The roles of DNA polymerase ζ and the Y family DNA polymerases in promoting or preventing genome instability.
Cancer cells display numerous abnormal characteristics which are initiated and maintained by elevated mutation rates and genome instability. Chromosomal DNA is continuously surveyed for the presence of damage or blocked replication forks by the DNA Damage Response (DDR) network. The DDR is complex and includes activation of cell cycle checkpoints, DNA repair, gene transcription, and induction of apoptosis. Duplicating a damaged genome is associated with elevated risks to fork collapse and genome instability. Therefore, the DNA damage tolerance (DDT) pathway is also employed to enhance survival and involves the recruitment of translesion DNA synthesis (TLS) polymerases to sites of replication fork blockade or single stranded DNA gaps left after the completion of replication in order to restore DNA to its double stranded form before mitosis. TLS polymerases are specialized for inserting nucleotides opposite DNA adducts, abasic sites, or DNA crosslinks. By definition, the DDT pathway is not involved in the actual repair of damaged DNA, but provides a mechanism to tolerate DNA lesions during replication thereby increasing survival and lessening the chance for genome instability. However this may be associated with increased mutagenesis. In this review, we will describe the specialized functions of Y family polymerases (Rev1, Polη, Polι and Polκ) and DNA polymerase ζ in lesion bypass, mutagenesis, and prevention of genome instability, the latter due to newly appreciated roles in DNA repair. The recently described role of the Fanconi anemia pathway in regulating Rev1 and Polζ-dependent TLS is also discussed in terms of their involvement in TLS, interstrand crosslink repair, and homologous recombination.


Niche partitioning among three snail-eating snakes revealed by dentition asymmetry and prey specialisation.
The level of dentition asymmetry in snail-eating snakes may reflect their prey choice and feeding efficiency on asymmetric land snails. The three species of Pareas snakes (Squamata: Pareidae) in Taiwan, which form partially sympatric distribution on the island, provide a potential case to test the hypothesis of niche partitioning and character displacement with regard to dentition asymmetry and specialisation in feeding behaviour. In this study, behavioural experiments confirmed that P. formosensis feeds exclusively on slugs, whereas P. atayal and P. komaii consumed both. However, P. atayal more efficiently preys on land snails than P. komaii, exhibiting a shorter handling time and fewer mandibular retractions. Micro-CT and ancestral character reconstruction demonstrated the lowest asymmetry in P. formosensis (the slug specialist), the highest dentition asymmetry in P. atayal (the land snail specialist) and flexibility in P. komaii (the niche switcher): increased dentition asymmetry when sympatrically distributed with the slug eater (character displacement), and decreased asymmetry when living alone (ecological niche release). Ecological niche modelling showed that the distribution of P. formosensis is associated with the presence of slugs, while that of P. atayal could be explained by the land snails. Combining the results from morphology, phylogeny, behavioural experiments and ecological niche modelling, we showed that competition in the sympatric region might have facilitated character displacement among congeners, while the absence of competition in allopatric region has led to ecological niche release.


Omalizumab for atopic dermatitis: case series and a systematic review of the literature.
Omalizumab is a recombinant humanized monoclonal antibody targeting the high-affinity Fc receptor of IgE, registered for the treatment of chronic spontaneous urticaria and severe allergic asthma. We present a case series of nine patients with atopic dermatitis (AD) treated off-label with omalizumab and a systematic review of the existing literature. Patients were selected consecutively from a tertiary dermatological referral center during a 5-year period. All patients were treated with omalizumab at a starting dose of 300 mg subcutaneously every 4 weeks. Systematic literature searches were performed in PubMed, Web of Science, EMBASE, and ClinicalTrials.gov to identify any study (case reports, case series, and controlled trials) evaluating the effect of treatment with omalizumab in AD. Based on physicians' assessment, 50% of our patients had a good or excellent response to treatment with omalizumab; a further 12.5% had a moderate response, while 37.5% experienced no response or deterioration of symptoms during treatment. Treatment was generally well tolerated. Twenty-six studies with a median of four patients each (range 1-21), comprising 174 patients, were included in the systematic review. Summed over all studies, a total of 129 patients (74.1%) experienced a beneficial effect of treatment ranging from little to complete response. Omalizumab appears to be a safe and well tolerated, however expensive, treatment with some clinical benefit in patients with severe recalcitrant AD. Recommendation for use in clinical practice awaits evidence from larger randomized controlled trials.


Use of digital dosemeters for supporting staff radiation safety in paediatric interventional radiology suites.
Modern-day interventional radiology (IR) procedures impart a wide range of occupational radiation doses to team members. Unlike thermoluminescent badges, digital dosemeters provide real-time dose readings, making them ideal for identifying different components during IR procedures, which influence staff radiation safety. This study focused solely on paediatric IR (PIR) cases. Digital dosemeters measured the impact of imaging modality, shielding, patient and operator specific factors, on the radiation dose received during various simulated and real live PIR procedures. They recorded potential dose reductions of 10- to 100-fold to each staff member with appropriate use of shielding, choice of imaging method, staff position in the room and complex interplay of other factors. The digital dosemeters were well tolerated by staff. Results highlight some unique radiation safety challenges in PIR that arise from dose increases with magnification use and close proximity of staff to the X-ray beam.


MicroRNA expression profiling of peripheral blood mononuclear cells associated with syphilis.
Treponema pallidum (T. pallidum) infection evokes significant immune responses, resulting in tissue damage. The immune mechanism underlying T. pallidum infection is still unclear, although microRNAs (miRNAs) have been shown to influence immune cell function and, consequently, the generation of antibody responses during other microbe infections. However, these mechanisms are unknown for T. pallidum. In this study, we performed a comprehensive analysis of differentially expressed miRNAs in healthy individuals, untreated patients with syphilis, patients in the serofast state, and serologically cured patients. miRNAs were profiled from the peripheral blood of patients obtained at the time of serological diagnosis. Then, both the target sequence analysis of these different miRNAs and pathway analysis were performed to identify important immune and cell signaling pathways. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed for microRNA analysis. A total of 74 differentially regulated miRNAs were identified. Following RT-qPCR confirmation, three miRNAs (hsa-miR-195-5p, hsa-miR-223-3p, hsa-miR-589-3p) showed significant differences in the serofast and serologically cured states (P < 0.05). One miRNA (hsa-miR-195-5p) showed significant differences between untreated patients and healthy individuals. This is the first study of miRNA expression differences in peripheral blood mononuclear cells (PBMCs) in different stages of T. pallium infection. Our study suggests that the combination of three miRNAs has great potential to serve as a non-invasive biomarker of T. pallium infections, which will facilitate better diagnosis and treatment of T. pallium infections.


Four treatment failures of pharyngeal gonorrhoea with ceftriaxone (500 mg) or cefotaxime (500 mg), Sweden, 2013 and 2014.
We describe four cases in Sweden of verified treatment failures of pharyngeal gonorrhoea with ceftriaxone (500 mg; n=3) or cefotaxime (500 mg; n=1) monotherapy. All the ceftriaxone treatment failures were caused by the internationally spreading multidrug-resistant gonococcal NG-MAST genogroup 1407 clone. Increased awareness of treatment failures is crucial particularly when antimicrobial monotherapy is used. Frequent test of cure and appropriate verification/falsification of suspected treatment failures, as well as implementation of recommended dual antimicrobial therapy are imperative.


Effectiveness of workplace interventions in the prevention of upper extremity musculoskeletal disorders and symptoms: an update of the evidence.
The burden of disabling musculoskeletal pain and injuries (musculoskeletal disorders, MSDs) arising from work-related causes in many workplaces remains substantial. There is little consensus on the most appropriate interventions for MSDs. Our objective was to update a systematic review of workplace-based interventions for preventing and managing upper extremity MSD (UEMSD). We followed a systematic review process developed by the Institute for Work & Health and an adapted best evidence synthesis. 6 electronic databases were searched (January 2008 until April 2013 inclusive) yielding 9909 non-duplicate references. 26 high-quality and medium-quality studies relevant to our research question were combined with 35 from the original review to synthesise the evidence on 30 different intervention categories. There was strong evidence for one intervention category, resistance training, leading to the recommendation: Implementing a workplace-based resistance training exercise programme can help prevent and manage UEMSD and symptoms. The synthesis also revealed moderate evidence for stretching programmes, mouse use feedback and forearm supports in preventing UEMSD or symptoms. There was also moderate evidence for no benefit for EMG biofeedback, job stress management training, and office workstation adjustment for UEMSD and symptoms. Messages are proposed for both these and other intervention categories.


Structural shifts of gut microbiota as surrogate endpoints for monitoring host health changes induced by carcinogen exposure.
This study monitored structural shifts of gut microbiota of rats developing precancerous mucosal lesions induced by carcinogen 1,2-dimethyl hydrazine (DMH) treatment using PCR-denaturing gradient gel electrophoresis (DGGE) and 454 pyrosequencing on the 16S rRNA gene V3 region. Partial least square discriminant analysis of DGGE fingerprints showed that the gut microbiota structure of treated animals was similar to that of the controls 1 and 3 weeks after DMH treatments, but significantly different 7 weeks after DMH treatments, when a large number of aberrant crypt foci (ACF) developed in their colons. Martens' uncertainty test, followed by anova test (P<0.05) identified Ruminococcus-like and Allobaculum-like bacteria as key variables for discrimination of DMH-treated rats from controls. Real-time PCR confirmed the significant increase of the Ruminococcus obeum and the Allobaculum-like bacteria in DMH-treated rats. UniFrac analysis based on V3 pyrosequencing further validated that the gut microbiota structures of treated and control animals were similar at an early stage, but segregated after ACF formation. Thirteen operational taxonomic units including Ruminococcus-like and Allobaculum-like bacteria were identified as key variables for the discrimination of DMH-treated rats from controls. Dynamic analysis of gut microbiota may become a noninvasive strategy for monitoring host health changes induced by carcinogen exposure.


