Are physical and mental abilities of older people related to gonadotropins and steroid hormones levels?
Aging is characterized by deep alterations of hormone secretion. In majority, hormone secretion, except gonadotropins, undergoes a pronounced decrease which is thought to contribute to the progression of aging. The recent data indicate that gonadotropin excess may also by itself influence the aging process. The aim of the present study was to investigate the relations between gonadotropins and steroid hormones with physical and mental abilities of older people. In a group of patients aged over 75 years, concentrations of FSH, LH, estradiol, testosterone, DHEAs and cortisol were measured. The mental ability was estimated by MMSE and CDT and the physical ability by TUG and SPPB tests. The positive correlation between SPPB scores and FSH and the negative correlations of SPPB with LH/FSH ratio were observed in men. The correlation of TUG scores and estradiol levels was also noted in men. The positive correlation between CDT scores and FSH in women and the negative correlation between CDT and LH/FSH ratio in men were found. The correlation between the results of CDT and cortisol levels in men was also observed. Thus, we did not confirm the simple deleterious effect of gonadotropins on cognitive abilities. FSH and LH seem exert different (antagonistic?) effects on cognitive functions, but this hypothesis needs further studies.


COVID-19 and liver surgery in France, Italy, Japan, and the United States: A report of a single topic conference of Eastern and Western Association for Liver Tumors (EWALT) 2021.
The Eastern and Western Association for Liver Tumors (EWALT) is an international association for clinical and basic scientists dedicated to worldwide study on hepatocellular carcinoma. A single topic conference of EWALT on "COVID-19 and Liver Surgery" was held online on April 23th, 2021. The presenters from France, Italy, Japan, and the United States, reported the current situation of COVID-19 in each country and the influence on the clinical practice and education in hepato-pancreato-biliary surgery. Here we would like to summarize the core of this single topic conference.


Retrograde, transneuronal spread of pseudorabies virus in defined neuronal circuitry of the rat brain is facilitated by gE mutations that reduce virulence.
The pseudorabies virus (PRV) gE gene encodes a multifunctional membrane protein found in infected cell membranes and in the virion envelope. Deletion of the gE gene results in marked attenuation of the virus in almost every animal species tested that is permissive for PRV. A common inference is that gE mutants are less virulent because they have reduced ability to spread from cell to cell; e.g., gE mutants infect fewer cells and, accordingly, animals live longer. In this report, we demonstrate that this inference does not hold in a rat experimental model for virus invasion of the brain. We find that animals infected with gE mutants live longer despite extensive retrograde, transneuronal spread of virus in the rat brain. In this model of brain infection, virus is injected into the stomach musculature and virions spread to the brain in long axons of brain stem neurons that give rise to the tenth cranial nerve (the vagus). The infection then spreads from neuron to neuron in well-defined, and physically separated, areas of the brain involved in autonomic regulation of the viscera. We examined the progression of infection of five PRV strains in this circuitry: the wild-type PRV-Becker strain, the attenuated PRV-Bartha vaccine strain, and three gE mutants isogenic with the PRV-Becker strain. By 60 to 67 h after infection, all PRV-Becker-infected animals were dead. Analysis of Becker-infected rats killed prior to virus-induced death demonstrated that the virus had established an infection only in the primary vagal neurons connected directly to the stomach and synaptically linked neurons in the immediate vicinity of the caudal brain stem. There was little spread to other neurons in the vagus circuitry. In contrast, rats infected with PRV-Bartha or PRV-Becker gE mutants survived to at least 96 h and exhibited few overt signs of disease. Despite this long survival and the lack of symptoms, brains of animals sacrificed at this time revealed extensive transsynaptic infection not only of the brain stem but also of areas of the forebrain synaptically linked to neurons in the brain stem. This finding provides evidence that the gE protein plays a role in promoting symptoms of infection and death in animals that is independent of neuron-to-neuron spread during brain infection. When this early virulence function is not active, animals live longer, resulting in more extensive spread of virus in the brain.


