Cancer incidence in participants in a long-distance ski race (Vasaloppet, Sweden) compared to the background population.
We studied the association between taking part in a long distance ski race and cancer incidence to address the hypothesis that a lifestyle involving a high degree of physical activity (PA) lowers cancer incidence with a pattern that is different by cancer site. Cancer incidence was estimated in a large cohort of skiers (n=185,412) participating in the Vasaloppet long distance ski race in Sweden 1989-2010 and non-participants in the ski race, randomly selected from the Swedish general population (n=184,617). Data include race finishing times as a measurement of physical fitness. Hazard ratios (HRs) and net probability of cancer over twenty years of follow-up were estimated for all invasive cancer, and separately for prostate, breast, colo-rectal and lung cancer, and groups of cancers with presumed relation to lifestyle. Participating in Vasaloppet was associated with a relative risk reduction for all invasive cancer of 6% (95% confidence interval 2-9%) and a relative risk reduction of 32% (95% confidence interval 28-37%) of cancer sites where there is epidemiological evidence that smoking, bodyweight, regular PA and consumption of fruit and vegetables are aetiological factors. For skin cancer the risk was increased, as for prostate cancer. Skiers with shorter finishing times had lower incidence of cancer. This study indicates that it is unrealistic to reduce overall population cancer incidence drastically with life style. However, cancers that are epidemiologically associated with life style factors were significantly reduced by what presumably is a blend of non-smoking, normal body weight, sound dietary habits and PA. Our data thus provide additional support for present days' recommendations about life style prevention. Higher health awareness is associated with attendance to screening, which may explain our results for prostate cancer. University fund, independent funds from an insurance company and a private foundation.


Mortality burden of diurnal temperature range and its temporal changes: A multi-country study.
Although diurnal temperature range (DTR) is a key index of climate change, few studies have reported the health burden of DTR and its temporal changes at a multi-country scale. Therefore, we assessed the attributable risk fraction of DTR on mortality and its temporal variations in a multi-country data set. We collected time-series data covering mortality and weather variables from 308 cities in 10 countries from 1972 to 2013. The temporal change in DTR-related mortality was estimated for each city with a time-varying distributed lag model. Estimates for each city were pooled using a multivariate meta-analysis. The results showed that the attributable fraction of total mortality to DTR was 2.5% (95% eCI: 2.3-2.7%) over the entire study period. In all countries, the attributable fraction increased from 2.4% (2.1-2.7%) to 2.7% (2.4-2.9%) between the first and last study years. This study found that DTR has significantly contributed to mortality in all the countries studied, and this attributable fraction has significantly increased over time in the USA, the UK, Spain, and South Korea. Therefore, because the health burden of DTR is not likely to reduce in the near future, countermeasures are needed to alleviate its impact on human health.


Neuroimaging of Human Balance Control: A Systematic Review.
This review examined 83 articles using neuroimaging modalities to investigate the neural correlates underlying static and dynamic human balance control, with aims to support future mobile neuroimaging research in the balance control domain. Furthermore, this review analyzed the mobility of the neuroimaging hardware and research paradigms as well as the analytical methodology to identify and remove movement artifact in the acquired brain signal. We found that the majority of static balance control tasks utilized mechanical perturbations to invoke feet-in-place responses (27 out of 38 studies), while cognitive dual-task conditions were commonly used to challenge balance in dynamic balance control tasks (20 out of 32 studies). While frequency analysis and event related potential characteristics supported enhanced brain activation during static balance control, that in dynamic balance control studies was supported by spatial and frequency analysis. Twenty-three of the 50 studies utilizing EEG utilized independent component analysis to remove movement artifacts from the acquired brain signals. Lastly, only eight studies used truly mobile neuroimaging hardware systems. This review provides evidence to support an increase in brain activation in balance control tasks, regardless of mechanical, cognitive, or sensory challenges. Furthermore, the current body of literature demonstrates the use of advanced signal processing methodologies to analyze brain activity during movement. However, the static nature of neuroimaging hardware and conventional balance control paradigms prevent full mobility and limit our knowledge of neural mechanisms underlying balance control.


Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer.
In this study, we identified microRNAs (miRNAs) involved in cisplatin (CDDP) resistance in bladder cancer (BCa). After establishing CDDP-resistant BCa cell lines (T24RC and EJ138RC), TaqMan arrays revealed that members of the miR-200 family (miR-200b, miR-200a and miR-429) were downregulated in T24RC as compared to parental T24 cells. miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2'-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2'-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. These results suggest downregulation of miR-200b is associated with CDDP resistance in BCa. Epigenetic silencing of miR-200b may be a marker of CDDP resistance and a useful therapeutic target for overcoming CDDP resistance in BCa.


Comparative study of two table grape varieties with contrasting texture during cold storage.
Postharvest softening of grape berries is one of the main problems affecting grape quality during export. Cell wall disassembly, especially of pectin polysaccharides, has been commonly related to fruit softening, but its influence has been poorly studied in grapes during postharvest life. In order to better understand this process, the Thompson seedless (TS) variety, which has significantly decreased berry texture after prolonged cold storage, was compared to NN107, a new table grape variety with higher berry firmness. Biochemical analysis revealed a greater amount of calcium in the cell wall of the NN107 variety and less reduction of uronic acids than TS during cold storage. In addition, the activity of polygalacturonase was higher in TS than NN107 berries; meanwhile pectin methylesterase activity was similar in both varieties. Polysaccharide analysis using carbohydrate gel electrophoresis (PACE) suggests a differential pectin metabolism during prolonged cold storage. Results revealed lower pectin fragments in TS after 60 days of cold storage and shelf life (SL) compared to 30 days of cold storage and 30 + SL, while NN107 maintained the same fragment profile across all time points evaluated. Our results suggest that these important differences in cell wall metabolism during cold storage could be related to the differential berry firmness observed between these contrasting table grape varieties.


Purification and characterization of diacetyl-reducing enzymes from Staphylococcus aureus.
A method was developed to purify diacetyl-reducing enzymes from Staphylococcus aureus. Two enzymes capable of catalysing diacetyl reduction were isolated, neither of which turned out to be a specific diacetyl reductase. One of them is a lactate dehydrogenase similar to the one from Staphylococcus epidermidis, which accepts diacetyl, although poorly. The other one uses as coenzyme beta-NAD and reduces uncharged alpha-dicarbonyls with more than three carbon atoms (especially the alpha-diketones diacetyl and pentane-2,3-dione), producing the L(+) form of the corresponding alpha-hydroxycarbonyls. This enzyme has an Mr of 68,000 and is, most probably, a monomer. Its optimum pH is 6.0. Its shows a high affinity for NADH and a rather low one for diacetyl, which, at least in vitro, does not seem to be as good a substrate as pentane-2,3-dione. We propose for it the systematic name L-alpha-hydroxyketone:NAD+ oxidoreductase and the recommended name of alpha-diketone reductase (NAD). We also suggest that the diacetyl reductase entry in the I.U.B. classification be suppressed.


Inpatient initiation of beta-blockade plus nurse management in vulnerable heart failure patients: a randomized study.
Predischarge beta-blocker initiation in hospitalized patients with heart failure due to reduced left ventricular ejection fraction (LVEF) is safe and improves adherence; improved outcomes with this approach have not been demonstrated in a randomized trial. This study compared 6-month rehospitalization rates among patients assigned to predischarge beta-blockade coupled with postdischarge nurse management (intervention) versus usual care. We randomized 64 patients with an LVEF </=0.40 to low-dose carvedilol coupled with nurse management or usual care. The nurse manager saw patients within 2 weeks of discharge, then biweekly until stable. Baseline characteristics reflected a vulnerable population (80% uninsured, 72% minorities, 80% unemployed or disabled), as did heart failure etiology (28% substance abuse, 27% ischemic, 19% hypertension, 17% idiopathic). Mean baseline LVEF was 0.23 in both groups. Among intervention patients at 6 -months, beta-blocker utilization was higher (96 vs. 48%, P < .001), mean New York Heart Association class improved (-1.44 vs. -0.77, P = .01), and total heart failure rehospitalizations were reduced by 84% (3 vs. 19, P = .02). A trend toward improved LVEF was also observed (+16 vs. +11 units, P = .17). Inpatient beta-blocker initiation coupled with nurse management improved outcomes among sociodemographically disadvantaged heart failure patients. Our results support a practice shift toward inpatient beta-blocker initiation with structured outpatient follow-up.


Diltiazem selectively inhibits cerebrovascular extrinsic but not intrinsic myogenic tone. A review.
The tone of blood vessels resulting from extrinsic influences is dependent on activator calcium derived from sequestered cellular and also extracellular sources. Experiments on rabbit blood vessels in vitro show that--in comparison to systemic vessels--the contractions of cerebral arteries are proportionately more dependent on extracellular calcium and have sequestered calcium sources that are more easily depleted. Both these observations suggest that activator calcium mechanisms differ at least quantitatively in cerebral compared to noncerebral vessels. Diltiazem antagonizes agonist-induced tone in cerebral arteries at a lower concentration than is required in systemic arteries and veins. For example, the concentration of diltiazem to halve the response of the rabbit basilar artery to norepinephrine (ED50) is 1 X 10(-8) M, whereas those for the ear and mesenteric arteries and the saphenous vein are 10.4, 2.0, and 1.8 X 10(-7) M, respectively. A similar selectivity has been found to K+ and serotonin-induced contractions. It has been argued that the neuroeffector mechanism in the portal vein reflects that in systemic resistance vessels. The drug is effective against the spontaneous rhythmic activity of the longitudinal muscle of the vein, reducing it to half at 1.5 X 10(-7) M. Diltiazem is relatively ineffective in antagonizing intrinsic smooth muscle tone, both cerebral (basilar) and extracerebral (facial vein) requiring ED50 values of 4 and 5 X 10(-4) M, respectively. In summary, our in vitro experiments on rabbit tissue show that diltiazem selectively antagonizes cerebrovascular extrinsic but not intrinsic tone.


