[Absorption of a vaginal contraceptive, nonoxynol (polyoxyethylene nonylphenyl ether) and its metabolism to nonylphenol in female rabbits].
After intravaginal administration of a spermicide, nonoxynol (polyoxyethylene nonylphenyl ether, NPE) in female rabbits, the pharmacokinetics of NPE were examined by the HPLC method. The plasma levels after administration of NPE revealed a considerable amount of absorption of NPE into the circulation and the bioavailability after intravaginal administration was calculated to be 66% by comparison with that after intravenous administration. Unchanged NPE was not excreted into the urine in significant amounts even on intravenous administration. Nonylphenol (NP), a presumed metabolite of NPE, was simultaneously analyzed using GC-MS to assess the risk by its endocrine disrupting effects. Although the NP concentrations in the plasma were all below the lower limit of quantitation (10 ng/ml), small amounts of NP and its glucuronide conjugate were detected in the urine after intravaginal administration of NPE. Thus it was suggested that at least part of NPE absorbed in the circulation was metabolized to give NP. However, the sum of NP and its conjugate excreted in the urine was very small amounts (0.22% of dose). Therefore, it was assumed that the production of NP was not in the major pathway of the NPE metabolism.


Multiple Facets of the Poisson Distribution Applicable to Health Physics Measurements.
This paper discusses several ways to view the standard Poisson distribution as applied to health physics scaler counts. The intent is not so much to present calculational details but rather to present some underlying concepts. Examples are provided that illustrate the various concepts for several types of specific measurements. The concepts presented involve purely Poisson-based contributions to variance; extra-Poisson variance is presently ignored, and any counting system would be presumed to function properly and without counting loss.


Cross-Seeding with Homologous Sequences Alters Amyloid Aggregation Kinetics and Fibril Structure.
Protein aggregation through homotypic interactions is a hallmark of neurodegenerative diseases. Recently, heterotypic amyloid interactions through cross-seeding were found to modify protein aggregation and are reported in the brain of Alzheimer's disease patients. However, whether amyloid-β (Aβ) assembly can be modulated by heterotypic interactions between Aβ aggregation-prone regions (APRs) and short homologous segments in unrelated human proteins needs to be elucidated. A recent study revealed that the aggregation kinetics and fibril morphology of Aβ is altered by heterotypic interactions between its APRs and homologous segments of unrelated proteins. The data provide novel insights into the structure, origins, and aggregation principles of the amyloid assembly process.


Allogeneic stem cell transplantation for patients with mantle cell lymphoma who failed autologous stem cell transplantation: a national survey of the SFGM-TC.
Poly-chemotherapy plus rituximab followed by autologous stem cell transplantation (auto-SCT) is standard care for untreated young patients with mantle cell lymphoma (MCL). Despite this intensive treatment, transplant patients remain highly susceptible to relapse over time. The French SFGM-TC performed a national survey on reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) for fit relapsed/refractory patients who failed after auto-SCT (n=106). Median times of relapse after auto-SCT, and from auto-SCT to RIC-allo-SCT were 28 months and 3.6 years, respectively. Sixty per cent of patients received at least three lines of treatment before RIC-allo-SCT. Conditioning regimens for RIC-allo-SCT were heterogeneous. Twenty patients experienced grade III/IV aGvHD, extensive cGvHD was reported in 28 cases. Median follow-up after RIC-allo-SCT was 45 months. Median PFS after RIC-allo-SCT was 30.1 months and median overall survival was 62 months. Treatment-related mortality (TRM) at 1 year and 3 years were estimated at 28% and 32%, respectively. A total of 52 patients died; major causes of death were related to toxicity (n=34) and MCL (n=11). Patients in good response before RIC-allo-SCT experienced a better PFS and OS. Our work highlights the need for new RIC-allo-SCT MCL-tailored approaches to reduce TRM, and early and late relapse.


Regulation of Exercise-Induced Autophagy in Skeletal Muscle.
Physical exercise is a highly effective method to prevent several pathogenic conditions, such as obesity, type 2 diabetes and cardiovascular diseases, largely due to metabolic adaptations induced by exercise in skeletal muscle. Yet how exercise induces the beneficial effects in muscle remains to be fully elucidated. Autophagy is a lysosomal degradation pathway that regulates nutrient recycling, energy production and organelle quality control. The autophagy pathway is upregulated in response to stress during exercise and muscle contraction, and may be an important mechanism mediating exercise-induced health benefits. A number of studies have indicated that physical exercise induces non-selective autophagy and selective mitophagy in skeletal muscle in animal models and humans. The AMPK-ULK1 and the FoxO3 signaling pathways play an essential role in the activation of the upstream autophagy machinery in skeletal muscle during exercise. The autophagy activity is required for health benefits of exercise, as in different autophagy-deficient mouse lines exercise-induced effects are abolished. This review aims to summarize and highlight the most recent findings on the role of autophagy in muscle maintenance, the molecular pathways that upregulate autophagy during exercise, and the potential functions of exercise-induced autophagy and mitophagy in skeletal muscle.


Description of Bucephalus anguillae n. sp. (Trematoda: Bucephalidae), a parasite of the eel Anguilla anguilla (Anguillidae) from a brackish water lagoon of the Adriatic Sea.
The digenetic trematode Bucephalus anguillae n. sp. is described from the intestine of eel, Anguilla anguilla L., originating from a brackish water fish farm on the Italian coast of the Adriatic Sea. The new taxon is 1 of 12 Bucephalus species characterized by an anterior rhynchus surrounded by 7 tentacular appendages, each when fully protruded with 2 prongs. Scanning electron microscopy reveals, for the first time in a Bucephalus species, the crescent-shaped, unspined field located between the rhynchus and the dorsal tentacles. A comparison of B. anguillae n. sp. with 11 congeneric species revealed its remarkable similarity with B. polymorphus Baer, 1827; however, the new species has a larger cirrus sac, larger pharynx, vitelline gland fields not extending the level of pharynx, ovary located in the pharyngeal area rather than fairly posterior to pharynx, smaller testes, relatively wider rhynchus, and tegumental armature comprising slightly larger spines. Multivariate discriminant analyses confirmed a differentiation of B. anguillae from populations of B. polymorphus; the combination of 4 variables, namely cirrus sac length, pharynx width, cirrus sac width, and rhynchus width yielded a total separation of compared species.


[Mode and size of HPA-typed platelet apheresis donor bank in Chinese Han population].
This study was purposed to determine the mode and size of human platelet antigens (HPA) typed platelet apheresis donor bank. The published data of HPA distribution collected from Chinese Han population of 16 provinces were analyzed. The combined data were tested with the Hardy-Weinberg equilibrium. The results showed that the bb homozygote was not detected in HPA-1, -4, -6, -10, and b gene was not found in HPA-7-9, 11-14, -16. There were 648 combined HPA 1-16 genotypes in Chinese Han population, and the cumulative frequency of 42 combinations higher than 0.001 were 0.9763. The highest frequency (0.2012) in combination was HPA-(7-8-9-11-12-13-14-16) aa - (1-4-5-6-10) aa-2aa-3ab-15ab. The probability of HPA dual antigen mismatch in HPA-15, -3 and -2 was higher than the 0.1, and the probability in the HPA-1, -5, and -6 was between 0.01 - 0.1. The probability of full-match in HPA1-16 antigens was 0.3195 in Chinese Han population after the random blood transfusion. According to the curve drawn by donor number (N) versus frequency (F), the regression equation LogN = -0.4394 x Ln (F) +0.4324 was derived at P = 95%. If the derived frequency (product of HPA frequency and ABO frequency) is 0.005, then the N should be 576.07 at least in Chinese Han population. It is concluded that the mode of regional, multi-center database of HPA-typed platelet apheresis donor bank may be acceptable in Chinese Han population, and the suitable number of HPA-typed platelet donor in one bank may be 600. Therefore, the bank can be used to treat the platelet transfusion refractoriness (PTR) caused by HPA-15, 3 and 2 mismatch mainly, and can be expanded effectively in similar genetic background to deal with the low-frequency HPA antigens mismatch. The number of HPA-typed platelet apheresis donor influences not only on the frequency of HPA, but also on the frequency of ABO group.


Improving Estimates of Sulfur, Nitrogen, and Ozone Total Deposition through Multi-Model and Measurement-Model Fusion Approaches.
Earth system and environmental impact studies need high quality and up-to-date estimates of atmospheric deposition. This study demonstrates the methodological benefits of multimodel ensemble and measurement-model fusion mapping approaches for atmospheric deposition focusing on 2010, a year for which several studies were conducted. Global model-only deposition assessment can be further improved by integrating new model-measurement techniques, including expanded capabilities of satellite observations of atmospheric composition. We identify research and implementation priorities for timely estimates of deposition globally as implemented by the World Meteorological Organization.


Site-specific tryptophan fluorescence spectroscopy as a probe of membrane peptide structure and dynamics.
The fluorescence from tryptophan contains valuable information about the environment local to the indole side-chain. This environment sensitivity coupled with the ability to synthetically or genetically incorporate a single tryptophan residue at specific sites in a polypeptide sequence has provided the membrane biophysicist with powerful tools for examining the structure and dynamics of membrane peptides and proteins. Here we briefly review the use of site-specific tryptophan fluorescence spectroscopy to probe aspects of peptide orientation, structure, and dynamics in lipid bilayers, focusing on recent developments in the literature.


Vascular Endothelial Growth Factor Receptor-1 Is Synthetic Lethal to Aberrant {beta}-Catenin Activation in Colon Cancer.
PURPOSE: The Wnt/beta-catenin (beta-cat) signaling cascade is a key regulator of development, and dysregulation of Wnt/beta-cat contributes to selected cancers, such as colorectal, breast, and hepatocellular carcinoma, through abnormal activation of Wnt target genes. To identify novel modulators of the Wnt/beta-cat pathway that may emerge as therapeutic targets, we did an unbiased high-throughput RNA interference screen. EXPERIMENTAL DESIGN: A synthetic oligonucleotide small interfering RNA library targeting 691 known and predicted human kinases was screened in Wnt3a-stimulated human cells in a live cell luciferase assay for modulation of Wnt/beta-cat-dependent transcription. Follow-up studies of a selected high-confidence "hit" were conducted. RESULTS: A robust quartile-based statistical analysis and secondary screen yielded several kinases worthy of further investigation, including Cdc2L1, Lmtk3, Pank2, ErbB3, and, of note, vascular endothelial growth factor receptor (VEGFR)1/Flt1, a receptor tyrosine kinase (TK) with putative weak kinase activity conventionally believed to be a negative regulator of angiogenesis. A series of loss-of-function, genetic null, and VEGFR TK inhibitor assays further revealed that VEGFR1 is a positive regulator of Wnt signaling that functions in a glycogen synthase kinase-3beta (GSK3beta)-independent manner as a potential synthetic lethal target in Wnt/beta-cat-addicted colon carcinoma cells. CONCLUSIONS: This unanticipated non-endothelial link between VEGFR1 TK activity and Wnt/beta-cat signaling may refine our understanding of aberrant Wnt signaling in colon carcinoma and points to new combinatorial therapeutics targeted to the tumor cell compartment, rather than angiogenesis, in the context of colon cancer. (Clin Cancer Res 2009;15(24):7529-37).


