Tasman-PCR: a genetic diagnostic assay for Tasmanian devil facial tumour diseases.
Tasmanian devils have spawned two transmissible cancer clones, known as devil facial tumour 1 (DFT1) and devil facial tumour 2 (DFT2). DFT1 and DFT2 are transmitted between animals by the transfer of allogeneic contagious cancer cells by biting, and both cause facial tumours. DFT1 and DFT2 tumours are grossly indistinguishable, but can be differentiated using histopathology, cytogenetics or genotyping of polymorphic markers. However, standard diagnostic methods require specialist skills and equipment and entail long processing times. Here, we describe Tasman-PCR: a simple polymerase chain reaction (PCR)-based diagnostic assay that identifies and distinguishes DFT1 and DFT2 by amplification of DNA spanning tumour-specific interchromosomal translocations. We demonstrate the high sensitivity and specificity of this assay by testing DNA from 546 tumours and 804 normal devils. A temporal-spatial screen confirmed the reported geographic ranges of DFT1 and DFT2 and did not provide evidence of additional DFT clones. DFT2 affects disproportionately more males than females, and devils can be co-infected with DFT1 and DFT2. Overall, we present a PCR-based assay that delivers rapid, accurate and high-throughput diagnosis of DFT1 and DFT2. This tool provides an additional resource for devil disease management and may assist with ongoing conservation efforts.


Genetic association studies of obesity in Africa: a systematic review.
Obesity is increasing in Africa, but the underlying genetic background largely remains unknown. We assessed existing evidence on genetic determinants of obesity among populations within Africa. MEDLINE and EMBASE were searched and the bibliographies of retrieved articles were examined. Included studies had to report on the association of a genetic marker with obesity indices and the presence/occurrence of obesity/obesity trait. Data were extracted on study design and characteristics, genetic determinants and effect estimates of associations with obesity indices. According to this data, over 300 polymorphisms in 42 genes have been studied in various population groups within Africa mostly through the candidate gene approach. Polymorphisms in genes such as ACE, ADIPOQ, ADRB2, AGRP, AR, CAPN10, CD36, C7orf31, DRD4, FTO, MC3R, MC4R, SGIP1 and LEP were found to be associated with various measures of obesity. Of the 36 polymorphisms previously validated by genome-wide association studies (GWAS) elsewhere, only FTO and MC4R polymorphisms showed significant associations with obesity in black South Africans, Nigerians and Ghanaians. However, these data are insufficient to establish the true nature of genetic susceptibility to obesity in populations within Africa. There has been recent progress in describing the genetic architecture of obesity among populations within Africa. This effort needs to be sustained via GWAS studies.


The crisis in human resources for health care and the potential of a 'retired' workforce: case study of the independent midwifery sector in Tanzania.
The human resource crisis in health care is an important obstacle to attainment of the health-related targets for the Millennium Development Goals. One suggested strategy to alleviate the strain upon government services is to encourage new forms of non-government provision. Detail on implementation and consequences is often lacking, however. This article examines one new element of non-government provision in Tanzania: small-scale independent midwifery practices. A multiple case study analysis over nine districts explored their characteristics, and the drivers and inhibitors acting upon their development since permitted by legislative change. Private midwifery practices were found concentrated in a 'new' workforce of 'later life entrepreneurs': retired, or approaching retirement, government-employed nursing officers. Provision was entirely facility-based due to regulatory requirements, with approximately 60 'maternity homes' located mainly in rural or peri-urban areas. Motivational drivers included fear of poverty, desire to maintain professional status, and an ethos of community service. However, inhibitors to success were multiple. Start-up loans were scarce, business training lacking and registration processes bureaucratic. Cost of set-up and maintenance were prohibitively high, registration required levels of construction and equipping similar to government sector dispensaries. Communities were reluctant to pay for services that they expected from government. Thus, despite offering a quality of basic maternity care comparable to that in government facilities, often in poorly-served areas, most private maternity homes were under-utilized and struggling for sustainability. Because of their location and emphasis on personalized care, small-scale independent practices run by retired midwives could potentially increase rates of skilled attendance at delivery at peripheral level. The model also extends the working life of members of a professional group at a time of shortage. However, the potential remains unrealized. Successful multiplication of this model in resource-poor communities requires more than just deregulation of private ownership. Prohibitive start-up expenses need to be reduced by less emphasis on facility-based provision. On-going financing arrangements such as micro-credit, contracting, vouchers and franchising models require consideration.


Alanine Represses γ-Aminobutyric Acid Utilization and Induces Alanine Transaminase Required for Mitochondrial Function in Saccharomyces cerevisiae.
The γ-aminobutyric acid (GABA) shunt constitutes a conserved metabolic route generating nicotinamide adenine dinucleotide phosphate (NADPH) and regulating stress response in most organisms. Here we show that in the presence of GABA, Saccharomyces cerevisiae produces glutamate and alanine through the irreversible action of Uga1 transaminase. Alanine induces expression of alanine transaminase (ALT1) gene. In an alt1Δ mutant grown on GABA, alanine accumulation leads to repression of the GAD1, UGA1, and UGA2 genes, involved in the GABA shunt, which could result in growth impairment. Induced ALT1 expression and negative modulation of the GABA shunt by alanine constitute a novel regulatory circuit controlling both alanine biosynthesis and catabolism. Consistent with this, the GABA shunt and the production of NADPH are repressed in a wild-type strain grown in alanine, as compared to those detected in the wild-type strain grown on GABA. We also show that heat shock induces alanine biosynthesis and ALT1, UGA1, UGA2, and GAD1 gene expression, whereas an uga1Δ mutant shows heat sensitivity and reduced NADPH pools, as compared with those observed in the wild-type strain. Additionally, an alt1Δ mutant shows an unexpected alanine-independent phenotype, displaying null expression of mitochondrial COX2, COX3, and ATP6 genes and a notable decrease in mitochondrial/nuclear DNA ratio, as compared to a wild-type strain, which results in a petite phenotype. Our results uncover a new negative role of alanine in stress defense, repressing the transcription of the GABA shunt genes, and support a novel Alt1 moonlighting function related to the maintenance of mitochondrial DNA integrity and mitochondrial gene expression.


Supplementing an immunomodulatory feed ingredient to improve thermoregulation and performance of finishing beef cattle under heat stress conditions.
This experiment compared physiological and productive responses in finishing beef cattle managed under heat stress conditions, and supplemented (SUPP) or not (CON) with an immunomodulatory feed ingredient (Omnigen-AF; Phibro Animal Health, Teaneck, NJ). Crossbred yearling cattle (¾ Bos taurus × ¼ Bos indicus; 64 heifers and 64 steers) were ranked by initial body weight (BW) (440 ± 3 kg) and sex, and allocated to 1 of 16 unshaded drylot pens (8 heifers or steers/pen). Pens within sex were randomly assigned to receive SUPP or CON (n = 8/treatment). Cattle received a total-mixed ration (91% concentrate inclusion and 1.21 Mcal/kg of net energy for gain; dry matter [DM basis]) during the experiment (day 0 to 106). The immunomodulatory feed was offered as a top-dress to SUPP pens (56 g/d per animal; as-fed basis) beginning on day 7. Cattle BW were recorded on day 0, 14, 28, 42, 56, 70, 84, 98, and 106. Feed intake was evaluated from each pen by recording feed offer daily and refusals biweekly. Intravaginal temperature of heifers was recorded hourly from day 1 to 6, 29 to 41, and 85 to 97. Environmental temperature humidity index (THI) was also recorded hourly throughout the experiment, and averaged 79.8 ± 0.6. Concurrently with BW assessment, hair samples from the tail-switch were collected (3 animals/pen) for analysis of hair cortisol concentrations. Blood samples were collected on day 0, 28, 56, 84, and 106 from all animals for plasma extraction. Whole blood was collected on day 0, 56, and 106 (3 animals/pen) for analysis of heat shock protein (HSP) 70 and HSP72 mRNA expression. Cattle were slaughtered on day 107 at a commercial packing facility. Results obtained prior to day 7 served as independent covariate for each respective analysis. Heifers receiving SUPP had less (P ≤ 0.05) vaginal temperature from 1500 to 1900 h across sampling days (treatment × hour, P < 0.01; 39.05 vs. 39.19 °C, respectively; SEM = 0.04), when THI ranged from 85.3 to 90.1. Expression of HSP70 and HSP72 was less (P ≥ 0.03) for SUPP cattle on day 106 (22.6- vs. 51.5-fold effect for HSP70, SEM = 9.7, and 11.0- vs. 32.8-fold effect for HSP72; treatment × day, P ≤ 0.04). No treatment effects were detected (P ≥ 0.22) for performance, carcass traits, plasma concentrations of cortisol and haptoglobin, or hair cortisol concentrations. Results from this study suggest that SUPP ameliorated hyperthermia in finishing cattle exposed to heat stress conditions, but such benefit was not sufficient to improve productive responses.


Drug therapy of portal hypertension.
Portal hypertension is the result of increased flow and increased resistance in the portal system. Pharmacological therapy is aimed at altering these factors by the use of vasoconstrictors to reduce flow and vasodilators to decrease intrahepatic resistance. The current status of pharmacological agents to achieve these effects is reviewed.


MiR-1 downregulation cooperates with MACC1 in promoting MET overexpression in human colon cancer.
MET, the tyrosine kinase receptor for hepatocyte growth factor, is frequently overexpressed in colon cancers with high metastatic tendency. We aimed to evaluate the role of its negative regulators, miR-1 and miR-199a*, and its transcriptional activator, the metastasis-associated in colon cancer 1 (MACC1), in controlling MET expression in human colon cancer samples. The expression of MET, miR-1, miR-199a*, and MACC1 was evaluated by real-time PCR in 52 matched pairs of colorectal cancers and nontumoral surrounding tissues. The biological role of miR-1 in controlling MET expression and biological activity was assessed in colon cancer cells either by its forced expression or by AntagomiR-mediated inhibition. MiR-1 was downregulated in 84.6% of the tumors and its decrease significantly correlated with MET overexpression, particularly in metastatic tumors. We found that concurrent MACC1 upregulation and miR-1 downregulation are required to elicit the highest increase of MET expression. Consistent with a suppressive role of miR-1, its forced in vitro expression in colon cancer cells reduced MET levels and impaired MET-induced invasive growth. Finally, we identified a feedback loop between miR-1 and MET, resulting in their mutual regulation. This study identifies an oncosuppressive role of miR-1 in colorectal cancer in which it acts by controlling MET expression through a feedback loop. Concomitant downregulation of miR-1 and increase of MACC1 can thus contribute to MET overexpression and to the metastatic behavior of colon cancer cells.