The use of fluorescein 5'-isothiocyanate for studies of structural and molecular mechanisms of soybean lipoxygenase.
Incubation of fluorescein 5'-isothiocyanate (FITC) with soybean lipoxygenase produces the coupling of 1 mol of fluorophore to 1 mol of enzyme. Derivatized lipoxygenase lost 40% activity through a mixed-type inhibitory mechanism. The quenching by IK of the fluorescence of FITC-labeled lipoxygenase shows that the fluorophore is located near the surface of the protein. The partial impediment of the FITC labeling when the substrate is present in the medium, together with data of the tryptic digestion, suggests that FITC is attached via the access channel of substrate to the catalytic site. Labeling does not induce appreciable modification of the enzyme specificity, suggesting that the position of substrate in the active site is not modified by the labeling. The results obtained strongly suggest that FITC labels soybean lipoxygenase specifically at a lysyl residue which contributes to fixation of the carboxylic end of the substrate to the active center. The experimental data obtained from the quenching of FITC fluorescence by NDGA reveal that this molecule interacts with the protein near the catalytic site.


Validation of an in-house assay for cytomegalovirus immunoglobulin G (CMV IgG) avidity and relationship of avidity to CMV IgM levels.
Measurement of cytomegalovirus (CMV)-specific immunoglobulin G (IgG) avidity has proven to be a powerful tool for distinguishing primary from nonprimary CMV infection. An in-house enzyme-linked immunosorbent assay (ELISA) for measuring CMV IgG avidity was validated using 84 sera from pregnant women who had recently seroconverted following primary CMV infection and 74 sera from individuals with past CMV infection (IgG-positive and IgM-negative profile). Of the 84 sera from pregnant women, 73 sera were collected within 120 days of the last IgG-negative sample, and 72 of these 73 sera (99%) exhibited an avidity index (AI) of <50%. In contrast, 71 of 74 (96%) sera from individuals with past CMV infection exhibited CMV AI values of > 60%. Thus, low avidity in the in-house ELISA was defined as an AI of < or = 50%, whereas high avidity was defined as an AI of > or = 60%. In additional studies, the relationship between CMV IgG avidity and CMV IgM levels was examined using 64 CMV IgG-positive sera (time since seroconversion unknown) exhibiting equivocal or positive results in a CMV IgM capture ELISA (Diamedix). Of these 64 sera, 29 exhibited IgM index values of > or = 3.0, and 27 of these 29 (93%) exhibited low IgG avidity. A similar trend was observed when a subset of these 64 sera (n = 48) was tested in another CMV IgM capture ELISA (Trinity); of 18 sera with IgM index values of > or = 3.0, 17 (94%) exhibited low IgG avidity. These findings demonstrate the validity of an in-house ELISA for CMV IgG avidity and further show that strong reactivity of CMV IgG-positive sera in either of two CMV IgM capture assays is a reliable indicator of low CMV IgG avidity, and thus, recent CMV infection.


An example where orbital relaxation is an important contribution to the Fukui function.
Density-functional electronic structure calculations are performed on the molecules Cr2(hpp)4, Mo2(hpp)4, and W2(hpp)4, where the bridging ligand, hpp, is the anion of 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine. The calculated electronic densities are used to determine the Fukui functions. These molecules are unique not only in their ability as electron donors but also because orbital relaxation plays a decisive role in their reactivity. Unlike other examples in the literature, the reactivity of these compounds cannot be expressed solely in terms of the highest occupied and lowest unoccupied Kohn-Sham orbitals but only using the Fukui function, which includes the effects of orbital relaxation.


MiRNAs and their association with locoregional staging and survival following surgery for esophageal carcinoma.
Prognostic and staging information for esophageal cancer impacts clinical decision making. miRNAs, a newly discovered class of biomarkers and their expression might add additional information relevant to this. In this study we evaluated the expression of selected miRNAs and their relationship to tumor stage and survival in patients with locally advanced tumors following esophagectomy. A total of 43 individuals undergoing esophagectomy (without neoadjuvant therapy) for locally advanced but not metastatic (pT2/3; pN0/1) disease (22 adenocarcinoma [EAC], 21 squamous cell carcinoma [SCC]) were included in this study. Perioperative clinical and survival data were collected and managed on a database. The expression of miR-21, miR-106a, miR-148a, miR-205 in formalin-fixed paraffin-embedded specimens was evaluated by TaqMan qPCR assays. Expression was compared with clinicopathological features of the cancers and outcome. In EAC, miR-148a expression levels were inversely associated with cancer differentiation. miR-21 expression levels were higher in SCC if distant lymph node metastases were present. miR-148a levels were lower when EAC was more proximally located, and miR-21 levels were lower when SCC was more proximal. miR-106a and miR-148a were lower in patients with SCC who developed recurrent disease or had a tumor-related death. In patients with locally advanced esophageal squamous cell carcinoma, but not adenocarcinoma, alterations in the expression of miR-21 correlate with tumor location and lymph node status. Furthermore, miR-106a and miR-148a expression correlates with disease recurrence and tumor-related mortality. miRNA markers might inform the initial assessment of these patients, and predict those at higher risk of postsurgical recurrence.


A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses.
Human GWAS of obesity have been successful in identifying loci associated with adiposity, but for the most part, these are non-coding SNPs whose function, or even whose gene of action, is unknown. To help identify the genes on which these human BMI loci may be operating, we conducted a high throughput screen in Drosophila melanogaster. Starting with 78 BMI loci from two recently published GWAS meta-analyses, we identified fly orthologs of all nearby genes (± 250KB). We crossed RNAi knockdown lines of each gene with flies containing tissue-specific drivers to knock down (KD) the expression of the genes only in the brain and the fat body. We then raised the flies on a control diet and compared the amount of fat/triglyceride in the tissue-specific KD group compared to the driver-only control flies. 16 of the 78 BMI GWAS loci could not be screened with this approach, as no gene in the 500-kb region had a fly ortholog. Of the remaining 62 GWAS loci testable in the fly, we found a significant fat phenotype in the KD flies for at least one gene for 26 loci (42%) even after correcting for multiple comparisons. By contrast, the rate of significant fat phenotypes in RNAi KD found in a recent genome-wide Drosophila screen (Pospisilik et al. (2010) is ~5%. More interestingly, for 10 of the 26 positive regions, we found that the nearest gene was not the one that showed a significant phenotype in the fly. Specifically, our screen suggests that for the 10 human BMI SNPs rs11057405, rs205262, rs9925964, rs9914578, rs2287019, rs11688816, rs13107325, rs7164727, rs17724992, and rs299412, the functional genes may NOT be the nearest ones (CLIP1, C6orf106, KAT8, SMG6, QPCTL, EHBP1, SLC39A8, ADPGK /ADPGK-AS1, PGPEP1, KCTD15, respectively), but instead, the specific nearby cis genes are the functional target (namely: ZCCHC8, VPS33A, RSRC2; SPDEF, NUDT3; PAGR1; SETD1, VKORC1; SGSM2, SRR; VASP, SIX5; OTX1; BANK1; ARIH1; ELL; CHST8, respectively). The study also suggests further functional experiments to elucidate mechanism of action for genes evolutionarily conserved for fat storage.


Circulating exosomal microRNA-203 is associated with metastasis possibly via inducing tumor-associated macrophages in colorectal cancer.
A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis. The mechanism by which tumor cells communicate with host cells to develop premetastatic niches is unclear. We focused on the role of microRNA (miR) signaling in promoting metastasis. Here, we identified miR-203 as a signaling molecule between tumors and monocytes in metastatic colorectal cancer (CRC) patients. Notably, high expression of serum exosomal miR-203, a major form in circulation, was associated with distant metastasis and an independent poor prognostic factor, whereas low expression in tumor tissues was a poor prognostic factor in CRC patients. We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro, suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs). In a xenograft mouse model, miR-203-transfected CRC cells developed more liver metastasis compared to control cells. In conclusion, serum exosomal miR-203 expression is a novel biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Furthermore, we propose the concept of site-dependent functions for miR-203 in tumor progression.


Characterization of sodium stibogluconate by online liquid separation cell technology monitored by ICPMS and ESMS and computational chemistry.
High-performance liquid chromatography (HPLC), mass spectrometry (MS), and computational chemistry has been applied to resolve the composition and structure of the Sb species present in dilutions of Pentostam, a first-line treatment drug against Leishmania parasites. Using HPLC-inductively coupled plasma-MS and electrospray-MS, it was shown that the original drug consists of large Sb(V)-glyconate complexes of polymeric nature that degrade upon dilution. In dilution solution, the drug is a mixture of noncomplexed Sb(V), large polymeric complexes as well as several low molecular mass Sb(V)-glyconate complexes of various stoichiometry (1:1, 1:2, 1:3, 2:2, 2:3, 2:4, 3:3, 3:4). The 1:1 complex became the most abundant low molecular mass Sb(V) complex with dilution time. A novel mixed-mode chromatographic system was applied in order to separate complexes of various stoichiometry and isomers. Density functional theory was used to study the structure of the 1:1 Sb-gluconate complex with three or four solvent molecules bound. By computing the structures and the free energies of the various possible isomers in aqueous solvation models, the most likely structures of the species were deduced. Importantly, 6-coordination is always preferred over 5-coordination, and the species commonly adopt conformations involving tris-coordination of deprotonated hydroxyl groups from gluconate.