Transforming growth factor beta 1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors.
The processes of bone resorption and bone formation are tightly coupled in young adults, which is crucial to maintenance of bone integrity. We have documented that osteoclasts secrete chemotactic agents to recruit osteoblast lineage cells, contributing to coupling. Bone formation subsequent to bone resorption becomes uncoupled with aging, resulting in significant bone loss. During bone resorption, osteoclasts release and activate transforming growth factor beta 1 (TGF-β1) from the bone matrix; thus, elevated bone resorption increases the level of active TGF-β in the local environment during aging. In this study, we examined the influences of TGF-β1 on the ability of osteoclasts to recruit osteoblasts. TGF-β1 increased osteoclast expression of the chemokine CXCL16 to promote osteoblast migration. TGF-β1 also directly stimulated osteoblast migration; however, this direct response was blocked by conditioned medium from TGF-β1-treated osteoclasts due to the presence of leukemia inhibitory factor (LIF) in the medium. CXCL16 and LIF expression was dependent on TGF-β1 activation of Smad2 and Smad3. These results establish that TGF-β1 induces CXCL16 and LIF production in osteoclasts, which modulate recruitment of osteoblasts to restore the bone lost during the resorptive phase of bone turnover.


Identification of differentially expressed genes in rat silicosis model by suppression subtractive hybridization analysis.
The critical molecular mechanism in the development of the pulmonary fibrosis remains unknown, leaving diagnosed patients with a poor prognosis. To isolate the genes specifically up-regulated in pulmonary fibrosis, we established a rat silicosis model 360 d after treatment with crystalline silica suspension. Radiographs of chests showed that some scattered high-density shadows appeared in the lung field. Typical microscopic fibrosing silicotic nodules formed in the lung, alveolar epithelial cells and bronchial epithelial cells, particularly around the partial fibrosing silicotic nodules; some of them showed atypical hyperplasia that suggested a correlation between silicosis and lung cancer. Suppression subtractive hybridization analysis was performed to compare gene expression in lung tissue with silicosis and normal lung tissue. Reverse transcription-polymerase chain reaction showed that the expressions of seven novel cDNA sequences identified by suppression subtractive hybridization in lung tissue with silicosis differed from normal lung tissue. Bioinformatics analysis showed that 47 positive clones represented 35 genes containing two putative proteins and four predicted similar proteins. The analysis also showed that some screened genes in silicosis, such as prolyl 4-hydroxylases, actin-related protein-2/3 complex and acidic mammalian chitinase, have not been previously reported. These genes may provide new clues for investigating the molecular mechanisms in the development of pulmonary fibrosis.


Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis.
To compare the serum concentrations of itraconazole and hydroxyitraconazole after treatment with itraconazole cyclodextrin solution and itraconazole capsules in human immunodeficiency virus (HIV) positive patients with oral candidosis. The pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole were assessed on days 1 and 7 of therapy in acquired immunodeficiency syndrome (AIDS) patients with oral candidosis taking either itraconazole solution or capsules and the serum concentrations (measured by high performance liquid chromatography) correlated with the clinical response to therapy. In addition, the in vitro susceptibility of Candida spp isolates taken from patients at the start of the therapy was assessed. Nine of 16 patients treated with itraconazole capsules and eight of 15 treated with the solution responded to treatment. Three of the non-responders in each treatment group were infected with isolates resistant to itraconazole in vitro. Although with both preparations there was considerable inter-patient variability in the maximum recorded serum concentrations of itraconazole, they were significantly lower on day 1 and day 7 in those receiving capsules compared with those taking the solution. Patients unresponsive to therapy, but infected with susceptible isolates, had significantly lower concentrations of itraconazole and hydroxyitraconazole levels on days 1 and 7 than patients responding to treatment. However, patients infected with itraconazole resistant isolates (tested in vitro) failed to respond to treatment despite achieving similar serum concentrations of itraconazole and hydroxy-itraconazole to the responsive patients. For patients with in vitro susceptible isolates a serum itraconazole concentration of < 1000 ng/ml on day 7 was predictive of therapeutic failure (specificity 71%, sensitivity 100%). Itraconazole cyclodextrin solution achieves higher serum itraconazole and hydroxy-itraconazole concentrations than the capsule formulation in AIDS patients, and this is associated with improved efficacy.


Allosteric threonine synthase. Reorganization of the pyridoxal phosphate site upon asymmetric activation through S-adenosylmethionine binding to a novel site.
Threonine synthase (TS) is a fold-type II pyridoxal phosphate (PLP)-dependent enzyme that catalyzes the ultimate step of threonine synthesis in plants and microorganisms. Unlike the enzyme from microorganisms, plant TS is activated by S-adenosylmethionine (AdoMet). The mechanism of activation has remained unknown up to now. We report here the crystallographic structures of Arabidopsis thaliana TS in complex with PLP (aTS) and with PLP and AdoMet (aTS-AdoMet), which show with atomic detail how AdoMet activates TS. The aTS structure reveals a PLP orientation never previously observed for a type II PLP-dependent enzyme and explains the low activity of plant TS in the absence of its allosteric activator. The aTS-AdoMet structure shows that activation of the enzyme upon AdoMet binding triggers a large reorganization of active site loops in one monomer of the structural dimer and allows the displacement of PLP to its active conformation. Comparison with other TS structures shows that activation of the second monomer may be triggered by substrate binding. This structure also discloses a novel fold for two AdoMet binding sites located at the dimer interface, each site containing two AdoMet effectors bound in tandem. Moreover, aTS-AdoMet is the first structure of an enzyme that uses AdoMet as an allosteric effector.


Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet.
Metabolic flexibility is the ability to switch metabolism between carbohydrate oxidation (CHO) and fatty acid oxidation (FAO) and is a biomarker for metabolic health. The effect on metabolic health of nicotinamide riboside (NR) as an exclusive source of vitamin B3 is unknown and is examined here for a wide range of NR. Nine-week-old male C57BL/6JRcc mice received a semi-purified mildly obesogenic (40 en% fat) diet containing 0.14% L-tryptophan and either 5, 15, 30, 180, or 900 mg NR per kg diet for 15 weeks. Body composition and metabolic parameters were analyzed. Metabolic flexibility was measured using indirect calorimetry. Gene expression in epididymal white adipose tissue (eWAT) was measured using qRT-PCR . The maximum delta respiratory exchange ratio when switching from CHO to FAO (maxΔRERCHO1→FAO ) and when switching from FAO to CHO (maxΔRERFAO→CHO2 ) were largest in 30 mg NR per kg diet (30NR). In eWAT, the gene expression of Pparγ, a master regulator of adipogenesis, and of Sod2 and Prdx3, two antioxidant genes, were significantly upregulated in 30NR compared to 5NR. 30NR is most beneficial for metabolic health, in terms of metabolic flexibility and eWAT gene expression, of mice on an obesogenic diet.


Investigation of the additive potential of teniposide and vincristine in non-Hodgkin's lymphoma. Australian and New Zealand Lymphoma Group.
Two hundred forty-seven patients with non-Hodgkin's lymphoma were randomized to receive doxorubicin, cyclophosphamide, and prednisolone in combination with vincristine (ACVP) or teniposide (ACTP) or both vincristine and teniposide (ACTVP). ACVP produced 44% complete remissions (CRs) and 32% partial remissions (PRs), whereas ACTP produced 46% CRs and 33% PRs and ACTVP produced 47% CRs and 36% PRs. Survival and relapse-free survival were also comparable for the three arms. The majority (59%) of patients had diffuse large cell lymphoma. Within this group, CR was achieved in 52% and no significant difference was observed in the response rates, survival, or relapse-free survival for the three treatment arms. Toxic effects occurred with equivalent frequency in the three regimens, except for neurotoxicity and myelosuppression. Moderate to severe neurotoxicity occurred in 20% of ACTVP-treated patients and in 8% of ACVP-treated patients but was not seen in any of the ACTP-treated patients (P = 0.0004). Severe myelosuppression occurred in 27% of ACTVP-treated patients and in 22% of ACTP-treated patients but only in 8% of ACVP-treated patients (P = 0.02), indicating an increased risk of myelosuppression for the combinations including teniposide. These results confirm our previous findings that teniposide can replace vincristine in the treatment of non-Hodgkin's lymphoma, with freedom from neurotoxicity and comparable survival and response rates. However, the combined use of teniposide and vincristine in the schedule as described has not increased response rates or survival but has instead added to neurotoxicity.


Adipose triglyceride lipase is implicated in fuel- and non-fuel-stimulated insulin secretion.
Reduced lipolysis in hormone-sensitive lipase-deficient mice is associated with impaired glucose-stimulated insulin secretion (GSIS), suggesting that endogenous beta-cell lipid stores provide signaling molecules for insulin release. Measurements of lipolysis and triglyceride (TG) lipase activity in islets from HSL(-/-) mice indicated the presence of other TG lipase(s) in the beta-cell. Using real time-quantitative PCR, adipose triglyceride lipase (ATGL) was found to be the most abundant TG lipase in rat islets and INS832/13 cells. To assess its role in insulin secretion, ATGL expression was decreased in INS832/13 cells (ATGL-knockdown (KD)) by small hairpin RNA. ATGL-KD increased the esterification of free fatty acid (FFA) into TG. ATGL-KD cells showed decreased glucose- or Gln + Leu-induced insulin release, as well as reduced response to KCl or palmitate at high, but not low, glucose. The K(ATP)-independent/amplification pathway of GSIS was considerably reduced in ATGL-KD cells. ATGL(-/-) mice were hypoinsulinemic and hypoglycemic and showed decreased plasma TG and FFAs. A hyperglycemic clamp revealed increased insulin sensitivity and decreased GSIS and arginine-induced insulin secretion in ATGL(-/-) mice. Accordingly, isolated islets from ATGL(-/-) mice showed reduced insulin secretion in response to glucose, glucose + palmitate, and KCl. Islet TG content and FFA esterification into TG were increased by 2-fold in ATGL(-/-) islets, but glucose usage and oxidation were unaltered. The results demonstrate the importance of ATGL and intracellular lipid signaling for fuel- and non-fuel-induced insulin secretion.


