An Automated Approach to Examining Conversational Dynamics between People with Dementia and Their Carers.
The progressive neuropathology involved in dementia frequently causes a gradual decline in communication skills. Communication partners who are unaware of the specific communication problems faced by people with dementia (PWD) can inadvertently challenge their conversation partner, leading to distress and a reduced flow of information between speakers. Previous research has produced an extensive literature base recommending strategies to facilitate conversational engagement in dementia. However, empirical evidence for the beneficial effects of these strategies on conversational dynamics is sparse. This study uses a time-efficient computational discourse analysis tool called Discursis to examine the link between specific communication behaviours and content-based conversational engagement in 20 conversations between PWD living in residential aged-care facilities and care staff members. Conversations analysed here were baseline conversations recorded before staff members underwent communication training. Care staff members spontaneously exhibited a wide range of facilitative and non-facilitative communication behaviours, which were coded for analysis of conversation dynamics within these baseline conversations. A hybrid approach combining manual coding and automated Discursis metric analysis provides two sets of novel insights. Firstly, this study revealed nine communication behaviours that, if used by the care staff member in a given turn, significantly increased the appearance of subsequent content-based engagement in the conversation by PWD. Secondly, the current findings reveal alignment between human- and computer-generated labelling of communication behaviour for 8 out of the total 22 behaviours under investigation. The approach demonstrated in this study provides an empirical procedure for the detailed evaluation of content-based conversational engagement associated with specific communication behaviours.


QM/MM Description of Newly Selected Catalytic Bioscavengers Against Organophosphorus Compounds Revealed Reactivation Stimulus Mediated by Histidine Residue in the Acyl-Binding Loop.
Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by altering its pKa, which in turn promotes the activation of water molecule in terms of its nucleophilicity. Observed re-protonation of catalytic serine residue at position 198 from histidine residue at position 438 recovers initial configuration of the enzyme's active center, facilitating next catalytic cycle. We therefore suggest that utilization of uHTS platform in combination with deciphering of molecular mechanisms by QM/MM calculations may significantly improve our knowledge of enzyme function, propose new strategies for enzyme design and open new horizons in generation of catalytic bioscavengers against OP poisons.


Biophysical studies of the c-MYC NHE III1 promoter: model quadruplex interactions with a cationic porphyrin.
Regulation of the structural equilibrium of G-quadruplex-forming sequences located in the promoter regions of oncogenes by the binding of small molecules has shown potential as a new avenue for cancer chemotherapy. In this study, microcalorimetry (isothermal titration calorimetry and differential scanning calorimetry), electronic spectroscopy (ultraviolet-visible and circular dichroism), and molecular modeling were used to probe the complex interactions between a cationic porphryin mesotetra (N-methyl-4-pyridyl) porphine (TMPyP4) and the c-MYC PU 27-mer quadruplex. The stoichiometry at saturation is 4:1 mol of TMPyP4/c-MYC PU 27-mer G-quadruplex as determined by isothermal titration calorimetry, circular dichroism, and ultraviolet-visible spectroscopy. The four independent TMPyP4 binding sites fall into one of two modes. The two binding modes are different with respect to affinity, enthalpy change, and entropy change for formation of the 1:1 and 2:1, or 3:1 and 4:1 complexes. Binding of TMPyP4, at or near physiologic ionic strength ([K(+)] = 0.13 M), is described by a "two-independent-sites model." The two highest-affinity sites exhibit a K(1) of 1.6 x 10(7) M(-1) and the two lowest-affinity sites exhibit a K(2) of 4.2 x 10(5) M(-1). Dissection of the free-energy change into the enthalpy- and entropy-change contributions for the two modes is consistent with both "intercalative" and "exterior" binding mechanisms. An additional complexity is that there may be as many as six possible conformational quadruplex isomers based on the sequence. Differential scanning calorimetry experiments demonstrated two distinct melting events (T(m)1 = 74.7 degrees C and T(m)2 = 91.2 degrees C) resulting from a mixture of at least two conformers for the c-MYC PU 27-mer in solution.


Binding of an X-Specific Condensin Correlates with a Reduction in Active Histone Modifications at Gene Regulatory Elements.
Condensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In Caenorhabditis elegans, a specialized condensin, which forms the core of the dosage compensation complex (DCC), binds to and represses X chromosome transcription. Here, we analyzed DCC localization and the effect of DCC depletion on histone modifications, transcription factor binding, and gene expression using chromatin immunoprecipitation sequencing and mRNA sequencing. Across the X, the DCC accumulates at accessible gene regulatory sites in active chromatin and not heterochromatin. The DCC is required for reducing the levels of activating histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces gene expression, thus establishing a direct link between DCC binding and repression. Together, our results indicate that DCC-mediated transcription repression is associated with a reduction in the activity of X chromosomal gene regulatory elements.


Tangeretin from Citrus reticulate Inhibits Respiratory Syncytial Virus Replication and Associated Inflammation in Vivo.
Human respiratory syncytial virus (RSV) is a common pathogen that causes pneumonia and bronchiolitis in infants and young children. Our previous study showed that tangeretin from Citrus reticulate possessed potent in vitro anti-RSV effects comparable to that of ribavirin. Therefore, in this study, we investigated the in vivo anti-RSV activity of tangeretin in 3-week-old male BALB/c mice. A plaque reduction assay and fluorescence quantitative polymerase chain reaction (FQ-PCR) showed that tangeretin inhibited RSV replication in the lung of mice. Moreover, a luminex assay indicated tangeretin relieved RSV-induced lung inflammation by attenuating interleukin (IL)-1β secretion. Possible anti-inflammatory mechanisms of tangeretin were preliminarily explored using a RSV-infected macrophage model. A FQ-PCR, enzyme-linked immunosorbent assay (ELISA), and luciferase assay revealed that tangeretin inhibited RSV-induced inflammation by suppressing nuclear factor-κB (NF-κB) activation. This study demonstrates that tangeretin inhibited RSV replication and RSV-induced lung inflammation in vivo and may be useful in preventing and treating RSV infections and inflammation.


Temperature and Rain Moderate the Effect of Neighborhood Walkability on Walking Time for Seniors in Barcelona.
Walking is the most accessible form for seniors to engage in daily light or moderate physical activity. Walking activity depends on both individual and environmental factors, the latter including how walkable a given setting is. Recent papers have pointed at the relevance of also considering meteorological conditions in relation to the walking behavior of older adults. This paper explores the combined effect of neighborhood walkability, temperature and rain on daily walking time among seniors residing in Barcelona. Daily walking time was extracted from 7-day GPS (Global Positioning System) devices and accelerometer data of 227 seniors residing in the Barcelona Metropolitan Region (Spain). Temperature and rain data were extracted from official governmental weather stations. Mixed-effects linear regression models were adjusted to test the combined association between weather and walkability on daily walking time. Neighborhood walkability is positively associated with walking time among seniors, while rain generally deters it. Additionally, this study demonstrates that temperature and rain modify the effect of residential walkability on senior walking activity: low temperatures are particularly associated with lower walking activity among those residing in low walkable areas, while the presence of rain presents a negative association with walking time in high walkable environments. The combined effect of walkability and weather should be considered both in design actions that aim at improving walking infrastructure and also in prevention programs aimed at encouraging daily walking among seniors.


Age-Dependent Association of Height Loss with Incident Fracture Risk in Postmenopausal Korean Women.
Height loss is a simple clinical measure associated with increased fracture risk. However, limited data exists on the association between height loss and fracture risk in postmenopausal Korean women. It is unknown whether this association varies with age. Data on height loss over a 6-year period were collected from a community-based longitudinal follow-up cohort (Ansung cohort of the Korean Genome and Epidemiology Study). Incident fractures were defined based on self-reported fractures after excluding those due to severe trauma or toes/fingers. The association between incident fractures and height loss was investigated using a Cox proportional hazards model. During a median follow-up of 10 years after the second visit, 259/1,806 participants (median age, 64 years) experienced incident fractures. Overall, a 1 standard deviation (SD) decrease in height (1.6 cm/median 5.8 years) was associated with 9% increased risk of fracture (hazard ratio [HR], 1.09; P=0.037), which lost statistical significance after adjustment for covariates. When stratified into age groups (50-59, 60-69, 70 years or older), a 1 SD decrease in height remained a robust predictor of fracture in the 50 to 59 years age group after adjusting for covariates (adjusted hazard ratio [aHR], 1.52; P=0.003), whereas height loss was not an independent predictor of fracture in the 60 to 69 (aHR, 1.06; P=0.333) or the 70 years or older age groups (aHR, 1.05; P=0.700; P for interaction <0.05, for all). Conclusion: Height loss during the previous 6 years was associated with an increased 10-year fracture risk in postmenopausal women in their 50s.