Nurses relate the contributing factors involved in medication errors.
Understanding the processes by which nurses administer medication is critical to the minimization of medication errors. This study investigates nurses' views on the factors contributing to medication errors in the hope of facilitating improvements to medication administration processes. A focus group of nine Registered Nurses discussed medication errors with which they were familiar as a result of both their own experiences and of literature review. The group, along with other researchers, then developed a semi-structured questionnaire consisting of three parts: narrative description of the error, the nurse's background and contributing factors. After the contributing factors had been elicited and verified with eight categories and 34 conditions, additional Registered Nurses were invited to participate by recalling one of the most significant medication errors that they had experienced and identifying contributing factors from those listed on the questionnaire. Identities of the hospital, patient and participants involved in the study remain confidential. Of the 72 female nurses who responded, 55 (76.4%) believed more than one factor contributed to medication errors. 'Personal neglect' (86.1%), 'heavy workload' (37.5%) and 'new staff' (37.5%) were the three main factors in the eight categories. 'Need to solve other problems while administering drugs,''advanced drug preparation without rechecking,' and 'new graduate' were the top three of the 34 conditions. Medical wards (36.1%) and intensive care units (33.3%) were the two most error-prone places. The errors common to the two were 'wrong dose' (36.1%) and 'wrong drug' (26.4%). Antibiotics (38.9%) were the most commonly misadministered drugs. Although the majority of respondents considered nurse's personal neglect as the leading factor in medication errors, analysis indicated that additional factors involving the health care system, patients' conditions and doctors' prescriptions all contributed to administration errors. Identification of the main factors and conditions contributing to medication errors allows clinical nurses and administration systems to eliminate situations that promote errors and to incorporate changes that minimize them, creating a safer patient environment.


Cost-effectiveness of combination peginterferon alpha-2a and ribavirin compared with interferon alpha-2b and ribavirin in patients with chronic hepatitis C.
Sustained virological response (SVR) is the primary objective in the treatment of chronic hepatitis C (CHC). Results from a recent clinical trial of patients with previously untreated CHC demonstrate that the combination of peginterferon alpha-2a and ribavirin produces a greater SVR than interferon alpha-2b and ribavirin combination therapy. However, the cost-effectiveness of peginterferon alpha-2a plus ribavirin in the U.S. setting has not been investigated. A Markov model was developed to investigate cost-effectiveness in patients with CHC using genotype to guide treatment duration. SVR and disease progression parameters were derived from the clinical trials and epidemiologic studies. The impact of treatment on life expectancy and costs were projected for a lifetime. Patients who had an SVR were assumed to remain virus-free for the rest of their lives. In genotype 1 patients, the SVRs were 46% for peginterferon alpha-2a plus ribavirin and 36% for interferon alpha-2b plus ribavirin. In genotype 2/3 patients, the SVRs were 76% for peginterferon alpha-2a plus ribavirin and 61% for interferon alpha-2b plus ribavirin. Quality of life and costs were based on estimates from the literature. All costs were based on published U.S. medical care costs and were adjusted to 2003 U.S. dollars. Costs and benefits beyond the first year were discounted at 3%. In genotype 1, peginterferon alpha-2a plus ribavirin increases quality-adjusted life expectancy (QALY) by 0.70 yr compared to interferon alpha-2b plus ribavirin, producing a cost-effectiveness ratio of $2,600 per QALY gained. In genotype 2/3 patients, peginterferon alpha-2a plus ribavirin increases QALY by 1.05 yr in comparison to interferon alpha-2b plus ribavirin. Peginterferon alpha-2a combination therapy in patients with HCV genotype 2 or 3 is dominant (more effective and cost saving) compared to interferon alpha-2b plus ribavirin. Results weighted by genotype prevalence (75% genotype 1; 25% genotype 2 or 3) also show that peginterferon alpha-2a plus ribavirin is dominant. Peginterferon alpha-2a and ribavirin remained cost-effective (below $16,500 per QALY gained) under sensitivity analyses on key clinical and cost parameters. Peginterferon alpha-2a in combination with ribavirin with duration of therapy based on genotype, is cost-effective compared with conventional interferon alpha-2b in combination with ribavirin when given to treatment-naïve adults with CHC.


Cashmeran as a potential endocrine disrupting chemical: What does the weight-of-the-evidence indicate?
Cashmeran is a fragrance ingredient. Risk assessments are available but have not focused on its endocrine disruptor potential. The objective was to evaluate Cashmeran as a potential endocrine-disrupting chemical (EDC). The assessment was based on data from US EPA's CompTox Chemicals Dashboard, the Danish (Q)SAR Database, in vitro assays, and in vivo studies. ToxCast assays related to estrogen, androgen, thyroid, and steroidogenesis modalities were Inactive at non-cytotoxic concentrations. In vitro assays demonstrated no estrogenic activity in a human cervical epithelioid carcinoma HeLa cell line and indicated only weak agonist estrogenic activity in Chinese Hamster Ovary (CHO)-K1 cells. In the same test, no agonist or antagonist activity was detected for human androgen receptor (hAR) and thyroid hormone receptor β (hTHRβ) binding. The Danish QSAR database didn't indicate any ED potential. There were no adverse endocrine related effects in either a 90-day repeated gavage dosing study or a reproductive and developmental screening study. Regarding ED potential for environment, the data from two limited environmental ED related studies on Cashmeran did not raise any concern. Data from in vitro and in vivo studies were considered for environmental ED concern. Based on the weight-of-the-evidence, Cashmeran is not expected to cause endocrine effects.


Respiratory Sinus Arrhythmia Attenuation via Targeted Lung Denervation in Sheep and Humans.
Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. TLD was performed in 5 sheep and 9 humans using a novel lung denervation system (Nu-vaira Inc., Minneapolis, MN, USA) with an electrocardiogram collected before and after the procedure. Frequency domain analysis of heart rate variability was performed in 5 sheep and 6 humans with presence of RSA approximated as high-frequency power (HF power). HF power decreased in 3 of 5 sheep with 1 animal reaching less than 7% of its baseline HF power 30 days after TLD. The average treatment location was more distal in the remaining 2 animals, which did not exhibit RSA attenuation, suggesting diminished denervation. HF power decreased in 5 of 6 humans, with 3 subjects reaching less than 50% of their baseline HF power 90 days after TLD. TLD appeared to attenuate RSA in both sheep and human cohorts of this sub-study. Further confirmation in humans is necessary to allow for RSA attenuation to be used as a marker of successful lung denervation via TLD.


Recurrence of subarachnoid hemorrhage due to the rupture of cerebral aneurysms in a patient with Sjögren's syndrome. Case report.
A 52-year-old woman with Sjögren's syndrome presented with multiple cerebral aneurysms, which resulted in recurrent subarachnoid hemorrhage (SAH) manifesting as severe headache. Computed tomography (CT) showed SAH. Cerebral angiography revealed aneurysms of the anterior communicating artery and the left middle cerebral artery. The necks of the aneurysms were successfully clipped. Postoperative course was uneventful and she was discharged without neurological deficit. Thirteen years later, she suddenly lost consciousness and was brought to our hospital. CT demonstrated recurrence of SAH. Cerebral angiography revealed cerebral aneurysms of the right internal carotid artery and the right middle cerebral artery. The clipped aneurysms were stable. The internal carotid artery aneurysm was successfully treated with endovascular coil embolization. However, she regained no neurological function and died. Patients with Sjögren's syndrome may develop cerebral aneurysm complicated with SAH.


Advanced imaging techniques for assessment of structure, composition and function in biofilm systems.
Scientific imaging represents an important and accepted research tool for the analysis and understanding of complex natural systems. Apart from traditional microscopic techniques such as light and electron microscopy, new advanced techniques have been established including laser scanning microscopy (LSM), magnetic resonance imaging (MRI) and scanning transmission X-ray microscopy (STXM). These new techniques allow in situ analysis of the structure, composition, processes and dynamics of microbial communities. The three techniques open up quantitative analytical imaging possibilities that were, until a few years ago, impossible. The microscopic techniques represent powerful tools for examination of mixed environmental microbial communities usually encountered in the form of aggregates and films. As a consequence, LSM, MRI and STXM are being used in order to study complex microbial biofilm systems. This mini review provides a short outline of the more recent applications with the intention to stimulate new research and imaging approaches in microbiology.


Facile and environmentally friendly solution-processed aluminum oxide dielectric for low-temperature, high-performance oxide thin-film transistors.
We developed a facile and environmentally friendly solution-processed method for aluminum oxide (AlOx) dielectrics. The formation and properties of AlOx thin films under various annealing temperatures were intensively investigated by thermogravimetric analysis-differential scanning calorimetry (TGA-DSC), X-ray diffraction (XRD), spectroscopic ellipsometry, atomic force microscopy (AFM), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), impedance spectroscopy, and leakage current measurements. The sol-gel-derived AlOx thin film undergoes the decomposition of organic residuals and nitrate groups, as well as conversion of aluminum hydroxides to form aluminum oxide, as the annealing temperature increases. Finally, the AlOx film is used as gate dielectric for a variety of low-temperature solution-processed oxide TFTs. Above all, the In2O3 and InZnO TFTs exhibited high average mobilities of 57.2 cm(2) V(-1) s(-1) and 10.1 cm(2) V(-1) s(-1), as well as an on/off current ratio of ∼10(5) and low operating voltages of 4 V at a maximum processing temperature of 300 °C. Therefore, the solution-processable AlOx could be a promising candidate dielectric for low-cost, low-temperature, and high-performance oxide electronics.