Early Electroencephalography Suppression and Postnatal Morbidities Correlate with Cerebral Volume at Term-Equivalent Age in Very Preterm Infants.
Early brain activity is associated with long-term outcome. Establishing a relation also with postnatal brain growth may increase our understanding of early life influences on preterm brain development. The aim of this study was to investigate whether early electroencephalography (EEG) activity in infants born very preterm is associated with brain volumes at term, and whether postnatal morbidity affects this association. Very preterm infants (n = 38) with a median gestational age (GA) of 25.6 weeks had early recordings of single-channel EEG. The percentage of suppressed EEG, i.e., interburst intervals (IBI%) between 24 and 72 h of age, was analyzed in relation to brain volumes on magnetic resonance imaging performed at term-equivalent age, taking into account neonatal morbidities. Early electrocortical depression and a higher IBI% were associated with increased cerebrospinal fluid volume (CSFV) and lower total brain volume relative to intracranial volume, also after adjustment for GA, postnatal morbidities, morphine administration, and postnatal head growth. Overall, an increase in IBI% to 1 SD from the mean corresponded with an increase in CSFV to +0.7 SD and a decrease in brain volume to -0.7 SD. The presence of 2 or more postnatal morbidities were associated with around 10% lower brain volumes. More suppressed early EEG activity of very preterm infants is associated with lower brain volume and increased CSFV at term age, also when adjusting for postnatal morbidities. The findings indicate the importance of pre- and early postpartal determinants of postnatal brain growth, possibly also including activity-dependent mechanisms for brain growth.


Plasma aldosterone and cortisol levels in psoriasis and atopic dermatitis.
The levels of plasma aldosterone were significantly raised in groups of patients with psoriasis and atopic dermatitis compared with a control group of patients with other skin diseases. Simultaneous assay of plasma cortisol indicated that these changes were not the effects of prior corticosteroid therapy. The reasons for the increased aldosterone levels are not clear, but our findings are compatible with a "permissive" role for this hormone in psoriasis and atopic dermatitis.


[Search for microorganisms among collectable bacterial strains capable of transforming nucleosides into virazole].
The ability of bacterial cultures to transform nucleosides to virazole, a riboside with antiviral activity, was studied. Qualitative and quantitative methods for estimation of the microbial activity in the biotransformation reaction were designed. A qualitative rapid method for analysis of a large number of cultures was developed. Thirty nine collection strains were tested for their capacity to bioconvert nucleosides to virazole. Intact cells grown in a liquid medium were used as a source of purine nucleoside phosphorylase. Purine nucleosides such as adenosine, inosine, guanosine and 30-percent ribose solution resulting from the riboxin hydrolysis were tested as the ribose donors. The best results were obtained with the ribose solution. No distinct correlation between the genus of the microorganisms and their capacity for bioconversion of certain substrates was observed. Several cultures which showed stable and high results with respect to all the tested substrates were detected.


Jeannette Wilkins Award: Can locally delivered gadolinium be visualized on MRI? A pilot study.
Management of orthopaedic infections relies on débridement and local delivery of antimicrobials; however, the distribution and concentration of locally delivered antimicrobials in postdébridement surgical sites is unknown. Gadolinium-DTPA (Gd-DTPA) has been proposed as an imaging surrogate for antimicrobials because it is similar in size and diffusion coefficient to gentamicin. Is in vivo distribution of locally delivered Gd-DTPA (1) visible on MRI; (2) reliably visualized by different observers; (3) affected by the anatomic delivery site; and (4) affected by the in vitro release rate from the delivery vehicle? Twenty-four local delivery depots were imaged in nine rabbits using two anatomic sites (intramedullary canal, quadriceps) with Gd-DTPA in intermediate-porosity polymethylmethacrylate (PMMA) or high-porosity PMMA; six of the nine rabbits also had Gd-DTPA delivered in collagen at a third site (hamstring). A total of 45,000 fat-suppressed T1-weighted RARE scans were acquired using a 7-T Bruker Biospec MRI: nine rabbits, 2-mm slices over 10 cm, four TR values, 25 time periods (pre, every 15 minutes for 6 hours). T1 maps were constructed at every time period. Gd-DTPA distribution was observed qualitatively on the T1 maps. Interobserver reliability was determined. Locally delivered Gd-DTPA was visible. Interobserver agreement was excellent. Intramuscular delivery followed intermuscular planes; intramedullary delivery was contained within the canal by bone. Distribution from collagen decreased after 1 hour but from PMMA increased over 6 hours. Locally delivered Gd-DTPA can be visualized on MRI; distribution is affected by anatomical location and delivery vehicle. Contrast-based imaging using locally delivered Gd-DTPA may be useful as an antibiotic surrogate to determine antibiotic distribution in surgical sites.


Signal-to-noise ratio improvement of swept-tone-generated transient otoacoustic emissions.
In this study, we utilized the swept-tone (ST) deconvolution method for comparing the signal-to-noise ratio (SNR) characteristics of ST otoacoustic emissions (OAE) to conventionally acquired click, or transient-evoked (TE), OAE. We generated a hearing-level equalized (HLeq) ST stimulus based on normative loudness metrics at the different frequencies present in the ST. Due to noise-shaping properties of the ST deconvolution method, we anticipated a theoretical SNR gain of +4.26 dB in STOAE compared to TEOAE acquired under comparable settings. This prediction was confirmed by computer simulation. HLeq STOAE and TEOAE were then acquired from each of the 22 ears that were tested at five stimulation levels from 5 to 45 dB HL, and analyzed responses in terms of their overall SNR. We found that the overall SNR of the HLeq STOAE responses at stimulation levels at or above 15 dB HL was significantly higher than that of TEOAE by an average of +3.6 dB. Importantly, this leads to recording quality and time-saving improvements in clinical hearing screenings.


Integrating Genomics Into Neuro-Oncology Clinical Trials and Practice.
Important advances in our understanding of the molecular biology of brain tumors have resulted in a rapid evolution in the taxonomy of central nervous system (CNS) tumors, which culminated in the revised 2016 World Health Organization classification of CNS tumors that incorporates an integrated molecular/histologic diagnostic approach. Our expanding understanding of brain tumor genomics and molecular evolution during the disease course has started to impact clinical management. Furthermore, incorporation of genomic information in ongoing and planned neuro-oncology clinical trials is expected to lead to improved outcomes and result in personalized treatment options for patients with CNS malignancies.


American foulbrood in a honeybee colony: spore-symptom relationship and feedbacks.
The most severe bacterial disease of honeybees is American foulbrood (AFB). The epidemiology of AFB is driven by the extreme spore resilience, the difficulty of bees to remove these spores, and the considerable incidence of undetected spore-producing colonies. The honeybee collective defence mechanisms and their feedback on colony development, which involves a division of labour at multiple levels of colony organization, are difficult to model. To better predict disease outbreaks we need to understand the feedback between colony development and disease progression within the colony. We therefore developed Bayesian models with data from forty AFB-diseased colonies monitored over an entire foraging season to (i) investigate the relationship between spore production and symptoms, (ii) disentangle the feedback loops between AFB epidemiology and natural colony development, and (iii) discuss whether larger insect societies promote or limit within-colony disease transmission. Rather than identifying a fixed spore count threshold for clinical symptoms, we estimated the probabilities around the relationship between spore counts and symptoms, taking into account modulators such as brood amount/number of bees and time post infection. We identified a decrease over time in the bees-to-brood ratio related to disease development, which should ultimately induce colony collapse. Lastly, two contrasting theories predict that larger colonies could promote either higher (classical epidemiological SIR-model) or lower (increasing spatial nest segregation and more effective pathogen removal) disease prevalence. AFB followed the predictions of the SIR-model, partly because disease prevalence and brood removal are decoupled, with worker bees acting more as disease vectors, infecting new brood, than as agents of social immunity, by removing infected brood. We therefore established a direct link between disease prevalence and social group size for a eusocial insect. We furthermore provide a probabilistic description of the relationship between AFB spore counts and symptoms, and how disease development and colony strength over a season modulate this relationship. These results help to better understand disease development within honeybee colonies, provide important estimates for further epidemiological modelling, and gained important insights into the optimal sampling strategy for practical beekeeping and honeybee research.


[Helicobacter pylori in patho- and morphogenesis of chronic gastritis and peptic ulcer].
Review of the literature on the role of Helicobacter pylori (HP) in the patho- and morphogenesis of chronic gastritis (CG) type B, gastric ulcer (GU) and duodenal ulcer (DU) is presented. Various hypotheses of pathogenetic effect of HP, histologic and ultrastructural characteristics of changes in the gastric and duodenal mucosa in HP infection are presented. The majority of authors consider HP as a possible pathogenic factor in CG type B, GU and DU. However, there are works in which HP is regarded as a saprophyte or a secondary infection. This indicates a necessity of further studies.


Digital Delivery of Cognitive Behavioral Therapy for Insomnia.
Digital cognitive behavioral therapy (dCBT) has been available for over a decade. We reviewed the evidence that accumulated over the past 5 years and discuss the implications for introducing dCBT into standard healthcare. Studies have consistently supported the use of dCBT to treat insomnia. Evidence is now demonstrating large short-term effects and smaller long-term effects up to 1.5 years after treatment across populations with various co-occurring health problems. The effects also extend into a range of psychological well-being factors. Mediators and moderators have been studied to understand mechanisms and create new opportunities to enhance effectiveness and reduce dropout. Incorporating personalized guidance in dCBT may further enhance effectiveness. The evidence for dCBT for insomnia is strong and suggests that dCBT is ready for application in standard healthcare. Further research, digital innovation, and development of effective implementation methods are required to ensure dCBT fulfills its potential.