Agrobacterium VirE2 protein mediates nuclear uptake of single-stranded DNA in plant cells.
Agrobacterium genetically transforms plant cells by transferring a single-stranded DNA (ssDNA) copy of the transferred DNA (T-DNA) element, the T-strand, in a complex with Agrobacterium proteins VirD2, bound to the 5' end, and VirE2. VirE2 binds single-stranded nucleic acid cooperatively, fully coating the T-strand, and the protein localizes to the plant cell nucleus when transiently expressed. The coupling of ssDNA binding and nuclear localizing activities suggests that VirE2 alone could mediate nuclear localization of ssDNA. In this study, fluorescently labeled ssDNA accumulated in the plant cell nucleus specifically when microinjected as a complex with VirE2. Microinjected ssDNA alone remained cytoplasmic. Import of VirE2-ssDNA complex into the nucleus via a protein import pathway was supported by (i) the inhibition of VirE2-ssDNA complex import in the presence of wheat germ agglutinin or a nonhydrolyzable GTP analog, both known inhibitors of protein nuclear import, and (ii) the retardation of import when complexes were prepared from a VirE2 mutant impaired in ssDNA binding and nuclear import.


Tracing TET1 expression in prostate cancer: discovery of malignant cells with a distinct oncogenic signature.
Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in DNA demethylation and transcriptional regulation, plays a key role in the maintenance of stem cell pluripotency, and is dysregulated in malignant cells. The identification of cancer stem cells (CSCs) driving tumor growth and metastasis is the primary objective of biomarker discovery in aggressive prostate cancer (PCa). In this context, we analyzed TET1 expression in PCa. A large-scale immunohistochemical analysis of TET1 was performed in normal prostate (NOR) and PCa using conventional slides (50 PCa specimens) and tissue microarrays (669 NOR and 1371 PCa tissue cores from 371 PCa specimens). Western blotting, RT-qPCR, and 450 K methylation array analyses were performed on PCa cell lines. Genome-wide correlation, gene regulatory network, and functional genomics studies were performed using publicly available data sources and bioinformatics tools. In NOR, TET1 was exclusively expressed in normal cytokeratin 903 (CK903)-positive basal cells. In PCa, TET1 was frequently detected in alpha-methylacyl-CoA racemase (AMACR)-positive tumor cell clusters and was detectable at all tumor stages and Gleason scores. Pearson's correlation analyses of PCa revealed 626 TET1-coactivated genes (r > 0.5) primarily encoding chromatin remodeling and mitotic factors. Moreover, signaling pathways regulating antiviral processes (62 zinc finger, ZNF, antiviral proteins) and the pluripotency of stem cells were activated. A significant proportion of detected genes exhibited TET1-correlated promoter hypomethylation. There were 161 genes encoding transcription factors (TFs), of which 133 were ZNF-TFs with promoter binding sites in TET1 and in the vast majority of TET1-coactivated genes. TET1-expressing cells are an integral part of PCa and may represent CSCs with oncogenic potential.


ATG 4B Serves a Crucial Role in RCE-4-Induced Inhibition of the Bcl-2-Beclin 1 Complex in Cervical Cancer Ca Ski Cells.
RCE-4, a steroidal saponin isolated from Reineckia carnea, has been studied previously and has exhibited promising anti-cervical cancer properties by inducing programmed cell death (PCD) of Ca Ski cells. Considering the cancer cells developed various pathways to evade chemotherapy-induced PCD, there is, therefore, an urgent need to further explore the potential mechanisms underlying its actions. The present study focused on targeting the Bcl-2-Beclin 1 complex, which is known as the key regulator of PCD, to deeply elucidate the molecular mechanism of RCE-4 against cervical cancer. The effects of RCE-4 on the Bcl-2-Beclin 1 complex were investigated by using the co-immunoprecipitation assay. In addition, autophagy-related genes (ATG) were also analyzed due to their special roles in PCD. The results demonstrated that RCE-4 inhibited the formation of the Bcl-2-Beclin 1 complex in Ca Ski cells via various pathways, and ATG 4B proteins involved in this process served as a key co-factor. Furthermore, based on the above, the sensitivity of RCE-4 to Ca Ski cells was significantly enhanced by inhibiting the expression of the ATG 4B by applying the ATG 4B siRNA plasmid.


Oxidative DNA damage in humans: comparison between high and low habitual fruit and vegetable consumption.
We investigated whether men with a habitual high consumption of vegetables and fruit have a lower excretion of 8 oxo 7,8 dihydro 2 deoxyguanosine 8 oxodG, a urinary marker for oxidative DNA damage, than men with a low consumption of vegetables and fruit. Ten pairs of healthy non smoking males aged between 28 and 59 years, matched for age 10 years and body mass index 2 kg m 2 were selected from a dietary validation study. Habitual food intake was estimated with 12 monthly 24 h recalls. Men in the high vegetable and fruit group consumed an average of 224 g day 1 range 101-330 g day 1 more vegetables and fruit than men in the low vegetable and fruit group. Excretion of 8 oxodG was 95 pmol kg 1 day 1 95 CI-29, 219 higher in the high vegetable and fruit group than in the low vegetable and fruit group paired t test, P = 0.11 . Excretion of 8 oxodG was not correlated with intake of vitamins, energy, fat, nor with blood concentrations of antioxidant pro vitamins, but it was inversely correlated with age. The present findings do not suggest that humans with a habitual high fruit and vegetables consumption have less oxidative DNA damage as measured by 8 oxodG excretion than men with low consumption of fruit and vegetables.


Effects of Green Tea Powder, Pomegranate Peel Powder, Epicatechin and Punicalagin Additives on Antimicrobial, Antioxidant Potential and Quality Properties of Raw Meatballs.
Alternative technologies, which have been developed in order to meet the consumers' demand for nourishing and healthy meat and meat products, are followed by the food industry. In the present study, it was determined, using the HPLC method, that green tea contains a high level of epicatechin (EP) under optimal conditions and that pomegranate peel contains a high level of punicalagin (PN). Green tea, pomegranate peel, EP and PN were added to meatballs at different concentrations in eight groups. The antioxidant capacities of extracts were measured. The antimicrobial activity was examined for 72 h using three different food pathogens. The highest level of antimicrobial activity was achieved in the 1% punicalagin group, whereas the minimum inhibition concentration (L. monocytogenes, S. typhimurium) was found to be 1.87 mg/mL. A statistically significant decrease was found in FFA, POV and TBARS levels of meatballs on different days of storage (p < 0.05). When compared to the control group, the bioactive compounds preserved the microbiological and chemical properties of meatballs during storage at +4 °C (14 days). It was concluded that the extracts with high EP and PN concentrations can be used as bio-preservative agents for meat and meat products.


Improvement of Methane-Framework Interaction by Controlling Pore Size and Functionality of Pillared MOFs.
The rational design of functionalized porous metal-organic frameworks (MOFs) for gas adsorption applications has been applied using three spacer ligands H2DPT (3,6-di(pyridin-4-yl)-1,4-dihydro-1,2,4,5-tetrazine), DPT (3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine), and BPDH (2,5-bis(4-pyridyl)-3,4-diaza-2,4-hexadiene) to synthesize TMU-34, [Zn(OBA)(H2DPT)0.5]n·DMF, TMU-34(-2H), [Zn(OBA)(DPT)0.5]n·DMF, and TMU-5, [Zn(OBA)(BPDH)0.5]n·1.5DMF, respectively. By controlling the pore size and chemical functionality of these three MOFs, we can improve the interactions between CO2 and especially CH4 with the frameworks. Calculated Qst(CH4) for TMU-5, TMU-34, and TMU-34(-2H) are 27, 23, and 22 kJ mol-1, respectively. These Qst values are among the highest for CH4-framework interactions. For systematic comparison, two reported frameworks, TMU-4 and TMU-5, have been compared with TMU-34 and TMU-34(-2H) in CO2 adsorption.


Evidence for the involvement of a capsaicin-sensitive innervation in the afferent branch of micturition reflex in rats.
Functional evidence is presented indicating the presence in the rat urinary bladder of a capsaicin-sensitive innervation which is involved in regulating micturition threshold. Endogenous substance P and/or related tachykinins appear to be present in the capsaicin-sensitive nerve endings of the rat bladder and may play a neurotransmitter role in relaying information concerned with bladder volume from the detrusor muscle to the central nervous system. In addition, neurotransmitter release from the peripheral ending of the capsaicin-sensitive fibers may play an efferent role in certain motor and/vascular responses at bladder muscle level.


Direct activation of human phospholipase C by its well known inhibitor u73122.
Phospholipase C (PLC) enzymes are an important family of regulatory proteins involved in numerous cellular functions, primarily through hydrolysis of the polar head group from inositol-containing membrane phospholipids. U73122 (1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione), one of only a few small molecules reported to inhibit the activity of these enzymes, has been broadly applied as a pharmacological tool to implicate PLCs in diverse experimental phenotypes. The purpose of this study was to develop a better understanding of molecular interactions between U73122 and PLCs. Hence, the effects of U73122 on human PLCβ3 (hPLCβ3) were evaluated in a cell-free micellar system. Surprisingly, U73122 increased the activity of hPLCβ3 in a concentration- and time-dependent manner; up to an 8-fold increase in enzyme activity was observed with an EC50=13.6±5 μm. Activation of hPLCβ3 by U73122 required covalent modification of cysteines as evidenced by the observation that enzyme activation was attenuated by thiol-containing nucleophiles, l-cysteine and glutathione. Mass spectrometric analysis confirmed covalent reaction with U73122 at eight cysteines, although maximum activation was achieved without complete alkylation; the modified residues were identified by LC/MS/MS peptide sequencing. Interestingly, U73122 (10 μm) also activated hPLCγ1 (>10-fold) and hPLCβ2 (∼2-fold); PLCδ1 was neither activated nor inhibited. Therefore, in contrast to its reported inhibitory potential, U73122 failed to inhibit several purified PLCs. Most of these PLCs were directly activated by U73122, and a simple mechanism for the activation is proposed. These results strongly suggest a need to re-evaluate the use of U73122 as a general inhibitor of PLC isozymes.


[Bony bridges of the lumbar transverse processes].
A traumatic osseous bridge between lumbar transverse processes is a bone formation occurring after severe or even mild trauma of the back. However, only few of the patients with a contusion of the back or a fracture of a lumbar transverse process develop such an osseous bridge. The localisation of the haematoma plays an important role in this process, but myositis ossificans is a mandatory condition. Anamnesis will not lead to traumatic aetiology in all cases, because sometimes the patient is not aware of the fact that a transverse process has been fractured. The diagnosis finally depends on the recognition of the different shapes. The traumatic osseous bridge is characterised by the kind of trauma that causes the fracture of the transverse process. The shapes can be classified as "h", "H", "K", or "Z". Among 72 patients with inter-transverse osseous bridges, only 11 patients have congenital bridges. The congenital osseous bridge shows typical features that can be explained by means of embryogenic and functional dynamic considerations. These symptoms are the O-shape, concavity of the lumbar spine of a pathological nature and the absence of degenerative changes in the corresponding intervertebral space.