Comparative oligonucleotide analysis of exogenous and endogenous primate type C viruses.
RNAs of representative viruses of the exogenous simian sarcoma virus-gibbon ape lymphosarcoma virus (SiSV/GALV) and endogenous baboon virus (BaEV) classes of subhuman primate type C viruses were compared and related to HEL-12 virus, an isolate derived from human embryonic lung cells. The extent of sequence identity between different viral RNA preparations was determined by comparison of fingerprint patterns obtained after electrophoretic separation of RNase T1-resistant oligonucleotides. The studies presented indicate that HEL-12 viral RNA and simian sarcoma-simian associated virus [SiSV(SSAV)] RNA share 90 to 95% of the large oligonucleotides. From 5 to 10% of virus-specific oligonucleotides were detected in each of several virus preparations examined and their occurrence was independent of the cell line on which the virus ws propagated. HEL-12 virus and GALV-SF have 50% unique oligonucleotides in common. These are the same oligonucleotides that are shared between GALV-SF and SisV(SSAV) RNA. Two BaEV isolates, M7 and BILN, and RD114, and BaEV-related endogenous virus of cats, each easily displayed distinguishable oligonucleotides patterns. Large oligonucleotides characteristic for these three endogenous virus isolates were not detected in the fingerprints of HEL-12 virus, SiSV(SSAV) and GALV-SF.


A new approach for an ultrasensitive tactile sensor covering an ultrawide pressure range based on the hierarchical pressure-peak effect.
Flexible tactile sensors that imitate the skin tactile system have attracted extensive research interest due to their potential applications in medical diagnosis, intelligent robots and so on. However, it is still a great challenge to date to fabricate tactile sensors with both high sensitivity and wide detection range due to the difficulties in modulating the resistance variation in the sensing materials in a wide pressure range. Here, a tactile sensor with a novel design based on the hierarchical pressure-peak effect (HPPE) consisting of PVP nanowires and electroless deposition (ELD) silver PDMS micro-pyramids is reported. The HPPE can effectively modulate the resistance change rate by adjusting the change of contact area during compression deformation, and the HPPE tactile sensor was demonstrated to have both ultrahigh sensitivity (11.60-1108.75 kPa-1) and ultrawide pressure range (0.04-600 kPa). The designed HPPE tactile sensor is successfully utilized in detecting multi-level pressures including respiration, finger heart rate, pulse and foot pressures. Moreover, it is used to sense a subtle clamping force in the Leonardo Da Vinci surgical robot demonstrating the potential of the sensor in surgical robot applications. In all these cases, the sensor exhibits enough capability to respond quickly to ultrawide-range pressures with high accuracy and stability.


Mapping the interactions between the Alzheimer's Aβ-peptide and human serum albumin beyond domain resolution.
Human serum albumin (HSA) is a potent inhibitor of Aβ self-association and this novel, to our knowledge, function of HSA is of potential therapeutic interest for the treatment of Alzheimer's disease. It is known that HSA interacts with Aβ oligomers through binding sites evenly partitioned across the three albumin domains and with comparable affinities. However, as of this writing, no information is available on the HSA-Aβ interactions beyond domain resolution. Here, we map the HSA-Aβ interactions at subdomain and peptide resolution. We show that each separate subdomain of HSA domain 3 inhibits Aβ self-association. We also show that fatty acids (FAs) compete with Aβ oligomers for binding to domain 3, but the determinant of the HSA/Aβ oligomer interactions are markedly distinct from those of FAs. Although salt bridges with the FA carboxylate determine the FA binding affinities, hydrophobic contacts are pivotal for Aβ oligomer recognition. Specifically, we identified a site of Aβ oligomer recognition that spans the HSA (494-515) region and aligns with the central hydrophobic core of Aβ. The HSA (495-515) segment includes residues affected by FA binding and this segment is prone to self-associate into β-amyloids, suggesting that sites involved in fibrilization may provide a lead to develop inhibitors of Aβ self-association.


DNA pol λ's extraordinary ability to stabilize misaligned DNA.
DNA polymerases have the venerable task of maintaining genome stability during DNA replication and repair. Errors, nonetheless, occur with error propensities that are polymerase specific. For example, DNA polymerase λ (pol λ) generates single-base deletions through template-strand slippage within short repetitive DNA regions much more readily than does the closely related polymerase β (pol β). Here we present in silico evidence to help interpret pol λ's greater tendency for deletion errors than pol β by its more favorable protein/DNA electrostatic interactions immediately around the extrahelical nucleotide on the template strand. Our molecular dynamics and free energy analyses suggest that pol λ provides greater stabilization to misaligned DNA than aligned DNA. Our study of several pol λ mutants of Lys544 (Ala, Phe, Glu) probes the interactions between the extrahelical nucleotide and the adjacent Lys544 to show that the charge of the 544 residue controls stabilization of the DNA misalignment. In addition, we identify other thumb residues (Arg538, Lys521, Arg517, and Arg514) that play coordinating roles in stabilizing pol λ's interactions with misaligned DNA. Interestingly, their aggregate stabilization effect is more important than that of any one component residue, in contrast to aligned DNA systems, as we determined from mutations of these key residues and energetic analyses. No such comparable network of stabilizing misaligned DNA exists in pol β. Evolutionary needs for DNA repair on substrates with minimal base-pairing, such as those encountered by pol λ in the non-homologous end-joining pathway, may have been solved by a greater tolerance to deletion errors. Other base-flipping proteins share similar binding properties and motions for extrahelical nucleotides.


Comparison of Ethos template-based planning and AI-based dose prediction: General performance, patient optimality, and limitations.
Ethos proposes a template-based automatic dose planning (Etb) for online adaptive radiotherapy. This study evaluates the general performance of Etb for prostate cancer, as well as the ability to generate patient-optimal plans, by comparing it with another state-of-the-art automatic planning method, i.e., deep learning dose prediction followed by dose mimicking (DP + DM). General performances and capability to produce patient-optimal plan were investigated through two studies: Study-S1 generated plans for 45 patients using our initial Ethos clinical goals template (EG_init), and compared them to manually generated plans (MG). For study-S2, 10 patients which showed poor performances at study-S1 were selected. S2 compared the quality of plans generated with four different methods: 1) Ethos initial template (EG_init_selected), 2) Ethos updated template-based on S1 results (EG_upd_selected), 3) DP + DM, and 4) MG plans. EG_init plans showed satisfactory performance for dose level above 50 Gy: reported mean metrics differences (EG_init minus MG) never exceeded 0.6 %. However, lower dose levels showed loosely optimized metrics, mean differences for V30Gy to rectum and V20Gy to anal canal were of 6.6 % and 13.0 %. EG_init_selected showed amplified differences in V30Gy to rectum and V20Gy to anal canal: 8.5 % and 16.9 %, respectively. These dropped to 5.7 % and 11.5 % for EG_upd_selected plans but strongly increased V60Gy to rectum for 2 patients. DP + DM plans achieved differences of 3.4 % and 4.6 % without compromising any V60Gy. General performances of Etb were satisfactory. However, optimizing with template of goals might be limiting for some complex cases. Over our test patients, DP + DM outperformed the Etb approach.


In vitro activation of NAD-dependent alcohol dehydrogenases by Nudix hydrolases is more widespread than assumed.
In the Gram-positive methylotroph Bacillus methanolicus, methanol oxidation is catalyzed by an NAD-dependent methanol dehydrogenase (Mdh) that belongs to the type III alcohol dehydrogenase (Adh) family. It was previously shown that the in vitro activity of B. methanolicus Mdh is increased by the endogenous activator protein Act, a Nudix hydrolase. Here we show that this feature is not unique, but more widespread among type III Adhs in combination with Act or other Act-like Nudix hydrolases. In addition, we studied the effect of site directed mutations in the predicted active site of Mdh and two other type III Adhs with regard to activity and activation by Act.


Novel insights in dimethyl carbonate-based extraction of polyhydroxybutyrate (PHB).
Plastic plays a crucial role in everyday life of human living, nevertheless it represents an undeniable source of land and water pollution. Polyhydroxybutyrate (PHB) is a bio-based and biodegradable polyester, which can be naturally produced by microorganisms capable of converting and accumulating carbon as intracellular granules. Hence, PHB-producing strains stand out as an alternative source to fossil-derived counterparts. However, the extraction strategy affects the recovery efficiency and the quality of PHB. In this study, PHB was produced by a genetically modified Escherichia coli strain and successively extracted using dimethyl carbonate (DMC) and ethanol as alternative solvent and polishing agent to chloroform and hexane. Eventually, a Life Cycle Assessment (LCA) study was performed for evaluating the environmental and health impact of using DMC. Extraction yield and purity of PHB obtained via DMC, were quantified, and compared with those obtained via chloroform-based extraction. PHB yield values from DMC-based extraction were similar to or higher than those achieved by using chloroform (≥ 67%). To optimize the performance of extraction via DMC, different experimental conditions were tested, varying the biomass state (dry or wet) and the mixing time, in presence or in absence of a paper filter. Among 60, 90, 120 min, the mid-value allowed to achieve high extraction yield, both for dry and wet biomass. Physical and molecular dependence on the biomass state and solvent/antisolvent choice was established. The comparative LCA analysis promoted the application of DMC/ethanol rather than chloroform/hexane, as the best choice in terms of health prevention. However, an elevated impact score was achieved by DMC in the environmental-like categories in contrast with a minor contribution by its counterpart. The multifaceted exploration of DMC-based PHB extraction herein reported extends the knowledge of the variables affecting PHB purification process. This work offers novel and valuable insights into PHB extraction process, including environmental aspects not discussed so far. The findings of our research question the DMC as a green solvent, though also the choice of the antisolvent can influence the impact on the examined categories.


The existence of dead cells in donor corneal endothelium preserved with storage media.
To investigate the viability of donor corneal endothelial cells (CECs) preserved in storage media by histological examination. Twenty-eight donor corneas were obtained from SightLife Eye Bank (Seattle, Washington), and redundant peripheral portions of those corneas were used for histological examination after removal of the centre corneal graft for transplantation. To assess cell viability in the corneal endothelium, biostaining experiments were performed using propidium iodide, calcein-AM, Hoechst 33 342, annexin V, anti-vimentin antibody and toluidine blue. Histological analysis of the endothelium showed that the cytoplasm of dead cells had low-intensity fluorescence and that their nuclei stained red, while almost all living cells had green cytoplasm and blue-stained nuclei. The mean dead cell rate in the 28 donor corneas was 4.9%±3.3% (mean ±SD) (range: 0.6%-10.5%). The propidium iodide-positive cells stained positive for annexin V, negative for vimentin and pale for toluidine blue. After the specimens were incubated in a culture medium, the red nucleus dead cells dropped off from the level of the blue nucleus living cells. Our findings showed the existence of dead cells in storage-media-preserved donor corneal endothelium and that they dropped off after incubation, thus suggesting that the decrease of CECs following keratoplasty may be related to the presence of dead cells.