Transcriptomics analysis revealing candidate genes and networks for sex differentiation of yesso scallop (Patinopecten yessoensis).
The Yesso scallop, Patinopecten (Mizuhopecten) yessoensis, is a commercially important bivalve in the coastal countries of Northeast Asia. It has complex modes of sex differentiation, but knowledge of the mechanisms underlying this sex determination and differentiation is limited. In this study, the gonad tissues from females and males at three developmental stages were used to investigate candidate genes and networks for sex differentiation via RNA-Req. A total of 901,980,606 high quality clean reads were obtained from 18 libraries, of which 417 expressed male-specific genes and 754 expressed female-specific genes. Totally, 10,074 genes differentially expressed in females and males were identified. Weighted gene co-expression network analysis (WGCNA) revealed that turquoise and green gene modules were significantly positively correlated with male gonads, while coral1 and black modules were significantly associated with female gonads. The most important gene for sex determination and differentiation was Pydmrt 1, which was the only gene discovered that determined the male sex phenotype during early gonadal differentiation. Enrichment analyses of GO terms and KEGG pathways revealed that genes involved in metabolism, genetic and environmental information processes or pathways are sex-biased. Forty-nine genes in the five modules involved in sex differentiation or determination were identified and selected to construct a gene co-expression network and a hypothesized sex differentiation pathway. The current study focused on screening genes of sex differentiation in Yesso scallop, highlighting the potential regulatory mechanisms of gonadal development in P. yessoensis. Our data suggested that WCGNA can facilitate identification of key genes for sex differentiation and determination. Using this method, a hypothesized P. yessoensis sex determination and differentiation pathway was constructed. In this pathway, Pydmrt 1 may have a leading function.


Chemistry, Biosynthesis, Physicochemical and Biological Properties of Rubiadin: A Promising Natural Anthraquinone for New Drug Discovery and Development.
Anthraquinones (AQs) are found in a variety of consumer products, including foods, nutritional supplements, drugs, and traditional medicines, and have a wide range of pharmacological actions. Rubiadin, a 1,3-dihydroxy-2-methyl anthraquinone, primarily originates from Rubia cordifolia Linn (Rubiaceae). It was first discovered in 1981 and has been reported for many biological activities. However, no review has been reported so far to create awareness about this molecule and its role in future drug discovery. Therefore, the present review aimed to provide comprehensive evidence of Rubiadin's phytochemistry, biosynthesis, physicochemical properties, biological properties and therapeutic potential. Relevant literature was gathered from numerous scientific databases including PubMed, ScienceDirect, Scopus and Google Scholar between 1981 and up-to-date. The distribution of Rubiadin in numerous medicinal plants, as well as its method of isolation, synthesis, characterisation, physiochemical properties and possible biosynthesis pathways, was extensively covered in this review. Following a rigorous screening and tabulating, a thorough description of Rubiadin's biological properties was gathered, which were based on scientific evidences. Rubiadin fits all five of Lipinski's rule for drug-likeness properties. Then, the in depth physiochemical characteristics of Rubiadin were investigated. The simple technique for Rubiadin's isolation from R. cordifolia and the procedure of synthesis was described. Rubiadin is also biosynthesized via the polyketide and chorismate/o-succinylbenzoic acid pathways. Rubiadin is a powerful molecule with anticancer, antiosteoporotic, hepatoprotective, neuroprotective, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antimalarial, antifungal, and antiviral properties. The mechanism of action for the majority of the pharmacological actions reported, however, is unknown. In addition to this review, an in silico molecular docking study was performed against proteins with PDB IDs: 3AOX, 6OLX, 6OSP, and 6SDC to support the anticancer properties of Rubiadin. The toxicity profile, pharmacokinetics and possible structural modifications were also described. Rubiadin was also proven to have the highest binding affinity to the targeted proteins in an in silico study; thus, we believe it may be a potential anticancer molecule. In order to present Rubiadin as a novel candidate for future therapeutic development, advanced studies on preclinical, clinical trials, bioavailability, permeability and administration of safe doses are necessary.


VIDAS Listeria monocytogenes II (LMO2).
This AOAC GovVal study compared the VIDAS Listeria monocytogenes II (LMO2) to the Health Products and Food Branch MFHPB-30 reference method for detection of L. monocytogenes in ready-to-eat (RTE) meats. The VIDAS LMO2 test is an automated enzyme-linked fluorescent immunoassay for the detection of L. monocytogenes in foods. The LMO2 test, following the enrichment procedure from the MFLP-33 method, also included use of the chromogenic media, chromID Ottaviani Agosti Agar (OAA) and chromID Lmono for confirmation of LMO2 presumptive results. In previous AOAC validation studies comparing the VIDAS LMO2 method to the U.S. Food and Drug Administration Bacteriological Analytical Manual and U.S. Department of Agriculture-Food Safety and Inspection Service reference methods, LMO2 was approved as AOAC Official Method 2004.02 for the detection of L. monocytogenes in dairy products, vegetables, seafood, raw meats and poultry, and processed meats and poultry. The GovVal comparative study included 20 replicate test portions, each at two contamination levels for each matrix, where fractionally positive results (5-15 positive results/20 replicate portions tested) were obtained by at least one method at one level. Five uncontaminated controls were included. Chi-square analysis of the comparative data in this study indicates no statistical differences between the VIDAS LMO2 and the MFHPB-30 standard methods at the 5% level of significance. Confirmation of presumptive LMO2 results with the chromogenic OAA and Lmono media was shown to be equivalent to the appropriate reference method agars. The data demonstrate that the VIDAS LMO2 method is an acceptable alternative method to the MFHPB-30 standard culture method for the detection of L. monocytogenes in RTE meats, including liver paté, hot dogs, raw fermented sausage, sliced deli turkey, and sliced deli ham.


Pro-community altruism and social status in a Shuar village.
Reciprocity theory (RT) and costly signaling theory (CST) provide different explanations for the high status of pro-community altruists: RT proposes that altruists are positively and negatively sanctioned by others, whereas CST proposes that altruists are attractive to others. Only RT, however, is beset by first- and higher-order free rider problems, which must be solved in order for RT to explain status allocations. In this paper, several solutions to RT's free rider problems are proposed, and data about status allocations to Ecuadorian Shuar pro-community altruists are analyzed in light of RT and CST. These data confirm that perceived pro-community altruists are indeed high status and suggest that (1) community residents skillfully monitor the altruism of coresidents, (2) residents who engage in opportunities to broadcast desirable qualities are high status only to the extent that they are considered altruistic, and (3) individuals who sanction coresidents based on coresidents' contributions to the community are themselves relatively high status. To a greater extent than CST, RT straightforwardly predicts all of these results.


Shape oscillations of microparticles on an optical microscope stage.
A modulated acoustic radiation pressure technique to produce quadrupole shape oscillations of drops ranging in diameter from 50-220 micron has been used by us. These drops have been suspended by acoustic levitation in a small chamber mounted on a stage of an optical microscope, which allowed easy viewing. The fission of drops and the deformation of sea urchin eggs were also observed.


Attempted reactivation of contagious ecthyma in Dall sheep.
Dexamethasone was administered to 2 Dall ewes that had clinically recovered from contagious ecthyma in an attempt to reactivate contagious ecthyma in the sheep. Clinical signs of disease were not detected within 24 days after corticosteroid injection, and virus was not detected in tissues collected at necropsy.


Osteoblast lineage cells expressing high levels of Runx2 enhance hematopoietic progenitor cell proliferation and function.
Although osteoblasts (OB) play a key role in the hematopoietic stem cell (HSC) niche, little is known as to which specific OB lineage cells are critical for the enhancement of stem and progenitor cell function. Unlike hematopoietic cells, OB cell surface phenotypic definitions are not well developed. Therefore, to determine which OB lineage cells are most important for hematopoietic progenitor cell (HPC) function, we characterized OB differentiation by gene expression and OB function, and determined whether associations existed between OB and HPC properties. OB were harvested from murine calvariae, used immediately (fresh OB) or cultured for 1, 2, or 3 weeks prior to their co-culture with Lin(-)Sca1(+)c-kit(+) (LSK) cells for 1 week. OB gene expression, alkaline phosphatase activity, calcium deposition, hematopoietic cell number fold increase, CFU fold increase, and fold increase of Lin(-)Sca1(+) cells were determined. As expected, HPC properties were enhanced when LSK cells were cultured with OB compared to being cultured alone. Initial alkaline phosphatase and calcium deposition levels were significantly and inversely associated with an increase in the number of LSK progeny. Final calcium deposition levels and OB culture duration were inversely associated with all HPC parameters, while Runx2 levels were positively associated with all HPC properties. Since calcium deposition is associated with OB maturation and high levels of Runx2 are associated with less mature OB lineage cells, these results suggest that less mature OB better promote HPC proliferation and function than do more mature OB.


Density functional theory study of multiply ionized weakly bound fullerene dimers.
Multiply ionized fullerene dimers ([C(60)](2) (q+),q=1-6) have been studied by means of state-of-the-art density functional theory methods. We found that the singly charged dimer is more strongly bound than the corresponding neutral van der Waals dimer at the binding distance of the latter; in contrast, multiply charged dimers (q>or=2) are unstable. For the latter dimers, the calculated kinetic energy release in the binary fission yielding intact fullerenes is lower than those reported in recent experimental work. This implies that, in such experiments, there are significant internal excitations in the separating monomers. We also show that electron transfer within the charged dimers occurs on the subfemtosecond time scale, in accordance with the high charge mobility observed in dimers and larger clusters of fullerenes. This provides an explanation for the even-odd effects in the measured multiple ionization yields of fullerene dimers.


Quinuronium levels in ovine plasma as determined by an in vitro/in vivo system with Babesia rodhaini.
Quinuronium was shown to have a babesicidal activity in vitro. In vitro/in vivo system with Babesia rodhaini gave an in vitro EC50 for 13.5 ng/ml. Quinuronium levels in ovine plasma increased to a maximum mean of approximately 27 ng/ml at 2 hours with a gradual decay from 8 hours up to almost no detectable levels at 48 hours following administration of therapeutic dose (1 mg/kg s.c.). This study supports previous reports of the use of Babesia rodhaini as an organism in screening antibabesials. The in vitro/in vivo model can be used to monitor quinuronium levels in ovine plasma. Second treatment with quinuronium may be administered after 24 to 48 hours whenever clinically indicated.