2007Autopsy Patterns in 2003.
Objectives-This report presents information on autopsy data in 2003 and compares data for 1993 and 2003. Methods-Death certificates are completed by funeral directors, attending physicians, medical examiners, and coroners. The original records are filed in the state registration offices. Statistical information is compiled into a national database through the Vital Statistics Cooperative Program of the Centers for Disease Control and Prevention's National Center for Health Statistics. This report focuses on the autopsy item on the death certificate and presents descriptive tabulations. Results-In 2003, autopsies were performed for 7.7 percent of deaths occurring in 47 states and the District of Columbia. This was less than in 1994, when the data was last available in this database. Decedents with particular characteristics were more likely to be autopsied than others. For example, almost one-third of infant deaths, more than one-half of decedents aged 15-24 years, and almost none of the decedents aged 85 years and over were autopsied.


Visual perspective in autobiographical memories: reliability, consistency, and relationship to objective memory performance.
Visual perspective in autobiographical memories was examined in terms of reliability, consistency, and relationship to objective memory performance in a sample of 99 individuals. Autobiographical memories may be recalled from two visual perspectives--a field perspective in which individuals experience the memory through their own eyes, or an observer perspective in which individuals experience the memory from the viewpoint of an observer in which they can see themselves. Participants recalled nine word-cued memories that differed in emotional valence (positive, negative and neutral) and rated their memories on 18 scales. Results indicate that visual perspective was the most reliable memory characteristic overall and is consistently related to emotional intensity at the time of recall and amount of emotion experienced during the memory. Visual perspective is unrelated to memory for words, stories, abstract line drawings or faces.


Neonatal malrotation with midgut volvulus mimicking duodenal atresia.
The purpose of this study was to describe the clinical, imaging, and surgical findings in the cases of four neonates with radiographic findings suggesting duodenal atresia (double-bubble sign) who were subsequently found to have malrotation with midgut volvulus. When the surgical treatment of a patient with the double-bubble sign is to be delayed, an upper gastrointestinal radiographic or ultrasound study is needed to evaluate for malrotation with midgut volvulus.


Workplace violence and its association with quality of life among mental health professionals in China during the COVID-19 pandemic.
Mental health professionals are often exposed to workplace violence (WPV) in China. This study examined the prevalence of WPV and the associated factors and quality of life (QOL) among frontline mental health professionals during the COVID-19 pandemic. This national survey was carried out between March 15 and March 20, 2020. WPV and QOL were assessed with standardized measures. A total of 10,516 participants were included. The prevalence of overall WPV was 18.5% (95% CI: 17.9%-19.3%), while verbal abuse/threats was 15.8% and physical violence was 8.4%. Multiple logistic regression analysis revealed that male gender (OR = 1.42, p < 0.01), higher educational level (OR = 1.40, p < 0.01), working in tertiary hospitals (OR = 1.33, p < 0.01), caring for COVID-19 patients (OR = 3.10, p < 0.01) and having more severe anxiety symptom (OR = 1.21, p < 0.01) were positively associated with WPV. In contrast, working in inpatient departments (OR = 0.74, p < 0.01), having longer work experience (OR = 0.99, p = 0.03), and being a junior nurse (OR = 0.73, p < 0.01) were negatively associated with WPV. After controlling for the covariates, mental health professionals who experienced WPV had a lower overall QOL compared to those without WPV (F(1, 10515) = 68.28, p < 0.01). This study found that WPV was common among mental health professionals in China during the COVID-19 pandemic. Considering the negative impact of WPV on QOL and quality of patient care, appropriate measures to prevent WPV should be developed.


A rapid, early detection of oral squamous cell carcinoma: Real time PCR based detection of tetranectin.
The current study is focused on determining the mRNA expression levels of tetranectin, to detect oral squamous cell carcinoma (OSCC) and thus aiding in its classification at an early stage. RNA was isolated and cDNA synthesis was performed from the saliva samples of the patients and healthy individuals. A semiquantitative PCR based analysis was performed prior to quantitative and expression based analysis using Real time PCR. The study showed that the mRNA levels are much lesser in patients suffering from dysplastic and metastatic tumors as compared to healthy individuals (P≤0.05). This study can be a breakthrough in medical and dentistry studies. One of the most common malignant carcinomas, OSCC is a type of cancer of the mouth. Though surgical methods have been quite effective in delaying the metastasis, the detection methods using histology parameters are not very efficient and the disease is diagnosed generally in the last stages of the cancer. Tetranectin is a protein biomarker which has been used for detection of several cancers including oral cancer where the protein quantity is calculated.


Prevalence of known and previously unknown diabetes mellitus and impaired glucose tolerance in an adult Norwegian population. Indications of an increasing diabetes prevalence. The Nord-Trøndelag Diabetes Study.
To establish the prevalence of known and undiagnosed diabetes mellitus and impaired glucose tolerance in a representative Norwegian adult population according to the 1980 World Health Organization Expert Committee diagnostic criteria. Screening survey applying questionnaire and non-fasting blood glucose followed by a fasting and an oral glucose tolerance test. The county of Nord-Trøndelag, Norway, 1984-86. All inhabitants aged > or = 20 years (85,100); 90.3% participated. For previously unknown diabetes: all inhabitants > or = 40 years (53,001)--participation rate 84.7%. Prevalence. The prevalence of previously known diabetes was 2.6% in men and 3.2% in women. Total diabetes prevalence > or = 40 years was 4.8% in men and 5.6% in women. The prevalence increased continuously with age until 90 years. One patient in five was previously undiagnosed. Impaired glucose tolerance in those with an abnormal non-fasting value was rare; only 0.9% in men and 0.2% in women. The prevalence of known diabetes was three times higher than 20-30 years ago and four times higher than 50 years ago. Except for known diabetes in the very old the prevalence corresponded well with recent Nordic studies. The present diabetes prevalence was so high that interested general practitioners will get sufficient experience in follow-up of diabetic patients to facilitate a good quality of the care.


Dynamic-intentional thalamic aphasia: a failure of lexical-semantic self-activation.
Previous research has described patients with aphasia from thalamic lesions, some of whom were non-fluent with intact comprehension, others who were fluent with impaired comprehension, and some of whom are non-fluent with impaired comprehension. Whereas these three subtypes usually have normal repetition, they had impaired naming, suggesting a deficit in lexical (phonological word forms)-semantic processing. We report a patient with a left thalamic hemorrhage in which lexical-semantic representations appear to be intact but the patient demonstrates an inability to spontaneously activate his lexical-semantic system. A 82-year-old, right-handed man presented with decreased verbal fluency and memory loss following a thalamic hemorrhage. Neuropsychological assessment revealed significant decrements in verbal fluency with intact naming, comprehension, repetition and vocabulary. To the best of our knowledge this pattern of language disturbance, which mirrors dynamic aphasia induced by frontal lesions, has not previously been described with thalamic injury. The thalamus has strong connections with the frontal lobe and rather than degradation of lexical-semantic representations, this patient's thalamic lesion probably induced frontal lobe dysfunction with a failure to spontaneously active lexical semantic representations.


Multicomponent Synthesis of 2-(2,4-Diamino-3-cyano-5H-chromeno[2,3-b]pyridin-5-yl)malonic Acids in DMSO.
Dimethyl sulfoxide is a widely used solvent in organic synthesis and in the pharmaceutical industry because of its low cost, stability, and low toxicity. Multicomponent reactions are an advanced approach that has become an efficient, economical, and eco-friendly substitute for the conventional sequential multi-step synthesis of various biologically active compounds. This approach was adopted for the synthesis of previously unknown 2-(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-5-yl)malonic acids via transformation of salicylaldehydes, malononitrile dimer, and malonic acid. It was shown that the use of DMSO at room temperature makes it possible to synthesize previously unavailable compounds. The investigation of the reaction mechanism using 1H-NMR monitoring made it possible to confirm the proposed mechanism of the transformation. The structure of synthesized 5H-chromeno[2,3-b]pyridines was confirmed by 2D-NMR spectroscopy.


Isoelectric forms of clusterin isolated from ram rete testis fluid and from secretions of primary cultures of ram and rat Sertoli-cell-enriched preparations.
Clusterin, a cell aggregating factor isolated from ram rete testis fluid (RTF), is shown to contain 14.7% hexoses, 13.6% glucosamine, and 7.9% sialic acid. The isoelectric point (pI) of the predominant electrophoretic form of clusterin from ram RTF is 3.7. After treatment with neuraminidase, the pI values become more basic, with the majority of the material being eluted from a chromatofocusing column at pH values between 4.9 and 5.1. Intact clusterin binds quantitatively to wheat germ agglutinin - Sepharose 6 MB, but after treatment with neuraminidase only 49% specifically binds. Clusterin isolated from proteins secreted by primary cultures of ram Sertoli-cell-enriched preparations was shown to have properties similar to those of intact clusterin isolated from ram RTF. In contrast, clusterin isolated from proteins secreted by primary cultures of rat Sertoli- or granulosa-cell-enriched preparations has isoelectric forms which more closely resemble those of neuraminidase-treated ram clusterin.


Squeezing lemons in the bathroom: contextual information modulates action recognition.
Most every day actions take place in domestic rooms that are specific for certain classes of actions. Contextual information derived from domestic settings may therefore influence the efficiency of action recognition. The present studies investigated whether action recognition is modulated by compatibility of the context an action is embedded in. To this end, subjects watched video clips of actions performed in compatible, incompatible, and neutral contexts. Recognition was significantly slower when actions took place in an incompatible as compared to a compatible or a neutral context (Experiment 1). Functional MRI revealed increased activation for incompatible context in Brodmann Areas (BA) 44, 45, and 47 of the left ventrolateral prefrontal cortex (vlPFC; Experiment 2). Results suggest that contextual information - even when task-irrelevant - informs a high processing level of action analysis. In particular, the functional profiles assigned to these prefrontal regions suggest that contextual information activates associated action representations as a function of (in-)compatibility. Thus, incompatibility effects may reflect the attempt to resolve the conflict between action and context by embedding the presented action step into an overarching action that is again compatible with the provided context.