Analytical separations in open-tubular capillary electrochromatography.
This review represents a summary of recent progress in open-tubular capillary electrochromatography (OT-CEC) for chiral and achiral separations. The OT-CEC approach is an alternative to packed-CEC that could eliminate the problems associated with retaining frits and silica particles. In OT-CEC, the stationary phase is immobilized on the inner walls of the capillary. Preparation of the stationary phase is critical for OT-CEC. The preparation methods for capillary columns include (i) adsorption, (ii) covalent bonding and/or cross-linking, (iii) porous layers, (iv) chemical bonding after etching, (v) sol-gel, and (vi) molecular imprinting. Major developments, potential applications, technical difficulties and advantages associated with these wall coatings in OT-CEC are presented. In addition, the coupling of OT-CEC with mass spectrometry (MS) is briefly reviewed. Several applications of this hyphenated technique for analytical separations are also summarized.


Multiple endocrine neoplasia type 2A in an Iranian family: clinical and genetic studies.
Multiple endocrine neoplasia (MEN) type 2A, a dominant inherited syndrome caused by germline activating mutations in the RET protooncogene, is characterized by association of medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism. There is limited data on this disease in the Middle East region. In this paper, we present clinical and genetic studies of an Iranian patient and her family members. The patient was a 49-year old Iranian woman who presented with hypertension due to bilateral pheochromocytoma. She had history of a medullary carcinoma of thyroid which had been operated 28 years ago. Analysis of the RET gene in the family revealed a C634R mutation in codon 11 and 3 polymorphisms, G691S, S836S and S904S in codons 11, 14 and 15, respectively, that might have been important in modifying the clinical picture. Due to paucity of information on MEN type 2 in the area, this study can be helpful in portraying the clinical and cytogenetic characteristics of the disease in the region.


Bedside procalcitonin and C-reactive protein tests in children with fever without localizing signs of infection seen in a referral center.
To assess the value of bedside tests for predicting the occurrence of severe bacterial infections (SBIs) in children with fever without source. We conducted a prospective study of 99 children, aged 7 days to 36 months, who were seen for fever >38 degrees C and no localizing sign of infection at the emergency department of the University Children's Hospital of Geneva. Blood procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) values were determined using rapid tests and were compared with the total white blood cell (WBC) count with differential and clinical score. Specificity, sensitivity, predictive values, and multilevel likelihood ratios (LRs) with posttest probabilities of disease were calculated. Twenty-nine (29%) children received a diagnosis of having an SBI. PCT had the best sensitivity (93%) and negative predictive value (96%). Band count had the best specificity (93%), but its positive predictive value was only 38%. Multilevel LRs revealed that a PCT concentration <0.5 ng/mL (LR: 0.093) almost ruled out SBI (posttest probability of disease: 3.7%) in 54 (54%) subjects, whereas a value >2 ng/mL (LR: 5.2) increased the probability of SBI to 68% in 19 (19%) children. For CRP, values <40 mg/L (LR: 0.263) and >100 mg/L (LR: 14.483) generated posttest probabilities for SBI of 9.7% (61 subjects) and 86.5% (14 subjects), respectively. For WBC count, the posttest probabilities of SBI were modestly changed from the pretest prevalence. PCT and CRP performed better than IL-6, WBC, and/or band count in predicting the occurrence of SBI. PCT and CRP bedside tests may be useful tools for emergency and private practice doctors and should be considered in the initial work-up of children with fever without source.


The Chemistry of Galanthamine. Classical Synthetic Methods and Comprehensive Study on its Analogues.
Galanthamine as an Amaryllidaceae alkaloid has an important role in the treatment of Alzheimer's disease. Some efforts were made to elaborate the total synthesis, and hundreds of its derivatives were prepared to find a more effective molecule with advantageous properties. Moreover, almost every part of the tetracycle was changed; in members of the rings, in the nature and position of the heteroatoms, and ring-opened analogues were also synthesized. In this review the basic synthetic works and the most important derivatives and analogues are overviewed.


Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence.
To compare bupropion to placebo for reducing methamphetamine (MA) use, increasing retention, and reducing the severity of depressive symptoms and MA-cravings. A secondary objective compared bupropion to placebo for reducing cigarette smoking among MA dependent participants. Following a 2-week, non-medication baseline screening period, 73 treatment-seeking MA dependent participants were randomly assigned to bupropion sustained release (150 mg twice daily; N=36) or placebo (twice daily; N=37) for 12-weeks under double-blind conditions. Participants attended clinic thrice weekly to provide urine samples analyzed for MA-metabolite, to complete research measures and assessments, and to receive contingency management and weekly cognitive behavioral therapy sessions. There were no statistically significant effects for bupropion relative to placebo on MA use verified by urine drug screens, for reducing the severity of depressive symptoms or MA-cravings, or on study retention. In a post hoc analysis, there was a statistically significant effect of bupropion treatment on MA use among participants with lighter (0-2 MA-positive urines), but not heavier (3-6 MA-positive urines) MA use during baseline (OR=2.81, 95% CI=1.61-4.93, p<0.001 for MA-free week with bupropion among light users). Bupropion treatment was also associated with significantly reduced cigarette smoking, by almost five cigarettes per day (p=0.0002). Bupropion was no more effective than placebo in reducing MA use in planned analyses, though bupropion did reduce cigarette smoking. Post hoc findings of an effect for bupropion among baseline light, but not heavy, MA users suggests further evaluation of bupropion for light-MA users is warranted.


(2,2'-Bipyridine-kappa2N,N')(dichromato-kappaO)copper(II).
The title compound, [Cu(Cr(2)O(7))(C(10)H(8)N(2))(2)], a new mixed-metal molecular compound, contains isolated molecular units, each comprised of one Cu(II) atom coordinated to two 2,2'-bipyridine ligands and also to an oxygen vertex of a dichromate anion. The Cu(II) atom has an approximate trigonal-bipyramidal geometry, which is consistent with previous studies. Both enantiomers of the chiral complex molecule are present and are related by inversion centers. In a reported pyridine analogue, achiral [Cu(Cr(2)O(7))(pyridine)(4)] chains pack in the non-centrosymmetric space group Pna2(1). Differences in the organic ligands influence the chirality and dimensionality of the Cu-Cr(2)O(7) bonding.


Effects of Photo-Depicted Pupil Diameter on Judgments of Others' Attentiveness and on Facial Recognition Memory.
Occasionally, individuals perceive that someone is no longer paying attention to the discussion at hand even when there are no overt cues of inattentiveness. As a preliminary study of this phenomenon, we examined whether pupil diameter might be implicitly used to infer others' attentiveness. Forty participants (27 women, 13 men, M age = 19.7 year, SD = 2.8) were presented with images of male faces with either large or small pupils, and, in the context of a personnel selection scenario, participants then judged the attentiveness of the person in the image. Images of faces with large pupils were judged as more attentive, compared with images of faces with small pupils. Face recognition memory performance was not affected by depicted pupil size. Our results are consistent with the proposal that pupillary fluctuations can be an index of perceived attention, and they provide preliminary evidence that pupil dilation may be implicitly relied upon to infer attentional states.


Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA).
Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biologically important molecules through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different (99m)Tc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea-based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [(99m)Tc(CO)3](+) core (L8-L10), traditional NxSy-based chelating agents with varying charge and polarity for the (99m)Tc-oxo core (L11-L18), and a (99m)Tc-organohydrazine-labeled radioligand (L19). (99m)Tc(I)-Tricarbonyl-labeled [(99m)Tc]L8 produced the highest PSMA+ PC3 PIP to PSMA- PC3 flu tumor ratios and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of (99m)Tc-labeled radiopharmaceuticals targeting PSMA.


Bioinspired colloidal materials with special optical, mechanical, and cell-mimetic functions.
Biological materials are usually characterized by sophisticate structures and hierarchical organizations, leading to remarkable and multiple functions, which has been a source of inspiration for the fabrication of a wide variety of colloidal materials mimicking the structure and functions of biological systems. In this feature article, we summarize recent progress in the research on fabrication and applications of bioinspired colloidal materials with special optical, mechanical, and cell-mimetic functions. Three typical kinds of bioinspired colloidal materials are highlighted, which include bioinspired photonic structures based on colloidal crystals, colloidal assemblies with a nacre-like structure and novel mechanical properties, and colloidal cellular systems consisting of colloidal particles enclosed by lipid bilayers and possessing certain cellular functions. In addition, the challenges and perspectives in the future development of bioinspired colloidal materials are discussed.


[Sanitary classification of publishing products].
The natural asthenopic pattern of the process of reading shows it necessary to set sanitary standards of publishing production, namely, printing type styling and the printing quality of publications. The necessity of sanitary classification of publishing production stems from the specificity of reading the publications of different functional uses and from the physiological features of vision in different age group readers. The developed sanitary classification of printing production is based on the researches into the actual visual load while reading the publications of different types by readers of different ages.


Ultra-high capacity microfluidic trapping of giant vesicles for high-throughput membrane studies.
Biomimetic systems such as model lipid membranes are vital to many research fields including synthetic biology, drug discovery and membrane biophysics. One of the most commonly used are giant unilamellar vesicles (GUVs) due to their size similarity with biological cells and their ease of production. Typical methods for handling such delicate objects are low-throughput and do not allow solution exchange or long-term observations, all of which limits the experimental options. Herein, we present a new device designed to confine large assemblies of GUVs in microfluidic traps but is still able to perform precise and fast solution exchanges. An optimised design allows efficient filling with as many as 114 GUVs per trap and over 23 000 GUVs per device. This allows high-throughput dataset acquisitions which we demonstrate with two proof-of-concept experiments: (i) end-point measurements of vesicle interior pH and (ii) membrane transport kinetics. Moreover, we show that the design is able to selectively trap sub-populations of specific vesicle sizes and assemble them in different layers. The device can easily be applied to other high-throughput membrane studies and will pave the way for future applications using vesicle assemblies to model cellular tissues or even prototissues.


