provide basis for the assessment of nutrition status of folate in population. A total of 258 serum samples were examined by improved microbial assay and electrochemiluminescence method. The correlation and consistence of the two method were analyzed. The result showed that the correlation coefficient of the two method was 0. 885, which indicated that the result of two method were highly correlated. Results of Bland-Altman method showed that 94. 5% of the values were within the consistency limit, and the Kappa value of Kappa test was 0. 665. The result of consistency analysis showed that there were some differences between the two methods, and the result of serum folate tested by improved microbial assay were higher than that of electrochemiluminescence method in general. The result of serum folate tested by electrochemiluminescence were highly correlated with the improved microbial assay, yet there are some differences in the consistency result between the two methods. Evaluating the nutrition status of folate by electrochemiluminescence may lead to a higher number of folate deficiency.


Time-Dependent Molecular Rearrangement of [Au(N9-adeninate)(PTA)] in Aqueous Solution and Aggregation-Induced Emission in a Hydrogel Matrix.
An in-depth study of the molecular rearrangement of the complex [Au(N9-adeninate)(PTA)] (1), promoted in aqueous solution, is presented. This complex, which has been previously described as forming dimers in its crystalline form, is also demonstrated as being able to assemble into an infinite AuI···AuI chain polymer. The structural motifs are tentatively related to the dramatic modification of the photoemissive properties of 1 in water solution at long times, with the aid of UV-vis and photoluminescence measurements, PGSE-NMR, and theoretical calculations. A subtle equilibrium in favor of aurophilically governed aggregates has been envisaged as the driving force of the molecular rearrangement. Furthermore, 1 has been explored as an additive of the hydrogel of [Au(N9-adeninate)(PMe3)] (2) for a further tuning of its photophysical properties without loss of the gel texture.


Pediatric cardiopulmonary bypass devices: trends in device use for cardiopulmonary bypass and postcardiotomy support.
Cardiopulmonary bypass (CPB) devices and techniques have continuously evolved. We have conducted surveys that chronicle the changes in CPB devices and techniques used at North American pediatric cardiac surgery centers since 1989. The aim of this article is to describe trends in cardiopulmonary bypass device use during cardiac surgery and changes in the devices used for extracorporeal life support (ECLS) following cardiac surgery for pediatric patients. The diffusion of innovation in pediatric cardiovascular surgery has not been solely driven by the availability of scientific evidence to support change but rather it has often been related to other factors that influence clinicians willingness to change including; tradition, ease of use, and cost related pressures. The current CPB systems used for cardiac surgery are more homogenous than in previous years. Most centers use a heparin coated or modified surface system comprised of a "hard shell" open venous reservoir, a roller pump, a hollow fiber membrane oxygenator, and arterial line filter. ECLS systems comprised of hollow fiber oxygenators and centrifugal pumps for are gradually replacing the classical ECLS circuit, servo regulated roller pumps and silicone rubber membranes. Nearly 40% of centers use these alternate components in their ECLS systems. Costs, utility, safety and measurable benefit to the patient should guide decisions related to device selection.


Investigating the relationship between the severity of periodontitis and rheumatoid arthritis: a cross-sectional study.
This paper evaluates the prevalence and severity of periodontitis (PD) in patients with rheumatoid arthritis (RA), focusing on the link between the severity of PD with RA disease activity/disability scores, the influence of RA treatment on PD, and levels of vitamin D. A total of 93 RA patients were enrolled in the cross-sectional study and analyzed accordingly as RA-PD (N = 63, 67.8%) and RA-only (N = 30, 32.2%) groups. A number of associations between rheumatological clinical data, i.e., Disease Activity Score (DAS28 CRP), health assessment questionnaires, and PD severity (measured by periodontal outcome parameters) with regard to serum levels of vitamin D were assessed. The outcome variables were compared by parametric and non-parametric tests. A total of 29% of RA patients were diagnosed with severe PD. The RA-PD group presented a higher mean DAS28 CRP score in moderate-severe PD compared to periodontally healthy-initial stage PD subjects (4.49 ± 1.22 vs. 3.86 ± 1.58, p = 0.033). RA patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) were less likely to be diagnosed with PD (p = 0.022) and revealed significantly lower PD outcome parameters, i.e., bleeding on probing (%) and bone loss (%) (p < 0.05). Vitamin D concentration was significantly lower in RA-PD group with diagnosed advanced severe PD (IV stage) compared to moderate PD (II stage) (39.61 ± 17.12 vs. 52.07 ± 18.23 nmol/l, p = 0.031). The study revealed a high prevalence of severe PD in RA patients, being significantly associated with higher RA disease activity and lower vitamin D level in RA-PD group, while bDMARD treatment was related to lower PD outcome parameters. Key Points • Severe PD is prevalent amongst RA patients and is associated with RA disease activity. The higher RA DAS28 CRP score is associated with moderate-severe PD compared to periodontally healthy-initial stage PD in RA patients. • Biologic DMARDs treatment used for RA is linked to lower PD rates and PD outcome parameters. • Significantly lower vitamin D level is found in advanced severe PD compared to moderate PD stage in RA-PD subjects.