Pepper mild mottle virus pathogenicity determinants and cross protection effect of attenuated mutants in pepper.
To determine the pathogenicity domain and to apply cross protection, Pepper mild mottle virus (PMMoV) point-mutations in the replicase (REP) gene between the methyl-transferase and helicase domains, and deletions truncating pseudoknots in the 3' non-coding region (NCR), were constructed. Some mutants substituting a single amino acid in REP residue 348 exhibited mild symptoms in Nicotiana benthamiana or pepper plants. Accumulation of these mutants was higher than that of other REP mutants or wild-type PMMoV. Deletion mutants in the 3' NCR pseudoknot showed the lowest virus replication and accumulation among the mutants tested. Six attenuated mutants, which combined 3' NCR deletions and single or double REP substitution mutations were constructed to investigate cross protection effects on pepper plants. All six of the attenuated mutants showed milder symptom development than wild-type virus. These results suggest that REP and the pseudoknot in the 3' NCR are major pathogenicity determinants of the virus, and engineered PMMoV attenuated mutants can be useful for protection against the virus in pepper plants.


Current morale issues that impede the caregiving process of substance abuse/addictions nurses.
A telephone survey was conducted with 25 nurse managers of substance abuse/addictions programs in a metropolitan area to ascertain what morale issues impede the caregiving processes of their nursing staff. Five issues were repeatedly identified by all 25 nurse managers. Those issues were: (a) lack of credibility and respect for the nurse in the eyes of other members of the multidisciplinary team, (b) lack of understanding of the role of nurses in the substance abuse/addictions program on an inpatient unit; (c) lack of adequate preparation for the role, (d) lack of acceptance of the nursing role as defined by nursing, and (e) the care of patients with concurrent diagnoses. This article analyzes these issues from the perspective of reasons for existence and possible solutions.


Neuroprotective Effects of Purpurin Against Ischemic Damage via MAPKs, Bax, and Oxidative Stress Cascades in the Gerbil Hippocampus.
Purpurin has various effects, including anti-inflammatory effects, and can efficiently cross the blood-brain barrier. In the present study, we investigated the effects of purpurin on oxidative stress in HT22 cells and mild brain damage in the gerbil hippocampal CA1 region induced by transient forebrain ischemia. Oxidative stress induced by H2O2 was significantly ameliorated by treatment with purpurin, based on changes in cell death, DNA fragmentation, formation of reactive oxygen species, and pro-apoptotic (Bax)/anti-apoptotic (Bcl-2) protein levels. In addition, treatment with purpurin significantly reduced the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK), and p38 signaling in HT22 cells. Transient forebrain ischemia in gerbils led to a significant increase in locomotor activity 1 day after ischemia and significant decrease in number of surviving cells in the CA1 region 4 days after ischemia. Administration of purpurin reduced the travel distance 1 day after ischemia and abrogates the neuronal death in the hippocampal CA1 region 4 days after ischemia based on immunohistochemical and histochemical staining for NeuN and Fluoro-Jade C, respectively. Purpurin treatment significantly decreased the activation of microglia and astrocytes as well as the increases of nuclear factor kappa-light-chain-enhancer of activated B cells p65 in the hippocampal CA1 region 4 days after ischemia and ameliorated the ischemia-induced transient increases of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the hippocampus 6 h after ischemia. In addition, purpurin significantly alleviated the ischemia-induced phosphorylation of JNK, ERK, and p38 in the hippocampus 1 day after ischemia. Furthermore, purpurin treatment significantly mitigated the increases of Bax in the hippocampus 1 day after ischemia and the lipid peroxidation based on malondialdehyde and hydroperoxides levels 2 days after ischemia. These results suggest that purpurin can be one of the potential candidates to reduce neuronal damage and inflammatory responses after oxidative stress in HT22 cells or ischemic damage in gerbils.


Koch's postulates, carnivorous cows, and tuberculosis today.
With Koch's announcement in 1882 of his work with the tubercle bacillus, his famous postulates launched the rational world of infectious disease and an abrupt social change--strict patient isolation. The postulates, so successful at their inception, soon began to show some problems, particularly with cholera, which clearly violated some of Koch's requirements. Subsequent studies of other diseases and the discovery of entirely new ones have so altered and expanded the original postulates that they now are little but a precious touch of history. The present additions and replacements of the original concepts are skillful changes that several authors have devised to introduce new order into understanding complex viral and prion diseases. In 1988, this knowledge, with the totally rational response of the British population and its cattle industry, was critical in promptly blocking the threatened epidemic of human prion disease. In contrast, the recent upsurge of tuberculosis (TB) in the worldwide AIDS epidemic in developing countries, and the sudden increase in metabolic syndrome in wealthy ones, suggests the need for focused sociobiologic research seeking ways to affect the damaging lifestyle behavior of many less educated populations in both settings. The world awaits an equivalent of Koch's Postulates in sociobiology to explain and possibly avert large self-destructive behaviors.


[Comparison of captopril with enalapril in the therapy of heart failure: effect on hemodynamics and kidney function].
24 patients with severe heart failure (NYHA III) were randomly assigned to an additional therapy with captopril or enalapril. The mean daily dose of captopril was 56 +/- 2 mg and of enalapril, 9.6 +/- 0.9 mg. After a mean of 9 days, the influence of both inhibitors of the angiotensin converting enzyme (ACE-inhibitors) on hemodynamics and renal function was evaluated. The mean arterial pressure in the group treated with captopril (group A) fell by 11 +/- 2 mm Hg (p less than 0.001), with enalapril (group B) by 13 +/- 3 mm Hg (p less than 0.01), the difference between the groups not being significant. Heart rate decreased in both groups to a similar degree. The change was significant only in the patients treated with enalapril (13 +/- 4/min; p less than 0.05 vs. 11 +/- 5/min in group A). Stroke volume index increased by 10 +/- 2 ml/m2 in group A vs. 12 +/- 2 ml/m2 in group B; both increases were highly significant (p less than 0.001). Mean decreases in pulmonary artery and right atrial pressure were comparable in both groups. The hemodynamic improvement was not different with both ACE-inhibitors. Serum sodium and potassium before therapy were 137 +/- 1 mmol/l and 4.1 +/- 0.2 mmol/l in group A and 139 +/- 1 mmol/l and 3.8 +/- 0.1 mmol/l in group B and serum creatinine was 1.2 +/- 0.1 mg/dl in both groups. Neither serum electrolytes nor serum creatinin were changed significantly by therapy with captopril or enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)


Reduced KIAA0471 mRNA expression in Alzheimer's patients: a new candidate gene product linked to the disease?
Alzheimer's disease (AD) phenotype complexity raises the question whether genetic features remain unknown. Although a few percentage of patients are familial cases linked to mutations in amyloid precursor protein, presenilin 1 or presenilin 2 genes, the remainder are considered mainly sporadic late-onset cases with a complex etiology. However, changes in gene expression or other genetic features of the individual can clearly contribute to develop the illness. Consequently, in this paper we have focused on the identification of new genes, the expression of which is altered in AD. We used the technique of differential display reverse transcriptase-polymerase chain reaction (DDRT-PCR) in order to study the gene expression differences in brain tissue from patients in an advanced stage of AD. After studying medial septum and hippocampus brain areas, we found an inhibition of the KIAA0471 gene expression in three out of six AD patients, including one with a presenilin 1 gene mutation. This gene encodes for a large protein that presents, in its predicted form, 95% homology with IDN4-GGTR sequences. These results may provide significant clues for understanding the molecular mechanisms underlying septohippocampal neurodegeneration. In addition, they may open a new area of research for diagnostic and therapeutic tools, the relevance of which is also considered.


A single nucleotide polymorphism and sequence analysis of CSN1S1 gene promoter region in Chinese Bos grunniens (yak).
The aim of this study was to investigate the polymorphism of the CSN1S1 gene promoter region in 4 Chinese yak breeds, and compare the yak CSN1S1 gene promoter region sequences with other ruminants. A Polymerase Chain Reaction-Single Strand Conformation Polymorphism protocol was developed for rapid genotyping of the yak CSN1S1 gene. One hundred fifty-eight animals from 4 Chinese yak breeds were genotyped at the CSN1S1 locus using the protocol developed. A single nucleotide polymorphism of the CSN1S1 gene promoter region has been identified in all yak breeds investigated. The polymorphism consists of a single nucleotide substitution G-->A at position 386 of the CSN1S1 gene promoter region, resulting in two alleles named, respectively, G(386) and A(386), based on the nucleotide at position 386. The allele G(386) was found to be more common in the animals investigated. The corresponding nucleotide sequences in GenBank of yak (having the same nucleotides as allele G(386) in this study), bovine, water buffalo, sheep, and goat had similarity of 99.68%, 99.35%, 97.42%, 95.14%, and 94.19%, respectively, with the yak allele A(386.).


N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain.
Morbidity and mortality from head trauma is highest among children. No animal model mimicking traumatic brain injury in children has yet been established, and the mechanisms of neuronal degeneration after traumatic injury to the developing brain are not understood. In infant rats subjected to percussion head trauma, two types of brain damage could be characterized. The first type or primary damage evolved within 4 hr and occurred by an excitotoxic mechanism. The second type or secondary damage evolved within 6-24 hr and occurred by an apoptotic mechanism. Primary damage remained localized to the parietal cortex at the site of impact. Secondary damage affected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus and striatum. Secondary apoptotic damage was more severe than primary excitotoxic damage. Morphometric analysis demonstrated that the N-methyl-D-aspartate receptor antagonists 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate and dizocilpine protected against primary excitotoxic damage but increased severity of secondary apoptotic damage. 2-Sulfo-alpha-phenyl-N-tert-butyl-nitrone, a free radical scavenger, did not affect primary excitotoxic damage but mitigated apoptotic damage. These observations demonstrate that apoptosis and not excitotoxicity determine neuropathologic outcome after traumatic injury to the developing brain. Whereas free radical scavengers may prove useful in therapy of head trauma in children, N-methyl-D-aspartate antagonists should be avoided because of their propensity to increase severity of apoptotic damage.


ASAS classification criteria for axial spondyloarthritis: time to modify.
The relationship between ankylosing spondylitis and the recently proposed entity called axial spondyloarthritis with its radiographic and non-radiographic forms that have been defined by the Assessment of Spondyloarthritis International Society (ASAS) criteria for axial spondyloarthritis (axSpA), is currently being debated. The Food and Drug Agency (FDA) had criticized the ASAS criteria and the studies which used these criteria to enroll patients in a clinical trial of certolizumab and adalimumab for the treatment of non-radiographic axial spondyloarthritis. The primary aim of classification criteria is to create homogenous patient populations for basic and clinical research. But the multi-arm construct of the ASAS criteria is a potential source of heterogeneity reducing their utility. Criteria sets should be regarded as dynamic concepts open to modifications or updates as our knowledge advances. We provide evidence to conclude that it is time to modify the ASAS Criteria for axSpA, and we propose some of the steps that can be taken to start moving forward in improving the validity of these criteria.