A conjoint appointment involving a nursing research management role.
Nursing conjoint appointments have taken a number of different forms and included various hospital roles such as ward manager, educator and consultant. This paper discusses an appointment trialed at a lecturer/middle manager level with a functional hospital role of Assistant Director of Nursing (research). The hospital role included activities categorized as: research consultations; research proposal reviews; committee membership; and research project involvement. The academic activities included a half-time teaching load, student clinical placement supervision and thesis/treatise student supervision. The development and implementation of the position, including background, role structure, appointment conditions and work practices are discussed. Issues that were highlighted during the 2 year trial included: the teaching load compared to reimbursement funding; the actual activities involved in the position; the level of appointment required to be most effective in the role; and concomitant university study by the appointee.


Intensive emission of Dy3+ in NaGd(PO3)4 for Hg-free lamps application.
The phosphor NaGd(PO(3))(4):Dy(3+) was synthesized by solid-state reaction technique at high temperature. The vacuum ultraviolet (VUV)-UV excitation spectra and visible emission spectra under VUV/UV excitation were investigated. The sample NaGd(PO(3))(4):Dy(3+) showed suitable spectroscopic characteristics such as broad and strong absorption around 172 nm, intensive emission with the chromaticity coordinates (0.33, 0.38) in warm-white light region. Additionally, this efficient white-emitting phosphor is activated by a single Dy(3+) ion and with a lower preparation temperature, which tend to decrease the consumption of rare earth resource and energy. Therefore, the phosphor NGP:Dy(3+) may be considered as a suitable candidate for Hg-free lamps application.


A rapid albumin-binding 5-fluorouracil prodrug with a prolonged circulation time and enhanced antitumor activity.
5-Fluorouracil (5-FU) is an antimetabolite widely used in the treatment of a variety of solid tumors. However, its clinical applications are greatly hindered by a very short residence time in blood circulation and non-specific distribution in the body. In order to overcome these challenges, 1-alkylcarbonyloxymethyl 5-FU was designed and linked with a maleimide group to form an albumin-binding 5-FU prodrug, named EMC-5-FU. In vitro incubation with bovine serum albumin (BSA) and fresh rat blood proved that the prodrug bound rapidly to cysteine-34 to form the drug-albumin conjugate nanomedicine. The conjugate BSA-EMC-5-FU was stable under acidic and neutral conditions but an unstable compound to release 5-FU in alkaline solution, and such a property was used for the determination of total 5-FU concentration in plasma. The t1/2 and AUC values of total 5-FU after an intravenous injection of EMC-5-FU to SD rats were significantly increased, about 43-fold and 93-fold higher than those of 5-FU following 5-FU intravenous administration, respectively. In vivo fluorescence images of EMC-Cy5 indirectly demonstrated the selective tumor accumulation of EMC-5-FU. In H22 tumor-bearing mice models, treatment with EMC-5-FU was more efficacious in tumor inhibition compared to 5-FU intravenous administration. In conclusion, a rapid albumin-binding prodrug strategy addresses concerns related to the poor circulation half-life and non-specific distribution of anticancer drugs, and paves the way for the development of in vivo-forming nanomedicines in clinical cancer therapy.


Impairment of lymphatic endothelial barrier function by X-ray irradiation.
Although the microvascular system is a significant target for radiation-induced effects, the lymphatic response to radiation has not been extensively investigated. This is one of the first investigations characterizing the lymphatic endothelial response to ionizing radiation. Rat mesenteric lymphatic endothelial cells (RMLECs) were exposed to X-ray doses of 0, 0.5, 1, 1.5, and 2 Gy. RMLEC cellular response was assessed 24 and 72-h post-irradiation via measures of cellular morphometry and junctional adhesion markers. RMLEC functional response was characterized through permeability experiments. Cell morphometry showed radiation sensitivity at all doses. Notably, there was a loss of cell-to-cell adhesion with irradiated cells increasing in size and cellular roundness. This was coupled with decreased β-catenin and VE-cadherin intensity and altered F-actin anisotropy, leading to a loss of intercellular contact. RMLEC monolayers demonstrated increased permeability at all doses 24 h post-irradiation and at 2-Gy 72 h post-irradiation. In summary, lymphatics show radiation sensitivity in the context of these cell culture experiments. Our results may have functional implications of lymphatics in tissue, with endothelial barrier dysfunction due to loss of cell-cell adhesion leading to leaky vessels and lymphedema. These preliminary experiments will build the framework for future investigations towards lymphatic radiation exposure response.


Sialoglycotherapeutics in protozoal diseases.
The manipulation of glycosylation, mainly sialylation, holds enormous potential for understanding the biological functions of glycoproteins and glycolipids to treat many diseases. The existing knowledge in the field of glycobiology is exploited by glycotherapeutics for combating protozoan diseases. This review focuses on the development of novel glycobiological therapeutic strategies in the field of protozoan infections.


Evidence for a specific seminiferous tubular factor affecting follicle-stimulating hormone secretion in man.
The interaction of the testis and gonadotropin secretion was studied in 15 men surviving chemotherapy for lymphoma. Azoospermia and complete destruction of all testicular germinal elements were present in 10 of the 15 men; however, Sertoli cells and Leydig cells were present. In these 10 men plasma follicle-stimulating hormone (FSH) levels were fourfold higher than in normal men of similar age whereas luteinizing hormone (LH) levels were normal. In contrast, both FSH and LH were normal in the remaining five men. Three had a full complement of spermatogenic tissue on biopsy and normal sperm concentrations. The other two men were azoospermic; one demonstrated full spermatogenesis in 30% of his tubules; the other had only a few spermatogonia in all tubules. In those patients with lower levels of gonadotropins pituitary insufficiency was excluded by the demonstration of appropriate responsiveness of FSH and LH to clomiphene administration. Similarly, Leydig cell function was normal since plasma testosterone was within the normal range in 13 of the 15 men and only slightly decreased in two. Thus, following chemotherapy, testicular damage was restricted to the germinal tissue, and this in turn was associated with a selective increase in FSH. The source of the FSH inhibitor is either the Sertoli cell or early germinal elements. However, since FSH levels are only half as high as those reported for castrate men, other testicular factors may modify FSH secretion.


Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators.
Evidence suggests that physiologic pacing (dual-chamber or atrial) may be superior to single-chamber (ventricular) pacing because it is associated with lower risks of atrial fibrillation, stroke, and death. These benefits have not been evaluated in a large, randomized, controlled trial. At 32 Canadian centers, patients without chronic atrial fibrillation who were scheduled for a first implantation of a pacemaker to treat symptomatic bradycardia were eligible for enrollment. We randomly assigned patients to receive either a ventricular pacemaker or a physiologic pacemaker and followed them for an average of three years. The primary outcome was stroke or death due to cardiovascular causes. Secondary outcomes were death from any cause, atrial fibrillation, and hospitalization for heart failure. A total of 1474 patients were randomly assigned to receive a ventricular pacemaker and 1094 to receive a physiologic pacemaker. The annual rate of stroke or death due to cardiovascular causes was 5.5 percent with ventricular pacing, as compared with 4.9 percent with physiologic pacing (reduction in relative risk, 9.4 percent; 95 percent confidence interval, -10.5 to 25.7 percent [the negative value indicates an increase in risk]; P=0.33). The annual rate of atrial fibrillation was significantly lower among the patients in the physiologic-pacing group (5.3 percent) than among those in the ventricular-pacing group (6.6 percent), for a reduction in relative risk of 18.0 percent (95 percent confidence interval, 0.3 to 32.6 percent; P=0.05). The effect on the rate of atrial fibrillation was not apparent until two years after implantation. The observed annual rates of death from all causes and of hospitalization for heart failure were lower among the patients with a physiologic pacemaker than among those with a ventricular pacemaker, but not significantly so (annual rates of death, 6.6 percent with ventricular pacing and 6.3 percent with physiologic pacing; annual rates of hospitalization for heart failure, 3.5 percent and 3.1 percent, respectively). There were significantly more perioperative complications with physiologic pacing than with ventricular pacing (9.0 percent vs. 3.8 percent, P<0.001). Physiologic pacing provides little benefit over ventricular pacing for the prevention of stroke or death due to cardiovascular causes.


[Vasoactive substances and the modulation of the hepatic microvascular system].
To review some aspects of the hepatic phylogeny and ontogeny, the hepatic microvascular system, and the modulation of the tonus on this vascular system by different vasoactive substances. Text books and articles from MEDLINE-indexed journals were consulted. Fifty-two articles, that were published between 1949 and 1997, were selected. They provided us with information concerning hepatic phylogeny and ontogeny, the hepatic microvascular system, and the modulation of the tonus in this vascular system. The architecture of the hepatic microvascular system, a unique and complex vascular system, is well suited to the functions of the organ. Different factors, including endothelial vasoactive substances, participate in the modulation of the vascular resistance through the liver adequating the liver perfusion to the homeostatic needs. The liver is eminently a maintainer of internal stability.


War experiences and war-related distress in Bosnia and Herzegovina eight years after war.
To examine the relationship between war experiences and war-related distress in Bosnia and Herzegovina. The survey was performed in the late 2003 on a representative sample of 3313 respondents. The face-to-face interviews included 15 items on war-related distress and 24 items on war experiences. From these items we developed the War-related Distress Scale, the Direct War Experiences Scale, and the Indirect War Experiences Scale. Regression analysis was used to examine the relationship between war-related distress symptoms and war experiences variables, controlling for a range of other variables. Almost half of the respondents did not report any war-related distress symptoms, while about 13% reported 7 or more symptoms. Direct war experiences had a significant effect on war-related distress even eight years after the war, while indirect war experiences showed no significant effect on war-related distress. We found that marital status weakly decreased war-related distress, while household size increased it. Direct war experiences seem to have a long-lasting traumatic effect on a substantial number of residents of Bosnia and Herzegovina.


A visible and near-infrared dual-fluorescent probe for discrimination between Cys/Hcy and GSH and its application in bioimaging.
Biothiols such as cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) play important roles in various physiological and pathological processes, and due to their similar structures and reaction activities, it is still challenging to simultaneously discriminate between GSH and Cys/Hcy in vivo. Hence, a novel fluorescent probe for simultaneously discriminating GSH and Cys/Hcy in biological samples is highly desirable. Herein, we presented two enhanced fluorescent probes (Cy1 and Cy2) with doubly-activated dual emission for sensitive and discriminative detection of Cys/Hcy and GSH. The probes were constructed with IR-780 and NBD linked via an ether bond, which responds to GSH with near infrared (NIR) emission at 810 nm (λex = 720 nm) and Cys/Hcy with visible green emission at 550 nm (λex = 470 nm). The probe Cy2 is operable in human serum samples, thus holding promise for its diagnosis-related application. Notably, the results of fluorescence microscopy imaging indicated that Cy2 is suitable for visualization of exogenous and endogenous biothiols in living cells. Furthermore, desirable results were obtained when the probe Cy2 was applied for bioimaging in tumor-bearing mice and acute liver injury (ALI) mice models, which revealed encouraging clinical values of this probe.