Hodgkin lymphoma involving extranodal and nodal head and neck sites: characteristics and outcomes.
Most Hodgkin lymphoma (HL) patients present with disease in nodal regions. However, in a small subset, disease develops in unique anatomic sites such as the head and neck area. This study aims to identify the characteristics and outcomes of patients who develop HL involving extranodal and nodal head and neck sites. The authors searched The University of Texas M. D. Anderson Cancer Center's database for HL patients treated between 1967 and 2007 and included those with HL at head and neck sites. They reviewed the records for site of involvement, pathology, treatment, and survival. The authors identified 39 patients with extranodal and nodal HL of the head and neck. Five patients with lymphocyte predominant HL were excluded. Specifically, 10 of 34 patients had disease in the tonsils, 9 in the nasopharynx, 8 in the thyroid, 3 in the parotid, 2 in the adenoids, and 1 each in Waldeyer's ring and nasal antrum. Median age at diagnosis was 31.5 years, average age at diagnosis was 38 years, and 22 of 34 were male; 23 had stage I or II disease. Pathologically, 14 of 34 had the nodular sclerosis subtype, whereas 15 had mixed cellularity. Twenty-nine of 34 had nodal neck disease at presentation. Five of 34 received chemotherapy alone, 5 received radiation alone, and 24 received combination therapy. Twenty-one of 34 received 39.6 gray of external beam radiation. The most commonly used chemotherapy regimens were ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and MOPP (mechlorethamine, vincristine, procarbazine, and prednisone). At last follow-up, 85% were disease-free. HL of the head and neck is primarily diagnosed as early stage disease of men and of young to middle-aged individuals. Chemotherapy and primary/adjuvant radiotherapy offer excellent local and systemic control. The extent to which nodal disease is present in the neck does not alter outcomes when combined modality therapy is offered. Despite the unique anatomic location of these lesions, standard HL protocols work effectively to promote disease-free survival.


Postoperative Symptoms, after-care, and return to routine activity after laparoscopic cholecystectomy.
Surgeons are usually not involved in the postdischarge care of patients after uncomplicated laparoscopic cholecystectomy (LC). The aim of this study was to document the the symptomatic recovery of patients following LC, because this has a bearing on the planning of a postoperative care package. Consecutive patients undergoing uncomplicated LC were followed up by a weekly telephone questionnaire survey for 6 weeks. The study cohort comprised 102 patients who all completed the study. Postoperatively, only 2.9% of all patients had postoperative nausea/vomiting lasting greater than or equal too 2 days. Pain was symptomatic in 11.7% of patients. Port-site wounds were a source of significant symptoms in 70.5% of the patients. Postoperative review by a community nurse and primary-care doctor were necessary in 77.4% and 32% patients, respectively, with a combined average of 3.1 reviews per patient. Less than 4% of patients believed that they would benefit from a surgeon's review 6 weeks after LC. Median time taken to return to routine preoperative activity after surgery was 22 days (IQR, 17 to 34), which was affected by the degree of activity undertaken, wound-related symptoms persisting for greater than or equal to 3, planned follow-up clinic appointment, and discharge as an outpatient. Wound-related symptoms are common after LC, require substantial input from the community health service in their management, and may delay return to preoperative routine.


Anesthesia for patients with psychiatric illnesses: a narrative review with emphasis on preoperative assessment and postoperative recovery and pain.
The physical and psychological fragility of patients with psychiatric illness poses critical importance in the preoperative assessment, evaluation, and choice of premedication, which includes regular therapy, as well as concerns about polypharmacy with possible interactions of anesthetics, analgesics, and psychiatric medications. A considerable effort is to reduce risks for exacerbations or relapses of imminent illness in the postoperative period. In this narrative review, the goal was also set towards the use of proper tools for the preoperative assessment of anxiety and management of postoperative pain. Indeed anxiety can be a manifestation of primary comorbidity within the spectrum of a major psychiatric condition and affects dramatically the presentations of other symptoms as well evolution. Pain perception is changed in patients with psychiatric illness; therefore, the postoperative bundle of measures including assessment of pain using tools adjusted to the patient's cognitive state and regular nonopioid analgesics is important aiming to minimize opioid use. Ketamine, esketamine, xenon, nitrous oxide, dexmedetomidine, and propofol seem to have a novel role and benefit the management of certain types of psychiatric illness during the perioperative period. Psychiatrist involvement is necessary throughout the perioperative period, starting preoperatively and continuing after discharge. Clinical pharmacologists should be part of the team during the management of critically ill patients when polypharmacy can cause undesirable effects. Psychosocial wellbeing of surgical patients with psychiatric co-morbidity depends deeply on the collaboration of medical staff, family, and friends and international guidelines aim to establish standards, including but not limited to postoperative management.


Catalytic hydrolysis of agar using magnetic nanoparticles: optimization and characterization.
Agar is used as a gelling agent that possesses a variety of biological properties; it consists of the polysaccharides agarose and porphyrin. In addition, the monomeric sugars generated after agar hydrolysis can be functionalized for use in biorefineries and biofuel production. The main objective of this study was to develop a sustainable agar hydrolysis process for bioethanol production using nanotechnology. Peroxidase-mimicking Fe3O4-MNPs were applied for agar degradation to generate agar hydrolysate-soluble fractions amenable to Saccharomyces cerevisiae and Escherichia coli during fermentation. Fe3O4-MNP-treated (Fe3O4-MNPs, 1 g/L) agar exhibited 0.903 g/L of reducing sugar, which was 21-fold higher than that of the control (without Fe3O4-MNP-treated). Approximately 0.0181% and 0.0042% of ethanol from 1% of agar was achieved using Saccharomyces cerevisiae and Escherichia coli, respectively, after process optimization. Furthermore, different analytical techniques (FTIR, SEM, TEM, EDS, XRD, and TGA) were applied to validate the efficiency of Fe3O4-MNPs in agar degradation. To the best of our knowledge, Fe3O4-MNP-treated agar degradation for bioethanol production through process optimization is a simpler, easier, and novel method for commercialization.


Does soil nitrogen influence growth, water transport and survival of snow gum (Eucalyptus pauciflora Sieber ex Sprengel.) under CO enrichment?
Eucalyptus pauciflora Sieber ex Sprengel. (snow gum) was grown under ambient (370 microL L(-1)) and elevated (700 microL L(-1)) atmospheric [CO2] in open-top chambers (OTCs) in the field and temperature-controlled glasshouses. Nitrogen applications to the soil ranged from 0.1 to 2.75 g N per plant. Trees in the field at high N levels grew rapidly during summer, particularly in CO2-enriched atmosphere, but suffered high mortality during summer heatwaves. Generally, wider and more numerous secondary xylem vessels at the root-shoot junction in CO2-enriched trees conferred fourfold higher below-ground hydraulic conductance. Enhanced hydraulic capacity was typical of plants at elevated [CO2] (in which root and shoot growth was accelerated), but did not result from high N supply. However, because high rates of N application consistently made trees prone to dehydration during heatwaves, glasshouse studies were required to identify the effect of N nutrition on root development and hydraulics. While the effects of elevated [CO2] were again predominantly on hydraulic conductivity, N nutrition acted specifically by constraining deep root penetration into soil. Specifically, 15-40% shallower root systems supported marginally larger shoot canopies. Independent changes to hydraulics and root penetration have implications for survival of fertilized trees under elevated atmospheric [CO2], particularly during water stress.


Neuropathy associated with gluten sensitivity.
To prospectively study the clinical, neurophysiological and neuropathological characteristics of axonal neuropathies associated with positive antigliadin antibodies and the prevalence of such neuropathies in a cohort of patients with sporadic axonal neuropathy. Prospective screening (using antigliadin, antiendomysium and tissue transglutaminase antibodies) of patients with peripheral neuropathy attending a neurology clinic. 215 patients with axonal neuropathy were screened. 141 patients had symmetrical sensorimotor neuropathy, 47 had mononeuropathy multiplex, 17 had motor neuropathy and 10 had small-fibre neuropathy. Despite extensive investigations of the 215 patients, 140 had idiopathic neuropathy. Positive immunoglobulin (Ig)G with or without IgA antigliadin antibodies was found in 34% (47/140) of the patients with idiopathic neuropathy. This compares with 12% prevalence of these antibodies in the healthy controls. The prevalence of coeliac disease as shown by biopsy in the idiopathic group was at least 9% as compared with 1% in the controls. The clinical features of 100 patients (47 from the prevalence study and 53 referred from elsewhere) with gluten neuropathy included a mean age at onset of 55 (range 24-77) years and a mean duration of neuropathy of 9 (range 1-33) years. Gluten-sensitive enteropathy was present in 29% of patients. The human leucocyte antigen types associated with coeliac disease were found in 80% of patients. Gluten sensitivity may be aetiologically linked to a substantial number of idiopathic axonal neuropathies.


Dysfunctional modulation of emotional interference in the medial prefrontal cortex in patients with schizophrenia.
Patients with schizophrenia have impairment in cognitive-emotional interaction that is reflected in delusion formation and poor social functioning. Although monitoring deficits in the anterior cingulate have been observed in schizophrenia, the involvement of the affective division of the anterior cingulate implicated in cognitive modulation of emotional processing has not been directly addressed in schizophrenia. In this study, we examined the function of the affective division of the anterior cingulate and the related neural systems by using a modified emotional Stroop fMRI paradigm. Fourteen patients with schizophrenia and fourteen healthy controls performed an emotional appraisal task with semantically relevant emotional interferences during fMRI scanning. The patients with schizophrenia were significantly less efficient than the healthy controls during the emotional incongruence trials. When emotionally incongruent trials were compared to congruent trials, relative deactivations of the subgenual cingulate gyrus and the ventromedial prefrontal cortex observed in the healthy controls were not found in the patient group and activities of these regions inversely correlated with emotional interference to performance efficiency and response accuracy respectively in the patient group. In addition, relative activation in the dorsolateral prefrontal cortex was observed only in the patient group. These findings suggest that deficit in cognitive modulation over emotional interference in patients with schizophrenia may be explained by failure in suppressing the affective division of the anterior cingulate despite attentional effort. This may provide evidence for the failure in suppressing the bottom-up processing of emotion during cognitive-emotional interaction in schizophrenia.