S100A14 promotes the growth and metastasis of hepatocellular carcinoma.
S100A14 has recently been implicated in the progress of several types of cancers. This study aimed to investigate the clinical significance and possible mechanisms of action of S100A14 in the invasion and metastasis of hepatocellular carcinoma (HCC). S100A14 expression in HCC was detected at mRNA and protein levels and its prognostic significance was assessed. Functional roles of S100A14 in HCC were investigated using MTT, BrdU, wound healing, transwell invasion assay and HCC metastatic mouse model. S100A14 was significantly elevated in HCC tissues, correlated with multiple tumor nodes, high Edmondson-Steiner grade and vascular invasion. Multivariate Cox analysis showed that the S100A14 expression level was a significant and independent prognostic factor for overall survival (OS) of HCC patients (hazard ratio=1.98, 95% confidence interval=1.14-3.46, P=0.013). S100A14 promoted cell proliferation, invasion and metastasis of HCC in vitro and in vivo. These results suggest S100A14 is a novel prognostic marker and therapeutic target for HCC.


An intervention to reduce HIV risk behavior of substance-using men who have sex with men: a two-group randomized trial with a nonrandomized third group.
Substance use during sex is associated with sexual risk behavior among men who have sex with men (MSM), and MSM continue to be the group at highest risk for incident HIV in the United States. The objective of this study is to test the efficacy of a group-based, cognitive-behavioral intervention to reduce risk behavior of substance-using MSM, compared to a randomized attention-control group and a nonrandomized standard HIV-testing group. Participants (n = 1,686) were enrolled in Chicago, Los Angeles, New York City, and San Francisco and randomized to a cognitive-behavioral intervention or attention-control comparison. The nonrandomized group received standard HIV counseling and testing. Intervention group participants received six 2-h group sessions focused on reducing substance use and sexual risk behavior. Attention-control group participants received six 2-h group sessions of videos and discussion of MSM community issues unrelated to substance use, sexual risk, and HIV/AIDS. All three groups received HIV counseling and testing at baseline. The sample reported high-risk behavior during the past 3 mo prior to their baseline visit: 67% reported unprotected anal sex, and 77% reported substance use during their most recent anal sex encounter with a nonprimary partner. The three groups significantly (p<0.05) reduced risk behavior (e.g., unprotected anal sex reduced by 32% at 12-mo follow-up), but were not different (p>0.05) from each other at 3-, 6-, and 12-mo follow-up. Outcomes for the 2-arm comparisons were not significantly different at 12-mo follow-up (e.g., unprotected anal sex, odds ratio = 1.14, confidence interval = 0.86-1.51), nor at earlier time points. Similar results were found for each outcome variable in both 2- and 3-arm comparisons. These results for reducing sexual risk behavior of substance-using MSM are consistent with results of intervention trials for other populations, which collectively suggest critical challenges for the field of HIV behavioral interventions. Several mechanisms may contribute to statistically indistinguishable reductions in risk outcomes by trial group. More explicit debate is needed in the behavioral intervention field about appropriate scientific designs and methods. As HIV prevention increasingly competes for behavior-change attention alongside other "chronic" diseases and mental health issues, new approaches may better resonate with at-risk groups. ClinicalTrials.gov NCT00153361. Please see later in the article for the Editors' Summary.


Outcomes of Nigeria's HIV/AIDS Treatment Program for Patients Initiated on Antiretroviral Treatment between 2004-2012.
The Nigerian Antiretroviral therapy (ART) program started in 2004 and now ranks among the largest in Africa. However, nationally representative data on outcomes have not been reported. We evaluated retrospective cohort data from a nationally representative sample of adults aged ≥15 years who initiated ART during 2004 to 2012. Data were abstracted from 3,496 patient records at 35 sites selected using probability-proportional-to-size (PPS) sampling. Analyses were weighted and controlled for the complex survey design. The main outcome measures were mortality, loss to follow-up (LTFU), and retention (the proportion alive and on ART). Potential predictors of attrition were assessed using competing risk regression models. At ART initiation, 66.4 percent (%) were females, median age was 33 years, median weight 56 kg, median CD4 count 161 cells/mm3, and 47.1% had stage III/IV disease. The percentage of patients retained at 12, 24, 36 and 48 months was 81.2%, 74.4%, 67.2%, and 61.7%, respectively. Over 10,088 person-years of ART, mortality, LTFU, and overall attrition (mortality, LTFU, and treatment stop) rates were 1.1 (95% confidence interval (CI): 0.7-1.8), 12.3 (95%CI: 8.9-17.0), and 13.9 (95% CI: 10.4-18.5) per 100 person-years (py) respectively. Highest attrition rates of 55.4/100py were witnessed in the first 3 months on ART. Predictors of LTFU included: lower-than-secondary level education (reference: Tertiary), care in North-East and South-South regions (reference: North-Central), presence of moderate/severe anemia, symptomatic functional status, and baseline weight <45kg. Predictor of mortality was WHO stage higher than stage I. Male sex, severe anemia, and care in a small clinic were associated with both mortality and LTFU. Moderate/Advanced HIV disease was predictive of attrition; earlier ART initiation could improve program outcomes. Retention interventions targeting men and those with lower levels of education are needed. Further research to understand geographic and clinic size variations with outcome is warranted.


Yeast oligo-mediated genome engineering (YOGE).
High-frequency oligonucleotide-directed recombination engineering (recombineering) has enabled rapid modification of several prokaryotic genomes to date. Here, we present a method for oligonucleotide-mediated recombineering in the model eukaryote and industrial production host Saccharomyces cerevisiae , which we call yeast oligo-mediated genome engineering (YOGE). Through a combination of overexpression and knockouts of relevant genes and optimization of transformation and oligonucleotide designs, we achieve high gene-modification frequencies at levels that only require screening of dozens of cells. We demonstrate the robustness of our approach in three divergent yeast strains, including those involved in industrial production of biobased chemicals. Furthermore, YOGE can be iteratively executed via cycling to generate genomic libraries up to 10 (5) individuals at each round for diversity generation. YOGE cycling alone or in combination with phenotypic selections or endonuclease-based negative genotypic selections can be used to generate modified alleles easily in yeast populations with high frequencies.


Silicon Nanocrystal Superlattice Nucleation and Growth.
Colloidal dodecene-passivated silicon (Si) nanocrystals were dispersed in hexane or chloroform and deposited onto substrates as face-centered cubic superlattices by slowly evaporating the solvent. The uniformity of the nanocrystals enables extended order; however, the solvent and the evaporation protocol significantly influence the self-assembly process, determining the morphology of the films, the extent of order, and the superlattice orientation on the substrate. Chloroform yielded superlattices with step-flow growth morphologies and (111)SL, (100)SL, and (110)SL orientations. Hexane led to mostly island morphologies when evaporated at room temperature with exclusively (111)SL orientations. Higher evaporation temperatures led to more extensive step-flow deposition. A model for the surface diffusion of nanocrystals adsorbed on the superlattice surface is developed.


Molecular cloning of bovine cardiac muscle heat-shock protein 70 kDa and its phosphorylation by cAMP-dependent protein kinase in vitro.
The 70-kDa heat-shock protein (Hsp70) has been cloned and sequenced from bovine cardiac muscle. On the basis of sequence features, the gene corresponds to the cytoplasmic form of Hsp70. This cardiac Hsp70 cDNA clone has an open reading frame of 1926 bp coding for 641 amino acids and a predicted molecular mass of 70.25 kDa. Comparison of the amino acid sequence revealed an extensive sequence identity with other species of Hsp70. Escherichia coli expressed cardiac Hsp70 stimulated a 2-fold increase in calcineurin (CaN) activity. Notably, we observed that Hsp70 directly interacts with CaN using a pull-down assay. Furthermore, expressed cardiac-specific Hsp70 was phosphorylated in vitro by cAMP-dependent protein kinase. Phosphorylation resulted in the incorporation of 0.1 mol of phosphate per mol of Hsp70. The phosphorylated Hsp70 was unable to activate the phosphatase activity of CaN. This is the first demonstration that Hsp70 is phosphorylated by cAMP-dependent protein kinase and provides an on/off switch for the regulation of CaN signaling by Hsp70.


Krook collisional models of the kinetic susceptibility of plasmas.
An assessment is made of Krook collisional models used to describe the kinetic behavior of collective oscillations, i.e., when Landau damping and collisions must be considered, as is often the case for low-frequency waves. The study focuses on an early energy-conserving model [B. D. Fried, A. N. Kaufman, and D. L. Sachs, Phys. Fluids 9, 292 (1966)] that is shown to be identical to a more modern version used in drift-wave stability studies [G. Rewoldt, W. M. Tang, and R. J. Hastie, Phys. Fluids 29, 2893 (1986)]. The inadequacy of the simpler, and often used, nonconserving model is illustrated. Comparisons are established with recent collisional studies of ion acoustic waves [V. Yu. Bychenkov, J. Myatt, W. Rozmus, and V. T. Tikhonchuk, Phys. Plasmas 1, 2419 (1994)] and electron plasma waves [C. S. Ng, A. Bhattacharjee, and F. Skiff, Phys. Rev. Lett. 83, 1974 (1999)]. A connection is also established with contemporary studies of condensed matter and quantum liquids [K. Morawetz and U. Fuhrmann, Phys. Rev. E 61, 2272 (2000); 62, 4382 (2000)]. A useful empirical fit is found that corrects the Braginskii susceptibility to incorporate the kinetic behavior associated with the Krook kinetic susceptibility.


Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype.
The type 1 ryanodine receptor (RyR1) is expressed widely in the brain, with high levels in the cerebellum, hippocampus, and hypothalamus. We have shown that L-type Ca(2+) channels in terminals of hypothalamic magnocellular neurons are coupled to RyRs, as they are in skeletal muscle, allowing voltage-induced Ca(2+) release (VICaR) from internal Ca(2+) stores without Ca(2+) influx. Here we demonstrate that RyR1 plays a role in VICaR in nerve terminals. Furthermore, in heterozygotes from the Ryr1(I4895T/WT) (IT/+) mouse line, carrying a knock-in mutation corresponding to one that causes a severe form of human central core disease, VICaR is absent, demonstrating that type 1 RyR mediates VICaR and that these mice have a neuronal phenotype. The absence of VICaR was shown in two ways: first, depolarization in the absence of Ca(2+) influx elicited Ca(2+)syntillas (scintilla, spark, in a nerve terminal, a SYNaptic structure) in WT, but not in mutant terminals; second, in the presence of extracellular Ca(2+), IT/+ terminals showed a twofold decrease in global Ca(2+) transients, with no change in plasmalemmal Ca(2+) current. From these studies we draw two conclusions: (i) RyR1 plays a role in VICaR in hypothalamic nerve terminals; and (ii) a neuronal alteration accompanies the myopathy in IT/+ mice, and, possibly in humans carrying the corresponding RyR1 mutation.