Virus-induced gene silencing in Solanum species.
Virus-induced gene silencing (VIGS) has been used routinely in Nicotiana benthamiana to assess functions of candidate genes and as a way to discover new genes required for diverse pathways, especially disease resistance signalling. VIGS has recently been shown to work in Arabidopsis thaliana and in tomato. Here, we report that VIGS using the tobacco rattle virus (TRV) viral vector can be used in several Solanum species, although the choice of vector and experimental conditions vary depending on the species under study. We have successfully silenced the phytoene desaturase (PDS) gene in the diploid wild species Solanum bulbocastanum and S. okadae, in the cultivated tetraploid S. tuberosum and in the distant hexaploid relative S. nigrum (commonly known as deadly nightshade). To test whether the system could be utilised as a rapid way to assess gene function of candidate resistance (R) genes in potato and its wild relatives, we silenced R1 and Rx in S. tuberosum and RB in S. bulbocastanum. Silencing of R1, Rx and RB successfully attenuated R-gene-mediated disease resistance and resulted in susceptible phenotypes in detached leaf assays. Thus, the VIGS system is an effective method of rapidly assessing gene function in potato.


Hyperammonaemia causes many of the changes found after portacaval shunting.
1. Portacaval shunting in rats results in several metabolic alterations similar to those seen in patients with hepatic encephalopathy. The characteristic changes include: (a) diminution of cerebral function; (b) raised plasma ammonia and brain glutamine levels; (c) increased neutral amino acid transport across the blood-brain barrier; (d) altered brain and plasma amino acid levels; and (e) changes in brain neurotransmitter content. The aetiology of these abnormalities remains unknown. 2. To study the degree to which ammonia could be responsible, rats were made hyperammonaemic by administering 40 units of urease/kg body weight every 12 h and killing the rats 48 h after the first injection. 3. The changes observed in the urease-treated rats were: (a) whole-brain glucose use was significantly depressed, whereas the levels of high-energy phosphates remained unchanged; (b) the permeability of the blood-brain to barrier to two large neutral amino acids, tryptophan and leucine, was increased; (c) blood-brain barrier integrity was maintained, as indicated by the unchanged permeability-to-surface-area product for acetate; (d) plasma and brain amino acid concentrations were altered; and (e) dopamine, 5-hydroxytryptamine (serotonin) and noradrenaline levels in brain were unchanged, but 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-hydroxytryptamine, was elevated. 4. The depressed brain glucose use, increased tryptophan permeability-to-surface-area product, elevated brain tryptophan content and rise in the level of cerebral 5-HIAA were closely correlated with the observed rise in brain glutamine content. 5. These results suggest that many of the metabolic alterations seen in rats with portacaval shunts could be due to elevated ammonia levels. Furthermore, the synthesis or accumulation of glutamine may be closely linked to cerebral dysfunction in hyperammonaemia.


Top Issues for Maternal/Child and Women's and Gender-Related Health.
Nurses must consider the complex and intersecting issues that affect the health of individuals and work toward a collective goal of health equality.


Aortic stent-grafting: successful introduction into the combined procedure for coronary artery bypass grafting and aortic aneurysm repair.
Coronary artery bypass grafting (CABG) and combined stent-grafting (SG) were evaluated to reduce morbidity and mortality of patients with descending or infrarenal aortic aneurysm. CABG and SG (thoracic n=6, infrarenal n=36) were performed during the same hospitalization in 42 patients (mean age of 73+/-14 years). In 29 patients (mean Euroscore: 9), SG was performed under local anesthesia 9+/-3 days after coronary surgery (simultaneous) and in 13 patients (mean Euroscore: 7) during the same anesthesia (synchronous). In the latter group, 11 out of 13 patients underwent off-pump CABG. All aneurysms were treated by implantation of commercially available self-expanding grafts. CABG was successful in all, but one patient with left internal mammary artery hypoperfusion syndrome, requiring an additional distal saphenous graft to the left anterior descending coronary artery. SG was uneventful in 98% (41/42 patients). Postoperative computerized tomography showed incomplete sealing in seven patients (17%), but only the two attachment endoleaks had to be treated by one proximal and one distal SG extension. Overall hospital stay for the synchronous repair was 12.5+/-6 days and that of the simultaneous group 17.5+/-7 days. Thirty-day mortality was 5% (2/42) as one patient of the simultaneous group experienced a lethal cerebral embolism during SG and one patient of the synchronous group developed an untreatable infection. In the follow-up of 4 years, there were two vascular reinterventions but no additional procedure-related morbidity or mortality. This experience shows that combined CABG and SG of thoracic or infrarenal aortic aneurysm is a safe and less-invasive alternative to the open graft repair, especially in the older patients or patients with severe comorbidities.


Analgesic effect of the flavonoid herbacetin in nociception animal models.
This study aimed to assess the antinociceptive activity of herbacetin using chemically and thermally induced nociception in a mouse model. The antinociceptive effects of various herbacetin doses (50, 100, 150, and 200 µg/kg) were assessed in mice using the acetic acid-induced writhing test, hot plate test, and formalin-induced paw-licking assay. The effects were compared to those of mice treated with acetylsalicylic acid or morphine in the presence or absence of naloxone (an opioid receptor antagonist). Capsaicin- and glutamate-induced paw-licking tests were also used to evaluate the involvement of the vanilloid and glutamatergic systems, respectively. Pro-inflammatory mediators: Interleukin-1-beta (IL-1β), Tumour Necrosis Factor alpha (TNF-α), Interferon-gamma (IFN-γ), and Nitric Oxide (NO) were also assessed. Herbacetin produced significant dose-dependent inhibition of nociceptive behavior in the acetic acid-induced writhing test, showing 65% inhibition at a dose of 200 µg/kg. Herbacetin also caused a significant increase in the latency period in response to the hot plate test (70% at 200 µg/kg), and significantly inhibited both the neurogenic and inflammatory phases in the formalin-induced paw-licking test. Naloxone significantly reverses the effect of herbacetin in both the hot plate and formalin-induced paw-licking test. Moreover, herbacetin significantly inhibited the neurogenic nociception induced by intraplantar injections of capsaicin and glutamate (75% and 48%, respectively, at a dose of 200 µg/kg). Pro-inflammatory cytokines IL-1β, TNF-α, IFN-γ, and NO in the serum of mice were assessed. These cytokines were significantly inhibited by herbacetin (100 and 200 µg/kg). Thus, herbacetin exhibited peripheral and central antinociception through the modulation of vanilloid receptors, opioid receptors, and the glutamatergic system. Herbacetin possesses antinociceptive activity in adult mice that is mediated through both central and peripheral pathways.


[Acamprosate--a novel treatment for alcoholism].
The properties of acamprosate (calcium acetylhomotaurate), a new remedy for the treatment of alcoholism, are reviewed. The efficacy of this drug has been verified by numerous clinical tests in West Europe. The pharmacological activity of acamprosate is related to the drug action upon central neuromediator systems. No side or addiction effects of the drug were reported. Data on the clinical and pharmacological characteristics of acamprosate are summarized.


The evolution of antibiotic therapy for neutropenic patients.
Considerable progress has been made in the treatment of infections in neutropenic patients during the past three decades. A major contribution to this progress has been the discovery of effective new therapies and their prompt administration. Unfortunately, successful therapy of each important pathogen has resulted in the emergence of new pathogens, usually with unique patterns of antibiotic susceptibility. Unfortunately, antibiotic resistance has become an increasing threat in recent years, raising the possibility of infections that will be difficult to eradicate. Fortunately, there are new classes of antimicrobials that hold promise for therapeutic success in the future.


Becoming a better listener.
Listening is the most overlooked, misunderstood, and undervalued communication skill for many people. Being a good listener, however, is at least as important as being a good speaker, writer, or reader. In fact, listening may be the most important communication skill for anyone who works in a medical practice. This article offers seven specific techniques for listening more actively in conversation, whether that conversation is with a medical practice coworker, supervisor, or patient. It offers an active listening strategy for medical practice employees who are about to attend a continuing education or enrichment course, seminar, workshop, or lecture. It suggests a self-reflective exercise to help listeners engage with the material presented at educational programs. Finally, this article offers guidance for listening actively at medical practice staff meetings.


Lifestyle Habits: Diet, physical activity and sleep duration among Omani adolescents.
This study aimed to investigate the lifestyle habits-physical activity (PA), eating habits (EH), and sleep duration (SD)-of Omani adolescents, and to examine gender differences in such variables. 802 Omani adolescents (442 females and 360 males), aged 15-18 years were randomly recruited. Anthropometric indices, PA level, and EH and SD were evaluated by the Arab Teenage Lifestyle questionnaire. A semi-quantitative food frequency questionnaire for dietary assessment was also administered. The results showed that although the study subjects had a sedentary lifestyle (lack of PA, average of 6.7 hours sleep, and consumption of high calorie foods), they maintained a normal body mass (less than 25 Kg/m(2)). Males were more than twice as active as females. With respect to EH, there were few gender differences, except in dairy and meat consumption where 62.5% and 55.5% of males consumed more than 3 servings, respectively, compared to 18.78 % and 35.2% of females, respectively. In addition, waist/height ratio, height, reasons for being active, energy drinks, potato consumption, eating sweets, vigorous PA and breakfast EHs were statistically significant independent predictors for BMI, P <0.05 for both males and females. This study revealed a high prevalence of sedentary behaviors and a low level of physical activity, especially among females. Unhealthy dietary habits were also widely found among both genders. There is an urgent need for more research as well as a national policy promoting active living and healthy eating and discouraging sedentary behaviour among Omani adolescents.