"It ain't what you do, it's the way that you do it": does obesity affect perceptual motor control ability of adults on the speed and accuracy of a discrete aiming task?
The ability to control speed and accuracy of goal directed aiming tasks underpins many activities of daily living. Recent evidence has begun to suggest that obesity can affect the control of movement. This study evaluated perceptual motor control of 183 normal weight, overweight, and obese participants using a discrete Fitts' task on a digital tablet. In addition, we manipulated tablet orientation to determine whether tablet orientation influences task difficulty with the view to increase the task's constraints. Our study found that the traditional relationship between target distance and target width hold true for each of the three weight groups in both tablet orientations. Interestingly, no significant differences were found for movement time between the groups, while movement kinematics differed between weight groups. Obese participants demonstrated significantly higher peak acceleration values in the horizontal tablet orientation when compared to their normal weight and overweight counterparts. Further to this, obese participants made significantly more errors than normal weight and overweight groups. These findings suggest that obese individuals have altered control strategies compared to their normal weight peers.


Adaptation of Surface-Associated Bacteria to the Open Ocean: A Genomically Distinct Subpopulation of Phaeobacter gallaeciensis Colonizes Pacific Mesozooplankton.
The marine Roseobacter group encompasses numerous species which occupy a large variety of ecological niches. However, members of the genus Phaeobacter are specifically adapted to a surface-associated lifestyle and have so far been found nearly exclusively in disjunct, man-made environments including shellfish and fish aquacultures, as well as harbors. Therefore, the possible natural habitats, dispersal and evolution of Phaeobacter spp. have largely remained obscure. Applying a high-throughput cultivation strategy along a longitudinal Pacific transect, the present study revealed for the first time a widespread natural occurrence of Phaeobacter in the marine pelagial. These bacteria were found to be specifically associated to mesoplankton where they constitute a small but detectable proportion of the bacterial community. The 16S rRNA gene sequences of 18 isolated strains were identical to that of Phaeobacter gallaeciensis DSM26640T but sequences of internal transcribed spacer and selected genomes revealed that the strains form a distinct clade within P. gallaeciensis. The genomes of the Pacific and the aquaculture strains were highly conserved and had a fraction of the core genome of 89.6%, 80 synteny breakpoints, and differed 2.2% in their nucleotide sequences. Diversification likely occurred through neutral mutations. However, the Pacific strains exclusively contained two active Type I restriction modification systems which is commensurate with a reduced acquisition of mobile elements in the Pacific clade. The Pacific clade of P. gallaeciensis also acquired a second, homolog phosphonate transport system compared to all other P. gallaeciensis. Our data indicate that a previously unknown, distinct clade of P. gallaeciensis acquired a limited number of clade-specific genes that were relevant for its association with mesozooplankton and for colonization of the marine pelagial. The divergence of the Pacific clade most likely was driven by the adaptation to this novel ecological niche rather than by geographic isolation.


Susceptibility loci for pigmentation and melanoma in relation to Parkinson's disease.
Growing evidence suggests that Parkinson's disease (PD) patients have a lower risk for most types of cancer except for melanoma, which has a modest positive association with PD. Pigmentation genes have been hypothesized to contribute to this association. We therefore examined whether genetic susceptibility loci for pigmentation or melanoma was associated with PD risk in 2 large independent datasets. In the Parkinson's Genes and Environment (PAGE) study, we examined 11 single-nucleotide polymorphisms (SNPs) identified from previous genome-wide association studies (GWAS) of pigmentation or melanoma in relation to PD among 808 PD cases and 1623 controls; furthermore, we also examined the colors of hair, eye, or skin and melanoma in relation to PD. In the International Parkinson's Disease Genomic Consortium (IPDGC), we examined a broader selection of 360 pigmentation or melanoma GWAS SNPs in relation to PD among 5,333 PD cases and 12,019 controls. All participants were non-Hispanic Whites. As expected, in the PAGE study, most SNPs were associated with 1 or more pigmentation phenotypes. However, neither these SNPs nor pigmentation phenotypes were associated with PD risk after Bonferroni correction with the exception of rs4911414 at the ASIP gene (p = .001). A total of 18 PD cases (2.2%) and 26 controls (1.6%) had a diagnosis of melanoma with an odds ratio of 1.3 (95% confidence interval: 0.7-2.4). In the IPDGC analysis, none of the 360 SNPs, including rs4911414, were associated with PD risk after adjusting for multiple comparisons. In conclusion, we did not find significant associations between GWAS SNPs of pigmentation or melanoma and the risk for PD.


Availability of amino acids supplied intravenously in healthy man as synthetic dipeptides: kinetic evaluation of L-alanyl-L-glutamine and glycyl-L-tyrosine.
1. For the first time utilization of intravenously administered L-alanyl-L-glutamine and glycyl-L-tyrosine was investigated by means of their kinetic behaviour after bolus injection in 10 and 11 apparently healthy male subjects (age 26.6 +/- 5.7 years), respectively. 2. The injection of the synthetic dipeptides was not accompanied by any side effects or complaints. 3. The synthetic dipeptides L-alanyl-L-glutamine and glycyl-L-tyrosine were rapidly cleared from plasma. By applying a monoexponential model the elimination half-lives were found to have very similar values (3.8 +/- 0.5 and 3.4 +/- 0.3 min) whether alanine or glycine was occupying the N-terminal position. The estimated volume of distribution was approximately that of the extracellular space. 4. Peptide disappearance was accompanied by a prompt equimolar increase in the concentrations of the constituent amino acids alanine and glutamine as well as glycine and tyrosine. 5. The study provides firm evidence that L-alanyl-L-glutamine and glycyl-L-tyrosine are rapidly (quantitatively) hydrolysed. The results of this study may indicate a safe and efficient parenteral use of the investigated peptides as sources of free glutamine and free tyrosine.


Temporal increase in mtDNA diversity in a declining population.
In small and declining populations levels of genetic variability are expected to be reduced due to effects of inbreeding and random genetic drift. As a result, both individual fitness and populations' adaptability can be compromised, and the probability of extinction increased. Therefore, maintenance of genetic variability is a crucial goal in conservation biology. Here we show that although the level of genetic variability in mtDNA of the endangered Fennoscandian lesser white-fronted goose Anser erythropus population is currently lower than in the neigbouring populations, it has increased six-fold during the past 140 years despite the precipitously declining population. The explanation for increased genetic diversity in Fennoscandia appears to be recent spontaneous increase in male immigration rate equalling 0.56 per generation. This inference is supported by data on nuclear microsatellite markers, the latter of which show that the current and the historical Fennoscandian populations are significantly differentiated (F(ST) = 0.046, P = 0) due to changes in allele frequencies. The effect of male-mediated gene flow is potentially dichotomous. On the one hand it may rescue the Fennoscandian lesser white-fronted goose from loss of genetic variability, but on the other hand, it eradicates the original genetic characteristics of this population.


Anthropometric measurements and lipid profiles to detect early lipodystrophy in antiretroviral therapy experienced HIV-infected children in the CHAPAS-3 trial.
Few studies have investigated objective markers of lipodystrophy in African children. We compared body circumferences, skin-fold thickness (SFT) and lipids in antiretroviral therapy (ART)-naive and stavudine (d4T)-exposed children with HIV-uninfected controls. In the CHAPAS-3 trial, HIV-infected children (ART-naive or on d4T for ≥2 years without clinical lipodystrophy) were randomized to d4T, abacavir or zidovudine with lamivudine (3TC) plus a non-nucleoside reverse transcriptase inhibitor. Mid-upper-arm circumference (MUAC) and calf circumference (CC), SFT (biceps, triceps, sub-scapular and supra-iliac) and fasting lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL] and triglycerides [TRIG]) were measured at randomization in all HIV-infected children, and in HIV-uninfected controls. Age- and sex-adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) using Dutch reference data were compared across groups using linear regression. Of 496 children, 49% were male, 299 (median age 2.5 years [IQR 1.5-4.0]) were ART-naive, 109 (median age 6 years [IQR 5.5-7.0]) were ART-experienced and 88 (median age 2.2 years [IQR 1.5-3.0]) were control children. Overall, 100% and 95% of ART-experienced children had been on d4T plus 3TC and nevirapine, respectively, for a median 3.5 years (IQR 2.6-4.2). Mean (sd) weight-for-age z-scores and MUAC z-scores were -1.51 (1.29) versus -0.90 (0.88) versus -0.33 (1.15) and -1.56 (1.25) versus -1.24 (0.97) versus -0.65 (1.06) in ART-naive versus -experienced versus controls, respectively (all P<0.02). The mean (sd) of SSF was lower in the ART-experienced (-0.78 [1.28]) than in the ART-naive (-0.32 [1.09]; P<0.0001) children and controls (-0.29 [0.88]; P<0.002). ART-experienced children had higher mean fasting TC, LDL and HDL but lower TRIG compared to ART-naive children (P-values <0.0001), and higher TC and HDL but lower TRIG compared to controls (P-values <0.01). In ART-experienced children on d4T-containing regimens, we observed lower SFT and higher TC and LDL values compared to ART-naive children and HIV-uninfected controls.


Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum.
Malaria is endemic in most developing countries, with nearly 500 million cases estimated to occur each year. The need to design a new generation of antimalarial drugs that can combat the most drug-resistant forms of the malarial parasite is well recognized. In this study, we wanted to develop inhibitors of key proteins that form the invasion machinery of the malarial parasite. A critical feature of host-cell invasion by apicomplexan parasites is the interaction between the carboxy terminal tail of myosin A (MyoA) and the myosin tail interacting protein (MTIP). Using the cocrystal structure of the Plasmodium knowlesi MTIP and the MyoA tail peptide as input to the hybrid structure-based virtual screening approach, we identified a series of small molecules as having the potential to inhibit MTIP-MyoA interactions. Of the initial 15 compounds tested, a pyrazole-urea compound inhibited P. falciparum growth with an EC(50) value of 145 nM. We screened an additional 51 compounds belonging to the same chemical class and identified 8 compounds with EC(50) values less than 400 nM. Interestingly, the compounds appeared to act at several stages of the parasite's life cycle to block growth and development. The pyrazole-urea compounds identified in this study could be effective antimalarial agents because they competitively inhibit a key protein-protein interaction between MTIP and MyoA responsible for the gliding motility and the invasive features of the malarial parasite.


Risky Sex and HIV Acquisition Among HIV Serodiscordant Couples in Zambia, 2002-2012: What Does Alcohol Have To Do With It?
In this paper we evaluate the effects of heavy alcohol consumption on sexual behavior, HIV acquisition, and antiretroviral treatment (ART) initiation in a longitudinal open cohort of 1929 serodiscordant couples in Lusaka, Zambia from 2002 to 2012. We evaluated factors associated with baseline heavy alcohol consumption and its association with condomless sex with the study partner, sex outside of the partnership, and ART initiation using multivariable logistic regression. We estimated the effect of alcohol consumption on HIV acquisition using multivariable Cox models. Baseline factors significantly associated with women's heavy drinking (drunk weekly or more in 12-months before enrollment) included woman's older age (adjusted prevalence odds ratio [aPOR] = 1.04), partner heavy drinking (aPOR = 3.93), and being HIV-infected (aPOR = 2.03). Heavy drinking among men was associated with less age disparity with partner (aPOR per year disparity = 0.97) and partner heavy drinking (aPOR = 1.63). Men's being drunk daily (aOR = 1.18), women's being drunk less than monthly (aOR = 1.39) vs. never drunk and being in a male HIV-negative and female HIV-positive union (aOR = 1.45) were associated with condomless sex. Heavy alcohol use was associated with having 1 or more outside sex partners among men (aOR drunk daily = 1.91, drunk weekly = 1.32, drunk monthly = 2.03 vs. never), and women (aOR drunk monthly = 2.75 vs. never). Being drunk weekly or more increased men's risk of HIV acquisition (adjusted hazard ratio [aHR] = 1.72). Men and women being drunk weekly or more was associated (p < 0.1) with women's seroconversion (aHR = 1.42 and aHR = 3.71 respectively). HIV-positive women who were drunk monthly or more had lower odds of initiating ART (aOR = 0.83; 95% CI = 0.70-0.99) adjusting for age, months since baseline and previous pregnancies. Individuals in HIV-serodiscordant couples who reported heavy drinking had more outside sex partnerships and condomless sex with their study partner and were more likely to acquire HIV. HIV-positive women had lower odds of initiating ART if they were heavy drinkers.


Structure of an acetyl-CoA binding protein from Staphylococcus aureus representing a novel subfamily of GCN5-related N-acetyltransferase-like proteins.
We have determined the solution NMR structure of SACOL2532, a putative GCN5-like N-acetyltransferase (GNAT) from Staphylococcus aureus. SACOL2532 was shown to bind both CoA and acetyl-CoA, and structures with and without bound CoA were determined. Based on analysis of the structure and sequence, a subfamily of small GCN5-related N-acetyltransferase (GNAT)-like proteins can be defined. Proteins from this subfamily, which is largely congruent with COG2388, are characterized by a cysteine residue in the acetyl-CoA binding site near the acetyl group, by their small size in relation to other GNATs, by a lack of obvious substrate binding site, and by a distinct conformation of bound CoA in relation to other GNATs. Subfamily members are found in many bacterial and eukaryotic genomes, and in some archaeal genomes. Whereas other GNATs transfer the acetyl group of acetyl-CoA directly to an aliphatic amine, the presence of the conserved cysteine residue suggests that proteins in the COG2388 GNAT-subfamily transfer an acetyl group from acetyl-CoA to one or more presently unidentified aliphatic amines via an acetyl (cysteine) enzyme intermediate. The apparent absence of a substrate-binding region suggests that the substrate is a macromolecule, such as another protein, or that a second protein subunit providing a substrate-binding region must combine with SACOL2532 to make a fully functional N-acetyl transferase.


Functional characterization of Hsp33 protein from Bacillus psychrosaccharolyticus; additional function of HSP33 on resistance to solvent stress.
Psychrophiles have been known as efficient organism to degrade organic solvent. To investigate the mechanism of solvent stress and identify the factors that affect the solvent stress in psychrophiles, we selected Bacillus psychrosaccharolyticus one of the psychrophiles and two-dimensional gel electrophoresis was performed. Among the protein spots analyzed by 2-DE, five spots induced in 3% IPA stress conditions were identified by MS/MS, and one of these spots was identified as a Hsp33 family. The Hsp33 protein sequence of B. psychrosaccharolyticus exhibited a high similarity with the corresponding proteins of other bacteria. The Hsp33 protein of B. psychrosaccharolyticus has a highly conserved zinc-binding domain (CXCX, CXXC) that includes four cysteine residues in the C-terminus. In addition, the transcriptional induction of the HSP33 of B. psychrosaccharolyticus was confirmed by Northern blot analysis, and formation of free thiol linkage was induced under stress conditions such as exposure to solvents, heat-shock, and oxidative stress. Furthermore, over-expressed strains of HSP33 of B. psychrosaccharolyticus in Escherichia coli improved stress tolerance to the organic solvent when compared with the wild-type. These data suggest that the solvent stress condition was similar to heat-shock or oxidative stress, especially through the triggering of induction and activation of a redox-regulatory chaperone, Hsp33, and Hsp33 plays a critical role in the tolerance to stress.


Adaptation of a polyphagous herbivore to a novel host plant extensively shapes the transcriptome of herbivore and host.
Generalist arthropod herbivores rapidly adapt to a broad range of host plants. However, the extent of transcriptional reprogramming in the herbivore and its hosts associated with adaptation remains poorly understood. Using the spider mite Tetranychus urticae and tomato as models with available genomic resources, we investigated the reciprocal genomewide transcriptional changes in both spider mite and tomato as a consequence of mite's adaptation to tomato. We transferred a genetically diverse mite population from bean to tomato where triplicated populations were allowed to propagate for 30 generations. Evolving populations greatly increased their reproductive performance on tomato relative to their progenitors when reared under identical conditions, indicative of genetic adaptation. Analysis of transcriptional changes associated with mite adaptation to tomato revealed two main components. First, adaptation resulted in a set of mite genes that were constitutively downregulated, independently of the host. These genes were mostly of an unknown function. Second, adapted mites mounted an altered transcriptional response that had greater amplitude of changes when re-exposed to tomato, relative to nonadapted mites. This gene set was enriched in genes encoding detoxifying enzymes and xenobiotic transporters. Besides the direct effects on mite gene expression, adaptation also indirectly affected the tomato transcriptional responses, which were attenuated upon feeding of adapted mites, relative to the induced responses by nonadapted mite feeding. Thus, constitutive downregulation and increased transcriptional plasticity of genes in a herbivore may play a central role in adaptation to host plants, leading to both a higher detoxification potential and reduced production of plant defence compounds.


TP53 gene polymorphism: importance to cancer, ethnicity and birth weight in a Brazilian cohort.
Arg72Pro SNP of p53 has been associated with many types of cancer as well as with survival and longevity. We evaluated the Arg72Pro SNP frequencies of a Brazilian birth cohort and their association with current, demographic and birth epidemiological parameters available. In 1982, all hospital births of Pelotas, southern Brazil, were identified and studied prospectively. In 2004-5, blood samples were collected and DNA extracted. PCR-RFLP was used to genotype the Arg72Pro SNP in 3794 individual samples of the Brazil birth cohort and DNA sequencing was performed to confirm the genotypes. The genotype distribution, which was in Hardy-Weinberg equilibrium, showed a predominance of the arginine amino acid with a frequency of 46.9% Arg/Arg, 42.2% Arg/Pro and 10.9% Pro/Pro. The allele frequency was 0.68 of Arginine and 0.32 of Proline. The Arg72Pro SNP genotype and allelic frequency were related to skin colour where proline amino acid was observed more among black subjects, while arginine amino acid was observed more among white subjects. The individuals without family history of cancer and those with low birth weight were associated with arginine amino acid. The Arg72Pro SNP was strongly associated with important epidemiological variables confirming that genetic profiles on cohort studies can improve our understanding of the susceptibility of diseases and its risk factors.


Phase II Study of Proton Beam Radiation Therapy for Patients With Breast Cancer Requiring Regional Nodal Irradiation.
To evaluate the safety and efficacy of proton beam radiation therapy (RT) for patients with breast cancer who require regional nodal irradiation. Patients with nonmetastatic breast cancer who required postoperative RT to the breast/chest wall and regional lymphatics and who were considered suboptimal candidates for conventional RT were eligible. The primary end point was the incidence of grade 3 or higher radiation pneumonitis (RP) or any grade 4 toxicity within 3 months of RT. Secondary end points were 5-year locoregional failure, overall survival, and acute and late toxicities per Common Terminology Criteria for Adverse Events (version 4.0). Strain echocardiography and cardiac biomarkers were obtained before and after RT to assess early cardiac changes. Seventy patients completed RT between 2011 and 2016. Median follow-up was 55 months (range, 17 to 82 months). Of 69 evaluable patients, median age was 45 years (range, 24 to 70 years). Sixty-three patients (91%) had left-sided breast cancer, two had bilateral breast cancer, and five had right-sided breast cancer. Sixty-five (94%) had stage II to III breast cancer. Sixty-eight (99%) received systemic chemotherapy. Fifty (72%) underwent immediate reconstruction. Median dose to the chest wall/breast was 49.7 Gy (relative biological effectiveness) and to the internal mammary nodes, 48.8 Gy (relative biological effectiveness), which indicates comprehensive coverage. Among 62 surviving patients, the 5-year rates for locoregional failure and overall survival were 1.5% and 91%, respectively. One patient developed grade 2 RP, and none developed grade 3 RP. No grade 4 toxicities occurred. The unplanned surgical re-intervention rate at 5 years was 33%. No significant changes in echocardiography or cardiac biomarkers after RT were found. Proton beam RT for breast cancer has low toxicity rates and similar rates of disease control compared with historical data of conventional RT. No early cardiac changes were observed, which paves the way for randomized studies to compare proton beam RT with standard RT.