The menopausal transition does not appear to accelerate age-related increases in arterial stiffness.
Arterial stiffness is an independent marker of cardiovascular risk that increases with age, hypertension, diabetes and hyperlipidemia, both for men and women (although more pronounced in women). This study was designed to establish whether menopause augments the age-dependent change. The study evaluated pulse wave analysis and pulse wave velocity using applanation tonometry in 468 women (aged 40-80 years) sampled from the general population. In multiple linear regression models, age was the predominant correlate of increasing aortic augmentation pressure (p < 0.0001), augmentation index (p < 0.0001), augmentation index adjusted to a heart rate of 75 beats/min (p < 0.0001) and carotid-femoral pulse wave velocity (p < 0.0001). Analysis of covariance showed no significant difference in adjusted mean of augmentation pressure, augmentation index or pulse wave velocity between menopause groups (pre-, peri-, postmenopause). Adjusted means of augmentation pressure and pulse wave velocity were comparable between women on hormone therapy (n = 130) and non-users (n = 338). The results of the present study challenge the assertion by some researchers that menopause accelerates age-dependent changes in arterial stiffness.


Further pharmacological characterization of 5-HT(2C) receptor agonist-induced inhibition of 5-HT neuronal activity in the dorsal raphe nucleus in vivo.
Recent experiments using non-selective 5-hydroxytryptamine (5-HT)(2C) receptor agonists including WAY 161503 suggested that midbrain 5-HT neurones are under the inhibitory control of 5-HT(2C) receptors, acting via neighbouring gamma-aminobutyric acid (GABA) neurones. The present study extended this pharmacological characterization by comparing the actions of WAY 161503 with the 5-HT(2C) receptor agonists, Ro 60-0275 and 1-(3-chlorophenyl) piperazine (mCPP), as well as the non-selective 5-HT agonist lysergic acid diethylamide (LSD) and the 5-HT releasing agent 3,4-methylenedioxymethamphetamine (MDMA). 5-HT neuronal activity was measured in the dorsal raphe nucleus (DRN) using extracellular recordings in anaesthetized rats. The activity of DRN GABA neurones was assessed using double-label immunohistochemical measurements of Fos and glutamate decarboxylase (GAD). Ro 60-0175, like WAY 161503, inhibited 5-HT neurone firing, and the 5-HT(2C) antagonist SB 242084 reversed this effect. mCPP also inhibited 5-HT neurone firing ( approximately 60% neurones) in a SB 242084-reversible manner. LSD inhibited 5-HT neurone firing; however, this effect was not altered by either SB 242084 or the 5-HT(2A/C) receptor antagonist ritanserin but was reversed by the 5-HT(1A) receptor antagonist WAY 100635. Similarly, MDMA inhibited 5-HT neurone firing in a manner reversible by WAY 100635, but not SB 242084 or ritanserin. Finally, both Ro 60-0275 and mCPP, like WAY 161503, increased Fos expression in GAD-positive DRN neurones. These data strengthen the hypothesis that midbrain 5-HT neurones are under the inhibitory control of 5-HT(2C) receptors, and suggest that the 5-HT(2C) agonists Ro 60-0175, mCPP and WAY 161503, but not LSD or MDMA, are useful probes of the mechanism(s) involved.


Retroperitoneoscopic partial nephrectomy using radiofrequency coagulation for small renal tumors.
Adoption of laparoscopic partial nephrectomy (LPN) has been limited by lack of reliable hemostatic techniques. We evaluated radiofrequency coagulation (RFC) in obtaining hemostasis during LPN for small renal masses. Over 4 years LPN was performed by a retroperitoneal approach in 11 patients with solitary, predominantly exophytic renal tumors. A retroperitoneal approach was used in all patients. The renal hilum was not exposed. RF energy was delivered to coagulate the lesion and a margin of normal parenchyma. Tumors were excised together with at least a 0.5-cm margin of normal parenchyma, with the use of ultrasonic shears. Mean tumor size was 2.2 cm (range, 1.5 to 3.0). Mean operative time was 222 minutes (range, 130 to 305 minutes) and mean blood loss was 51 mL (range, 10 to 200 mL). During excision bleeding from the cut renal surface was minimal, and structure of the cortex and medulla still could be clearly distinguished after coagulation. No serious complications such as uncontrolled bleeding or urine leakage occurred. One patient had a thermal burn develop at the site of needle electrode insertion and hydronephrosis caused by pyeloureteral junction (PUJ) stricture. In follow-up, ranging from 8 to 53 months, no local recurrence or distant metastasis was detected by computed tomography. Hemostatic capability of RFC is excellent, improving visibility and ease of operation during LPN, and eliminating need for hilar clamping. Further experience and advancement of RF technology will be needed for the application of this method to larger, centrally located tumors.


spliceR: an R package for classification of alternative splicing and prediction of coding potential from RNA-seq data.
RNA-seq data is currently underutilized, in part because it is difficult to predict the functional impact of alternate transcription events. Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential. spliceR uses the full-length transcript output from RNA-seq assemblers to detect single or multiple exon skipping, alternative donor and acceptor sites, intron retention, alternative first or last exon usage, and mutually exclusive exon events. For each of these events spliceR also annotates the genomic coordinates of the differentially spliced elements, facilitating downstream sequence analysis. For each transcript isoform fraction values are calculated to identify transcript switching between conditions. Lastly, spliceR predicts the coding potential, as well as the potential nonsense mediated decay (NMD) sensitivity of each transcript. spliceR is an easy-to-use tool that extends the usability of RNA-seq and assembly technologies by allowing greater depth of annotation of RNA-seq data. spliceR is implemented as an R package and is freely available from the Bioconductor repository ( http://www.bioconductor.org/packages/2.13/bioc/html/spliceR.html).


Segmentation and Modelling of the Nuclear Envelope of HeLa Cells Imaged with Serial Block Face Scanning Electron Microscopy.
This paper describes an unsupervised algorithm, which segments the nuclear envelope of HeLa cells imaged by Serial Block Face Scanning Electron Microscopy. The algorithm exploits the variations of pixel intensity in different cellular regions by calculating edges, which are then used to generate superpixels. The superpixels are morphologically processed and those that correspond to the nuclear region are selected through the analysis of size, position, and correspondence with regions detected in neighbouring slices. The nuclear envelope is segmented from the nuclear region. The three-dimensional segmented nuclear envelope is then modelled against a spheroid to create a two-dimensional (2D) surface. The 2D surface summarises the complex 3D shape of the nuclear envelope and allows the extraction of metrics that may be relevant to characterise the nature of cells. The algorithm was developed and validated on a single cell and tested in six separate cells, each with 300 slices of 2000 × 2000 pixels. Ground truth was available for two of these cells, i.e., 600 hand-segmented slices. The accuracy of the algorithm was evaluated with two similarity metrics: Jaccard Similarity Index and Mean Hausdorff distance. Jaccard values of the first/second segmentation were 93%/90% for the whole cell, and 98%/94% between slices 75 and 225, as the central slices of the nucleus are more regular than those on the extremes. Mean Hausdorff distances were 9/17 pixels for the whole cells and 4/13 pixels for central slices. One slice was processed in approximately 8 s and a whole cell in 40 min. The algorithm outperformed active contours in both accuracy and time.


Surveillance of HIV Transmitted Drug Resistance in Latin America and the Caribbean: A Systematic Review and Meta-Analysis.
HIV transmitted drug resistance (TDR) remains at moderate level in Latin America and the Caribbean (LAC). However, different epidemiologic scenarios could influence national and sub-regional TDR levels and trends. We performed a systematic review of currently available publications on TDR in antiretroviral treatment-naïve adults in LAC. Ninety-eight studies published between January 2000 and June 2015 were included according to critical appraisal criteria and classified by sub-region: Brazil (50), Mesoamerica (17), Southern Cone (16), Andean (8) and Caribbean (7). From these, 81 studies encompassing 11,441 individuals with data on DR mutation frequency were included in a meta-analysis. Overall TDR prevalence in LAC was 7.7% (95% CI: 7.2%-8.2%). An increasing trend was observed for overall TDR when comparing 2000-2005 (6.0%) and 2006-2015 (8.2%) (p<0.0001), which was associated with significant NNRTI TDR increase (p<0.0001). NRTI TDR decreased (4.5% vs. 2.3%, p<0.0001). NNRTI TDR increase was associated mainly with K101E, K103N and G190A. NRTI TDR decrease was associated mainly with M184V, K70R and T215Y. All sub-regions reached moderate overall TDR levels. The rapid increase in TDR to all antiretroviral classes in the Caribbean is notable, as well as the significant increase in NNRTI TDR reaching moderate levels in the Southern Cone. NRTI TDR was dominant in 2000-2005, mainly in the Caribbean, Mesoamerica and Brazil. This dominance was lost in 2006-2015 in all sub-regions, with the Southern Cone and the Caribbean switching to NNRTI dominance. PI TDR remained mostly constant with a significant increase only observed in the Caribbean. Given the high conceptual and methodological heterogeneity of HIV TDR studies, implementation of surveys with standardized methodology and national representativeness is warranted to generate reliable to inform public health policies. The observed increasing trend in NNRTI TDR supports the need to strengthen TDR surveillance and programme monitoring and evaluation in LAC.