Living donor liver transplantation for hepatocellular carcinoma: the Japanese experience.
Treatment strategies against hepatocellular carcinoma have progressed remarkably over the past decade. In Asia, evidence-based guidelines for the management of hepatocellular carcinoma have evolved, including the option of liver transplantation. Due to severe organ shortage, however, living donor liver transplantation has become mainstream in Japan. Unlike deceased donor transplantation, living donor transplantation is not limited by the restrictions imposed by the nationwide allocation system. The decision for transplantation often depends on institutional or case-by-case considerations, balancing the will of the donor, the operative risk, and the overall survival benefit for the recipient. Cumulative data from the national multicenter registry analysis as well as individual center experience suggest that expansion of the Milan criteria is warranted.


Health literacy among neurosurgery and other surgical subspecialties: Readability of online patient materials found with Google.
To both determine whether the most high-yield online patient materials for surgical specialties meet the 6th grade readability level recommended by the National Institutes of Health (NIH) and American Medical Association (AMA), and to discover differences in readability across specialties. We hypothesize average readability scores will exceed an 11th grade level. The top five most common procedures for each of seven surgical specialties (neurological, orthopedic, plastic, general, thoracic, pediatric, and vascular) were searched using an incognito Google query to minimize location bias. The text from the top five patient-relevant links per procedure, excluding Wikipedia, journal articles, and videos, was extracted and inserted into Readability Studio Software for analysis. The combined average grade level of materials (± standard deviation) was: 10.47 ± 2.51 Flesh-Kincaid Grade Level (FKGL), 11-12 New Dale-Chall (NDC), 10.09 ± 1.97 Simple Measure of Gobbledygook (SMOG), 12 Fry Graph (FG). Thoracic, neurologic, vascular, plastic, and orthopedic were least readable (grade level 10+ by all metrics). High readability of procedure materials for patients is not unique to neurosurgery: all specialties exceeded the recommended 6th grade level by three or more grades. Online patient education materials related to surgical subspecialties must be written more comprehensibly.


Inter-rater and test-retest reliability of the Danish version of the everyday technology use questionnaire.
Everyday technologies are naturally integrated in people's daily life. For older adults and adults living with a chronic disease like chronic obstructive pulmonary disease (COPD), the ability to use technologies for health management has become increasingly important. The aim of this study was to investigate inter-rater and test-retest reliability of the Danish version of the Everyday Technology Use Questionnaire (ETUQ) in a sample of older adults with (n = 23) and without (n = 24) COPD. The ETUQ was initially translated in accordance with the dual panel approach and then administered to a sample of 47 participants. Svensson's method for paired ordinal data was utilized to calculate and analyze reliability. Overall, inter-rater and test-retest reliability of the Danish version of the ETUQ demonstrated excellent percentage agreement (PA) (>75%), although for test-retest reliability, nine items demonstrated fair (53%) to good (73%) agreement. This study supports the use of the Danish version of the ETUQ in a sample of older adults with or without COPD. Application to practice: The Danish version of the ETUQ is an evidence-based evaluation that can reliably contribute to clinical occupational therapy and research in Denmark focusing on everyday technology use.


Clip-induced biliary stone.
Surgical clip migration is a well-known phenomenon ever since their first use in surgery. The mechanism of clip migration is poorly understood, and can occur from days to years after laparoscopic cholecystectomy. Migration of the surgical clips may be a complex process involving necrosis, pressure exerted from intra-abdominal movement, formation of stones over the exposed clip within the bile duct, and eventual migration into the common bile duct. We report two cases, a 58-year-old man and a 54-year-old woman, of clip- induced biliary stones resulting from surgical clip migration a few years after laparoscopic cholecystectomy.