Functional organization of thalamic projections to the motor cortex. An anatomical and electrophysiological study in the rat.
In rats, horseradish peroxidase crystals were injected in motor cortical foci functionally identified by means of the motor effects evoked by electrical stimulations. The location in the thalamus of the neurons linked to different motor cortical foci was studied. Thalamic neurons were retrogradely labeled in both "motor" (ventralis lateralis and ventralis medialis) and "non-motor" nuclei: centralis lateralis, lateralis posterior, mediodorsalis and posterior thalamic nuclear group, as well as the ventrobasal complex. The ventrobasal complex was labeled after horseradish peroxidase injections in hindlimb and trunk motor areas. The ascending projections toward the motor cortex from both "motor" and "non-motor" thalamic nuclei are organized more precisely and more elaborately than previously reported. The motor cortical afferents from the nucleus ventralis lateralis are organized in three planes, rostrocaudally, dorsoventrally and mediolaterally. An inverted relation exists in the rostrocaudal plane between the nucleus ventralis lateralis and the motor cortex: the caudal motor cortex region (hindlimb) receives fiber inputs from the rostral region of the nucleus ventralis lateralis, whereas the caudal zone of the nucleus ventralis lateralis projects to the rostral motor cortex region (forelimb and vibrissae). A dorsoventral organization has also been observed in the rostral region of the nucleus ventralis lateralis: the ventral aspect is the source of fibers directed to the distal hindlimb region, whereas fibers originating from the dorsal aspect are directed to the proximal hindlimb area. A mediolateral relationship exists between medial and lateral sides of the nucleus ventralis lateralis and, respectively, proximal and distal forelimb cortical areas. There is some overlap between the various nuclear regions thus delineated. Four functional zones were found in the lateral half of the nucleus ventralis medialis and were classified according to their projection to the motor cortex; these are involved in motor control of the proximal and distal forelimb, vibrissae and ocular movements. The projection is topographically organized according to both an inverted rostrocaudal and a direct dorsoventral-mediolateral arrangement. Caudally, dorsal and ventral nuclear parts project to rostromedial (vibrissae) and rostrolateral (distal forelimb) regions of the motor cortex, respectively. More rostral nuclear zones project to more caudal (proximal forelimb, eye) cortical regions. There is little overlap between these four nuclear subdivisions. The nucleus centralis lateralis projects to vibrissae and proximal, as well as distal, forelimb areas.(ABSTRACT TRUNCATED AT 400 WORDS)


The complex vaginal flora of West African women with bacterial vaginosis.
The spectrum of bacteria associated with bacterial vaginosis (BV) has recently expanded through taxonomic changes and the use of molecular methods. These methods have yet to be used in large-scale epidemiological studies in Africa where BV is highly prevalent. An analysis of samples obtained during a clinical trial of the management of vaginal discharge in four West African countries. Samples were available from 1555 participants; 843 (54%) had BV. Nucleic acids of 13 bacterial genera or species potentially associated with BV were detected through the polymerase chain reaction. The associations between various components of the vaginal flora were complex. Excluding Lactobacillus, the other 12 micro-organisms were all associated with each other at the p≤0.001 level. The prevalence of various bacterial genera or species varied according to age, sexual activity and HIV status. In multivariate analysis, the presence of Gardnerella vaginalis, Bifidobacterium, Megasphaera elsdenii, Dialister, Mycoplasma hominis, Leptotrichia, and Prevotella were independently associated with BV as was the absence of Lactobacillus and Peptoniphilus. However, Mobiluncus, Atopobium vaginae, Anaerococcus, and Eggerthella were not independently associated with BV. Unexpectedly, after treatment with a regimen that included either metronidazole or tinidazole, the proportion of patients with a complete resolution of symptoms by day 14 increased with the number of bacterial genera or species present at enrolment. Numerous bacterial genera or species were strongly associated with each other in a pattern that suggested a symbiotic relationship. BV cases with a simpler flora were less likely to respond to treatment. Overall, the vaginal flora of West African women with BV was reminiscent of that of their counterparts in industrialized countries.


Intake of Flavonoids and Flavonoid-Rich Foods and Mortality Risk Among Individuals With Parkinson Disease: A Prospective Cohort Study.
Although flavonoids have the potential to exert neuroprotective benefits, evidence of their role in improving survival rates among individuals with Parkinson disease (PD) remains lacking. We aimed to prospectively study the association between prediagnosis and postdiagnosis flavonoid intakes and risk of mortality among individuals with PD identified from 2 large ongoing cohorts of US men and women. Included in the current analysis were 599 women from the Nurses' Health Study and 652 men from the Health Professionals Follow-Up Study who were newly diagnosed with PD during follow-up. Dietary intakes of total flavonoid and its subclasses, together with major flavonoid-rich foods (tea, apples, berries, orange and orange juice, and red wine), were repeatedly assessed with a validated food frequency questionnaire every 4 years. Mortality was ascertained via the National Death Index and state vital statistics records. We documented 944 deaths during 32 to 34 years of follow-up. A higher total flavonoid intake before PD diagnosis was associated with a lower future risk for all-cause mortality in men (hazard ratio [HR] comparing 2 extreme quartiles 0.53, 95% confidence interval [CI] 0.39, 0.71; p for trend < 0.001) but not in women (HR 0.93, 95% CI 0.68, 1.28; p for trend = 0.69) after adjustment for age, smoking status, total energy intake, and other covariates. The pooled HR comparing the extreme quartiles was 0.70 (95% CI 0.40, 1.22; p for trend = 0.25) with significant heterogeneity (p = 0.01). For flavonoid subclasses, the highest quartile of anthocyanins, flavones, and flavan-3-ols intakes before diagnosis had a lower mortality risk compared to the lowest quartile (pooled HR 0.66, 0.78, and 0.69, respectively; p < 0.05 for all); for berries and red wine, participants consuming ≥3 servings per week had a lower risk (pooled HR 0.77, 95% CI 0.58, 1.02; and pooled HR 0.68, 95% CI 0.51, 0.91, respectively) compared to <1 serving per month. After PD diagnosis, greater consumptions of total flavonoid, subclasses including flavonols, anthocyanins, flavan-3-ols, and polymers, and berries and red wine were associated with lower mortality risk (p < 0.05 for all). Among individuals with PD, higher consumption of flavonoids, especially anthocyanins and flavan-3-ols, and flavonoid-rich food such as berries and red wine was likely to be associated with a lower risk of mortality.


Utility of multimaterial 3D printers in creating models with pathological entities to enhance the training experience of neurosurgeons.
The advent of multimaterial 3D printers allows the creation of neurosurgical models of a more realistic nature, mimicking real tissues. The authors used the latest generation of 3D printer to create a model, with an inbuilt pathological entity, of varying consistency and density. Using this model the authors were able to take trainees through the basic steps, from navigation and planning of skin flap to performing initial steps in a craniotomy and simple tumor excision. As the technology advances, models of this nature may be able to supplement the training of neurosurgeons in a simulated operating theater environment, thus improving the training experience.


Search for top squark pair production using dilepton final states in pp collision data collected at s = 13 TeV.
A search is presented for supersymmetric partners of the top quark (top squarks) in final states with two oppositely charged leptons (electrons or muons), jets identified as originating from b quarks, and missing transverse momentum. The search uses data from proton-proton collisions at s = 13 TeV collected with the CMS detector, corresponding to an integrated luminosity of 137 fb - 1 . Hypothetical signal events are efficiently separated from the dominant top quark pair production background with requirements on the significance of the missing transverse momentum and on transverse mass variables. No significant deviation is observed from the expected background. Exclusion limits are set in the context of simplified supersymmetric models with pair-produced lightest top squarks. For top squarks decaying exclusively to a top quark and a lightest neutralino, lower limits are placed at 95 % confidence level on the masses of the top squark and the neutralino up to 925 and 450 GeV , respectively. If the decay proceeds via an intermediate chargino, the corresponding lower limits on the mass of the lightest top squark are set up to 850 GeV for neutralino masses below 420 GeV . For top squarks undergoing a cascade decay through charginos and sleptons, the mass limits reach up to 1.4 TeV and 900 GeV respectively for the top squark and the lightest neutralino.


Diagnosis and treatment of mesenteric volvulus in a red kangaroo (Macropus rufus).
An 8-year-old male red kangaroo (Macropus rufus) was evaluated with a 2-week history of vomiting and anorexia. Four days prior, the patient became refractory to medical management. The kangaroo was admitted for diagnostic testing and treatment including whole body CT, blood work, and emergency laparotomy. CT findings of a severely enlarged stomach, splenic displacement, and a whirl sign were indicative of mesenteric volvulus with gastric dilatation-volvulus (GDV). Contrast enhancement of abdominal viscera suggested intact arterial blood supply; however, compression of the caudal vena cava and portal vein indicated venous obstruction. Results of preoperative blood work suggested biliary stasis without evidence of inflammation. Additionally, a tooth root abscess was diagnosed on the basis of results of CT. Exploratory laparotomy confirmed the diagnosis of mesenteric volvulus and GDV. The volvuli were corrected by clockwise derotation, and a gastropexy was performed. Tissue samples were obtained from the spleen and liver for evaluation. The kangaroo recovered from surgery, and the abscessed tooth was extracted 6 days later. Eight days after initial evaluation, the kangaroo was discharged. In the present report, the CT whirl sign was used to diagnose volvulus of the abdominal viscera, which suggests that this diagnostic indicator has utility in veterinary patients. Mesenteric volvulus with GDV was successfully treated in a nondomestic species. The tooth root abscess, a common condition in macropods, may explain the historic episodes of anorexia reported by the owner and may have contributed to the development of mesenteric volvulus and GDV in this kangaroo.


Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo.
Dysregulation of the 5-HT(2A) receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT(2A) receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT(2A) down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT(2A) receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT(2A) antagonists [ketanserin, altanserin, α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), α-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT(2A) receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT(2A) antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT(2A) receptors and potentiated PCP-hyperlocomotion; the other 5-HT(2A) receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed.


Unintended consequences of US immigration policy: explaining the post-1965 surge from Latin America.
Immigration reforms in the United States initiated in the 1960s are widely thought to have opened the door to mass immigration from Asia and Latin America by eliminating past discriminatory policies. While this may be true for Asians, it is not the case for Latin Americans, who faced more restrictions to legal migration after 1965 than before. The boom in Latin American migration occurred in spite of rather than because of changes in US immigration law. In this article we describe how restrictions placed on the legal entry of Latin Americans, and especially Mexicans, set off a chain of events that in the ensuing decades had the paradoxical effect of producing more rather than fewer Latino immigrants. We offer an explanation for how and why Latinos in the United States, in just 40 years, increased from 9.6 million people and 5 percent of the population to 51 million people and 16 percent of the population, and why so many are now present without authorization.


Microvascular changes in renal allografts associated with FK506 (Tacrolimus) therapy.
FK506 (Tacrolimus) recently has been shown to be an effective immunosuppressant after renal transplantation. It is associated with less hypertension, hypercholesterolemia and steroid use compared with cyclosporine. We report 10 patients on FK506 who showed fibrin thrombi within the glomerular capillaries and/or arterioles at renal allograft biopsy. These biopsies were generally performed to assess increasing serum creatinine levels; laboratory evidence of hemolytic uremic syndrome was present in one instance. Plasma or whole blood FK506 levels were elevated in eight of 10 cases. Reduction of immunosuppression led to clinical improvement or biopsy-proven resolution of thrombi in all cases. These observations suggest that FK506 may occasionally produce microvascular changes in the renal allograft. The estimated incidence of this occurrence (1%) is comparable with that reported with cyclosporine (3%).


Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK).
Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days. Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6.0-17.0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4-7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803) The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1.14, 95% CI 0.86-1.51, p=0.37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0.57 mmol/L, p<0.001; mean difference in blood pressure 9.0 mmHg, p<0.0001). GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded.


Clonal variation in cell surface display of an H-2 protein lacking a cytoplasmic tail.
Truncated variants of the gene encoding H-2Ld, an integral membrane protein encoded by the major histocompatibility complex, were constructed by in vitro mutagenesis to elucidate the function of charged amino acids found on the cytoplasmic side of the transmembrane (TM) region. Analysis of cloned L cells transfected with these genes shows that the seven amino acids following the TM segment, four of which are basic, enhance the cell surface expression of H-2Ld protein but are not required for it. However, some clones do not express a tailless H-2Ld protein on the cell surface but express it intracellularly where it has a long half-life. Turnover measurements on cell surface H-2Ld proteins suggest that the basic residues following the TM segment are not a "stop transfer" sequence (Blobel, G., 1980, Proc. Natl. Acad. Sci. USA., 77:1496-1500) which anchors the H-2Ld protein in the membrane. Pulse-chase and endoglycosidase H sensitivity studies show that H-2Ld proteins lacking some or all of the basic residues and H-2Ld proteins which have a full-length cytoplasmic tail are processed with different kinetics. These results suggest an involvement of the membrane-proximal region of the cytoplasmic tail in the intracellular transport of H-2Ld. We further suggest that the L cell clones which do and do not express a tailless H-2Ld protein on the cell surface differ in the ability to transport a tailless integral membrane protein to the cell surface.


Increased muscarinic receptor messenger RNA in Alzheimer's disease temporal cortex demonstrated by in situ hybridization histochemistry.
A 35S-labelled synthetic oligonucleotide directed against part of the mRNA coding for the M1 subtype muscarinic receptor was used for in situ hybridization histochemistry in sections of human temporal cortex. M1 receptor mRNA was found in cell populations throughout the grey matter, especially in pyramidal cells. Quantitative densitometric analysis of autoradiograms was used to compare levels of this mRNA between Alzheimer's disease and controls. A significant (2.7-fold) increase in hybridization signal was found in Alzheimer's disease cases, both in absolute terms and relative to total polyadenylated mRNA as determined by hybridization with an oligodeoxythymidine probe. Elevated levels of muscarinic receptor mRNA may reflect up-regulation of transcription of this gene in response to the cholinergic deficits occurring in the disease.


Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer.
The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and evaluate the imaging properties, of the bombesin analogue BAY 864367 for PET/CT in a small group of patients with primary and recurrent prostate cancer (PCa). Ten patients with biopsy-proven PCa (5 with primary PCa and 5 with prostate-specific antigen recurrence after radical prostatectomy) were prospectively selected for this exploratory clinical trial with BAY 864367, a new (18)F-labeled bombesin analogue. PET scans were assessed at 6 time points, up to 110 min after intravenous administration of 302 ± 11 MBq of BAY 864367. Imaging results were compared with (18)F-fluorocholine PET/CT scans. Dosimetry was calculated using the OLINDA/EXM software. Three of 5 patients with primary disease showed positive tumor delineation in the prostate, and 2 of 5 patients with biochemical relapse showed a lesion suggestive of recurrence on the BAY 864367 scan. Tumor-to-background ratio averaged 12.9 ± 7.0. The ratio of malignant prostate tissue to normal prostate tissue was 4.4 ± 0.6 in 3 patients with tracer uptake in the primary PCa. Mean effective dose was 4.3 ± 0.3 mSv/patient (range, 3.7-4.9 mSv). BAY 864367, a novel (18)F-labeled bombesin tracer, was successfully investigated in a first-in-man clinical trial of PCa and showed favorable dosimetric values. Additionally, the application was safe and well tolerated. The tracer delineated tumors in a subset of patients, demonstrating the potential of gastrin-releasing-peptide receptor imaging.


Using a priori knowledge to align sequencing reads to their exact genomic position.
The use of a priori knowledge in the alignment of targeted sequencing data is investigated using computational experiments. Adapting a Needleman-Wunsch algorithm to incorporate the genomic position information from the targeted capture, we demonstrate that alignment can be done to just the target region of interest. When in addition use is made of direct string comparison, an improvement of up to a factor of 8 in alignment speed compared to the fastest conventional aligner (Bowtie) is obtained. This results in a total alignment time in targeted sequencing of around 7 min for aligning approximately 56 million captured reads. For conventional aligners such as Bowtie, BWA or MAQ, alignment to just the target region is not feasible as experiments show that this leads to an additional 88% SNP calls, the vast majority of which are false positives (≈ 92%).


A dynamic network of transcription in LPS-treated human subjects.
Understanding the transcriptional regulatory networks that map out the coordinated dynamic responses of signaling proteins, transcription factors and target genes over time would represent a significant advance in the application of genome wide expression analysis. The primary challenge is monitoring transcription factor activities over time, which is not yet available at the large scale. Instead, there have been several developments to estimate activities computationally. For example, Network Component Analysis (NCA) is an approach that can predict transcription factor activities over time as well as the relative regulatory influence of factors on each target gene. In this study, we analyzed a gene expression data set in blood leukocytes from human subjects administered with lipopolysaccharide (LPS), a prototypical inflammatory challenge, in the context of a reconstructed regulatory network including 10 transcription factors, 99 target genes and 149 regulatory interactions. We found that the computationally estimated activities were well correlated to their coordinated action. Furthermore, we found that clustering the genes in the context of regulatory influences greatly facilitated interpretation of the expression data, as clusters of gene expression corresponded to the activity of specific factors or more interestingly, factor combinations which suggest coordinated regulation of gene expression. The resulting clusters were therefore more biologically meaningful, and also led to identification of additional genes under the same regulation. Using NCA, we were able to build a network that accounted for between 8-11% genes in the known transcriptional response to LPS in humans. The dynamic network illustrated changes of transcription factor activities and gene expressions as well as interactions of signaling proteins, transcription factors and target genes.


A comparison of fertility control and lethal control of bovine tuberculosis in badgers: the impact of perturbation induced transmission.
In this paper we use mathematical modelling to consider the broad advantages and disadvantages of fertility control over lethal control for bovine tuberculosis in badger populations. We use a deliberately simple model, attempting to capture only the key transmission processes. The model is parametrized with reference to the long-term Woodchester Park study. Estimates of mortality rate from this study suggest no significant extra mortality risk for animals with evidence of infection as indicated by the presence of anti-Mycobacterium bovis antibodies or M. bovis isolation. We find that large reductions in prevalence are sometimes the consequence of only moderate reductions in population numbers. If we assume that the act of control does not in itself affect transmission rates, then as far as eradication is concerned, both fertility control and mortality control operate through the same epidemiological mechanism, the removal of susceptibles: if one is in principle capable of keeping a population low enough to be infection free then so is the other. It is necessary to continue either form of control at regular intervals to maintain a constant level of infection in the long term. If control were to be stopped, return to precontrol levels of badger population and infection prevalence would be expected within a few years. Fertility control is less effective in reducing population density than lethal control since it can only act, at maximum, to remove one age cohort per year. It is also less effective in reducing transmission as it can only ever remove susceptibles, while lethal control also removes infectious badgers. However, if the social disturbance caused by lethal control does in fact increase contact rates for the remaining infectious badgers, the relative efficacies of the two strategies become a great deal less clear. While we have no quantitative data on the extent to which social perturbation does act to promote transmission, model simulations show that it is possible to develop plausible scenarios in which the lethal control may actually act to increase the absolute numbers of animals infected, while reducing the number of uninfected animals to very low numbers.