The health-related quality of life of Chinese patients with lower urinary tract symptoms in primary care.
The aim of this study was to evaluate the health-related quality of life (HRQOL) of Chinese primary care patients with lower urinary tract symptoms (LUTS). Five hundred and nineteen primary care subjects with LUTS completed a structured questionnaire containing the International Prostate Symptom Score, the adapted Incontinence Impact Questionnaire-7, the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form, the Chinese (HK) SF-12 Health Survey Version 2 (SF-12 v2) and the Depression, Anxiety and Stress Scale-21. LUTS patients had poorer HRQOL for the General Health and the Vitality domains and lower Physical Component Summary scores, but better HRQOL for the Role Emotion domain than the adjusted Hong Kong population norms. Clinical factors associated with poorer HRQOL measured by the SF-12 v2 included having more severe LUTS and having more severe depressive, anxiety and stress symptoms. Socio-demographic factors associated with poorer SF-12 v2 were consistent with those found in the general populations. Clinical and socio-demographic factors associated with poorer HRQOL assessed by condition-specific measures included having more severe LUTS (excluding intermittency and straining), the presence of mixed urinary incontinence, having more severe anxiety and stress symptoms, younger age, being not married, being in employment and having a lower household income. LUTS had substantial negative impact on patients' overall health perception and global well-being in Chinese population. A decline in HRQOL might be a key determinant for Chinese patients with LUTS to seek treatment. Patients with nocturia, frequency, urgency or mixed urinary incontinence and younger patients deserve more treatment attention because they appear to have poorer HRQOL.


The Food Warden: An Exploration of Issues in Distributing Responsibilities for Safe-by-Design Synthetic Biology Applications.
The Safe-by-Design approach in synthetic biology holds the promise of designing the building blocks of life in an organism guided by the value of safety. This paves a new way for using biotechnologies safely. However, the Safe-by-Design approach moves the bulk of the responsibility for safety to the actors in the research and development phase. Also, it assumes that safety can be defined and understood by all stakeholders in the same way. These assumptions are problematic and might actually undermine safety. This research explores these assumptions through the use of a Group Decision Room. In this set up, anonymous and non-anonymous deliberation methods are used for different stakeholders to exchange views. During the session, a potential synthetic biology application is used as a case for investigation: the Food Warden, a biosensor contained in meat packaging for indicating the freshness of meat. Participants discuss what potential issues might arise, how responsibilities should be distributed in a forward-looking way, who is to blame if something would go wrong. They are also asked what safety and responsibility mean at different phases, and for different stakeholders. The results of the session are not generalizable, but provide valuable insights. Issues of safety cannot all be taken care of in the R&D phase. Also, when things go wrong, there are proximal and distal causes to consider. In addition, capacities of actors play an important role in defining their responsibilities. Last but not least, this research provides a new perspective on the role of instruction manuals in achieving safety.


MicroRNA-592 targets DEK oncogene and suppresses cell growth in the hepatocellular carcinoma cell line HepG2.
MicroRNAs (miRNAs) are classes of small, non-coding RNAs that regulate the translation of target mRNA transcripts. In this study, we demonstrated that miR-592 was downregulated in human hepatocellular carcinoma (HCC) and could suppress growth of the human HCC cell line HepG2. A tumor oncogene, DEK, was identified as a direct target of miR-592. Luciferase report assay indicated miR-592 regulates DEK expression though bind to its 3'UTR. Furthermore, knockdown of DEK also suppressed cell proliferation of HepG2 cells, which was consist with miR-592. At last, we suggested that DEK was upregulated in HCC tissues inversely with miR-592. These results demonstrated that miR-592 targets DEK transcript and suppresses HCC cell growth, and may provide potential therapeutic target in human HCC.


Defect engineering of oxide perovskites for catalysis and energy storage: synthesis of chemistry and materials science.
Oxide perovskites have emerged as an important class of materials with important applications in many technological areas, particularly thermocatalysis, electrocatalysis, photocatalysis, and energy storage. However, their implementation faces numerous challenges that are familiar to the chemist and materials scientist. The present work surveys the state-of-the-art by integrating these two viewpoints, focusing on the critical role that defect engineering plays in the design, fabrication, modification, and application of these materials. An extensive review of experimental and simulation studies of the synthesis and performance of oxide perovskites and devices containing these materials is coupled with exposition of the fundamental and applied aspects of defect equilibria. The aim of this approach is to elucidate how these issues can be integrated in order to shed light on the interpretation of the data and what trajectories are suggested by them. This critical examination has revealed a number of areas in which the review can provide a greater understanding. These include considerations of (1) the nature and formation of solid solutions, (2) site filling and stoichiometry, (3) the rationale for the design of defective oxide perovskites, and (4) the complex mechanisms of charge compensation and charge transfer. The review concludes with some proposed strategies to address the challenges in the future development of oxide perovskites and their applications.


Intermediate trapping on a mutant retaining alpha-galactosyltransferase identifies an unexpected aspartate residue.
Lipopolysaccharyl-alpha-1,4-galactosyltransferase C (LgtC), a glycosyltransferase family 8 alpha-1,4-galactosyltransferase from Neisseria meningitidis, catalyzes the transfer of galactose from UDP galactose to terminal lactose-containing acceptor sugars with net retention of anomeric configuration. To investigate the potential role of discrete nucleophilic catalysis suggested by the double displacement mechanism generally proposed for retaining glycosyltransferases, the side chain amide of Gln-189, which is suitably positioned to act as the catalytic nucleophile of LgtC, was substituted with the more nucleophilic carboxylate-containing side chain of glutamate in the hope of accumulating a glycosyl-enzyme intermediate. The resulting mutant was subjected to kinetic, mass spectrometric, and x-ray crystallographic analysis. Although the K(m) for UDP-galactose is not significantly altered, the k(cat) was reduced to 3% that of the wild type enzyme. Electrospray mass spectrometric analysis revealed that a steady state population of the Q189E variant contains a covalently bound galactosyl moiety. Liquid chromatographic/mass spectrometric analysis of fragmented proteolytic digests identified the site of labeling not as Glu-189 but, surprisingly, as the sequentially adjacent Asp-190. However, the side chain carboxylate of Asp-190 is located 8.9 A away from the donor substrate in the available crystal structure. Kinetic analysis of a D190N mutant at this position revealed a k(cat) value 3000-fold lower than that of the wild type enzyme. A 2.6-A crystal structure of the Q189E mutant with bound uridine 5'-diphospho-2-deoxy-2-fluoro-alpha-d-galactopyranose revealed no significant perturbation of the mode of donor sugar binding nor of active site configuration. This is the first trapping of an intermediate in the active site of a retaining glycosyltransferase and, although not conclusive, implicates Asp-190 as an alternative candidate catalytic nucleophile, thereby rekindling a longstanding mechanistic debate.


Strategic Developments & Future Perspective on Gene Therapy for Breast Cancer: Role of mTOR and Brk/ PTK6 as Molecular Targets.
Breast cancer is a serious health issue and a major concern in biomedical research. Alteration in major signaling (viz. PI3K-AKT-mTOR, Ras-Raf-MEK-Erk, NF-kB, cyclin D1, JAK-STAT, Wnt, Notch, Hedgehog signaling and apoptotic pathway) contributes to the development of major subtypes of mammary carcinoma such as HER2 positive, TNBC, luminal A and B and normal-like breast cancer. Further, mutation and expression parameters of different genes involved in the growth and development of cells play an important role in the progress of different types of carcinoma, making gene therapy an emerging new therapeutic approach for the management of life-threatening diseases like cancer. The genetic targets (oncogenes and tumor suppressor genes) play a major role in the formation of a tumor. Brk/PTK6 and mTOR are two central molecules that are involved in the regulation of numerous signaling related to cell growth, proliferation, angiogenesis, survival, invasion, metastasis, apoptosis, and autophagy. Since these two proteins are highly upregulated in mammary carcinogenesis, this can be used as targeted genes for the treatment of breast cancer. However, not much work has been done on them. This review highlights the therapeutic significance of Brk and mTOR and their associated signaling in mammary carcinogenesis, which may provide a strategy to develop gene therapy for breast cancer management.


[Use of TNFalpha antibodies in treatment of inflammatory bowel disease].
TNFalpha-antibodies have been used increasingly in treatment of inflammatory bowel disease (IBD) during the last years. This article provides an overview of indications, contraindications, efficacy, and side effects of this so-called biological treatment of IBD. Based on the clinical experience of the authors, literature was selected through a non-systematic search in PubMed. TNFalpha-antibodies have a documented initial effect in 60-70 % of patients with moderate to severe luminal and/or fistulising IBD. Approximately 30 % of patients achieve remission after a relatively short treatment period. However, the effect seems to decrease during long-term treatment. It is still unsettled whether these drugs prevent colectomy in ulcerative colitis. The treatment seems to increase the risk of serious infections and there are also some indications of an increased risk of malignancy. Combination therapy with azathioprin is common and probably increases both the effect and the risk of side effects. TNFalpha-antibodies have become an important part of the treatment for moderate to severe IBD, but the effect decreases during long-term treatment and has to be evaluated in light of potential side effects. Further long-term studies are necessary.


Understanding of factors that enable health promoters in implementing health-promoting schools: a systematic review and narrative synthesis of qualitative evidence.
Health-promoting schools have been regarded as an important initiative in promoting child and adolescent health in school settings using the whole-school approach. Quantitative research has proved its effectiveness in various school-based programmes. However, few qualitative studies have been conducted to investigate the strategies used by health promoters to implement such initiatives. In this study, the researchers conducted a systematic review and narrative synthesis of the qualitative literature to identify important enablers assisting the implementation of health-promoting schools from the perspectives of health promoters. Five enablers have been identified from the review: (a) Following a framework/guideline to implement health-promoting schools; (b) Obtaining committed support and contributions from the school staff, school board management, government authorities, health agencies and other stakeholders; (c) Adopting a multidisciplinary, collaborative approach to implementing HPS; (d) Establishing professional networks and relationships; and (e) Continuing training and education in school health promotion. This highlights the importance of developing school health policies that meet local health needs, and socio-cultural characteristics that can foster mutual understanding between the health and education sectors so as to foster health promotion in children and adolescents.