Biota from the coastal wetlands of Praia da Vitória (Terceira, Azores, Portugal): Part 3 - Birds.
The data presented here come from field observations of Aves between August 2013 and October 2018 as part of a LIFE research project aiming to preserve and restore three coastal wetlands from Praia da Vitória (Terceira Island, Azores, Portugal). Systematic monthly observations were carried out for five years in order to provide a checklist and monitoring of bird species and subspecies observed in three sites: Paul da Praia da Vitória (PPV), Paul do Belo Jardim (PBJ) and Paul da Pedreira do Cabo da Praia (PPCP). Main objectives were to determine their ornithological richness while also adding data to the overall knowledge of Azorean Avifauna and to monitor seasonal and between-year variation on species abundance. During a five-year observation period (2013-2018), a total of 82,985 birds belonging to 108 species/subspecies were observed. From this, 16,663 were in PPV, 11,793 from PBJ and 54,529 from PPCP. The total richness was 55, 40 and 85, respectively. Three species are first records for the Azores: Aythya americana (Eyton, 1838); Chlidonias leucopterus (Temminck, 1815) and Tringa brevipes (Vieillot, 1816). One species is a new record for Terceira Island: Lophodytes cucullatus (Linnaeus, 1758).


Race and the inheritance of low birth weight.
This paper uses intergenerational data from the Panel Study of Income Dynamics (PSID) to address the black-white difference in propensities toward low birth weight (LBW). We determine that socioeconomic conditions account for some variation in low birth weight across race. Further, while race differences in the risk of low birth weight cannot be explained entirely, we find that the inheritance of parental birth weight status dramatically reduces the black-white gap in low birth weight. Intergenerational legacies of poor infant health explain the largest share of racial disparities in filial birth weight. We then try to assess whether this intergenerational transmission of low birth weight is indeed genetic by using grandparent-fixed effects models to factor out, to a great extent, family socioeconomic circumstances. We find that even within this framework, both father's and mother's birth weight status have an important impact on filial outcomes. However, the degree of inheritance is weaker for African Americans than for other races. Finally, we theorize that the importance of paternal birth weight status implies a genetic association that does not work through the uterine environment but rather through the fetus itself.


Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2.
The prognosis of breast cancer in young women is influenced by reproductive history. Women diagnosed within 5 years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. Here we describe a mouse model of postpartum breast cancer that identifies mammary gland involution as a driving force of tumor progression. In this model, human breast cancer cells exposed to the involuting mammary microenvironment form large tumors that are characterized by abundant fibrillar collagen, high cyclooxygenase-2 (COX-2) expression and an invasive phenotype. In culture, tumor cells are invasive in a fibrillar collagen and COX-2-dependent manner. In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung. These data support further research to determine whether women at high risk for postpartum breast cancer would benefit from treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) during postpartum involution.


Chronic rhinosinusitis and emerging treatment options.
This review describes the epidemiology and various treatments in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Evidence for short-term use of systemic corticosteroids has been shown to be favorable in CRSwNP, but still limited in CRSsNP. Topical corticosteroids improve symptom scores in both CRS subgroups. The role of microbes in CRS is still controversial. Culture-directed antibiotics are recommended for CRSsNP with exacerbation. Long-term use of low dosage antibiotics is recommended for CRSsNP for their anti-inflammatory effects. Other emerging treatment options are also discussed.


Quality Control of the Traditional Patent Medicine Yimu Wan Based on SMRT Sequencing and DNA Barcoding.
Substandard traditional patent medicines may lead to global safety-related issues. Protecting consumers from the health risks associated with the integrity and authenticity of herbal preparations is of great concern. Of particular concern is quality control for traditional patent medicines. Here, we establish an effective approach for verifying the biological composition of traditional patent medicines based on single-molecule real-time (SMRT) sequencing and DNA barcoding. Yimu Wan (YMW), a classical herbal prescription recorded in the Chinese Pharmacopoeia, was chosen to test the method. Two reference YMW samples were used to establish a standard method for analysis, which was then applied to three different batches of commercial YMW samples. A total of 3703 and 4810 circular-consensus sequencing (CCS) reads from two reference and three commercial YMW samples were mapped to the ITS2 and psbA-trnH regions, respectively. Moreover, comparison of intraspecific genetic distances based on SMRT sequencing data with reference data from Sanger sequencing revealed an ITS2 and psbA-trnH intergenic spacer that exhibited high intraspecific divergence, with the sites of variation showing significant differences within species. Using the CCS strategy for SMRT sequencing analysis was adequate to guarantee the accuracy of identification. This study demonstrates the application of SMRT sequencing to detect the biological ingredients of herbal preparations. SMRT sequencing provides an affordable way to monitor the legality and safety of traditional patent medicines.


Synthesis and characterization of Pi4, a scorpion toxin from Pandinus imperator that acts on K+ channels.
Pi4 is a 38-residue toxin cross-linked by four disulfide bridges that has been isolated from the venom of the Chactidae scorpion Pandinus imperator. Together with maurotoxin, Pi1, Pi7 and HsTx1, Pi4 belongs to the alpha KTX6 subfamily of short four-disulfide-bridged scorpion toxins acting on K+ channels. Due to its very low abundance in venom, Pi4 was chemically synthesized in order to better characterize its pharmacology and structural properties. An enzyme-based cleavage of synthetic Pi4 (sPi4) indicated half-cystine pairings between Cys6-Cys27, Cys12-32, Cys16-34 and Cys22-37, which denotes a conventional pattern of scorpion toxin reticulation (Pi1/HsTx1 type). In vivo, sPi4 was lethal after intracerebroventricular injection to mice (LD50 of 0.2 microg per mouse). In vitro, addition of sPi4 onto Xenopus laevis oocytes heterologously expressing various voltage-gated K+ channel subtypes showed potent inhibition of currents from rat Kv1.2 (IC50 of 8 pm) and Shaker B (IC50 of 3 nm) channels, whereas no effect was observed on rat Kv1.1 and Kv1.3 channels. The sPi4 was also found to compete with 125I-labeled apamin for binding to small-conductance Ca(2+)-activated K+ (SK) channels from rat brain synaptosomes (IC50 value of 0.5 microm). sPi4 is a high affinity blocker of the Kv1.2 channel. The toxin was docked (BIGGER program) on the Kv channel using the solution structure of sPi4 and a molecular model of the Kv1.2 channel pore region. The model suggests a key role for residues Arg10, Arg19, Lys26 (dyad), Ile28, Lys30, Lys33 and Tyr35 (dyad) in the interaction and the associated blockage of the Kv1.2 channel.


Study of the absorption coefficient of graphene-polymer composites.
In this work, we have prepared a series of polydimethylsiloxane (PDMS) composites containing various graphene flakes loadings (0.02-2 wt%), and their broadband optical properties are being investigated. We demonstrate the tunability and evolution of transmittance and reflection spectra of the composites in a wide spectral range (0.4-200 μm) as a function of graphene content. Using these data we derive the broadband wavelength-dependent absorption coefficient (α) values. Our results show that α is roughly constant in the visible and IR ranges, and, surprisingly, is approximately one order of magnitude lower in the terahertz regime, suggesting different terahertz radiation scattering mechanism in our composite. Our material could be useful for applications in optical communication, sensing or ultrafast photonics.


Evidence of Increased Hydrophobicity and Dynamics inside the Tail Region of Glycolipid Self-Assemblies Using 2-n-Alkyl-Pyrene Derivatives to Probe Different Locations.
New designer biofluorophores are being increasingly used in the investigation of complex cellular processes. In this study, we utilized new derivatives of pyrene (Py), i.e., 2-n-alkyl-pyrenes (Py-C4 and Py-C8), in order to probe different regions inside the hydrophobic tail of n-dodecyl β-d-maltoside (βMal-C12) in two different phases (cubic ↔ lamellar). Although the sensitivity to the local environment is reduced compared to that of Py, attaching C4 and C8 at the 2-position of Py can provide a possible means to probe the local hydrophobicity in different parts of the tail region. The absence of excimer fluorescence and the ratio of the vibronic fluorescence peak intensities (I1/I3) in a lipid environment indicate the existence of Py as monomers in the hydrophobic region, similar to hydrophobic solvation, yet close to the headgroup region. When Py is replaced by Py-C4 and Py-C8, there is a small increase in hydrophobicity (reduction in I1/I3) as the Py moiety is pulled deeper inside the tail region of both cubic and lamellar phases. The larger space of the tail region in the lamellar phase is reflected as more local hydrophobicity measured by the probes which can penetrate deep inside, whereas the curved structure of the cubic phase limits the available space for the probes. Three fluorescence lifetime components were measured in lipid, indicating the heterogeneous nature of the hydrophobic region. In the lamellar phase, a large reduction in the average lifetime value, led by the long decay component, was measured for Py-C4 (reduction by 25%) and Py-C8 (45%) compared to that of the parent Py. This observation suggests the presence of a mechanism of interaction more collisional than static between the Py moiety and the tail region of the bilayer unit due to the ample space provided by the lamellar phase as the probe is buried deeper inside the hydrophobic region. A much smaller effect was observed in the cubic phase and was correlated with the tight environment around the probes, which stems from the increased curvature of the cubic phase. The current results provide a deeper understanding of the hydrophobic region during phase transition of lipid self-assembly which is important for better control during the process of membrane-protein crystallization.


Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits.
A reduction in nerve blood flow in chronic experimental diabetes has been linked to impaired conduction. Recently, there have been reports that this is preceded by a period of functional hyperemia. The present investigation explored early changes in sciatic nerve endoneurial blood flow and function in streptozocin-treated rats with durations of diabetes from 1 wk to 4 mo. Blood flow was monitored by microelectrode polarography and hydrogen clearance in thiobutabarbital (Inactin)-anesthetized animals. It was reduced by 41% as early as 1 wk after diabetes induction. There was no evidence of an early functional hyperemia, flow remaining 44% depressed up to 4 mo. In another investigation, similar reductions in blood flow were acutely induced in normal rats rendered hyperglycemic by glucose infusion. In diabetic animals, conduction velocity in sciatic branches supplying gastrocnemius and tibialis anterior muscles was correlated with blood flow. The link was further tested using a group of 2-mo diabetic rats treated with guanethidine. Treatment caused a functional adrenergic sympathectomy, and blood flow increased to within the normal range. Conduction velocity, depressed by 26% with diabetes, was normalized by treatment. These observations support the hypothesis that hyperglycemia-induced blood flow reductions and resultant endoneurial hypoxia are important factors underlying nerve conduction deficits early in the development of diabetic neuropathy.


Determinants of variation in food cost and availability in two socioeconomically contrasting neighbourhoods of Hamilton, Ontario, Canada.
This study addresses links between economic and nutritional variation in an urban North American setting. We employed a mixed-methods approach including mapping, semi-structured interviews, and food outlet surveys to investigate the public health impact of variation in the cost and availability of food between two socioeconomically distinct neighbourhoods of the City of Hamilton, Ontario, Canada. Food cost in supermarkets was not found to be higher in the low-income neighbourhood, though it was much higher in the variety stores that predominate in the low-income neighbourhood. Moreover, there was a very low availability of produce in the variety stores. Reduced fresh produce availability and lower incomes have the potential to negatively influence public health in the less-affluent study area by increasing the difficulty of acquiring healthy foods.


Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
HFE is an MHC-related protein that is mutated in the iron-overload disease hereditary hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The 2.6 A crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH-dependent interactions. We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TfR, consistent with our demonstration that HFE, transferrin, and TfR form a ternary complex.


Black-white differences in cancer prevention knowledge and behavior.
Data from the 1987 National Health Interview Survey Cancer Control Supplement were used to estimate multivariate logistic regression models of diet change, mammography utilization, stool blood test utilization, and smoking. Predictor variables included race, sex, age, income, dietary concerns, and four knowledge-related variables: education and three measures of cancer prevention knowledge. When knowledge variables were included in the models, race was not a significant predictor of behavior, with one exception: among women, Blacks were found to smoke less than Whites.


Ketamine concentrations during cardiopulmonary bypass.
To describe the serum concentrations of ketamine following a clinically relevant dosing schedule during cardiopulmonary bypass (CPB). Prospective case series. Tertiary care teaching hospital. Six patients undergoing coronary artery bypass grafting and over age 60 yr. Following induction of anaesthesia each patient received a bolus of ketamine 2 mg.kg-1 followed by an infusion of 50 micrograms.kg-1.min-1 which ran continuously until two hours after bypass. Ketamine serum concentrations were measured at five minutes after bolus, immediately following aortic cannulation, 10 and 20 min on CPB, termination of CPB, termination of the drug infusion and three and six hours after infusion termination. At the time of aortic cannulation, ketamine concentrations were 3.11 +/- 0.81 micrograms.ml-1, these levels decreased by one third with the initiation of CPB. By the end of CPB the concentrations had returned to levels roughly equivalent to those observed at the time of aortic cannulation. Following cessation of the infusion, ketamine concentration declined in a log-linear fashion with a half-life averaging 2.12 hr. (range 1.38-3.09 hr). This dosage regimen maintained general anaesthetic concentrations of ketamine throughout the operative period. These levels should result in brain tissue concentrations in excess of those previously shown to be neuroprotective in animals. Thus we conclude that this infusion regimen would be reasonable to be use in order to assess the potential neuroprotective effects of ketamine in humans undergoing CPB.


Infection of mouse neurones by West Nile virus is modulated by the interferon-inducible 2'-5' oligoadenylate synthetase 1b protein.
Over the past 7 years, West Nile zoonosis has been an emerging concern for public health in Europe, Middle East and more recently in North America. West Nile virus causes epidemic outbreaks in humans and infected patients may exhibit severe neurological symptoms. Because susceptibility and sensitivity to West Nile virus infections may depend on host genetic factors, a mouse model has been established to investigate the genetic determinism of host susceptibility to West Nile virus. A nonsense mutation in gene encoding the 1b isoform of the 2'-5'oligoadenylate synthetase (OAS1b) was constantly associated with the susceptibility of mouse strains to experimental West Nile virus infection. Oligoadenylate synthetase are interferon-inducible proteins playing a role in the endogeneous antiviral pathway. It was of interest to establish whether interferon-alpha and OAS 1B were sufficient to mediate resistance to West Nile virus infection. In the present study, we showed that interferon-alpha had the ability to modulate West Nile virus infection in mouse. In vitro, interferon-alpha protected mouse neuroblastoma cells against West Nile virus infection if cells have been pretreated with the cytokine for several hours. As a consequence of the presence of a stop codon, the Oas1b gene of the susceptible mice encodes a truncated and presumably inactive form, while resistant mice have a normal copy of the gene. Stable mouse neuroblastoma cell clones overexpressing mutant or wild-type OAS 1B were established. Replication of West Nile virus was less efficient in cells that produce the normal copy of OAS 1B as compared to those expressing the truncated form. Our data illustrate the notion that interferon-alpha and Oas genes may be critical for West Nile virus pathogenesis.


Reorganization of Substance Use Treatment and Harm Reduction Services During the COVID-19 Pandemic: A Global Survey.
Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted people with substance use disorders (SUDs) worldwide, and healthcare systems have reorganized their services in response to the pandemic. Methods: One week after the announcement of the COVID-19 as a pandemic, in a global survey, 177 addiction medicine professionals described COVID-19-related health responses in their own 77 countries in terms of SUD treatment and harm reduction services. The health responses were categorized around (1) managerial measures and systems, (2) logistics, (3) service providers, and (4) vulnerable groups. Results: Respondents from over 88% of countries reported that core medical and psychiatric care for SUDs had continued; however, only 56% of countries reported having had any business continuity plan, and 37.5% of countries reported shortages of methadone or buprenorphine supplies. Participants of 41% of countries reported partial discontinuation of harm-reduction services such as needle and syringe programs and condom distribution. Fifty-seven percent of overdose prevention interventions and 81% of outreach services were also negatively impacted. Conclusions: Participants reported that SUD treatment and harm-reduction services had been significantly impacted globally early during the COVID-19 pandemic. Based on our findings, we highlight several issues and complications resulting from the pandemic concerning people with SUDs that should be tackled more efficiently during the future waves or similar pandemics. The issues and potential strategies comprise the following: (1) helping policymakers to generate business continuity plans, (2) maintaining the use of evidence-based interventions for people with SUDs, (3) being prepared for adequate medication supplies, (4) integrating harm reduction programs with other treatment modalities, and (5) having specific considerations for vulnerable groups such as immigrants and refugees.


Short-term benefit of neoadjuvant hormone therapy in patients with localized high-risk or limited progressive prostate cancer.
Purpose: Radical surgery is the preferred method for local high-risk and limited progressive prostate cancer in the routine clinical setting. However, current guidelines do not recommend neoadjuvant hormone therapy (NHT). Opinions regarding NHT vary among individual clinicians. According to the experience gained at our center, we explored the benefits of NHT for patients with prostate cancer during the perioperative period in this study. Methods: In this retrospective study, we explored the perioperative benefits of NHT among 189 patients with local high-risk or limited progressive prostate cancer who underwent radical prostatectomy and divided them into two groups: the NHT group and the non-NHT group. The NHT regimens were a gonadotropin-releasing hormone (GnRH) agonist alone (3.75/11.25 mg of leuprolide or 3.6/10.8 mg of goserelin acetate), an androgen receptor antagonist (ARA) alone, or a combination of the two. The duration of treatment was <3 months, 3 to 6 months, or >6 months. Results: We found that NHT could reduce the surgery time and intraoperative hemorrhage, thus reducing the difficulty of surgery; NHT could also improve the postoperative recovery of patients. However, it did not reduce the stage of prostate cancer or positive surgical margin rate. Conclusions: Neoadjuvant therapy is optional for some patients. We believe that NHT will improve the overall prognosis of patients as progress continues in the medical field in the future.