The co-evolution of multiply-informed dispersal: information transfer across landscapes from neighbors and immigrants.
Dispersal plays a key role in natural systems by shaping spatial population and evolutionary dynamics. Dispersal has been largely treated as a population process with little attention to individual decisions and the influence of information use on the fitness benefits of dispersal despite clear empirical evidence that dispersal behavior varies among individuals. While information on local density is common, more controversial is the notion that indirect information use can easily evolve. We used an individual-based model to ask under what conditions indirect information use in dispersal will evolve. We modeled indirect information provided by immigrant arrival into a population which should be linked to overall metapopulation density. We also modeled direct information use of density which directly impacts fitness. We show that immigrant-dependent dispersal evolves and does so even when density dependent information is available. Use of two sources of information also provides benefits at the metapopulation level by reducing extinction risk and prolonging the persistence of populations. Our results suggest that use of indirect information in dispersal can evolve under conservative conditions and thus could be widespread.


Lysis Profiles of Salmonella Phages on Salmonella Isolates from Various Sources and Efficiency of a Phage Cocktail against S. Enteritidis and S. Typhimurium.
Salmonella enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium are major foodborne pathogens of concern worldwide. Bacteriophage applications have gained more interest for biocontrol in foods. This study isolated 36 Salmonella phages from several animal farms in Thailand and tested them on 47 Salmonella strains from several sources, including farms, seafood processing plant and humans in Thailand and USA. Phages were classified into three major groups. The estimated phage genome size showed the range from 50 ± 2 to 200 ± 2 kb. An effective phage cocktail consisting of three phages was developed. Approximately 4 log CFU/mL of S. Enteritidis and S. Typhimurium could be reduced. These phages revealed a burst size of up to 97.7 on S. Enteritidis and 173.7 PFU/cell on S. Typhimurium. Our phage cocktail could decrease S. Enteritidis on chicken meat and sunflower sprouts by 0.66 log CFU/cm² and 1.27 log CFU/g, respectively. S. Typhimurium on chicken meat and sunflower sprouts were decreased by 1.73 log CFU/cm² and 1.17 log CFU/g, respectively. Overall, animal farms in Thailand provided high abundance and diversity of Salmonella phages with the lysis ability on Salmonella hosts from various environments and continents. A developed phage cocktail suggests a potential biocontrol against Salmonella in fresh foods.


Induced senescence of intact wheat seedlings and its reversibility.
Intact wheat seedlings (Triticum aestivum L.) were induced to senesce by placing them in the dark and at various stages of senescence were placed back in the light and their recoverability observed. Seedlings demonstrated complete recovery of chlorophyll, protein, and rate of photosynthesis after 2 days in the dark, but were unable to recover fully after 4 days. This suggests the onset of an irreversible stage in senescence by day 4. Foliar applied cytokinins delayed senescence, and zeatin at 0.1 mm delayed the onset of the irreversible stage for 6 days. In addition to delaying the loss of total soluble protein, zeatin maintained the net protein recovery capacity of the tissue. Control seedlings, however, lost their potential for net protein recovery at a rate similar to their loss of total soluble protein. Treatment with zeatin had no apparent effect on dark respiration during senescence, and although treatment did delay the loss of membrane permeability to substrate, the change in permeability occurred too late to have a causal role in senescence.


Controlling the degradation of covalently cross-linked carboxymethyl chitosan utilizing bimodal molecular weight distribution.
Degradability is often a critical property of materials utilized in tissue engineering. Although chitosan, a naturally derived polysaccharide, is an attractive material due to its biocompatibility and ability to form scaffolds, its slow and uncontrollable rate of degradation can be an undesirable feature. In this study, we characterize chitosan derivatives formed using a combination of carboxymethylation and a bimodal molecular weight distribution. Specifically, chitosan is carboxymethylated to a theoretical extent of approximately 30% as described in our previous work, in which carboxyl groups possessing negative charges are created at a physiological pH. Carboxymethyl chitosan is used to form films and constructs by varying the ratio of high to low molecular weight (MW) while maintaining the mechanical properties of the polymer. The rate of degradation is found to be dependent upon both the carboxymethylation and the ratio of high to low MW polymer, as determined by dry weight loss in lysozyme solution in PBS. Subsequently, biocompatibility is examined to determine the effects of these modifications upon Neuro-2a cells cultured on these films. Neuro-2a cells adhere and proliferate on the modified films at a comparable rate to those cultured on unmodified films. This data indicates that these chitosan derivatives exhibit tunable degradation rates and result in a promising material system for neural tissue engineering.


Temperature-Regulated IncX3 Plasmid Characteristics and the Role of Plasmid-Encoded H-NS in Thermoregulation.
Carbapenem-resistant Enterobacteriaceae (CRE) are a critical public health problem worldwide. Globally, IncX3-type plasmids have emerged as the predominant vehicles carrying the metallo-β-lactamase gene bla NDM. Although bla NDM-bearing IncX3 plasmids have been found in various hosts from diverse environments, whether their transfer and persistence properties vary under different conditions and what factors influence any variation is unknown. By observing the effects of different temperatures on IncX3 plasmid conjugation rates, stability, and effects on host fitness in Escherichia coli, we demonstrate that temperature is an important determinant of plasmid phenotypes. The IncX3 plasmid pGZIncX3 transferred at highest frequencies, was most stable and imposed lower fitness costs at 37°C. Temperature-regulated variation in pGZIncX3 properties involved a thermoregulated plasmid-encoded H-NS-like protein, which was produced at higher levels at 30°C and 42°C and inhibited the expression of type IV secretion system genes involved in conjugation. These findings suggest that bla NDM-bearing IncX3 plasmids are adapted to carriage by enterobacteria that colonize mammalian hosts and could explain the rapid dissemination of these plasmids among human-associated species, particularly in hospital settings.


Stable Q-switched and mode-locked Nd:GdVO4/KTP green laser with dual-loss-modulation.
A diode-pumped dual-loss-modulated Q-switched and mode-locked (QML) Nd:GdVO(4)/KTP green laser with an acousto-optic modulator (AOM) and GaAs saturable absorber is presented. The experimental results show that the stability and the peak power of the dual-loss-modulated QML Nd:GdVO(4)/KTP green laser are significantly improved. The pulse width of the Q-switched pulse envelope in the dual-loss-modulation QML green laser has a compression of 50% compared with that in the singly passively QML green laser with GaAs. By using a hyperbolic secant square function and considering the Gaussian distribution of the intracavity photon density, the coupled equations for diode-pumped dual-loss-modulated QML Nd:GdVO(4) green laser are given, and the numerical solutions of the equations are in good agreement with the experimental results.


Parkin gene causing benign autosomal recessive juvenile parkinsonism.
Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset parkinsonism caused by exonic deletions or point mutations in the parkingene. The relationship between the type of the genetic defect and the clinical presentation, the response to therapy, and the evolution have not been yet determined. The authors describe a single-basepair deletion at nucleotide 202 in exon 2 of the parkin gene in a kindred with a benign clinical course.


Numb/Notch/PLK1 signaling pathway mediated hyperglycemic memory in pancreatic cancer cell radioresistance and the therapeutic effects of metformin.
Diabetes mellitus has presented a positive role in the progression of pancreatic cancer and "Hyperglycemic memory" could be an important cause for diabetic damage. While limited information is available regarding the role of "hyperglycemic memory" in the pancreatic cancer and its radio-resistance. We therefore investigated correlation among hyperglycemic memory, Numb and metformin in pancreatic cancer radio-resistance. High glucose and hyperglycemic memory models were established in vitro and in vivo. Western blot, real-time PCR were accordingly used to detect Numb /Notch/ Polo-like kinase1 (PLK1) signaling at the level of molecular, cellular and experimental animal model, respectively. The apoptosis rate was evaluated by TUNEL assay and Capase-3 activity. The therapeutic effect of metformin was revealed by detecting the level of Numb / Notch /PLK1 through Western blot and real-time PCR. Inactivation of Numb promotes the pancreatic cancer radio-resistance through hyperglycemic memory and metformin could suppress the radio-resistance by activating Numb in vitro and in vivo. In addition, PLK1 and Notch signaling pathway (Notch1, HEY1) elevated in pancreatic cancer radio-resistance condition, which was induced by hyperglycemic memory. Moreover, Numb overexpression or metformin could suppress Notch pathway to alleviate pancreatic cancer radio-resistance. Our data demonstrated that Numb might be a promising target for the improvement of hyperglycemic memory damage and the effect of metformin deserved urgent attention on pancreatic cancer radio-resistance therapy.


Thyroid antigen-antibody nephritis: possible involvement of fucosyl-GM1 as the antigen.
Hyperthyroidism, microscopic hematuria, and proteinuria developed in an 11-year-old girl. Proteinuria decreased during treatment of hyperthyroidism with an antithyroid drug. On admission, serum anti-thyroglobulin antibody, antimicrosomal antibody, and immune complex were present. The thyrotropin binding inhibitory immunoglobulin (TBII) level was low. On the other hand, an antibody to the ganglioside component (fucosyl-GM1) was detected by an enzyme linked immunosolvent assay (ELISA). A thyroid biopsy specimen showed massive lymphocytic infiltration and interstitial fibrosis. A renal biopsy specimen showed marked proliferation of mesangial cells and increased mesangial matrix with focal segmental capillary wall abnormality. Electron microscopec studies demonstrated mild paramesangial dense deposits. By indirect immunofluorescence, granular glomerular basement membrane and mesangial staining were not detected with rabbit antibody to thyroglobulin, but were detected with rabbit antibody to fucosyl GM1. Fucosyl GM1 was also seen along the basilar aspect of the thyroid follicular epithelial cells. These observation suggests the development of glomerulonephritis mediated by thyroid antigen, particularly ganglioside component.


Vascular endothelium: checkpoint for inflammation and immunity.
Vascular endothelial cells play a threefold role in the interaction with leukocytes. First, they are gatekeepers in leukocyte recruitment to inflammatory foci and lymphocyte homing to secondary lymphoid organs. Second, they modulate leukocyte activation. Finally, they are targets of leukocyte-derived molecules, resulting either in endothelial cell activation or death.