Understanding the Reactivity and Regioselectivity of Methylation of Nitronates [R(1)R(2)CNO2](-) by CH3I in the Gas Phase.
Methylation of [R(1)R(2)CNO2](-), where R(1) = R(2) = H (1), R(1) = CH3 and R(2) = H (2), R(1) = R(2) = CH3 (3), and R(1) + R(2) = c-(CH2)2 (4), by CH3I was studied by an ab initio MP2/CBS method, RRKM theory, and kinetic simulations. Contrary to a previous proposal for the reaction mechanism, C-methylation is the preferred pathway of thermodynamics and kinetics. This is corroborated by the agreement between the calculated and experimental reactivity trend 4 ≫ 3 > 2 > 1. The regioselectivity toward C-alkylation is explained by the much larger exothermicity of this reaction channel compared to that of O-alkylation. The increase in reactivity with an increase in the crowdedness of the central carbon atom is explained by differences in sp(3) character at this atom and the decrease in the vibrational frequency associated with pyramidalization around this carbon atom.


Triacontanol and Its Second Messenger 9-beta-l(+)-Adenosine as Plant Growth Substances.
Triacontanol (TRIA), a common constituent of plant waxes, was first shown in 1977 to be an active growth substance which at nanomolar concentrations increased the growth and yield of crops. TRIA is used to increase crop yields on millions of hectares, particularly in Asia. Many investigators have shown that it affects several basic metabolic processes including photosynthesis, nutrient uptake, and enzyme activity. However, the initial site of action has not been elucidated. TRIA rapidly elicits a second messenger (TRIM) in rice (Oryza sativa L.), which at nanomolar concentrations causes plants to respond in a manner similar to TRIA. TRIM has been identified as 9-beta-l(+)-adenosine (9H-purin-6-amine, 9-beta-l-ribofuranosyl). During the process of isolating and identifying 9-beta-l(+)-adenosine, it was shown that this enantiomer, which previously has not been reported as occurring in nature, made up about 1% of the total adenosine pool in roots from untreated rice seedlings.


T cells in atherosclerosis.
Atherosclerosis is a chronic inflammatory disease of the artery wall. Atherosclerotic lesions contain monocytes, macrophages, smooth muscle cells and T lymphocytes. Here, we review the role of T-lymphocyte subsets in atherosclerosis. Among CD4⁺T cells, T(h)1 cells are pro-atherogenic, T(reg) cells are athero-protective and the role of T(h)2 and T(h)17 cells remains unclear. The role of follicular helper T cells in atherosclerosis remains unknown, as is the role of CD8⁺T cells. NKT cells bind glycolipid antigens and exert a pro-atherogenic role. The antigen specificity of T-cell responses in atherosclerosis is poorly understood. In order to enable antigen-specific prevention or therapy, a better understanding of these mechanisms is needed.


B-1 cells modulate oral tolerance in mice.
Although the origin and functions of B-1 cells are controversial, they are considered as a cellular element of innate immunity due to their ability to produce natural autoantibodies of the IgM type. These antibodies are encoded by a relatively limited repertoire of V genes, and their resulting diversity is smaller than that produced by conventional B cells. B-1 cells constitute the larger fraction of B cells in the peritoneal cavity and migrate to non-specific inflammation sites. In addition, they contribute to the production of IgA antibodies in the intestinal lamina propria. It has been demonstrated that they participate in the induction and maintenance of peripheral tolerance. Herein, the participation of B-1 cells in inducing oral tolerance is evaluated. Unexpectedly, BALB/Xid mice, the animals deficient in B-1 cells, are not tolerized to OVA but instead are responsive to oral immunization. Conversely, BALB/c mice respond to oral tolerance to this antigen. We used these biological characteristics of these animals to investigate whether B-1 cells are involved in the induction of oral tolerance to OVA. Results show that B-1 cells from BALB/c mice, treated orally with OVA and adoptively transferred to BALB/Xid mice were able to suppress local hypersensitivity reaction and lymphoproliferative cellular response observed in BALB/Xid mice. These data demonstrate that B-1 cells have regulatory properties and are involved in the induction of oral tolerance.