Ethnic differences in body mass index, weight and height among school children in the north of iran.
Overweight and obesity are common health problems among adolescents. This study was set up to evaluate these problems and certain socio-demographic-related factors among three ethnic groups as represented by primary school children in northern Iran in 2010. This was a descriptive and cross-sectional study performed on 7433 students (Fars-native=3268, Turkman=2852, Sisstani=1313) from 112 schools in urban and rural areas. The schools and students were chosen by cluster and stratified sampling. The data were collected by interviewers for all samples throughout the study. Overweight and obesity were identified on the basis of the BMI cut-off Centers for Disease Control and Prevention (CDC) values (in excess of the 85(th) and 95(th) percentiles, respectively). SPSS 16.0 software for Windows was used for the analysis. Linear regression analyses revealed that weight, height and BMI increased by 2.70 kg, 4.62 cm and 0.42 kgm(-2), respectively, in boys (p=0.001) and 3.12 kg, 5.19 cm and 0.52 kgm(-2), respectively, in girls (p=0.001) for each year increase in age. In total, overweight was identified in 8.4% of those studied, while obesity was common in 14.1% of students. The rates of overweight and obesity were significantly different among all three ethnic groups (p=0.001). These rates were higher among the Fars-native individuals and lower among the Sisstani individuals as compared with the other groups. Logistic regression analyses showed that the risk of overweight and obesity was 2.104 (1.769-2.502, CI: 95%)-fold greater in the Fars-native as compared with the Sisstanish ethnic group and 2.297 (1.911-2.761, CI 95)-fold greater in the good economic group as compared with the poor economic group. One out of seven primary school children in northern Iran suffers from obesity and overweight, although the rates differed among the three ethnic groups examined. This study emphasizes the importance of public health training about obesity for children, especially those living in urban areas and those from high-income families.


TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis.
Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNF-related apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of the E3 ubiquitin ligase Midline (MID)-1 and subsequent downregulation of protein phosphatase 2A (PP2A), but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels. Wild-type and TRAIL-deficient (Tnfsf10-/-) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10-/- mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.


Applying evolutionary biology to address global challenges.
Two categories of evolutionary challenges result from escalating human impacts on the planet. The first arises from cancers, pathogens, and pests that evolve too quickly and the second, from the inability of many valued species to adapt quickly enough. Applied evolutionary biology provides a suite of strategies to address these global challenges that threaten human health, food security, and biodiversity. This Review highlights both progress and gaps in genetic, developmental, and environmental manipulations across the life sciences that either target the rate and direction of evolution or reduce the mismatch between organisms and human-altered environments. Increased development and application of these underused tools will be vital in meeting current and future targets for sustainable development.


Oxalic acid excretion after intravenous ascorbic acid administration.
Ascorbic acid is frequently administered intravenously by alternative health practitioners and, occasionally, by mainstream physicians. Intravenous administration can greatly increase the amount of ascorbic acid that reaches the circulation, potentially increasing the risk of oxalate crystallization in the urinary space. To investigate this possibility, we developed gas chromatography mass spectrometry methodology and sampling and storage procedures for oxalic acid analysis without interference from ascorbic acid and measured urinary oxalic acid excretion in people administered intravenous ascorbic acid in doses ranging from 0.2 to 1.5 g/kg body weight. In vitro oxidation of ascorbic acid to oxalic acid did not occur when urine samples were brought immediately to pH less than 2 and stored at -30 degrees C within 6 hours. Even very high ascorbic acid concentrations did not interfere with the analysis when oxalic acid extraction was carried out at pH 1. As measured during and over the 6 hours after ascorbic acid infusions, urinary oxalic acid excretion increased with increasing doses, reaching approximately 80 mg at a dose of approximately 100 g. We conclude that, when studied using correct procedures for sample handling, storage, and analysis, less than 0.5% of a very large intravenous dose of ascorbic acid is recovered as urinary oxalic acid in people with normal renal function.


COVID-19 and the Nordic Paradox: a call to measure the inequality reducing benefits of welfare systems in the wake of the pandemic.
The Nordic Paradox of inequality describes how the Nordic countries have puzzlingly high levels of relative health inequalities compared to other nations, despite extensive universal welfare systems and progressive tax regimes that redistribute income. However, the veracity and origins of this paradox have been contested across decades of literature, as many scholars argue it relates to measurement issues or historical coincidences. Disentangling between potential explanations is crucial to determine if widespread adoption of the Nordic model could represent a sufficient panacea for lowering health inequalities, or if new approaches must be pioneered. As newfound challenges to welfare systems continue to emerge, evidence describing the benefits of welfare systems is becoming ever more important. Preliminary evidence indicates that the COVID-19 pandemic is drastically exacerbating social inequalities in health across the world, via direct and indirect effects. We argue that the COVID-19 pandemic therefore represents a unique opportunity to measure the value of welfare systems in insulating their populations from rising social inequalities in health. However, COVID-19 has also created new measurement challenges and interrupted data collection mechanisms. Robust academic studies will therefore be needed-drawing on novel data collection methods-to measure increasing social inequalities in health in a timely fashion. In order to assure that policies implemented to reduce inequalities can be guided by accurate and updated information, policymakers, academics, and the international community must work together to ensure streamlined data collection, reporting, analysis, and evidence-based decision-making. In this way, the pandemic may offer the opportunity to finally clarify some of the mechanisms underpinning the Nordic Paradox, and potentially more firmly establish the merits of the Nordic model as a global example for reducing social inequalities in health.


Rock weathering creates oases of life in a high Arctic desert.
During primary colonization of rock substrates by plants, mineral weathering is strongly accelerated under plant roots, but little is known on how it affects soil ecosystem development before plant establishment. Here we show that rock mineral weathering mediated by chemolithoautotrophic bacteria is associated to plant community formation in sites recently released by permanent glacier ice cover in the Midtre Lovénbreen glacier moraine (78 degrees 53'N), Svalbard. Increased soil fertility fosters growth of prokaryotes and plants at the boundary between sites of intense bacterial mediated chemolithotrophic iron-sulfur oxidation and pH decrease, and the common moraine substrate where carbon and nitrogen are fixed by cyanobacteria. Microbial iron oxidizing activity determines acidity and corresponding fertility gradients, where water retention, cation exchange capacity and nutrient availability are increased. This fertilization is enabled by abundant mineral nutrients and reduced forms of iron and sulfur in pyrite minerals within a conglomerate type of moraine rock. Such an interaction between microorganisms and moraine minerals determines a peculiar, not yet described model for soil genesis and plant ecosystem formation with potential past and present analogues in other harsh environments with similar geochemical settings.


Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade.
To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab. Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (< or =3.3), low (>3.3 to < or =11), moderate (>11 to < or =26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score. At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy. With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.


A prospective study of venous thromboembolism in relation to factor V Leiden and related factors.
The aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V-related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V-deficient plasma conferred an OR of 2.58 (95% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.


Oral ondansetron is highly active as rescue antiemetic treatment for moderately emetogenic chemotherapy: results of a randomized phase II study.
In the present phase II randomized study, two different schedules of ondansetron were investigated as rescue antiemetic treatment for delayed emesis related to moderately emetogenic chemotherapy (MEC). Patients scheduled to receive a first course of MEC were randomized to ondansetron 8 mg intramuscularly (arm A) or ondansetron 16 mg orally (arm B) as rescue antiemetic treatment for delayed emesis. Efficacy and safety evaluation was performed from days 2 to 6 through the administration of a diary plus a questionnaire in which the emetic episodes and the use of the assigned rescue treatment were recorded. All patients received standard prophylaxis for delayed emesis with oral dexamethasone 8 mg daily for 4 days starting on day 2. Eighty-nine patients were enrolled into the study, of whom 44 were randomized to arm A and 45 to arm B. Twenty-two patients in each arm developed grade 1-2 delayed nausea/vomiting, all of which recurred to the rescue study treatment. Oral ondansetron resulted superior to intramuscular ondansetron in terms of complete response for nausea (77.3% vs 40.9%, respectively, p = 0.01) and vomiting (81.8% vs 31.8%, respectively, p = 0.001). Both schedules resulted to be very well tolerated, and no differences in toxicity were observed between the two arms of treatment. Furthermore, personal satisfaction about the use of the assigned rescue study medication was significantly higher in arm B. Due to its high efficacy and excellent tolerability, oral ondansetron is an important option in the management of MEC-related delayed emesis refractory to standard antiemetic prophylaxis.


Introducing the cranial approach in osteopathy and the treatment of infants and mothers.
Osteopathy is one of the most commonly known treatments for lower back pain. However, media coverage is increasingly recognizing the potential of osteopathic care for a wide range of conditions across all age groups. In this article the role of osteopathic care in the treatment of pregnant mothers, the newborn and infants is considered. The aim of this paper is to stimulate further investigation by health care professionals into the potential benefits of osteopathic care for a range of clients. I have avoided lengthy technical aspects, hoping rather to expand on the thinking behind the approach, and welcome correspondence on any aspect of this paper. Unfortunately, there is a lack of good research evidence to data to support many of the claims and assertions made by osteopathy. However, with recent accreditation of the first Osteopathic MSc, a significant accumulation of such data over the next decade is anticipated.