A unified perspective on the nature of bonding in pairwise interatomic interactions.
Different classes of ground electronic state pairwise interatomic interactions are referenced to a single canonical potential using explicit transformations. These approaches have been applied to diatomic molecules N2, CO, H2(+), H2, HF, LiH, Mg2, Ca2, O2, the argon dimer, and one-dimensional cuts through multidimensional potentials of OC-HBr, OC-HF, OC-HCCH, OC-HCN, OC-HCl, OC-HI, OC-BrCl, and OC-Cl2 using accurate semiempirically determined interatomic Rydberg-Klein-Rees (RKR) and morphed intermolecular potentials. Different bonding categories are represented in these systems, which vary from van der Waals, halogen bonding, and hydrogen bonding to strongly bound covalent molecules with binding energies covering 3 orders of magnitude from 84.5 to 89,600.6 cm(-1) in ground state dissociation energies. Such approaches were then utilized to give a unified perspective on the nature of bonding in the whole range of diatomic and intermolecular interactions investigated.


Strategies for vascularization of polymer scaffolds.
Biocompatible, degradable polymer scaffolds combined with cells or biological signals are being investigated as alternatives to traditional options for tissue reconstruction and transplantation. These approaches are already in clinical use as engineered tissues that enhance wound healing and skin regeneration. The continued enhancement of these material strategies is highly dependent on the ability to promote rapid and stable neovascularization (new blood vessel formation) within the scaffold. Whereas neovascularization therapies have shown some promise for the treatment of ischemic tissues, vascularization of polymer scaffolds in tissue engineering strategies provides a unique challenge owing to the volume and the complexity of the tissues targeted. In this article, we examine recent advances in research focused on promoting neovascularization in polymer scaffolds for tissue engineering applications. These approaches include the use of growth factors, cells, and novel surgical approaches to both enhance and control the nature of the vascular networks formed. The continued development of these approaches may lead to new tissue engineering strategies for the generation of skin and other tissues or organs.


Electrochemical sensing of total antioxidant capacity and polyphenol content in wine samples using amperometry online-coupled with microdialysis.
This work describes the method for total antioxidant capacity (TAC) and/or total content of phenolics (TCP) analysis in wines using microdialysis online-coupled with amperometric detection using a carbon microfiber working electrode. The system was tested on 10 selected wine samples, and the results were compared with total reactive antioxidant potential (TRAP), oxygen radical absorbance capacity (ORAC), and chemiluminescent determination of total antioxidant capacity (CL-TAC) methods using Trolox and catechin as standards. Microdialysis online-coupled with amperometric detection gives similar results to the widely used cyclic voltammetry methodology and closely correlates with ORAC and TRAP. The problem of electrode fouling is overcome by the introduction of an electrochemical cleaning step (1-2 min at the potential of 0 V vs Ag/AgCl). Such a procedure is sufficient to fully regenerate the electrode response for both red and white wine samples as well as catechin/Trolox standards. The appropriate size of microdialysis probes enables easy automation of the electrochemical TAC/TCP measurement using 96-well microtitration plates.


Large-sample evidence on the impact of unconventional oil and gas development on surface waters.
The impact of unconventional oil and gas development on water quality is a major environmental concern. We built a large geocoded database that combines surface water measurements with horizontally drilled wells stimulated by hydraulic fracturing (HF) for several shales to examine whether temporal and spatial well variation is associated with anomalous salt concentrations in United States watersheds. We analyzed four ions that could indicate water impact from unconventional development. We found very small concentration increases associated with new HF wells for barium, chloride, and strontium but not bromide. All ions showed larger, but still small-in-magnitude, increases 91 to 180 days after well spudding. Our estimates were most pronounced for wells with larger amounts of produced water, wells located over high-salinity formations, and wells closer and likely upstream from water monitors.


Toxic Peptide From Palythoa caribaeorum Acting on the TRPV1 Channel Prevents Pentylenetetrazol-Induced Epilepsy in Zebrafish Larvae.
PcActx peptide, identified from the transcriptome of zoantharian Palythoa caribaeorum, was clustered into the phylogeny of analgesic polypeptides from sea anemone Heteractis crispa (known as APHC peptides). APHC peptides were considered as inhibitors of transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 is a calcium-permeable channel expressed in epileptic brain areas, serving as a potential target for preventing epileptic seizures. Through in silico and in vitro analysis, PcActx peptide was shown to be a potential TRPV1 channel blocker. In vivo studies showed that the linear and oxidized PcActx peptides caused concentration-dependent increases in mortality of zebrafish larvae. However, monotreatment with PcActx peptides below the maximum tolerated doses (MTD) did not affect locomotor behavior. Moreover, PcActx peptides (both linear and oxidized forms) could effectively reverse pentylenetetrazol (PTZ)-induced seizure-related behavior in zebrafish larvae and prevent overexpression of c-fos and npas4a at the mRNA level. The excessive production of ROS induced by PTZ was markedly attenuated by both linear and oxidized PcActx peptides. It was also verified that the oxidized PcActx peptide was more effective than the linear one. In particular, oxidized PcActx peptide notably modulated the mRNA expression of genes involved in calcium signaling and γ-aminobutyric acid (GABA)ergic-glutamatergic signaling, including calb1, calb2, gabra1, grm1, gria1b, grin2b, gat1, slc1a2b, gad1b, and glsa. Taken together, PcActx peptide, as a novel neuroactive peptide, exhibits prominent anti-epileptic activity, probably through modulating calcium signaling and GABAergic-glutamatergic signaling, and is a promising candidate for epilepsy management.


Decision-making, errors, and confidence in the brain.
To provide a fundamental basis for understanding decision-making and decision confidence, we analyze a neuronal spiking attractor-based model of decision-making. The model predicts probabilistic decision-making with larger neuronal responses and larger functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) responses on correct than on error trials because the spiking noise-influenced decision attractor state of the network is consistent with the external evidence. Moreover, the model predicts that the neuronal activity and the BOLD response will become larger on correct trials as the discriminability ΔI increases and confidence increases and will become smaller as confidence decreases on error trials as ΔI increases. Confidence is thus an emergent property of the model. In an fMRI study of an olfactory decision-making task, we confirm these predictions for cortical areas including medial prefrontal cortex and the cingulate cortex implicated in choice decision-making, showing a linear increase in the BOLD signal with ΔI on correct trials, and a linear decrease on error trials. These effects were not found in a control area, the orbitofrontal cortex, where reward value useful for the choice is represented on a continuous scale but that is not implicated in the choice itself. This provides a unifying approach to decision-making and decision confidence and to how spiking-related noise affects choice, confidence, synaptic and neuronal activity, and fMRI signals.


What insects can tell us about the origins of consciousness.
How, why, and when consciousness evolved remain hotly debated topics. Addressing these issues requires considering the distribution of consciousness across the animal phylogenetic tree. Here we propose that at least one invertebrate clade, the insects, has a capacity for the most basic aspect of consciousness: subjective experience. In vertebrates the capacity for subjective experience is supported by integrated structures in the midbrain that create a neural simulation of the state of the mobile animal in space. This integrated and egocentric representation of the world from the animal's perspective is sufficient for subjective experience. Structures in the insect brain perform analogous functions. Therefore, we argue the insect brain also supports a capacity for subjective experience. In both vertebrates and insects this form of behavioral control system evolved as an efficient solution to basic problems of sensory reafference and true navigation. The brain structures that support subjective experience in vertebrates and insects are very different from each other, but in both cases they are basal to each clade. Hence we propose the origins of subjective experience can be traced to the Cambrian.


Post-training reversible inactivation of hippocampus reveals interference between memory systems.
A post-training reversible lesion technique was used to examine the effects of neural inactivation of the dorsal hippocampus on place and response learning. Male Long-Evans rats trained in one of two versions of a water plus-maze task received post-training intra-hippocampal infusions of the local anesthetic drug bupivacaine (0.75% solution, 0.5 microl), or saline. Post-training intra-hippocampal infusions of bupivacaine attenuated acquisition of the place task and enhanced acquisition of the response task. Delayed (2-h) post-training infusions of bupivacaine did not affect retention in either task. The findings demonstrate (1) enhanced learning after reversible hippocampal lesions that is independent of treatment influences on non-mnemonic factors, and (2) inactivation of the dorsal hippocampus during the post-training memory consolidation period is sufficient to enhance response learning.


[Inhalational antibacterial therapy for an exacerbation of chronic obstructive pulmonary disease].
The clinical efficiency of inhalational antibacterial therapy for Stage II chronic obstructive pulmonary disease (COPD) was evaluated in 100 patients who had been randomized to an inhalational fusafungine group (n = 50) and a systemic (per os or parenteral) antibiotics group (n = 50). Inhalational antibacterial therapy for exacerbations of Stage II COPD was found to be as effective as systemic use of antibiotics. Moreover, side effects of inhalational therapy were much less pronounced.


Regulation of mammalian protein synthesis in vivo. Protein synthesis in rat liver and kidney after the administration of sublethal doses of cyclohyximide.
Protein synthesis in vivo was studied at various times after the administration of sublethal doses of cycloheximide to rats. Cycloheximide caused an inhibition, followed by a dose-and time-dependent stimulation, of incorportation of labelled precursor into proteins of the liver and kidney. The stimulation of protein synthesis at 24h was not due to a change of precursor pool or the specific radioactivity of the precursor used. During the stimulatory period, leucine incorporation into various cellular protein fractions varied; incorporation into total nuclear protein was the most affected.


Preventive medicine. When to screen for disease in older patients.
Goals for health promotion and disease prevention in older patients include reducing premature mortality caused by chronic and acute illnesses, maintaining functional independence, extending life expectancy, and maintaining or enhancing quality of life. Determining whether a screen or intervention is warranted depends upon several key factors: whether the disease or condition will significantly impact a patient's quality of life, whether acceptable methods of treatment are available, and implications of delaying treatment. Although most diseases progress insidiously and undetected, there is a window of opportunity for screening and prevention during the asymptomatic phase. Some of the most effective interventions involve lifestyle changes such as smoking cessation and regular physical activity.