The non-conventional use of 99mTc-Tetrofosmine for dynamic hepatobiliary scintigraphy.
Classic dynamic hepatobiliary scintigraphy (DHBS) is commonly performed with 99mTc-Iminodiacetic Acid (IDA) derivatives and represents a non-invasive diagnosis method for biliary dyskinesia, fistulas, surgical anastomosis, etc (1). This study assesses the possibility of performing DHBS with 99mTc-Tetrofosmine (TF), a radiopharmaceutical (RF) dedicated to myocardial perfusion scintigraphy (MPS), but being excreted through the liver. The possibility to use 99mTc-TF for DHBS may be important in situations when the standardized RF for this procedure (IDA derivatives) is not available. We performed DHBS for 30 patients referred for investigation by internal medicine and surgery departments. The patients had been fasting for 12 hours. The dynamic investigation started simultaneously with the intravenous (IV) administration of 37-110 MBq (1-3 mCi) 99mTc-TF. Dynamic images were recorded for 30-45 minutes, one image per minute, followed by static scintigraphy at 1 h, 1.5 h, 2 h, and 3 h after IV injection. The quality of scintigraphic images of the liver and biliary tree obtained at DHBS with 99mTc-TF ensured the correct diagnosis of biliary dyskinesia, stasis, stenosis, and fistulas. DHBS using 99mTc-TF is justified by the image quality and by the good cost/benefits ratio. Because the IDA derivatives are not always available, this finding may be important for medical practice. 99mTc-TF evacuated through the bile duct allows DHBS interpretation, while the necessary dose is approximately 8 to 20 times smaller than that used for myocardial perfusion scintigraphy.


Computationally modeling mammalian succinate dehydrogenase kinetics identifies the origins and primary determinants of ROS production.
Succinate dehydrogenase (SDH) is an inner mitochondrial membrane protein complex that links the Krebs cycle to the electron transport system. It can produce significant amounts of superoxide ([Formula: see text]) and hydrogen peroxide (H2O2); however, the precise mechanisms are unknown. This fact hinders the development of next-generation antioxidant therapies targeting mitochondria. To help address this problem, we developed a computational model to analyze and identify the kinetic mechanism of [Formula: see text] and H2O2 production by SDH. Our model includes the major redox centers in the complex, namely FAD, three iron-sulfur clusters, and a transiently bound semiquinone. Oxidation state transitions involve a one- or two-electron redox reaction, each being thermodynamically constrained. Model parameters were simultaneously fit to many data sets using a variety of succinate oxidation and free radical production data. In the absence of respiratory chain inhibitors, model analysis revealed the 3Fe-4S iron-sulfur cluster as the primary [Formula: see text] source. However, when the quinone reductase site is inhibited or the quinone pool is highly reduced, [Formula: see text] is generated primarily by the FAD. In addition, H2O2 production is only significant when the enzyme is fully reduced, and fumarate is absent. Our simulations also reveal that the redox state of the quinone pool is the primary determinant of free radical production by SDH. In this study, we showed the importance of analyzing enzyme kinetics and associated side reactions in a consistent, quantitative, and biophysically detailed manner using a diverse set of experimental data to interpret and explain experimental observations from a unified perspective.


Interactions of chlorophyll-derived photosensitizers with human serum albumin are determined by the central metal ion.
Two structurally similar derivatives of chlorophyll a, chlorophyllide a (Chlide) and zinc-pheophorbide a (Zn-Pheide), differing only in central metal ion (Mg2+ or Zn2+, respectively) substituting the tetrapyrrole ring, were investigated with regard to their binding to human serum albumin (HSA). Chlide and Zn-Pheide are very promising photosensitizers with potential application in photodynamic therapy, therefore it is desirable to investigate their interactions with serum proteins. The studies included absorption and steady-state fluorescence spectroscopy, as well as molecular docking. It was found that both investigated compounds form complexes with HSA. Experimental data revealed two classes of binding sites for each compound. The affinities (Ka) for the first class were in the range of 105 and 106 M-1 for Chlide and Zn-Pheide, respectively, while the second class was characterized by the affinities of the order of 104 M-1 for both derivatives. Molecular docking simulations together with displacement studies revealed that the primary binding site of the studied compounds is the heme site, localized in the subdomain IB, however the best characterized binding sites of HSA, namely the Sudlow's sites I and II are also involved. The interactions between the derivatives of chlorophyll and HSA were found to be predominantly hydrophobic and to a lesser extent hydrogen bonding. Our results demonstrate that the centrally bound metal ion determines both the affinity and mode of binding to HSA, which may be a feature differentiating these compounds in terms of their pharmacokinetics.Communicated by Ramaswamy H. Sarma.