Xanthine oxidase inhibition improves left ventricular dysfunction in dilated cardiomyopathic hamsters.
Oxidative stress is implicated in cardiac remodeling and failure. We tested whether xanthine oxidase (XO) inhibition could decrease myocardial oxidative stress and attenuate left ventricular (LV) remodeling and dysfunction in the TO-2 hamster model of dilated cardiomyopathy. TO-2 hamsters were randomized to treatment with the XO inhibitor, allopurinol, or vehicle from 6 to 12 weeks of age. F1B hamsters served as controls. TO-2 hamsters treated with vehicle progressively developed severe LV systolic dysfunction and dilation between 6 and 12 weeks. Marked cardiac fibrosis was apparent in these hamsters at 12 weeks in comparison with F1B controls. The ratio of reduced to oxidized glutathione (GSH/GSSG) was decreased and malondialdehyde levels were increased in the hearts of vehicle-treated TO-2 hamsters. Treatment with allopurinol from 6 to 12 weeks attenuated LV dysfunction and dilation as well as myocardial fibrosis and the upregulation of a fetal-type cardiac gene. Allopurinol also inhibited both the decrease in GSH/GSSG ratio and the increase in malondialdehyde levels in the heart. These results indicate that chronic XO inhibition with allopurinol attenuates LV remodeling and dysfunction as well as myocardial oxidative stress in this model of heart failure. Allopurinol may prove beneficial for the treatment of heart failure.


Multiple regions within 8q24 independently affect risk for prostate cancer.
After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.


Sequence Effect on the Activity of DNAzyme with Covalently Attached Hemin and Their Potential Bioanalytical Application.
In this work we investigated the effect of a DNA oligonucleotide sequence on the activity of a DNAzyme with covalently attached hemin. For this purpose, we synthesized seven DNA-hemin conjugates. All DNA-hemin conjugates as well as DNA/hemin complexes were characterized using circular dichroism, determination of melting temperatures and pKa of hemin. We observed that hemin conjugation in most cases led to the formation of parallel G-quadruplexes in the presence of potassium and increased thermal stability of all studied systems. Although the activity of DNA-hemin conjugates depended on the sequence used, the highest activity was observed for the DNA-hemin conjugate based on a human telomeric sequence. We used this DNAzyme for development of "sandwich" assay for detection of DNA sequence. For this assay, we used electric chip which could conduct electricity after silver deposition catalyzed by DNAzyme. This method was proved to be selective towards DNA oligonucleotides with mismatches and could be used for the detection of the target. To prove the versatility of our DNAzyme probe we also performed experiments with streptavidin-coated microplates. Our research proved that DNAzyme with covalently attached hemin can be used successfully in the development of heterogeneous assays.


Activation of src-family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP-1 formation.
The role of src-family tyrosine kinases in LPS-induced DC maturation has not been fully addressed. We show that LPS induces activation of c-Src and Lyn in human DC. Inhibition of these kinasesby PP1 uncoupled LPS-induced cytokine production from the up-regulation of costimulatory molecules, resulting in DC still capable of stimulating T cell proliferation but much less efficient in inducing Th1 differentiation. This is the first example of a pharmacological inhibitor able to modulate the capacity of DC to induce a particular type of immune response. Inhibition of src-family kinases impaired phosphorylation and accumulation of c-Jun, leading to reduced formation of AP-1 complexes upon LPS stimulation. Thus, src-kinases control cytokine production in LPS-induced DC maturation through a timely formation of AP-1.


Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease.
Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid beta-peptide (A beta(42)) is considered central to Alzheimer's disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid A beta(42) deposits have to mature in the presence of A beta(40) into fibrillar amyloid plaques to cause neurodegeneration. Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T714I) directly involving gamma-secretase cleavages of APP. The mutation had the most drastic effect on A beta(42)/A beta(40) ratio in vitro of approximately 11-fold, simultaneously increasing A beta(42) and decreasing A beta(40) secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry. This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated A beta(42) in complete absence of A beta(40). These data indicate that N-truncated A beta(42) as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length A beta(42 )by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated A beta(42).


[TECHNICAL CHARACTERISTICS OF SPECIFIC FOOD PRODUCTS FOR PATIENTS WITH DYSPHAGIA].
Dysphagia is a common problem among elderly and also in some pathological conditions such as neurodegenerative diseases or tumors. Making an adequate diet for this disease may present some difficulties. The aim of this document is to make a detailed technical report about the characteristics of the products that are available in Spain to hydrate and to feed patients with dysphagia. Food and pharmaceutical industries have developed a range of products designed to ensure homogeneous texture and a suitable viscosity to guaranty an adequate hydration. An adequate nutritional status is also achieved with these products for patients with dysphagia, without compromising their safety. The ingredients used to achieve a suitable viscosity are different types of starches, gums and other substances. It has been developed thickeners and gellified water for hydratation, and in case of food there are purees (dehydrated, lyophilized, pasteurized and sterilized), fruit purees, fruit pudding, and dehydrated cereal. Patients who do not meet their nutritional needs have also oral supplements with different viscosities. The industry offers extensive information about the technical characteristics of the products, except for viscosity. It would be recommended for the manufacturers to include in detail the technical specifications of the used methodology and the measurement and the results obtained in the analysis of viscosity that can be consulted by professionals of the Clinical Nutrition and Dietetics Units who treat these patients.


The effect of an educational intervention to improve tuberculosis infection control among nurses in Ibadan, south-west Nigeria: a quasi-experimental study.
Nurses are particularly vulnerable to acquiring tuberculosis (TB) because they are in the frontline of patient care. There is inadequate implementation of cost-effective TB infection control (TBIC) measures in most health facilities. Training has been shown to be effective in improving the knowledge and work practices of nurses. This study sought to utilize a multi-method educational intervention to improve the TBIC-related knowledge and practices of nurses in two secondary health facilities in Ibadan, South-West Nigeria. This quasi-experimental study involved 200 nurses (100 each in the intervention and comparison groups). Baseline data were collected in May 2014. This was followed by training of the nurses in the intervention group. After 6 months, the second wave of data was collected and the nurses in the comparison group also received the training thereafter. The final wave of data collection took place 12 months after the commencement of the study. The mean scores of the nurses were determined and comparison was made between both groups at different time points using independent t-test. The nurses in both groups were statistically comparable in their socio-demographic characteristics, and baseline mean knowledge (68.6 and 67.7%) and practice scores (79.1 and 80.6%) respectively. After the intervention group received the intervention, there were appreciable improvements in the scores at 6 months (knowledge - 85.9%, practice - 98.5%), which were significantly different from those of the comparison group (knowledge - 69.5%, practice - 78.8%). A large effect size was demonstrated in the improvement in knowledge score in the intervention group at 6 months compared with the other group (Cohen's d = 1.7). Similarly, there were improvements in the scores of the nurses in the comparison group at 12 months after the group had also received the intervention (knowledge - 88.2%, practice - 93.5%). At this point, the mean scores between both groups were no longer significantly different. The improvement in post-intervention scores implies that the educational intervention adopted for this study was effective in improving TBIC among the nurses. It also underscores the importance of continuous training/retraining of nurses and other healthcare workers in improving and sustaining TBIC at health facilities.


Expression of collagen types I and II on articular cartilage in a rat knee contracture model.
The purpose of our study was to clarify the expression patterns of collagen types I and II on articular cartilage after immobilization in a rat knee contracture model in 3 specific areas (noncontact area, transitional area, contact area). The unilateral knee joints of adult male rats were rigidly immobilized at 150 degrees of flexion using screws and a rigid plastic plate. Sham-operated animals had holes drilled in the femur and the tibia and screws inserted but were not plated. The expression patterns of collagen types I and II in each area were evaluated by in situ hybridization (ISH), immunohistochemistry (IHC), and quantitative real-time polymerase chain reaction (qPCR). The expression of collagen type II in the noncontact area was decreased by ISH but appeared unchanged when examined by IHC. In the transitional and contact areas, the expression of collagen type II was initially shown to have decreased and then increased at the hypertrophic chondrocytes by ISH but appeared decreased by IHC. Quantitative PCR revealed the decreased expression of type II collagen in the contact area. Immunostaining of collagen type I was increased at the noncontact area and transitional areas. Alterations of collagen types I and II expression may also affect the degeneration of articular cartilage after immobilization and the changes were different in the three areas.


Intracranial pressure following aneurysmal subarachnoid hemorrhage: monitoring practices and outcome data.
Elevated intracranial pressure (ICP) is an important consequence of aneurysmal subarachnoid hemorrhage (SAH) that often results in decreased cerebral perfusion and secondary clinical decline. No definitive guidelines exist regarding methods and techniques for ICP management following aneurysm rupture. The authors describe monitoring practices and outcome data in 621 patients with aneurysmal SAH admitted to their neurological intensive care unit during an 8-year period (1996-2003). A fiberoptic catheter tip probe or external ventricular drain (EVD) was used to record ICP values. The percentage of monitored patients varied, as expected, according to admission Hunt and Hess grade (p < 0.0001). Intracranial pressure monitoring devices were used in 27 (10%) of 264 Grade I to II patients, 72 (38%) of 189 Grade III patients, and 134 (80%) of 168 Grade IV to V patients. There was a strong propensity to favor transduced ventricular drains over parenchymal fiberoptic bolts, with the former used in 221 (95%) of 233 cases. This tendency was particularly strong in the poor-grade cohort, in which EVDs were placed in 99% of monitored individuals. The rates of cerebrospinal fluid infection in patients in whom ICP probes (0%) and ventricular drains (12%) were placed accorded with those in the literature. Following aneurysmal SAH, ICP monitoring prevalence and techniques differ with respect to admission Hunt and Hess grade and are associated with the patient's functional status at discharge.