Oral Health, Nutritional Choices, and Dental Fear and Anxiety.
Oral health is an integral part of overall health. Poor oral health can lead to an increased risk of chronic diseases including diabetes mellitus, cardiovascular disease, and some types of cancer. The etiology of these diseases could be linked to the individual's inability to eat a healthy diet when their dentition is compromised. While periodontal or implant surgery may be necessary to reconstruct tissue around natural teeth or replace missing teeth, respectively, some individuals avoid such interventions because of their associated fear and anxiety. Thus, while the relationship between poor oral health, compromised nutritional choices and fear and anxiety regarding periodontal procedures is not entirely new, this review provides an up-to-date summary of literature addressing aspects of this complex relationship. This review also identifies potential strategies for clinicians to help their patients overcome their fear and anxiety associated with dental treatment, and allow them to seek the care they need.


How reproducible is bioluminescent imaging of tumor cell growth? Single time point versus the dynamic measurement approach.
To determine the most robust and reproducible parameters for noninvasively estimating tumor cell burden in a murine model, we used real-time in vivo bioluminescent imaging to assess the growth kinetics and dissemination of luciferase-transfected Raji B-cell lymphoma. Bioluminescent signals were acquired every minute for 40 minutes after luciferin injection every other day post-tumor injection. The total 40-minute area under the curve (AUC) of photon intensity (photons/second) was calculated and compared with simplified fixed time point observations (every 5 minutes from 5 to 40 minutes after substrate injection). There was substantial variability in the shape of the time signal intensity curves at different stages of tumor growth in both the intravenous and subcutaneous models. The coefficient of variance in the AUC was 0.27 (intravenous) and 0.36 (subcutaneous) as values determined by fitting the curve, whereas the 20-minute time point measurement varied at 0.29 (intravenous) and 0.37 (subcutaneous). In both the subcutaneous and intravenous models, single time point measurements at 20 minutes had the highest correlation value with AUC. This simplified single time point measurement appears appropriate to estimate the total tumor burden in this model, but the substantial variance at each measurement must be considered in experimental designs.


Long-term treatment of calcium nephrolithiasis with potassium citrate.
The long-term effects of potassium citrate therapy (usually 20 mEq. 3 times daily during 1 to 4.33 years) were examined in 89 patients with hypocitraturic calcium nephrolithiasis or uric acid lithiasis, with or without calcium nephrolithiasis. Hypocitraturia caused by renal tubular acidosis or chronic diarrheal syndrome was associated with other metabolic abnormalities, such as hypercalciuria or hyperuricosuria, or occurred alone. Potassium citrate therapy caused a sustained increase in urinary pH and potassium, and restored urinary citrate to normal levels. No substantial or significant changes occurred in urinary uric acid, oxalate, sodium or phosphorus levels, or total volume. Owing to these physiological changes, uric acid solubility increased, urinary saturation of calcium oxalate decreased and the propensity for spontaneous nucleation of calcium oxalate was reduced to normal. Therefore, the physicochemical environment of urine following treatment became less conducive to the crystallization of calcium oxalate or uric acid, since it stimulated that of normal subjects without stones. Commensurate with the aforementioned physiological and physicochemical changes the treatment produced clinical improvement, since individual stone formation decreased in 97.8 per cent of the patients, remission was obtained in 79.8 per cent and the need for surgical treatment of newly formed stones was eliminated. In patients with relapse after other treatment, such as thiazide, the addition of potassium citrate induced clinical improvement. Thus, our study provides physiological, physicochemical and clinical validation for the use of potassium citrate in the treatment of hypocitraturic calcium nephrolithiasis and uric acid lithiasis with or without calcium nephrolithiasis.


Intracellular signaling pathways and size, shape, and rupture history of human intracranial aneurysms.
Size and morphological features are associated with intracranial aneurysm (IA) rupture. The cellular mechanisms of IA development and rupture are poorly known. We studied the expression and phosphorylation of different intracellular signaling molecules in the IA wall compared with IA morphological features to understand better the cellular pathways involved in IA development and wall degeneration. Nine ruptured and 17 unruptured human IA samples were collected intraoperatively. The expression levels and phosphorylation state of 3 mitogen-activated protein kinases (c-Jun N-terminal kinase [JNK], p38, extracellular signal-regulated kinase [ERK]), Bcl-2 antagonist of cell death (Bad), mammalian target of rapamycin (mTOR), cyclic AMP response element binding protein (CREB), and Akt were determined by Western blotting. The localization of signaling proteins was determined by immunofluorescence. From 3-dimensional segmentation of computed tomography angiographic data, size and shape indexes were calculated. We found a 5-fold difference in phospho-Bad levels between ruptured and unruptured IAs. Phospho-mTOR was downregulated 2.5-fold in ruptured IAs. Phospho-p54 JNK, phospho-p38, and phospho-Akt levels correlated positively with IA size. Phospho-CREB levels were significantly associated with nonsphericity and ellipticity indexes. Phospho-Akt and phospho-p38 correlated negatively with undulation index. The signaling pathway profile (apoptosis, cell proliferation, stress signaling) differs between ruptured and unruptured IAs and is associated with IA geometry. Our results increase the knowledge of IA development and wall degeneration.


R1 Regulates Prostate Tumor Growth and Progression By Transcriptional Suppression of the E3 Ligase HUWE1 to Stabilize c-Myc.
Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc-interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc-targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis. IMPLICATIONS: These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.


More frequent requests for day-case cataract surgery : An impressive mind switch in the Austrian population within 7 years.
Cataract surgery is the most commonly performed elective surgical procedure worldwide. While the operation has been mainly conducted as day-case (outpatient) surgery throughout the world since the beginning of this millennium, this development has been much slower in Austria. The number of patients requesting day-case surgery has markedly increased in the last few years. Prior to the introduction of a day clinic at our department in 2007, we evaluated the patients' acceptance of day-case surgery using a questionnaire. At the time, less than half of the patients wished to undergo day-case surgery. Another survey was performed 7 years later to determine if there were any changes. The desire for day-case surgery increased significantly from 38.8 to 87.1%. The mean age of the patients and their visual impairment had decreased. Home care improved, but not to the same extent. The number of patients who had to travel more than an hour to reach the hospital had significantly increased. Improvements in perioperative limitations and most of all patients becoming accustomed to the idea have led to an impressive mind switch, culminating in a clear desire for day-case cataract surgery.


Controlled programmed trial of Ocimum sanctum leaf on generalized anxiety disorders.
Ocimumn sanctum, an Indian medicinal plant, has been on trial for its role in generalized anxiety disorder (GAD) in hospital based clinical set-up. Hamilton's brief psychiatric rating scale (BPRS) and thorough clinical investigations were used to screen the subjects. Thirty-five subjects (21 male and 14 female; average age 38.4 years) were medicated with the plant extract in a fixed dose regime (500 mg/capsule, twice daily, p.o. after meal). They were thoroughly investigated clinically and using standard questionnaires based on different psychological rating scale at baseline (day 0), mid-term (day 30) and final (day 60). The observations exhibited that, O. sanctum significantly (p<0.001) attenuated generalized anxiety disorders and also attenuated its correlated stress and depression. It further significantly (p<0.001) improved the willingness to adjustment and attention in human. Therefore, it may be concluded that O. sanctum may be useful in the treatment of GAD in human and may be a promising anxiolytic agent in near future.


Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.
Multiple sclerosis (MS) is believed to be initiated by myelin-reactive CD4(+) Th cells. IL-12-polarized Th1 cells, IL-23-polarized Th17 cells, and Th17 cells that acquire Th1 characteristics were each implicated in autoimmune pathogenesis. It is debated whether Th cells that can drive the development of demyelinating lesions are phenotypically diverse or arise from a single lineage. In the current study, we assessed the requirement of IL-12 or IL-23 stimulation, as well as Th plasticity, for the differentiation of T cells capable of inducing CNS axon damage. We found that stable murine Th1 and Th17 cells independently transfer experimental autoimmune encephalomyelitis (widely used as an animal model of MS) in the absence of IL-23 and IL-12, respectively. Plastic Th17 cells are particularly potent mediators of demyelination and axonopathy. In parallel studies, we identified MS patients who consistently mount either IFN-γ- or IL-17-skewed responses to myelin basic protein over the course of a year. Brain magnetic resonance imaging revealed that patients with mixed IFN-γ and IL-17 responses have relatively high T1 lesion burden, a measure of permanent axon damage. Our data challenge the dogma that IL-23 and Th17 plasticity are universally required for the development of experimental autoimmune encephalomyelitis. This study definitively demonstrates that autoimmune demyelinating disease can be driven by distinct Th-polarizing factors and effector subsets, underscoring the importance of a customized approach to the pharmaceutical management of MS.


The clinical utility of circulating tumour cells in patients with small cell lung cancer.
Small cell lung cancer (SCLC) accounts for 15% of lung cancer diagnosed worldwide. It is aggressive and characterised by early metastatic spread with rapid development of chemo resistance such that less than 5% of patients diagnosed survive 5 years. Surgery is rarely performed and failure to identify new effective treatments has been attributed in a large part to lack of good quality tumour biopsies available for translational research. Liquid biopsies provide a minimally invasive alternative to traditional tumour biopsy. Circulating tumour cells (CTCs) are abundant in SCLC and can be enriched and isolated from a venous blood sample. In recent years progress has been made into the molecular characterisation of CTCs and their use to form tumour xenografts in mice for preclinical studies. This review will discuss the current status of the clinical utility of CTCs in patients with SCLC, highlighting their potential application to treatment decision making, drug development in clinical trials and preclinical testing.


Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo.
Pulmonary metastasis remains the major cause of mortality in osteosarcoma. Src tyrosine kinase is a key player involved in metastatic pathways in multiple human cancers. c-Src has been shown to be expressed and phosphorylated in osteosarcoma cell lines and inhibiting Src phosphorylation in these cells causes inhibition of the metastatic phenotype in vitro. We studied the effect of inhibition of Src phosphorylation in preventing the growth and development of pulmonary metastases in osteosarcoma. Dasatinib, a dual Src-Abl kinase inhibitor, was used to study the effect of Src kinase inhibition on proliferation, adhesion, and invasion of osteosarcoma cell lines in vitro and in preventing the development of pulmonary metastases in a spontaneously metastatic mouse model. In vitro, phosphorylation of Src and its downstream signaling molecules such as focal adhesion kinase, Crk-associated substrate, and c-Jun was inhibited at nanomolar concentrations of dasatinib. Dasatinib was not cytotoxic against the osteosarcoma cells with the IC(50) ranging from 10 to 20 micromol/L but effectively inhibited the adhesion and migration of osteosarcoma cells at 10 to 100 nmol/L. However, in vivo, dasatinib did not inhibit the development of pulmonary metastases despite complete inhibition of Src phosphorylation in the primary tumors. No effect was seen in the primary tumor growth and the degree of apoptosis. These results suggest that Src kinase activation might not be the primary pathway involved in the development of pulmonary metastases in osteosarcoma.


Epidemiology of cryptosporidiosis among European AIDS patients.
To study epidemiology and possible risk factors associated with the development of cryptosporidiosis among European patients with AIDS. An inception cohort of 6548 patients with AIDS, consecutively diagnosed from 1979 to 1989, from 52 centres in 17 European countries was studied. Data on all AIDS defining events were collected retrospectively from patients' clinical records. Kaplan-Meier estimates, log rank tests and Cox proportional hazard models were used to examine for possible risk factors associated with cryptosporidiosis. Cryptosporidiosis was diagnosed in 432 (6.6%) patients, 216 at time of the AIDS diagnosis and 216 during follow-up. The probability of being diagnosed with cryptosporidiosis at AIDS diagnosis was significantly lower for intravenous drug users (1.3%) than for homosexual men (4.1%) and for patients belonging to other transmission categories (4.0%) (p < 0.001). The probability was also higher for patients from Central Europe compared with patients from South Europe (4.1% versus 2.5%, p = 0.005). The rate of developing cryptosporidiosis after the diagnosis of AIDS was 3 per 100 patient years of follow-up. The rate was significantly lower for intravenous drug users than for homosexual men (relative risk 0.34, 95% confidence limits 0.22-0.54) and for women compared with men (RR 0.43 (0.21-0.87)). The risk was higher in North Europe than in South and Central Europe. In a multivariate analysis only transmission category remained a significant predictor for the development of cryptosporidiosis. The development of cryptosporidiosis in AIDS patients may be associated with sexual risk behaviour.


Shear stress regulates angiotensin type 1 receptor expression in endothelial cells.
Shear stress (SS) has an established role in atherosclerotic plaque localization, but how it exerts its protective effect is not fully understood. To test the hypothesis that SS may downregulate angiotensin type 1 receptors (AT(1)Rs). Angiotensin II has been shown to be proinflammatory and to promote atherosclerosis. Using immunohistochemistry, we found a pronounced expression of AT(1)R in the inner, atheroprone regions of the aortic arch of C57BL/6 and endothelial NO synthase-deficient (eNOS(-/-)) mice but not eNOS-overexpressing mice. In human umbilical vein endothelial cells (HUVECs), laminar SS (15 dyn/cm(2)) induced a biphasic decrease in AT(1)R protein expression characterized by a first reduction at 1 hour (31+/-4% of static control, P<0.01), partial recovery at 3 hours (65+/-9%), and a second more prolonged decline at 6, 12, and 24 hours (48+/-9%, 36+/-9%, 33+/-5%, respectively, P<0.05). One and 24 hours of SS significantly reduced fluorescent angiotensin binding compared to static HUVECs. Shear-induced downregulation of AT(1)R was abolished by treatment with protein kinase A and G inhibitors or N(G)-nitro-l-arginine methyl ester (L-NAME). Fittingly, stimulating static HUVECs with an NO donor decreased AT(1)R protein levels. RT-PCR revealed a significant (P<0.05) decrease of AT(1)R mRNA in HUVECs exposed to SS during 3 (6+/-2% of static control), 6 (4+/-1%), 12 (4+/-1%), and 24 hours (15+/-4%), suggesting a transcriptional downregulation of AT(1)R at length. Finally, angiotensin-induced vascular cell adhesion molecule was abated in HUVECs exposed to SS and in the outer aortic arch of mice. Our results demonstrate that SS may convey some of its atheroprotective effects through downregulation of AT(1)R in endothelial cells.


Age- and gravity-related changes in facial morphology: 3-dimensional analysis of facial morphology in mother-daughter pairs.
There is increasing focus on the effects of gravity and age on facial appearance. Understanding these effects on facial morphology requires an accurate means of measuring surface topography. We present a preliminary study on the changes in facial topographic landmarks in a cohort of mothers and their daughters. The faces of mother-daughter pairs (N = 15, aged 13 to 61 years) were imaged by stereophotogrammetry in the upright and supine positions. Twenty anthropometric surface landmarks were placed, and the corresponding x, y, and z coordinates were generated with custom software. The relative excursion of each landmark from the upright to the supine position was calculated. Movement of up to 7.3 mm occurred in the horizontal (x) plane, 5.7 mm in the vertical (y) plane, and 7.6 mm in the dorsoventral (z) plane. Significant movement (P < .05) in the vertical plane occurred in the upper lip, lateral canthi, labial commissures, and gonia. There was no significant movement in the dorsoventral plane. Maximal movement occurred in the lower third of the face in both groups but was more marked in the mothers. Age- and gravity-related effects on the face can be accurately measured and documented with 3-dimensional imaging. This technique will allow comparison of rejuvenation techniques and a better understanding of the mechanisms of facial aging.


Modeling the integration of motion signals across space.
Experiments by Loffler and Orbach on the integration of motion signals across space [J. Opt. Soc. Am. A 20, 1461 (2003)] revealed that both three-dimensional analysis and object interpretation play a much smaller role than previously assumed. These results motivated the quantitative description of a low-level, bottom-up model presented here. Motion is computed in parallel at different spatial sites, and excitatory interactions operate between sites. The strength of these interactions is determined mainly by distance. Simulations correctly predict behavior for a variety of manipulations on multi-aperture stimuli: aligned and skewed lines, different presentation times, different inter-aperture gaps, and different spatial frequencies. However, strictly distance-dependent mechanisms are too simplistic to account for all experimental data. Mismatches for grossly misoriented lines suggest collinear facilitation as a promising extension. Once incorporated, collinear facilitation not only correctly predicts results for misoriented patterns but also accounts for the lack of motion integration between heterogeneous stimuli such as lines and dots.


Patients Referred to a Norwegian Trauma Centre: effect of transfer distance on injury patterns, use of resources and outcomes.
Triage and interhospital transfer are central to trauma systems. Few studies have addressed transferred trauma patients. This study investigated transfers of variable distances to OUH (Oslo University Hospital, Ullevål), one of the largest trauma centres in Europe. Patients included in the OUH trauma registry from 2001 to 2008 were included in the study. Demographic, injury, management and outcome data were abstracted. Patients were grouped according to transfer distance: ≤20 km, 21-100 km and > 100 km. Of the 7.353 included patients, 5.803 were admitted directly, and 1.550 were transferred. The number of transfers per year increased, and there was no reduction in injury severity during the study period. Seventy-six per cent of the transferred patients were severely injured. With greater transfer distances, injury severity increased, and there were larger proportions of traffic injuries, polytrauma and hypotensive patients. With shorter distances, patients were older, and head injuries and injuries after falls were more common. The shorter transfers less often activated the trauma team: ≤20 km -34%; 21-100 km -51%; > 100 km -61%, compared to 92% of all directly admitted patients. The mortality for all transferred patients was 11%, but was unequally distributed according to transfer distance. This study shows heterogeneous characteristics and high injury severity among interhospital transfers. The rate of trauma team assessment was low and should be further examined. The mortality differences should be interpreted with caution as patients were in different phases of management. The descriptive characteristics outlined may be employed in the development of triage protocols and transfer guidelines.


The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation.
The foreign body reaction (FBR) develops in response to the implantation of almost all biomaterials and can be detrimental to their function. The formation of foreign body giant cells (FBGC), which damage the surface of biomaterials, is considered a hallmark of this reaction. FBGC derive from blood-borne monocytes that enter the implantation site after surgery in response to the release of chemotactic signals. In this study, we implanted biomaterials subcutaneous (s.c.) in mice that lack the monocyte chemoattractant CC chemokine ligand 2 (CCL2) and found that biomaterials were encapsulated despite reduced FBGC formation. The latter was due to compromised macrophage fusion rather than migration. Consistent with the reduction in FBGC formation, biodegradable biomaterials sustained reduced damage in CCL2-null mice. Furthermore, blockade of CCL2 function by localized gene delivery in wild-type mice hindered FBGC formation, despite normal monocyte recruitment. The requirement for CCL2 in fusion was confirmed by the ability of both a CCL2 inhibitory peptide and an anti-CCL2 Ab to reduce FBGC formation from peripheral blood monocytes in an in vitro assay. Our findings demonstrate a previously unreported involvement of CCL2 in FBGC formation, and suggest that FBGC are not the primary determinants of capsule formation in the FBR.