Hand hygiene in hospitals: an observational study in hospitals from two southern states of India.
Hand hygiene is a simple and low-cost measure to reduce healthcare associated infection yet it has always been a concern in low as well as high resource settings across the globe. Poor hand hygiene during intra-partum and newborn care may result in sepsis, which is a major cause of death among newborns and puts a financial burden on already strained health systems. We conducted non-participatory observations in newborn care units and labour rooms from secondary and tertiary level, public and private hospitals, as part of a baseline evaluation of a quality improvement collaborative across two southern states of India. We assessed hand hygiene compliance during examinations and common procedures, using tools adapted from internationally recommended checklists and World Health Organization's concept of five moments of hand hygiene. We assessed differences in compliance by type (public/private), level (secondary/tertiary) and case load (low/intermediate/high). Analysis was adjusted for clustering and weighted as appropriate. We included 49 newborn care units (19 private, 30 public) and 35 labour rooms (5 private, 30 public) that granted permission. We observed 3661 contacts with newborns and their environment, 242 per-vaginal examinations and 235 deliveries. For the newborns, a greater proportion of contacts in private newborn units than public complied with all steps of hand hygiene (44% vs 12%, p < 0.001), and similarly in tertiary than secondary units (33% vs 12%, p < 0.001) but there was no evidence of a difference by case load of the facility (low load-28%; intermediate load-14%; high load- 24%, p = 0.246). The component with lowest compliance was glove usage where indicated (20%). For deliveries, hand hygiene compliance before delivery was universal in private facilities but seen in only about one-quarter of observations in public facilities (100% vs 27%, p = 0.012). Average overall compliance for hand-hygiene during per-vaginal examinations was 35% and we found no evidence of differences by type of facility. Observed compliance with hand hygiene was low overall, although better in private than public facilities in both newborn units and labour rooms. Glove usage was a particular problem in newborn care units. Retrospectively registered with Clinical Trials Registry- India ( CTRI/2018/04/013014 ).


Ovarian steroids modulate leu-enkephalin levels and target leu-enkephalinergic profiles in the female hippocampal mossy fiber pathway.
In the hippocampal formation (HF), the enkephalin opioids and estrogen are each known to modulate learning and cognitive performance relevant to drug abuse. Within the HF, leu-enkephalin (LENK) is most prominent in the mossy fiber (MF) pathway formed by the axons of dentate gyrus (DG) granule cells. To examine the influence of ovarian steroids on MF pathway LENK levels, we used quantitative light microscopic immunocytochemistry to evaluate LENK levels in normal cycling rats and in estrogen-treated ovariectomized rats. Rats in estrus had increased levels of LENK-immunoreactivity (ir) in the DG hilus compared to rats in diestrus or proestrus. Rats in estrus and proestrus had higher levels of LENK-ir in CA3a-c compared to rats in diestrus. Ovariectomized (OVX) rats 24 h (but not 6 or 72 h) after estradiol benzoate (EB; 10 microg) administration had increased LENK-ir in the DG hilus and CA3c. Electron microscopy showed a larger proportion of LENK-labeled small terminals and axons in the DG hilus compared to CA3 which may have contributed to region-specific changes in LENK-ir densities. Next we evaluated the subcellular relationships of estrogen receptor (ER) alpha, ERbeta and progestin receptor (PR) with LENK-labeled MF pathway profiles using dual-labeling electron microscopy. ERbeta-ir colocalized in some LENK-labeled MF terminals and smaller terminals while PR-ir was mostly in CA3 axons, some of which also showed colocalization with LENK. ERalpha-ir was in dendritic spines, but no colocalization with LENK-labeled profiles was observed. The present studies indicate that estrogen can modulate LENK in subregions of the MF pathway in a dose-and time-dependent manner. These effects might be triggered by direct activation of ERbeta or PR in LENK-containing terminals.