Structural and functional changes across the visual cortex of a patient with visual form agnosia.
Loss of shape recognition in visual-form agnosia occurs without equivalent losses in the use of vision to guide actions, providing support for the hypothesis of two visual systems (for "perception" and "action"). The human individual DF received a toxic exposure to carbon monoxide some years ago, which resulted in a persisting visual-form agnosia that has been extensively characterized at the behavioral level. We conducted a detailed high-resolution MRI study of DF's cortex, combining structural and functional measurements. We present the first accurate quantification of the changes in thickness across DF's occipital cortex, finding the most substantial loss in the lateral occipital cortex (LOC). There are reduced white matter connections between LOC and other areas. Functional measures show pockets of activity that survive within structurally damaged areas. The topographic mapping of visual areas showed that ordered retinotopic maps were evident for DF in the ventral portions of visual cortical areas V1, V2, V3, and hV4. Although V1 shows evidence of topographic order in its dorsal portion, such maps could not be found in the dorsal parts of V2 and V3. We conclude that it is not possible to understand fully the deficits in object perception in visual-form agnosia without the exploitation of both structural and functional measurements. Our results also highlight for DF the cortical routes through which visual information is able to pass to support her well-documented abilities to use visual information to guide actions.


Meditation, mindfulness and cognitive flexibility.
This study investigated the link between meditation, self-reported mindfulness and cognitive flexibility as well as other attentional functions. It compared a group of meditators experienced in mindfulness meditation with a meditation-naïve control group on measures of Stroop interference and the "d2-concentration and endurance test". Overall the results suggest that attentional performance and cognitive flexibility are positively related to meditation practice and levels of mindfulness. Meditators performed significantly better than non-meditators on all measures of attention. Furthermore, self-reported mindfulness was higher in meditators than non-meditators and correlations with all attention measures were of moderate to high strength. This pattern of results suggests that mindfulness is intimately linked to improvements of attentional functions and cognitive flexibility. The relevance of these findings for mental balance and well-being are discussed.


Impact of Digital Mammography on Cancer Detection and Recall Rates: 11.3 Million Screening Episodes in the English National Health Service Breast Cancer Screening Program.
Purpose To report the impact of changing from screen-film mammography to digital mammography (DM) in a large organized national screening program. Materials and Methods A retrospective analysis of prospectively collected annual screening data from 2009-2010 to 2015-2016 for the 80 facilities of the English National Health Service Breast Cancer Screening Program, together with estimates of DM usage for three time periods, enabled the effect of DM to be measured in a study of 11.3 million screening episodes in women aged 45-70 years (mean age, 59 years). Regression models were used to estimate percentage and absolute change in detection rates due to DM. Results The overall cancer detection rate was 14% greater with DM (P < .001). There were higher rates of detection of grade 1 and 2 invasive cancers (both ductal and lobular), but no change in the detection of grade 3 invasive cancers. The recall rate was almost unchanged by the introduction of DM. At prevalent (first) screening episodes for women aged 45-52 years, DM increased the overall detection rate by 19% (P < .001) and for incident screening episodes in women aged 53-70 years by 13% (P < .001). Conclusion The overall cancer detection rate was 14% greater with digital mammography with no change in recall rates and without confounding by changes in other factors. There was a substantially higher detection of grade 1 and grade 2 invasive cancers, including both ductal and lobular cancers, but no change in the detection of grade 3 invasive cancers. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by C.I. Lee and J.M. Lee in this issue.


Abnormal insulin sensitivity persists up to three years in pediatric patients post-burn.
The acute hypermetabolic response post-burn is associated with insulin resistance and hyperglycemia, significantly contributing to adverse outcome of these patients. The aim of the study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree of insulin resistance in severely burned children for up to 3 yr after the burn injury. A total of 194 severely burned pediatric patients, admitted to our institute between 2002 and 2007, were enrolled in this prospective study and compared to a cohort of 95 nonburned, noninjured children. Urinary cortisol, epinephrine, and norepinephrine, serum cytokines, and resting energy requirements were determined at admission and 1, 2, 6, 9, 12, 18, 24, and 36 months post-burn. A 75-g oral glucose tolerance test was performed at similar time points; serum glucose, insulin, and C-peptide were measured; and insulin sensitivity indices, such as ISI Matsuda, homeostasis model assessment, quantitative insulin sensitivity check index, and ISI Cederholm, were calculated. Statistical analysis was performed by ANOVA with Bonferroni correction with significance accepted at P < 0.05. Urinary cortisol and catecholamines, serum IL-7, IL-10, IL-12, macrophage inflammatory protein-1b, monocyte chemoattractant protein-1, and resting energy requirements were significantly increased for up to 36 months post-burn (P < 0.05). Glucose values were significantly augmented for 6 months post-burn (P < 0.05), associated with significant increases in serum C-peptide and insulin that remained significantly increased for 36 months compared to nonburned children (P < 0.05). Insulin sensitivity indices, ISI Matsuda, ISI quantitative insulin sensitivity check index, and homeostasis model assessment were abnormal throughout the whole study period, indicating peripheral and whole body insulin resistance. The insulinogenic index displayed physiological values, indicating normal pancreatic beta-cell function. A severe burn is associated with stress-induced insulin resistance that persists not only during the acute phase but also for up to 3 yr post-burn.


A water-processable cellulose-based resist for advanced nanofabrication.
The ideal nanofabrication technique is one that allows the mass production of high resolution submicrometric features in a cost efficient and environmentally friendly fashion. A great step towards achieving this goal has been the development of nanoimprinting lithography, a procedure with tenths of nanometres resolution while being compatible with roll-to-roll manufacturing. However, an ecofriendly resist that can be efficiently combined with this process is still missing. In this work, we demonstrate the use of hydroxypropyl cellulose (HPC) as a biocompatible, biodegradable, and water processable resist for temperature assisted nanoimprint lithography (tNIL) by fabricating different photonic architectures. The cellulose derivative is easily patterned with submicrometric features with aspect ratios greater than 1 using an elastomeric stamp and a hot plate. Silicon photonic crystals and metal nanoparticle arrays are fabricated combining cellulose with traditional nanofrabrication processes such as spincasting, reactive ion etching and metal lift off. Furthermore, advanced nanofabrication possibilities are within reach by combining the HPC with traditional resists. In particular, poly(methyl methacrylate) and HPC stacks are easily produced by liquid phase processing, where one of the two materials can be selectively removed by developing in orthogonal solvents. This capability becomes even more interesting by including nanoimprinted layers in the stack, leading to the encapsulation of arrays of air features in the resist.


Rapid surface oxidation as a source of surface degradation factor for Bi₂Se₃.
Bismuth selenide (Bi(2)Se(3)) is a topological insulator with metallic surface states (SS) residing in a large bulk bandgap. In experiments, synthesized Bi(2)Se(3) is often heavily n-type doped due to selenium vacancies. Furthermore, it is discovered from experiments on bulk single crystals that Bi(2)Se(3) gets additional n-type doping after exposure to the atmosphere, thereby reducing the relative contribution of SS in total conductivity. In this article, transport measurements on Bi(2)Se(3) nanoribbons provide additional evidence of such environmental doping process. Systematic surface composition analyses by X-ray photoelectron spectroscopy reveal fast formation and continuous growth of native oxide on Bi(2)Se(3) under ambient conditions. In addition to n-type doping at the surface, such surface oxidation is likely the material origin of the degradation of topological SS. Appropriate surface passivation or encapsulation may be required to probe topological SS of Bi(2)Se(3) by transport measurements.


Structural, functional, and perceptual differences in Heschl's gyrus and musical instrument preference.
The musical pitch of harmonic complex sounds, such as instrumental sounds, is perceived primarily by decoding either the fundamental pitch (keynote) or spectral aspects of the stimuli, for example, single harmonics. We divided 334 professional musicians, including symphony orchestra musicians, 75 amateur musicians, and 54 nonmusicians, into either fundamental pitch listeners or spectral pitch listeners. We observed a strong correlation between pitch perception preference and asymmetry of brain structure and function in the pitch-sensitive lateral areas of Heschl's gyrus (HG), irrespective of musical ability. In particular, fundamental pitch listeners exhibited both larger gray matter volume measured using magnetic resonance imaging (MRI) and enhanced P50m activity measured using magnetoencephalography (MEG) in the left lateral HG, which is sensitive to rapid temporal processing. Their chosen instruments were percussive or high-pitched instruments that produce short, sharp, or impulsive tones (e.g., drums, guitar, piano, trumpet, or flute). By contrast, spectral pitch listeners exhibited a dominant right lateral HG, which is known to be sensitive to slower temporal and spectral processing. Their chosen instruments were lower-pitched melodic instruments that produce rather sustained tones with characteristic changes in timbre (e.g., bassoon, saxophone, french horn, violoncello, or organ). Singers also belonged to the spectral pitch listeners. Furthermore, the absolute size of the neural HG substrate depended strongly on musical ability. Overall, it is likely that both magnitude and asymmetry of lateral HG, and the related perceptual mode, may have an impact on preference for particular musical instruments and on musical performance.