Glial cell line-derived neurotrophic factor-levodopa interactions and reduction of side effects in parkinsonian monkeys.
Glial cell line-derived neurotrophic factor (GDNF) stimulates the nigrostriatal dopaminergic pathway and improves motor functions in animal models of parkinsonism. Sinemet is currently the most widely used drug for treating Parkinson's disease. The present study has evaluated GDNF-Sinemet interactions in parkinsonian rhesus monkeys. Both GDNF and Sinemet, when given alone, significantly improved total parkinsonian scores. The response to Sinemet did not change after intracerebroventricular vehicle injections. In contrast, there was a functional interaction between GDNF and levodopa. When comparing the levodopa dose response before and after GDNF treatment, significant behavioral improvements were seen after trophic factor administration at every levodopa dose level except 500 mg. Adverse responses to Sinemet treatment alone in parkinsonian animals included vomiting, dykinesias, dystonias, and stereotypic movements. Combined GDNF-Sinemet treatment significantly reduced the occurrence of these levodopa-induced side effects, with a >90% decrease in adverse responses seen at the mid-Sinemet (250 mg levodopa-25 mg carbidopa) dose level. The only side effect from GDNF treatment was a transitory weight loss. Thus, combined GDNF-Sinemet treatment could be of therapeutic value in treating parkinsonism, by producing a greater functional response and by mitigating adverse responses to Sinemet treatment.


Evaluation of oral phytogenic microbeaded Newcastle Disease vaccine delivery in indigenous chicken.
This study describes the evaluation of microbeaded oral vaccine delivery for Newcastle Disease (ND) in village chicken. Microbeads containing vaccine were prepared by ionotropic-gelation technique using aluminum sulfate. Lasota Vaccine strain (2 g) was well mixed with Boswellia caterii gum extract at ratio 1:1. The wet beads were washed twice with distilled water and dried at 37℃ overnight. Microbeads without vaccine were prepared as control. A tablet dissolution machine was used to evaluate peak adhesion time (PAT). Sixty local chickens sourced from a recognized breeder were separated into four groups for in in-vivo evaluation. Group A was administered with the bead-loaded vaccine mixed with their feed, group B had vaccine alone administered in their drinking water, group C had the bead alone mixed with their feed, and group D, which served as negative control received no vaccination against ND nor gum beads.The PAT on both trachea and jejunum was 4 ± 10 hours. Post-vaccination antibody titer revealed higher response in group B than (6.6) in group A (5.3); the micro-beaded vaccine gave delayed but enhanced and prolonged immune response. This noninvasive and easy to administer method may be useful in the prevention of ND outbreaks in backyard poultry production.


Ethical Considerations in Electronic Monitoring of the Cognitively Impaired.
Cognitive impairment afflicts an estimated 16 million people in the United States. Wandering is a concerning behavior associated with cognitive impairment, as it may threaten patient safety. The risks posed by wandering place severe burdens on both professional and informal caregivers, as well as law enforcement institutions throughout the United States. As such, location trackers that could reduce this burden have become increasingly prevalent. As with many assistive technologies, the substantial promise of location trackers is counterbalanced by potential pitfalls with respect to loss of privacy and autonomy. This article reviews the ethical issues raised by electronic monitoring of cognitively impaired persons, with the goal of transcending a narrow focus on decisional capacity in favor of a patient-centered framework that is applicable and adjustable at different stages of cognitive decline. Balancing the ethical principles of beneficence and respect in treating cognitively impaired persons goes beyond the necessary step of evaluating decision-making capacity to include partnering with families, caretakers, and cognitively impaired individuals who wander in a collaborative coalition of care. An approach emphasizing the individual needs of patients and caretakers is best suited to finding solutions that implement tracking technologies in ways that both protect and empower the cognitively impaired.


Influence of psychostimulants on bone mineral density and content among children with attention deficit hyperactivity disorder. A systematic review.
There is a controversy over the influence of psychostimulant medications on bone mineral density (BMD) and bone mineral content (BMC) among children with attention-deficit-hyperactivity-disorder (ADHD). The aim of the present systematic review was to assess the influence of psychostimulant medications on BMD and BMC among children with ADHD. A comprehensive search of electronic databases, including PubMed, Scopus, Embase, and Cochrane Library, was conducted to identify relevant studies published up until July 2023. Clinical studies that addressed the focused question "Do psychostimulant medications affect bone mineral density and content in children with ADHD?" were included. Letters to the Editor, studies on animal-models, ex-vivo and in-vitro studies, commentaries and reviews were excluded. The primary outcome measures were changes in BMD and BMC. Study quality was assessed using the risk of bias for non-randomized studies-exposure tool. Five non-randomized clinical studies were included. The number of participants ranged from 18 to 6489 with mean ages ranging from 7.3 to 13.75 years. The study durations ranged between five and seven years. In all studies osseous evaluation was done using dual-energy X-ray absorptiometry. The bone locations examined included total body, lumbar-spine, femur, femoral-neck, femoral body, and pelvis. Two studies reported that psychostimulant medications reduce BMC and BMD. In one study, bone turnover, serum leptin and fat levels were reduced in children using psychostimulant medications but no unusual reduction recorded among controls. In general, 80 % of the studies concluded that psychostimulant medications compromise BMC and BMD. Power analysis was done in one study. One study had a low RoB and the remaining demonstrated some concerns. Given the methodological concerns observed in the included studies, arriving at a definitive conclusion regarding the effects of psychostimulant medications on BMC, BMD, and bone turnover in children with ADHD is challenging. However, it is important to acknowledge that an association between psychostimulant medications and these bone-related parameters cannot be disregarded.


Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer.
Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. The objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. Chemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510-520 mg/m2 (T1) and 1020-1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. Latent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.


Patients with diabetic neuropathy are at risk of a greater intraoperative reduction in core temperature.
Core hypothermia develops after the induction of general anesthesia, but intraoperative vasoconstriction usually prevents its progression. However, diabetes mellitus is often associated with autonomic neuropathy, which leads to abnormal peripheral neurovascular function. Accordingly, we tested the hypothesis that diabetic patients experience a greater reduction in core temperature during general anesthesia than nondiabetic patients. We studied 36 nondiabetic patients (control group) and 27 diabetic patients (diabetic group) undergoing elective abdominal surgery. Both groups were divided into young (< 60 yr) and older age (>/= 60 yr) groups. Standard noninvasive autonomic tests (heart rate variation at deep periodical breathing, Valsalva maneuver, and head-up tilt) were carried out for each patient. The relation between the results of these tests of autonomic function and the tympanic membrane temperature during general anesthesia was assessed in relation to peripheral vasoconstriction. Thirteen patients in the diabetic group showed abnormal responses to two or more of the basal autonomic function tests (patients with autonomic dysfunction). Changes in core temperature among the groups were similar at 90 min after the induction of anesthesia. However, the core temperature of the diabetic patients with autonomic dysfunction was lower from 120 min (35.1 degrees C) onward compared with the young or older nondiabetic patients and the diabetic patients with normal autonomic function. Peripheral vasoconstriction, evaluated using the forearm-fingertip skin surface temperature gradient, was delayed in patients with autonomic dysfunction compared with the others. The current results indicate that diabetic autonomic neuropathy is associated with more severe intraoperative hypothermia. We postulate that diabetic patients become more hypothermic because their peripheral neuropathy delays the onset of thermoregulatory vasoconstriction and reduces its efficacy once triggered. These patients may therefore fail to develop a normal core temperature plateau.


Accurate measurement of the 12.6 GHz "clock" transition in trapped (171)Yb(+) ions.
We have measured the frequency of the (171)Yb(+) 12.6 GHz M(F)=0-->0 ground state hyperfine "clock" transition in buffer gas-cooled ion clouds confined in two similar, but not identical, linear Paul traps. After correction for the known differences between the two ion traps, including significantly different second-order Doppler shifts, the frequencies agree within an uncertainty of less than 2 parts in 10(13). Our best value, based on an analytic model for the second-order Doppler shift, for the frequency of the clock transition of an isolated ion at zero temperature, velocity, electric field and magnetic field, is 12642812118.466+0.002 Hz.


Hyperglycemia and hypoinsulinemia in patients with Fanconi-Bickel syndrome.
Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by the combination of hepatorenal glycogen accumulation and Fanconi-type nephropathy. Mutations in GLUT2, the gene for facilitative glucose transporter protein 2 (GLUT2), cause FBS. To evaluate glucose and insulin responses to oral glucose load in patients with FBS. Ten children (7.3 +/- 4.8 years) diagnosed with FBS in early infancy underwent a standard oral glucose tolerance test (OGTT); plasma glucose (PG) and serum insulin concentrations were measured at 30-min intervals for 2 hours. HbA1c, insulin-like growth factor-I, and fasting lipid profiles were also measured. Mean fasting and 2-h PG concentrations were 3.8 +/- 0.9 mmol/l and 8.6 +/- 3.0 mmol/1, respectively. 2-hour PG levels were above 11.1 mmol/l in two patients (20%) and between 7.75 and 11.1 mmol/ in four patients (40%). HbA1c was normal in all the patients with a mean of 5.4 +/- 0.3%. Mean fasting and peak serum insulin levels were 8.7 +/- 0.8 pmol/ and 98.6 +/- 43.0 pmol/l, respectively, and did not differ between the patients with normal and abnormal OGTT. Patients with abnormal OGTT were younger (4.8 +/- 3.2 vs 11.0 +/- 4.8 yr; p = 0.04). Fasting PG increased with age (r = 0.80, p < 0.01). Total and LDL cholesterol as well as triglyceride concentrations were elevated. Most but not all patients with FBS have impaired glucose tolerance/diabetes range hyperglycemia after OGTT while maintaining normal HbA1c. Patients with FBS are relatively hypoinsulinemic. Both fasting hypoglycemia and post-OGTT hyperglycemia seem to improve with age.