Eight-year operation status and data analysis of the first human milk bank in East China.
Human milk banks (HMBs) are essential facilities for the selection, collection, testing, transportation,storage, and distribution of DHM for special medical needs. The aim of this analysis was to analyze the operation status and data over the last 8 years of operation of the first human milk bank (HMB) in East China. Data related to the costs, donors, donation, pasteurization, and recipients were extracted from the web-based electronic monitoring system of the HMB for the period August 1, 2013 to July 31, 2021. Over the 8 years of operation, 1,555 qualified donors donated 7,396.5L of qualified milk at a cost of ¥1.94 million($306,051), with the average cost per liter of donor human milk being ¥262.3($41.4). The donors were between 25 and 30 years of age, and the majority (80.1%) were primipara. All the donated milk was pasteurized and subjected to bacteriological tests before and after pasteurization: 95.4% passed the pre-pasteurization tests, and 96.3% passed the post-pasteurization tests. A total of 9,207 newborns received 5,775.2L of pasteurized donor milk. The main reason for the prescription of donor human milk was preterm birth. As a result of continuous quality improvements, January 2016 witnessed a significant increase in the volume of qualified DHM and the number of qualified donors. However, in 2020, as a result of the restrictions related to the COVID-19 pandemic, the volume of qualified DHM and the number of qualified donors decreased. Over its 8 years of operation, our HMB has made steady quality improvements in its screening and information processes. Continuous quality improvement is on ongoing need, along with recruiting more qualified donors and collecting donor human milk for vulnerable newborns.


Epidemiological aspects of heart diseases.
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Coronary heart disease (CHD) is the main cause of mortality in heart patients following stroke, rheumatic heart disease and myocardial infarctions. Approximately 80% of individuals succumb to CVDs, due to poor living conditions in low and middle income families and malnutrition. Infectious diseases, human immunodeficiency, tuberculosis, malaria, high blood pressure or hypertension, obesity and overweight, and nutritional disorders including smoking, excessive alcohol consumption, high salt and sugar intake, as well as other factors are responsible for CVDs and CHDs in young as well as elderly individuals. The focus of the present review are recent epidemiological aspects of CVD and CHD as well as the usefulness of a Mediterranean diet for heart patients and the prevention of heart diseases.


Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes.
Streptozotocin (STZ), a glucose analogue known to induce diabetes in experimental animals, causes DNA strand breaks and subsequent activation of poly(ADPribose) polymerase (Parp). Because Parp uses NAD as a substrate, extensive DNA damage will result in reduction of cellular NAD level. In fact, STZ induces NAD depletion and cell death in isolated pancreatic islets in vitro. Activation of Parp therefore is thought to play an important role in STZ-induced diabetes. In the present study, we established Parp-deficient (Parp-/-) mice by disrupting Parp exon 1 by using the homologous recombination technique. These mice were used to examine the possible involvement of Parp in STZ-induced beta-cell damage in vivo. The wild-type (Parp+/+) mice showed significant increases in blood glucose concentration from 129 mg/dl to 218, 370, 477, and 452 mg/dl on experimental days 1, 7, 21, and 60, respectively, after a single injection of 180 mg STZ/kg body weight. In contrast, the concentration of blood glucose in Parp-/- mice remained normal up to day 7, slightly increased on day 21, but returned to normal levels on day 60. STZ injection caused extensive necrosis in the islets of Parp+/+ mice on day 1, with subsequent progressive islet atrophy and loss of functional beta cells from day 7. In contrast, the extent of islet beta-cell death and dysfunction was markedly less in Parp-/- mice. Our findings clearly implicate Parp activation in islet beta-cell damage and glucose intolerance induced by STZ in vivo.