Time of useful consciousness determination in aircrew members with reference to prior altitude chamber experience and age.
Hypoxia tolerance has been evaluated by the secondary responses to oxyhemoglobin deoxygenation: the time of useful consciousness (TUC), subjective symptoms, ventilatory responses, and cardiovascular changes. It is not clear whether the deoxygenation rate per se reflects hypoxia tolerance or how it relates to the former parameters. In Study 1, we monitored arterial oxygen saturation (SaO2) by pulse oximetry in the nonsmoking subjects experiencing hypoxia at the simulated altitude of 25,000 ft. Male subjects were divided into two groups: junior (< or =39 yr, n = 108) and senior (> or =40 yr, n = 44). The duration from mask-off to mask-on (TUC), the duration from mask-off to the time of SaO2 of 90%(T90), the duration from 90% to 70% of SaO2(T70), and the SaO2 value at mask-on (bottom SaO2) were compared between the two groups. (In a separate, but related study, 10 medical variables were analyzed by stepwise regression to investigate the contributing factors to hypoxia tolerance in 77 other subjects, including 11 female subjects.) In study 2, 12 subjective hypoxic symptoms at 25,000 ft were compared between junior (n = 369) and senior (n = 160) groups. TUC was significantly longer in the junior group, but T70 was longer and bottom SaO2 was higher in the senior group. Age was adopted as a contributing variable in three out of six dependent parameters. Subjective symptoms were in the similar rank order for both groups. Pulse oximetry reconfirmed that age is a major influencing factor for acute hypoxia tolerance. This may be due not only to the physiological effect but also to the training experience to recognize hypoxic deterioration more quickly.


Increase in MICs of ciprofloxacin in vivo in two closely related clinical isolates of Enterobacter cloacae.
The mechanisms of fluoroquinolone resistance in two isolates of Enterobacter cloacae, Ecl#1 and Ecl#2, from the same patient and with identical pulsed-field gel electrophoresis patterns, have been analysed. MICs of ciprofloxacin were 0.25 and 1 mg/L for Ecl#1 and Ecl#2, respectively. Ecl#2 was also more resistant to chloramphenicol and organic solvents. The quinolone resistance determining regions of gyrA/B and parC/E, and the marORA and acrB genes, were sequenced. Expression of marR, acrB, soxS, robA, ramA and fis was analysed by northern blotting. The activity of a 90 bp E. cloacae mar promoter fragment was examined with the reporter plasmid pIGJ-1mar. Sequencing the gyrAB and parCE genes revealed a single amino acid substitution in GyrA (corresponding to position 83 in GyrA of Escherichia coli) in Ecl#1 and Ecl#2 (Phe83) compared with reference strain E. cloacae DSMZ 3264 (Thr83). Ecl#2 accumulated significantly less norfloxacin and displayed higher levels of expression of marR and acrB than Exl#1, indicative of greater fluoroquinolone efflux activity. Sequencing gyrB, parC/E and marORA, and northern blotting of robA, ramA and fis, did not reveal any further differences between the two strains. No homologue of soxRS was detected in E. cloacae. Expression of GFP from pIGJ1-mar in Ecl#2 was higher than in Ecl#1. In these two closely related clinical isolates of E. cloacae, a target mutation in GyrA (Ecl#1 and Ecl#2) and increased fluoroquinolone efflux by AcrAB (Ecl#2) contribute to the resistance phenotypes, corroborating findings in vitro and in vivo about the sequential development of fluoroquinolone resistance.


Sex Differences in Endovascular Treatment for Stroke: A Population-based Analysis.
Acute ischemic stroke may affect women and men differently. We aimed to evaluate sex differences in outcomes of endovascular treatment (EVT) for ischemic stroke due to large vessel occlusion in a population-based study in Alberta, Canada. Over a 3-year period (April 2015-March 2018), 576 patients fit the inclusion criteria of our study and constituted the EVT group of our analysis. The medical treatment group of the ESCAPE trial had 150 patients. Thus, our total sample size was 726. We captured outcomes in clinical routine using administrative data and a linked database methodology. The primary outcome of our study was home-time. Home-time refers to the number of days that the patient was back at their premorbid living situation without an increase in the level of care within 90 days of the index stroke event. In adjusted analysis, EVT was associated with an increase of 90-day home-time by an average of 6.08 (95% CI -2.74-14.89, p-value 0.177) days in women compared to an average of 11.20 (95% CI 1.94-20.46, p-value 0.018) days in men. Further analysis revealed that the association between EVT and 90-day home-time in women was confounded by age and onset-to-treatment time. We found a nonsignificant nominal reduction of 90-day home-time gain for women compared to men in this province-wide population-based study of EVT for large vessel occlusion, which was only partially explained by confounding.


What influences a woman to choose vaginal birth after cesarean?
To discover what influences women in the decision to deliver via vaginal birth after cesarean (VBAC). Descriptive and qualitative, influenced by principles of phenomenology and using content analysis to describe the lived experiences of women who choose VBAC. Women were recruited from a postpartum unit in a hospital in the rural southeastern United States. Five women who had delivered via VBAC within 2 to 4 months before the study. The major influences that affect a woman's decision to choose VBAC are described. The dominant themes found were the woman's sense of control in the decision-making process; physician encouragement for VBAC; and delivery type outcome advantages, incorporating physical and emotional factors. Women are influenced by internal and external factors in their decision to choose VBAC. Their choices come from their personal experiences and should be encouraged by health care providers during all aspects of the childbearing process.


Sudden hearing loss as a presenting symptom of acoustic neuroma.
Retrocochlear pathological findings may be suggested by findings on the brainstem response and acoustic sensorineural reflex (AR) tests. We describe the incidence of acoustic neuroma presenting as sudden hearing loss (SHL) and the effectiveness of the discrimination (DISC) test, the brainstem-evoked response, and AR test in predicting acoustic neuroma in patients with SHL. We retrospectively reviewed the charts of all adult patients who presented to our center with sensorineural SHL between 1989 and 1995. Two groups were defined: those with cerebellopontine angle (CPA) tumor and those with negative imaging findings. Results of the brainstem-evoked response, AR, and DISC tests were compared. Forty patients were admitted with sensorineural SHL, of whom 19 (47.5%) had a CPA tumor. The latter group showed a significantly lower mean age and better results for the low frequencies on pure tone audiometry, as well as better brainstem-evoked response test results than the patients with negative imaging findings. There was also a significant difference between the groups for both the affected and unaffected ears on the discrimination test. Acoustic tumors may be a more common cause of sudden sensorineural hearing loss than previously suspected. The DISC test is a useful screening tool for acoustic tumor, whereas the brainstem-evoked response test shows poorer results in affected patients with sensorineural hearing loss than in other subgroups with different signs of acoustic neuroma. We recommend that young patients presenting with mild SHL who have normal results on the AR and brainstem-evoked response tests undergo magnetic resonance imaging to rule out CPA tumor.


Endurance exercise ameliorates Western diet-induced atherosclerosis through modulation of microbiota and its metabolites.
The World Health Organization determined cardiovascular disease to be the leading cause of death globally; atherosclerosis is the primary cause of the high morbidity and mortality rates. Regular physical activity is an effective strategy for maintaining endothelial health and function to prevent the development of atherosclerosis. Obesity is also a crucial risk factor for atherosclerotic progression in combination with various complications and systemic inflammation. Physiological homeostasis is modulated by the intestinal microbiota, but the mechanisms through which exercise attenuates atherosclerosis through the microbiota have not been elucidated. Therefore, we investigated the effects of endurance exercise on atherosclerosis induced by a Western diet (WD) and apolipoprotein E (ApoE) knockout in terms of microbiota parameters and metabolites. Genetically modified ApoE knockout mice (C57BL/6-Apoeem1Narl/Narl, ApoEKO) and wild-type mice (C57BL6/J) were divided into the following four groups (n = 6), namely, wild-type mice fed a chow diet (WT CD), ApoEKO mice fed a chow diet (ApoE CD), ApoEKO mice fed a WD (ApoE WD), and ApoEKO mice fed a WD and performing endurance exercise (ApoE WD EX), for a 12-week intervention. The WD significantly induced obesity and atherosclerotic syndrome in the ApoE WD group. Severe atherosclerotic lesions and arterial thickness were significantly elevated and accompanied by increases in VCAM-1, MCP-1, TNF-α, and IL-1β for immune cell chemotaxis and inflammation during atherosclerotic pathogenesis in the ApoE WD group. In addition, dysbiosis in the ApoE WD group resulted in the lowest short-chain fatty acid (SCFA) production. Endurance exercise intervention (ApoE WD EX) significantly alleviated atherosclerotic syndrome by reducing obesity, significantly inhibiting VCAM-1, MCP-1, TNF-α, and IL-1β expression, and increasing the production of SCFAs. Modulation of the microbiota associated with inflammation, such as Desulfovibrio, Tyzzerella, and Lachnospiraceae_ge, and increased SCFA production, particularly through an abundance of Rikenellaceae and Dubosiella, were also observed after exercise intervention. Endurance exercise can alleviate WD-induced atherosclerosis through the amelioration of obesity, inflammation, and chemotaxis signaling, which are modulated by the microbiota and derived SCFAs.


Brachial gradient in cardiac surgical patients.
Review of the clinical and therapeutic implications of difference in arm blood pressure detected preoperatively in patients having heart surgery. Prospective study of 53 patients (Group 1) with gradient and comparison with a group of 175 patients without gradient (Group 2). All patients had preoperative carotid duplex interrogation and operative epiaortic scanning. There was no statistical difference regarding age, sex, status, redo, diabetes, ejection fraction, prior myocardial infarct, hyperlipidemia, or creatinine level. Risks factors for Group 1 included peripheral vascular disease (P<0.0001) and cerebrovascular symptoms (P=0.0196). Severe carotid disease (>80% stenosis) was seen in 41.5% of Group 1 and 13.7% of Group 2 (P<0.0001) patients. Severe atherosclerotic proximal aortic disease was found in 39.6% of Group 1 and 10.8% of Group 2 (P<0.0001) patients. There were 7 patients with strokes in Group 1 (13.20%) and 9 in Group 2 (5.14%; P=0.06). Four patients died in Group 1 (7.54%) and 10 died in Group 2 (5.71%; P=0.74). Brachial gradient is a marker for increased carotid and proximal atherosclerotic aortic disease. Preoperative arch study at the time of catheterization is strongly recommended, as well as preoperative carotid Doppler and operative epiaortic ultrasound.


Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α.
The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.


Microsurgery in andrologic urology. II. Alloplastic spermatocele.
Experimental studies in rats and bulls demonstrated the feasibility of using a silicone-Dacron prosthesis as a sperm reservoir in cases of excretory azoospermia. In the study of bulls, 50% of the cows inseminated with spermatozoa aspirated from the alloplastic spermatocele conceived and delivered healthy calves. The clinical results of a series of 14 humans suffering from excretory azoospermia not treatable by other means (e.g., epididymovasostomy or vasovasostomy) also are presented. THe aspirations from these spermatoceles produced motile spermatozoa; however, none of the patients'p spouses conceived after insemination.