Gender differences in fibrosis remodeling in patients with long-standing persistent atrial fibrillation.
The success rate of catheter ablation in atrial fibrillation (AF) is known to be lower in females than in males. However, while the exact mechanism for this phenomenon remains to be elucidated, tissue fibrosis may play an important role in this regard. It has been shown that fibrosis promotes AF and its recurrence, thereby substantially reducing the efficacy of catheter ablation in AF patients. Thus, we hypothesized that fibrosis may contribute to gender differences in the outcomes of AF catheter ablation. Here we systematically assessed pulmonary vein sleeves obtained from 166 patients with and without long-standing persistent-AF (LSP-AF) in order to identify gender-specific mechanistic differences in fibrosis remodeling of AF patients. Histological analysis revealed that the female LSP-AF group, rather than its male counterpart, had a higher degree of fibrosis when compared to the NON-AF group. Further analysis using microarray, immunohistochemistry and Western Blot displayed that gender differences in fibrosis remodeling of LSP-AF were mainly due to the inherent differential expression of fibrosis-related genes (n=32) and proteins (n=6). Especially, those related to the TGFβ/Smad3 pathway appeared to be up-regulated in the female LSP-AF group thus promoting an aggravation of fibrosis remodeling. In summary, our data suggest that the aggravation of fibrosis remodeling in women may be an important reason for the low success rate of AF catheter ablation when compared to men. Therefore, inhibiting the TGFβ/Smad3 pathway-mediated fibrosis could represent an interesting target for future therapeutic concepts to improve the success rate of AF catheter ablation in women.


The ingestible telemetric body core temperature sensor: a review of validity and exercise applications.
An ingestible telemetric temperature sensor for measuring body core temperature (Tc) was first described 45 years ago, although the method has only recently gained widespread use for exercise applications. This review aims to (1) use Bland and Altman's limits of agreement (LoA) method as a basis for quantitatively reviewing the agreement between intestinal sensor temperature (Tintestinal), oesophageal temperature (Toesophageal) and rectal temperature (Trectal) across numerous previously published validation studies; (2) review factors that may affect agreement; and (3) review the application of this technology in field-based exercise studies. The agreement between Tintestinal and Toesophageal is suggested to meet our delimitation for an acceptable level of agreement (ie, systematic bias <0.1 degrees C and 95% LoA within +/-0.4 degrees C). The agreement between Tintestinal and Trectal shows a significant systematic bias >0.1 degrees C, although the 95% LoA is acceptable. Tintestinal responds less rapidly than Toesophageal at the start or cessation of exercise or to a change in exercise intensity, but more rapidly than Trectal. When using this technology, care should be taken to ensure adequate control over sensor calibration and data correction, timing of ingestion and electromagnetic interference. The ingestible sensor has been applied successfully in numerous sport and occupational applications such as the continuous measurement of Tc in deep sea saturation divers, distance runners and soldiers undertaking sustained military training exercises. It is concluded that the ingestible telemetric temperature sensor represents a valid index of Tc and shows excellent utility for ambulatory field-based applications.


Terminal decline from within- and between-person perspectives, accounting for incident dementia.
The terminal cognitive decline hypothesis has been debated for almost 50 years. This hypothesis implies a change in rate of decline within an individual. Therefore, we examine the hypothesis from a within-person perspective using a time to death chronological structure. Scores on a Swedish version of the Wechsler Adult Intelligence Scale Information and Block Design scores from 461 OCTO-Twin Study participants with confirmed death dates were modeled using quadratic growth curve models including both age and distance from death at study entry, sex, education, and dementia diagnosis as covariates of initial performance and of linear and quadratic change over time. Information scores showed statistically significant evidence of slight within-person acceleration of declines in the no dementia group. Individuals with incident dementia declined more quickly, and those who were closer to death at study baseline had a stronger acceleration. Block Design scores declined but did not show evidence of such acceleration either within or across individuals. Decline was faster in incident cases closer to death at study entry. Within-person evidence of terminal decline is not as strong as previously published between-person results. Strategies for focusing models on longitudinal aspects of available data and the extent to which lack of within-person evidence for terminal decline may stem from common data limitations are discussed.


The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation.
Endothelium-dependent relaxations are achieved by a combination of endothelium-derived prostacyclin (PGI2), nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). However, it remains to be fully clarified whether the relative contribution of these three mechanisms to endothelium-dependent relaxations varies as a function of the vessel size. This study was designed to clarify this point. Acetylcholine (ACh)-induced endothelium-dependent relaxations were examined in isolated blood vessels taken from the aorta and the proximal and distal mesenteric arteries of the rat. The contributions of PGI2, NO, and EDHF were evaluated by the inhibitory effects of indomethacin, N omega-nitro-L-arginine methyl ester (L-NAME) in the presence of indomethacin, and KCl in the presence of indomethacin and L-NAME, respectively. The membrane potentials were recorded with microelectrodes. The expression of endothelial No synthase (eNOS) was examined by both immunostaining and immunoblotting. The contribution of PGI2 was negligible in three different-sized blood vessels. The contribution of NO was most prominent in the aorta, whereas that of EDHF was most prominent in the distal mesenteric arteries. The resting membrane potential was significantly deeper and the ACh-induced hyperpolarization was greater in the distal mesenteric arteries than those in the aorta. The expression of eNOS was the highest in the aorta and the lowest in the distal mesenteric arteries. These results indicate that the importance of EDHF increases as the vessel size decreases in endothelium-dependent relaxations in the rat mesenteric circulation.


Spatiotemporal object continuity in human ventral visual cortex.
Coherent visual experience requires that objects be represented as the same persisting individuals over time and motion. Cognitive science research has identified a powerful principle that guides such processing: Objects must trace continuous paths through space and time. Little is known, however, about how neural representations of objects, typically defined by visual features, are influenced by spatiotemporal continuity. Here, we report the consequences of spatiotemporally continuous vs. discontinuous motion on perceptual representations in human ventral visual cortex. In experiments using both dynamic occlusion and apparent motion, face-selective cortical regions exhibited significantly less activation when faces were repeated in continuous vs. discontinuous trajectories, suggesting that discontinuity caused featurally identical objects to be represented as different individuals. These results indicate that spatiotemporal continuity modulates neural representations of object identity, influencing judgments of object persistence even in the most staunchly "featural" areas of ventral visual cortex.


Quantitative comparison of the OCT imaging depth at 1300 nm and 1600 nm.
One of the present challenges in optical coherence tomography (OCT) is the visualization of deeper structural morphology in biological tissues. Owing to a reduced scattering, a larger imaging depth can be achieved by using longer wavelengths. In this work, we analyze the OCT imaging depth at wavelengths around 1300 nm and 1600 nm by comparing the scattering coefficient and OCT imaging depth for a range of Intralipid concentrations at constant water content. We observe an enhanced OCT imaging depth for 1600 nm compared to 1300 nm for Intralipid concentrations larger than 4 vol.%. For higher Intralipid concentrations, the imaging depth enhancement reaches 30%. The ratio of scattering coefficients at the two wavelengths is constant over a large range of scattering coefficients and corresponds to a scattering power of 2.8 ± 0.1. Based on our results we expect for biological tissues an increase of the OCT imaging depth at 1600 nm compared to 1300 nm for samples with high scattering power and low water content.


Regulatory and functional connection of microphthalmia-associated transcription factor and anti-metastatic pigment epithelium derived factor in melanoma.
Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.


Venom ophthalmia caused by venoms of spitting elapid and other snakes: Report of ten cases with review of epidemiology, clinical features, pathophysiology and management.
Venom ophthalmia caused by venoms of spitting elapid and other snakes: report of ten cases with review of epidemiology, clinical features, pathophysiology and management. Chu, ER, Weinstein, SA, White, J and Warrell, DA. Toxicon XX:xxx-xxx. We present ten cases of ocular injury following instillation into the eye of snake venoms or toxins by spitting elapids and other snakes. The natural history of spitting elapids and the toxinology of their venoms are reviewed together with the medical effects and management of venom ophthalmia in humans and domestic animals including both direct and allergic effects of venoms. Although the clinical features and management of envenoming following bites by spitting elapids (genera Naja and Hemachatus) are well documented, these snakes are also capable of "spraying" venom towards the eyes of predators, a defensive strategy that causes painful and potentially blinding ocular envenoming (venom ophthalmia). Little attention has been given to the detailed clinical description, clinical evolution and efficacy of treatment of venom ophthalmia and no clear management guidelines have been formulated. Knowledge of the pathophysiology of ocular envenoming is based largely on animal studies and a limited body of clinical information. A few cases of ocular exposure to venoms from crotaline viperids have also been described. Venom ophthalmia often presents with pain, hyperemia, blepharitis, blepharospasm and corneal erosions. Delay or lack of treatment may result in corneal opacity, hypopyon and/or blindness. When venom is "spat" into the eye, cranial nerve VII may be affected by local spread of venom but systemic envenoming has not been documented in human patients. Management of venom ophthalmia consists of: 1) urgent decontamination by copious irrigation 2) analgesia by vasoconstrictors with weak mydriatic activity (e.g. epinephrine) and limited topical administration of local anesthetics (e.g. tetracaine) 3) exclusion of corneal abrasions by fluorescein staining with a slit lamp examination and application of prophylactic topical antibiotics 4) prevention of posterior synechiae, ciliary spasm and discomfort with topical cycloplegics and 5) antihistamines in case of allergic kerato-conjunctivitis. Topical or intravenous antivenom and topical corticosteroids are contraindicated. Clinical outcome of venom ophthalmia is largely dependent on prompt treatment and appropriate follow-up.