Topography of the neurotensin (NT)(8-9) binding site of human NT receptor-1 probed with NT(8-13) analogs.
A series of neurotensin (NT)(8-13) analogs featuring substitution of the Arg8 and/or Arg9 residues with non-natural cationic amino acids was synthesized and evaluated for binding to the human NT receptor-1 (hNTR-1). The modifications were designed to probe specific steric and electrostatic requirements in the N-terminal cationic region of NT(8-13) for receptor binding as a general evaluation of the feasibility of incorporating minor structural changes into a peptide at a crucial polar receptor binding site. Many of the non-natural amino acids are more or less isosteric to Arg but more lipophilic as a result of addition of alkyl groups or through removal or replacement of NH character with methylene or methyl substituents, whereas others vary the distance between the cation and the alpha-amino acid carbon. Substitution of Arg8 with N(G)-alkylated Arg derivatives or homolysine (Hlys) maintained the subnanomolar affinity of NT(8-13) to the hNTR-1. Position 8 incorporation of Hlys produced the most favorable primary amine side-chain substitution to date. Moderate losses in affinity observed with position 9 substitutions were attributed to adverse steric effects. Doubly substituted [Hlys8, DAB9]NT(8-13), in which DAB is 2,4-diaminobutyric acid, was also prepared and tested as the shorter side-chain of DAB is known to be favored in position 9 of NT(8-13). This analog maintained 60% of NT(8-13) binding affinity making it the most favored des-guanidinium-containing analog known. These results demonstrate that adequate receptor binding affinity can be maintained over a structural range of Arg analogs, thus providing a range of peptides expected to exhibit altered pharmacokinetic properties. From the standpoint of the hNTR-1 cationic binding sites, these results help to map out the structural stringency inherent in the formation of a tight binding complex with NT(8-13) and related analogs.


[Ototoxic effect and its prevention in administration of cisplatin].
Short-latent acoustic evoked potentials were registered in examination of hearing function in guinea pigs given platinum compounds. A protective action of thiol compounds (sodium thiosulfate and unitiol) was tried in relation to hypoacusis induced by cisplatinum.


Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma.
Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O6-methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.


Assessing the plausibility of life on other worlds.
As the field of astrobiology matures and search strategies for life on other worlds are developed, the need to analyze in a systematic way the plausibility for life on other planetary systems becomes increasingly apparent. We propose the adoption of a simple plausibility of life (POL) rating system based on specific criteria. Category I applies to any body shown to have conditions essentially equivalent to those on Earth. Category II applies to bodies for which there is evidence of liquid water and sources of energy and where organic compounds have been detected or can reasonably be inferred (Mars, Europa). Category III applies to worlds where conditions are physically extreme but possibly capable of supporting exotic forms of life unknown on Earth (Titan, Triton). Category IV applies to bodies that could have seen the origin of life prior to the development of conditions so harsh as to make its perseverance at present unlikely but conceivable in isolated habitats (Venus, Io). Category V would be reserved for sites where conditions are so unfavorable for life by any reasonable definition that its origin or persistence there cannot be rated a realistic probability (the Sun, gas giant planets). The proposed system is intended to be generic. It assumes that life is based on polymeric chemistry occurring in a liquid medium with uptake and degradation of energy from the environment. Without any additional specific assumptions about the nature of life, the POL system is universally applicable.


Addressing the clinical unmet needs in primary Sjögren's Syndrome through the sharing, harmonization and federated analysis of 21 European cohorts.
For many decades, the clinical unmet needs of primary Sjögren's Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing. Federated AI algorithms were trained across the harmonized databases, with reduced execution time complexity, yielding robust lymphoma classification models with 85% accuracy, 81.25% sensitivity, 85.4% specificity along with 5 biomarkers for lymphoma development. To our knowledge, this is the first GDPR compliant platform that provides federated AI services to address the pSS clinical unmet needs.


Use of intravenous immunoglobulin to delay xenogeneic hyperacute rejection. An in vivo and in vitro evaluation.
The delaying action of intravenous immunoglobulin (IVIG) from human origin on hyperacute xenogeneic rejection was assessed in the guinea pig-to-rat combination. IVIG (1500 mg/kg) injected i.v. into Lewis rats 1 hr before grafting significantly prolonged the mean guinea pig heart survival time (167 min, P < 0.005) compared with control injections using NaCl (12 min) or the IVIG glycine vehicle (11 min). The effect of IVIG was also assessed in vitro in the pig-to-human combination. A dose-dependent inhibition of the complement-mediated direct cytotoxicity of human serum on pig RBC was shown using IVIG. The weak direct cytotoxicity of IVIG to pig RBC, which was abolished after preincubating IVIG with pig RBC, was attributed to the anti-pig xenoreactive natural antibodies (XNA) contained in the IVIG preparation. In vitro, XNA-depleted IVIG exerted a significantly stronger inhibitory effect than non-XNA-depleted IVIG, suggesting the use XNA-depleted IVIG in the pig-to-human combination. Although the mechanism of the inhibitory effect of IVIG remains to be clarified, IVIG may represent a new and simple therapeutic modality against xenogeneic hyperacute rejection.