MIS Distal Metatarsal Metaphyseal Osteotomy in the treatment of metatarsalgia: MOXFQ patient reported outcomes.
The aim of this paper is to present validated patient reported outcomes for MIS Distal Metatarsal Metaphyseal Osteotomy (DMMO) in the treatment of metatarsalgia. The study aims to evaluate the DMMO procedure, report patient satisfaction with the operated foot and report any complications of this procedure. Between 2014 and 2016, patients who had failed conservative treatment for metatarsalgia were identified in the orthopaedic outpatient clinic. Twenty four consecutive patients requiring DMMO plus/minus toe straightening were prospectively studied. Patients requiring additional procedures at the time of surgery were excluded. Patients completed the validated Manchester-Oxford Foot Questionnaire (MOXFQ) three weeks pre-operatively and 1 year postoperatively. The MOXFQ results were analysed using Paired t-tests. A supplementary question was asked regarding patient satisfaction with the operated foot. There were 20 women and 4 men with a mean age of 64 years (sd 8.6). Statistically significant differences were found between the pre and postoperative MOXFQ. The postoperative MOXFQ score demonstrated a poorer result for two patients, no change for two patients and improvement in 20 patients, with four of these patients recording the lowest possible score. There was a 29.5 point improvement in mean metric MOXFQ Index score. Seventy-nine percent (n = 19) of patients were satisfied or very satisfied with the operated foot. The average recoil of the metatarsal heads following DMMO was M2 4.01 mm, M3 4.55 mm, M4 4.16 mm. There was one delayed union and no non-unions. Further reported complications were a gastric bleed, pulmonary embolism (VTE), and one intra operative broken burr. Our study demonstrates a clinically important and statistically significant improvement in patient reported outcomes following DMMO, with 79% of patients satisfied or very satisfied with this procedure. The average recoil of the metatarsal heads following DMMO was M2 4.01 mm, M3 4.55 mm, M4 4.16 mm with one delayed union and no non-unions.


The Anxiety Level of Caregivers of Neurological Patients with Dysphagia.
We aimed to investigate anxiety level of caregivers of neurological patients with dysphagia, and the relationship of patient-related factors to anxiety level of dysphagia caregivers. A total of 103 adult neurological patients with dysphagia (study group), 30 without dysphagia (control group), and their primary caregivers were included. Types of feeding, condition of dependency in eating and drinking, dysphagia duration, and history of previous dysphagia treatment were recorded for study group. In study group, the Turkish version of the Eating Assessment Tool-10 (T-EAT-10) was used to determine dysphagia symptom severity. Penetration and aspiration severity was determined with the penetration-aspiration scale (PAS). The Spielberger State-Trait Anxiety Inventory (STAI) that has two subscales including state anxiety (S-STAI) and trait anxiety (T-STAI) was used to determine anxiety level of caregivers. There was no difference between groups in terms of age, gender, weight, and height. The mean S-STAI was 42.56 ± 10.10 for the study group and 29.20 ± 6.64 for the control group (p < 0.001). The mean T-STAI was 44.81 ± 8.98 for the study group and 29.37 ± 6.46 for the control group (p < 0.001). Significant correlation was detected between only T-STAI and history of previous dysphagia treatment (p = 0.01, r = 0.25). No correlation was found between STAI (in terms of both S-STAI and T-STAI) and T-EAT-10, PAS, types of feeding, condition of dependency in eating and drinking, dysphagia duration (p > 0.05). Caregivers of neurological patients with dysphagia have greater anxiety level than caregivers of neurological patients without dysphagia.


Saccharomyces cerevisiae Afr1 protein is a protein phosphatase 1/Glc7-targeting subunit that regulates the septin cytoskeleton during mating.
Glc7, the type1 serine/threonine phosphatase in the yeast Saccharomyces cerevisiae, is targeted by auxiliary subunits to numerous locations in the cell, where it regulates a range of physiological pathways. We show here that the accumulation of Glc7 at mating projections requires Afr1, a protein required for the formation of normal projections. AFR1-null mutants fail to target Glc7 to projections, and an Afr1 variant specifically defective in binding to Glc7 [Afr1(V546A F548A)] forms aberrant projections. The septin filaments in mating projections of AFR1 mutants initiate normally but then rearrange asymmetrically as the projection develops, suggesting that the Afr1-Glc7 holoenzyme may regulate the maintenance of septin complexes during mating. These results demonstrate a previously unknown role for Afr1 in targeting Glc7 to mating projections and in regulating the septin architecture during mating.


Synthesis, in vitro cytotoxic and apoptotic effects, and molecular docking study of novel adamantane derivatives.
[4-(Adamantane-1-carboxamido)-3-oxo-1-thia-4-azaspiro[4.4]nonan-2-yl]acetic acid (4a) and [4-(adamantane-1-carboxamido)-8-nonsubstituted/substituted-3-oxo-1-thia-4-azas-piro[4.5]decane-2-yl]acetic acid (4b-g) derivatives were synthesized; their structures were verified by elemental analysis, infrared spectroscopy, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectroscopy data; and their in vitro cytotoxicity activities were investigated against human hepatocellular carcinoma, human prostate adenocarcinoma, and human lung carcinoma cell lines (HepG2, PC-3, and A549, respectively), and a mouse fibroblast cell line (NIH/3T3). All compounds, except compound 4e, were found as cytotoxic, especially on A549 cells as compared with the other cells (selectivity index = 2.01-11.6). As a further step, the effects of compounds 4a-c on apoptosis induction were tested and the expression of selected apoptosis genes was analyzed. Among the selected compounds, compound 4a induced apoptosis remarkably. Moreover, computational calculations of the binding of compounds 4a-c to the BIR3 domain of the human inhibitor of apoptosis protein revealed ligand-protein interactions at the atomistic level and emphasized the importance of a hydrophobic moiety on the ligands for better binding.


Effects of microsaccades on contrast detection and V1 responses in macaques.
Microsaccades can elevate contrast detection thresholds of human observers and modulate the activity of neurons in monkey visual cortex. Whether microsaccades elevate contrast detection thresholds in monkey observers is not known and bears on the interpretation of neurophysiological experiments. To answer this question, we trained two monkeys to perform a 2AFC contrast detection task. Performance was worse on trials in which a microsaccade occurred during the stimulus presentation. The magnitude of the effect was modest (threshold changes of <0.2 log unit) and color specific: achromatic sensitivity was impaired, but red-green sensitivity was not. To explore the neural basis of this effect, we recorded the responses of individual V1 neurons to a white noise stimulus. Microsaccades produced a suppression of spiking activity followed by an excitatory rebound that was similar for L - M cone-opponent and L + M nonopponent V1 neurons. We conclude that microsaccades in the monkey increase luminance contrast detection thresholds and modulate the spiking activity of V1 neurons, but the luminance specificity of the behavioral suppression is likely implemented downstream of V1.


Heterogeneous Phase Transfer Catalysis in Solid Phase Syntheses of Anth-Cyclic Tetrapeptides.
This study features solid phase syntheses of cyclic tetrapeptides containing anthranilic acid (Anth) on relatively inexpensive resins derived from polystyrene. It proved to be difficult to hydrolyze a supported Anth-methyl ester unless a phase transfer catalyst was added to facilitate transport of hydroxide into the swollen hydrophobic gel state of the resin. We suggest this may be an under-appreciated strategy for improving syntheses on polystyrene supports.


Mitochondria with Morphology Characteristic for Alzheimer's Disease Patients Are Found in the Brain of OXYS Rats.
Growing evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of sporadic Alzheimer's disease (AD). One of the key contributors to various aspects of AD pathogenesis, along with metabolic dysfunction, is mitochondrial dynamics, involving balance between fusion and fission, which regulates mitochondrial number and morphology in response to changes in cellular energy demand. Recently, Zhang et al. ((2016) Sci. Rep., 6, 18725) described a previously unknown mitochondrial phenotype manifesting as elongated chain-linked mitochondria termed "mitochondria-on-a-string" (MOAS) in brain tissue from AD patients and mouse models of AD. The authors associated this phenotype with fission arrest, but implications of MOAS formation in AD pathogenesis remain to be understood. Here we analyze the presence and number of MOAS in the brain of OXYS rats simulating key signs of sporadic AD. Using electron microscopy, we found MOAS in OXYS prefrontal cortex neuropil in all stages of AD-like pathology, including manifestation (5-month-old rats) and progression (12-18-month-old rats). The most pronounced elevation of MOAS content (8-fold) in OXYS rats compared to Wistar controls was found at the preclinical stage (20 days) on the background of decreased numbers of non-MOAS elongated mitochondria. From the age of 20 days through 18 months, the percentage of MOAS-containing neuronal processes increased from 1.7 to 8.3% in Wistar and from 13.9 to 16% in OXYS rats. Our results support the importance of the disruption of mitochondrial dynamics in AD pathogenesis and corroborate the existence of a causal link between impaired mitochondrial dynamics and formation of the distinctive phenotype of "mitochondria-on-a-sting".


Copper differentially regulates the activity and degradation of yeast Mac1 transcription factor.
Copper is an essential metal ion that is toxic when accumulated to high intracellular concentrations. The yeast Mac1 protein is a copper-sensing transcription factor that is essential for both the activation and inactivation of genes required for high affinity copper ion transport. Here we demonstrate that in response to low copper ion concentrations Mac1 protein is rendered inactive for copper transporter gene transcription. Under high copper ion concentrations Mac1 is degraded in a rapid, copper-specific manner. This degradation is critical to prevent copper toxicity that would otherwise result from sustained expression of the copper transport genes. These results demonstrate that nutritional and toxic copper concentrations elicit distinct fates for the Mac1 copper-sensing transcription factor and establish a new mechanism by which trace metals regulate gene expression.


[Analysis of risk factors for low bone mineral density in patients with inflammatory bowel disease].
Several clinical risk factors for low bone mineral density (BMD) in the patients with inflammatory bowel disease (IBD) have been suggested. However, its prevalence and pathophysiology in Korean population have not been fully studied. The aim of this study was to investigate the prevalence and risk factors for low BMD in Korean IBD patient. BMD of the lumbar spine and femur was evaluated using dual-energy X-ray absorptiometry in 30 patients with IBD. Biochemical parameters of bone metabolism, such as serum calcium, phosphorus, osteocalcin, and deoxypyridinoline were measured. The associations between low BMD and clinical parameters such as disease duration, disease activity, drug history, body mass index (BMI), and others were evaluated retrospectively using medical records. Low BMD at the lumbar spine or femur was observed in 63.3% of the patients, and there was no significant difference between the patients with Crohns disease and ulcerative colitis. Clinical and biochemical parameters were irrelevant to BMD. In the patients without glucocorticoid treatment prior to BMD measurement, already 50.0% of patients had low BMD. Low BMD is a common feature in Korean IBD patients, even those who do not use glucocorticoid. The multiple factors may be involved in the pathogenesis of low BMD. Therefore, BMD should be examined in all IBD patients, irrespective of glucocorticoid treatment.