Comparison of brief group therapies for depressed cancer patients receiving radiation treatment.
Although many studies have documented patterns of emotional distress in persons undergoing radiation treatment for cancer, there have been few controlled evaluations of counseling or psychotherapy outcomes with these persons. In this research, the effects of cognitive-behavioral and socially supportive group therapy were evaluated. A total of 72 depressed cancer patients were randomly assigned to one of three conditions--cognitive-behavioral treatment, social support, or a no-treatment control condition. Before and after intervention and at 6-month followup, study participants were individually assessed by using measures of symptom distress. Relative to the comparison group, both the cognitive-behavioral and social support therapies resulted in less depression, hostility, and somatization. The social support intervention also resulted in fewer psychiatric symptoms and reduced maladaptive interpersonal sensitivity and anxiety. It was concluded that both group therapies can reduce symptoms of distress for depressed persons undergoing radiation treatment for cancer. Both forms of therapy resulted in improvements in psychosocial function (compared with no treatment at all), but social support groups demonstrated more changes that were evident at 6-month followup. Further research is needed to evaluate the differential effectiveness of mental health services provided to cancer patients undergoing radiation.


Characterization of halotolerant Bicosoecida and Placididea (Stramenopila) that are distinct from marine forms, and the phylogenetic pattern of salinity preference in heterotrophic stramenopiles.
Recent culture-based studies demonstrate the distinctiveness of the microbial eukaryote biota of very hypersaline environments. In contrast, microscopy-based faunistic studies suggest that the biota of habitats of more moderate hypersalinity (60-150 per thousand) overlaps substantially with that of marine environments, but this has barely been studied with modern techniques. To investigate the diversity and salinity tolerance range of these organisms, eight cultures of heterotrophic stramenopiles were established from (or from nearby) moderately hypersaline locations. These isolates represent five independent groups; Groups A, B and C are bicosoecids; Groups D and E belong to Placididea. One isolate (Group A) is a strain of the widespread marine species Cafeteria roenbergensis, and cannot grow above 100 per thousand salinity. The other isolates - Groups B-E - can all grow at 150-175 per thousand salinities and are probably moderate halophiles. Groups B-E all represent previously unsequenced species or even genera, although Group B is the sister group of the borderline extreme halophile Halocafeteria. The high level of novelty en countered suggests that moderately hypersaline environments may harbour a heterotrophic stramenopile biota distinct from that of marine environments. Interestingly, our new isolates are all most closely related to marine or halophilic forms, and our phylogenies show large clades defined by saline/non-saline habitats within bicosoecids, placidomonads and related lineages. In particular, most freshwater/soil bicosoecids form one well-supported clade. The sole major exception is Bicosoeca, which is intermixed with marine environmental sequences originally referred to as 'MAST-13', which are from brackish water, not typical seawater. It seems that the freshwater/marine barrier has been crossed very few times in the evolutionary history of these heterotrophic stramenopile flagellates.


Direct visualization of Propionibacterium acnes in prostate tissue by multicolor fluorescent in situ hybridization assay.
Prostate tissues from patients with prostate cancer and benign prostatic hyperplasia (BPH) frequently contain histological inflammation, and a proportion of these patients show evidence of Propionibacterium acnes infection in the prostate gland. We developed a multicolor fluorescent in situ hybridization (FISH) assay targeting P. acnes 23S rRNA along with a 14-kb region of the P. acnes genome. This assay was used to analyze prostate tissues from patients with prostate cancer and BPH. P. acnes infection of the prostate gland was demonstrated in prostatic tissue in 5 of 10 randomly selected prostate cancer patients. FISH analysis and confocal laser microscopy imaging revealed intracellular localization and stromal biofilm-like aggregates as common forms of P. acnes infection in prostate tissues from both prostate cancer and BPH patients. A sequential analysis of prostate tissue from individual patients suggested that P. acnes can persist for up to 6 years in the prostate gland. These results indicate that P. acnes can establish a persistent infection in the prostate gland. Further study is needed to clarify the link between this bacterium and prostatic inflammation which may contribute to the development of BPH and prostate cancer.


A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease.
Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.


A multi-center study of ACE and the risk of late-onset Alzheimer's disease.
A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.


Middle cerebral artery flow velocity increases more in patients with delayed intraparenchymal hemorrhage after Pipeline.
Pipeline Embolization Devices (PED) are commonly used for endovascular treatment of cerebral aneurysms but can be associated with delayed ipsilateral intraparenchymal hemorrhage (DIPH). The role that altered intracranial hemodynamics may play in the pathophysiology of DIPH is poorly understood. We assess middle cerebral artery (MCA) flow velocity changes after PED deployment. Patients with aneurysms located proximal to the internal carotid artery terminus treated with PED at our institution between 2015 and 2016 were retrospectively reviewed. Patients were included if MCA flow velocities were measured using transcranial Doppler. Bilateral MCA flow velocities, ratio of ipsilateral to contralateral MCA flow velocity, and bilateral MCA pulsatility index before and after PED deployment were assessed. 10 patients of mean age 52 years were included. Two patients had DIPH within 48 hours after PED deployment. We observed that these two patients had a higher increase in ipsilateral MCA mean flow velocity after treatment compared with patients without DIPH (39.5% vs 5.5%). Additionally, before PED deployment, patients with DIPH had a higher ipsilateral MCA pulsatility index (1.55 vs 0.98) and a higher ratio of ipsilateral to contralateral MCA mean flow velocity (1.35 vs 1.04). After PED, ipsilateral MCA mean flow velocity increases more in patients with DIPH. These flow velocity changes suggest the possible role of altered distal intracranial hemodynamics in DIPH after PED treatment of cerebral aneurysms. Further data are required to confirm this observation.


Preconcentration and Determination of Trace Vanadium(V) in Beverages by Combination of Ultrasound Assisted-cloud Point Extraction with Spectrophotometry.
A novel ultrasound assisted-cloud point extraction method was developed for preconcentration and determination of V(V) in beverage samples. After complexation by pyrogallol in presence of safranin T at pH 6.0, V(V) ions as ternary complex are extracted into the micellar phase of Triton X-114. The complex was monitored at 533 nm by spectrophotometry. The matrix effect on the recovery of V(V) from the spiked samples at 50 μg L-1 was evaluated. In optimized conditions, the limits of detection and quantification of the method, respectively, was 0.58 and 1.93 μg L-1 in linear range of 2-500 μg L-1 with sensitivity enhancement and preconcentration factors of 47.7 and 40 for preconcentration from 15 mL of sample solution. The recoveries from spiked samples were in range of 93.8-103.2% with a relative standard deviation ranging from 2.6% to 4.1% (25, 100 and 250 μg L-1, n: 5). The accuracy was verified by analysis of two certified samples, and the results were in a good agreement with the certified values. The intra-day and inter-day precision were tested by reproducibility (as 3.3-3.4%) and repeatability (as 3.4-4.1%) analysis for five replicate measurements of V(V) in quality control samples spiked with 5, 10 and 15 μg L-1. Trace V(V) contents of the selected beverage samples by the developed method were successfully determined.


Large Circular Plasmids from Groundwater Plasmidomes Span Multiple Incompatibility Groups and Are Enriched in Multimetal Resistance Genes.
Naturally occurring plasmids constitute a major category of mobile genetic elements responsible for harboring and transferring genes important in survival and fitness. A targeted evaluation of plasmidomes can reveal unique adaptations required by microbial communities. We developed a model system to optimize plasmid DNA isolation procedures targeted to groundwater samples which are typically characterized by low cell density (and likely variations in the plasmid size and copy numbers). The optimized method resulted in successful identification of several hundred circular plasmids, including some large plasmids (11 plasmids more than 50 kb in size, with the largest being 1.7 Mb in size). Several interesting observations were made from the analysis of plasmid DNA isolated in this study. The plasmid pool (plasmidome) was more conserved than the corresponding microbiome distribution (16S rRNA based). The circular plasmids were diverse as represented by the presence of seven plasmid incompatibility groups. The genes carried on these groundwater plasmids were highly enriched in metal resistance. Results from this study confirmed that traits such as metal, antibiotic, and phage resistance along with toxin-antitoxin systems are encoded on abundant circular plasmids, all of which could confer novel and advantageous traits to their hosts. This study confirms the ecological role of the plasmidome in maintaining the latent capacity of a microbiome, enabling rapid adaptation to environmental stresses.IMPORTANCE Plasmidomes have been typically studied in environments abundant in bacteria, and this is the first study to explore plasmids from an environment characterized by low cell density. We specifically target groundwater, a significant source of water for human/agriculture use. We used samples from a well-studied site and identified hundreds of circular plasmids, including one of the largest sizes reported in plasmidome studies. The striking similarity of the plasmid-borne ORFs in terms of taxonomical and functional classifications across several samples suggests a conserved plasmid pool, in contrast to the observed variability in the 16S rRNA-based microbiome distribution. Additionally, the stress response to environmental factors has stronger conservation via plasmid-borne genes as marked by abundance of metal resistance genes. Last, identification of novel and diverse plasmids enriches the existing plasmid database(s) and serves as a paradigm to increase the repertoire of biological parts that are available for modifying novel environmental strains.