LRP1 is a master regulator of tau uptake and spread.
The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies-including Alzheimer's disease, frontotemporal dementia and chronic traumatic encephalopathy1. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity2. This observation and complementary experimental studies3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.


Evaluation of Factors in Relation with the Non-Compliance to Curative Intent Radiotherapy among Patients of Head and Neck Carcinoma: A Study from the Kumaon Region of India.
Radiotherapy (RT)-based curative regimens for head and neck squamous cell carcinomas (HNSCC) deliver a dose of 66-70 Gray (Gy) over a period of 6-7 weeks, and incomplete treatments are unlikely to result in cure. Non-compliance to RT is major contributory factor to treatment failure. To assess the proportion of patients who do not complete planned treatment after initiation of curative RT. This study also aims to explore a possible relationship of non-compliance due to socio-economic, disease-related and treatment-related factors. The records of HNSCC patients treated from January 2012-December 2013 were audited. Data from the treatment records were to collect patient-related, disease-related, and social demographic parameters. Of the patients who had not completed treatment, the reasons behind the same were investigated. Of the 324 patients of HNSCC who were initiated on radical RT, a total of 76 patients were found to have discontinued treatment without authorization of the treating clinician. There was no significant predilection for treatment non-compliance with regards to patient age, educational status, religion, site of the disease, use of neoadjuvant chemotherapy, or use of concurrent chemotherapy. There tended to be a higher association of treatment non-compliance among patients residing >100 km away from the treatment center, patients hailing from hilly regions, patients without the below poverty line (BPL) card, unemployed patients, and patients with stage IV-A/B disease. Of the 76 patients who did not complete treatment, telephonic questionnaire could be obtained from 54 patients. Causes for non-compliance included preference for traditional healers (22.2%), fear of toxicity (7.4%), logistic reasons (18.5%), financial reasons (24.1%), and lack of interest/faith in RT (5.6%). There is a high incidence of treatment default among patients of HNSCC during RT in this region. The revelation of the higher propensity for treatment default among patients from distant, hilly regions, unemployed, patients without BPL cards, and stages-IVA/IVB highlights the need for specific interventions for these special populations.


Multiple strategies are required to address the information and support needs of gay and bisexual men with hepatitis C in Australia.
Hepatitis C virus (HCV) infection is increasingly reported among gay and bisexual men. However, little is known about the personal and social dimensions of HCV-related experience among these men in Australia. An online survey of 474 Australian gay and bisexual men was conducted from August to December 2013. A subsample of 48 HCV mono-infected and HIV/HCV co-infected men was analysed to explore HCV knowledge, sources of information, unmet information needs and use of HCV-related services. More than half of respondents in the subsample were unaware that HIV infection increases the risk of sexually acquired HCV and most wanted information about how to prevent the sexual transmission of HCV. A majority of respondents requested gay-specific HCV services, and approximately similar proportions of men indicated that they would like these services delivered by a hepatitis organization, a lesbian, gay, bisexual, transgender and intersex (LGBTI) organization and a HIV organization. Men in receipt of HIV antiretroviral treatments were most likely to request that gay-specific HCV information and support services be delivered by a LGBTI or HIV organization (OR = 8.63). These findings suggest that a variety of organizations are required to address the information and support needs of Australian gay and bisexual men with HCV.


Blockchain-Based Digital Contact Tracing Apps for COVID-19 Pandemic Management: Issues, Challenges, Solutions, and Future Directions.
The COVID-19 pandemic has caused substantial global disturbance by affecting more than 42 million people (as of the end of October 2020). Since there is no medication or vaccine available, the only way to combat it is to minimize transmission. Digital contact tracing is an effective technique that can be utilized for this purpose, as it eliminates the manual contact tracing process and could help in identifying and isolating affected people. However, users are reluctant to share their location and contact details due to concerns related to the privacy and security of their personal information, which affects its implementation and extensive adoption. Blockchain technology has been applied in various domains and has been proven to be an effective approach for handling data transactions securely, which makes it an ideal choice for digital contact tracing apps. The properties of blockchain such as time stamping and immutability of data may facilitate the retrieval of accurate information on the trail of the virus in a transparent manner, while data encryption assures the integrity of the information being provided. Furthermore, the anonymity of the user's identity alleviates some of the risks related to privacy and confidentiality concerns. In this paper, we provide readers with a detailed discussion on the digital contact tracing mechanism and outline the apps developed so far to combat the COVID-19 pandemic. Moreover, we present the possible risks, issues, and challenges associated with the available contact tracing apps and analyze how the adoption of a blockchain-based decentralized network for handling the app could provide users with privacy-preserving contact tracing without compromising performance and efficiency.


Relation of plasma selenium and lipid peroxidation end products in patients with Alzheimer's disease.
Increased oxidative stress in the brain during the course of Alzheimer's disease (AD) leads to an imbalance of antioxidants and formation of free radical reaction end-products which may be detected in blood as fluorescent lipofuscin-like pigments (LFPs). The aim of this study was to evaluate and compare LFPs with plasma selenium concentrations representing an integral part of the antioxidant system. Plasma samples from subjects with AD dementia (ADD; n=11), mild cognitive impairment (MCI; n=17) and controls (n=12), were collected. The concentration of selenium was measured using atomic absorption spectroscopy. LFPs were analyzed by fluorescence spectroscopy and quantified for different fluorescent maxima and then correlated with plasma selenium. Lower levels of selenium were detected in MCI and ADD patients than in controls (P=0.003 and P=0.049, respectively). Additionally, higher fluorescence intensities of LFPs were observed in MCI patients than in controls in four fluorescence maxima and higher fluorescence intensities were also observed in MCI patients than in ADD patients in three fluorescence maxima, respectively. A negative correlation between selenium concentrations and LFPs fluorescence was observed in the three fluorescence maxima. This is the first study focused on correlation of plasma selenium with specific lipofuscin-like products of oxidative stress in plasma of patients with Alzheimer´s disease and mild cognitive impairment.


Adaptive resistance to the "last hope" antibiotics polymyxin B and colistin in Pseudomonas aeruginosa is mediated by the novel two-component regulatory system ParR-ParS.
As multidrug resistance increases alarmingly, polymyxin B and colistin are increasingly being used in the clinic to treat serious Pseudomonas aeruginosa infections. In this opportunistic pathogen, subinhibitory levels of polymyxins and certain antimicrobial peptides induce resistance toward higher, otherwise lethal, levels of these antimicrobial agents. It is known that the modification of lipid A of lipopolysaccharide (LPS) is a key component of this adaptive peptide resistance, but to date, the regulatory mechanism underlying peptide regulation in P. aeruginosa has remained elusive. The PhoP-PhoQ and PmrA-PmrB two-component systems, which control this modification under low-Mg2+ conditions, do not appear to play a major role in peptide-mediated adaptive resistance, unlike in Salmonella where PhoQ is a peptide sensor. Here we describe the identification and characterization of a novel P. aeruginosa two-component regulator affecting polymyxin-adaptive resistance, ParR-ParS (PA1799-PA1798). This system was required for activation of the arnBCADTEF LPS modification operon in the presence of subinhibitory concentrations of polymyxin, colistin, or the bovine peptide indolicidin, leading to increased resistance to various polycationic antibiotics, including aminoglycosides. This study highlights the complexity of the regulatory network controlling resistance to cationic antibiotics and host peptides in P. aeruginosa, which has major relevance in the development and deployment of cationic antimicrobials.


Evaluation of adjunct immunohistochemistry on reporting patterns of non-small cell lung carcinoma diagnosed histologically in a regional pathology centre.
Morphological sub-classification of non-small cell carcinoma in small biopsy specimens presents difficulties for pathologists and recent advances in chemotherapy have resulted in increased pressure to more robustly differentiate between squamous carcinoma and adenocarcinoma. The results of audits examining classification of non-small cell lung carcinoma by pathologists working in a specialist team within a regional centre and the effect of introducing adjunct immunohistochemistry into the reporting pathway are presented. It is concluded that the use of a limited immunohistochemical panel substantially reduces the number of cases when a specific cell type cannot be identified or 'favoured' (34% to 6%) and that the classification obtained correlates well with that found in subsequent resection specimens. In addition the introduction of immunohistochemistry substantially reduces the variability in reporting practice between pathologists.


Computational study of glucosepane-water and hydrogen bond formation: an electron topology and orbital analysis.
The collagen protein provides tensile strength to the extracellular matrix in addition to localising cells, proteins and protein cofactors. Collagen is susceptible to a build up of glycation modifications as a result of an exceptionally long half-life. Glucosepane is a collagen cross-linking advanced glycation end product; the structural and mechanical effects of glucosepane are still the subjects of much debate. With the prospect of an ageing population, the management and treatment of age-related diseases is becoming a pressing concern. One area of interest is the isolation of hydrated glucosepane, which has yet to be reported at an atomistic level. This study presents a series of glucosepane-water complexes within an implicit aqueous environment. Electronic structure calculations were performed using density functional theory and a high level basis set. Hydrogen bonds between glucosepane and explicit water were identified by monitoring changes to covalent bonds, calculating levels of electron donation from Natural Bonding Orbital analysis and the detection of bond critical points. Hydrogen bond strength was calculated using second-order perturbation calculations. The combined results suggest that glucosepane is very hydrophilic, with the imidazole feature being energetically more attractive to water than either hydroxyl group, although all hydrogen bonds, regardless of bond strength, were electrostatic in nature. Our results are in growing support of an earlier hypothesis that cross-links may result in an increase in interstitial water retention, which would permit the collagen fibril to swell, thereby potentially affecting the tensile and compression properties and biological function of connective tissues.