Choosing and using screening criteria for palliative care consultation in the ICU: a report from the Improving Palliative Care in the ICU (IPAL-ICU) Advisory Board.
To review the use of screening criteria (also known as "triggers") as a mechanism for engaging palliative care consultants to assist with care of critically ill patients and their families in the ICU. We searched the MEDLINE database from inception to December 2012 for all English-language articles using the terms "trigger," "screen," "referral," "tool," "triage," "case-finding," "assessment," "checklist," "proactive," or "consultation," together with "intensive care" or "critical care" and "palliative care," "supportive care," "end-of-life care," or "ethics." We also hand-searched reference lists and author files and relevant tools on the Center to Advance Palliative Care website. Two members (a physician and a nurse with expertise in clinical research, intensive care, and palliative care) of the interdisciplinary Improving Palliative Care in the ICU Project Advisory Board presented studies and tools to the full Board, which made final selections by consensus. We critically reviewed the existing data and tools to identify screening criteria for palliative care consultation, to describe methods for selecting, implementing, and evaluating such criteria, and to consider alternative strategies for increasing access of ICU patients and families to high-quality palliative care. The Improving Palliative Care in the ICU Advisory Board used data and experience to address key questions relating to: existing screening criteria; optimal methods for selection, implementation, and evaluation of such criteria; and appropriateness of the screening approach for a particular ICU. Use of specific criteria to prompt proactive referral for palliative care consultation seems to help reduce utilization of ICU resources without changing mortality, while increasing involvement of palliative care specialists for critically ill patients and families in need. Existing data and resources can be used in developing such criteria, which should be tailored for a specific ICU, implemented through an organized process involving key stakeholders, and evaluated by appropriate measures. In some settings, other strategies for increasing access to palliative care may be more appropriate.


Intravital imaging reveals improved Kupffer cell-mediated phagocytosis as a mode of action of glycoengineered anti-CD20 antibodies.
Anti-CD20 monoclonal antibodies (mAbs) represent an effective treatment for a number of B cell malignancies and autoimmune disorders. Glycoengineering of anti-CD20mAb may contribute to increased anti-tumor efficacy through enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP) as reported by in vitro studies. However, where and how glycoengineered Ab may potentiate therapeutic responses in vivo is yet to be elucidated. Here, we have performed mouse liver transplants to demonstrate that the liver is sufficient to mediate systemic B cells depletion after anti-CD20 treatment. Relying on intravital two-photon imaging of human CD20-expressing mice, we provide evidence that ADP by Kupffer cells (KC) is a major mechanism for rituximab-mediated B cell depletion. Notably, a glycoengineered anti-mouse CD20 Ab but not its wild-type counterpart triggered potent KC-mediated B cell depletion at low doses. Finally, distinct thresholds for KC phagocytosis were also observed for GA101 (obinutuzumab), a humanized glycoengineered type II anti-CD20 Ab and rituximab. Thus, we propose that enhanced phagocytosis of circulating B cells by KC represents an important in vivo mechanism underlying the improved activity of glycoengineered anti-CD20 mAbs.


Mechanistic and structural analysis of human spermidine/spermine N1-acetyltransferase.
The N1-acetylation of spermidine and spermine by spermidine/spermine acetyltransferase (SSAT) is a crucial step in the regulation of the cellular polyamine levels in eukaryotic cells. Altered polyamine levels are associated with a variety of cancers as well as other diseases, and key enzymes in the polyamine pathway, including SSAT, are being explored as potential therapeutic drug targets. We have expressed and purified human SSAT in Escherichia coli and characterized its kinetic and chemical mechanism. Initial velocity and inhibition studies support a random sequential mechanism for the enzyme. The bisubstrate analogue, N1-spermine-acetyl-coenzyme A, exhibited linear, competitive inhibition against both substrates with a true Ki of 6 nM. The pH-activity profile was bell-shaped, depending on the ionization state of two groups exhibiting apparent pKa values of 7.27 and 8.87. The three-dimensional crystal structure of SSAT with bound bisubstrate inhibitor was determined at 2.3 A resolution. The structure of the SSAT-spermine-acetyl-coenzyme A complex suggested that Tyr140 acts as general acid and Glu92, through one or more water molecules, acts as the general base during catalysis. On the basis of kinetic properties, pH dependence, and structural information, we propose an acid/base-assisted reaction catalyzed by SSAT, involving a ternary complex.


Chromosomal double-strand break repair in Ku80-deficient cells.
The x-ray sensitive hamster cell line xrs-6 is deficient in DNA double-strand break (DSB) repair and exhibits impaired V(D)J recombination. The molecular defect in this line is in the 80-kDa subunit of the Ku autoantigen, a protein that binds to DNA ends and recruits the DNA-dependent protein kinase to DNA. Using an I-SceI endonuclease expression system, chromosomal DSB repair was examined in xrs-6 and parental CHO-K1 cell lines. A DSB in chromosomal DNA increased the yield of recombinants several thousand-fold above background in both the xrs-6 and CHO-K1 cells, with recombinational repair of DSBs occurring in as many as 1 of 100 cells electroporated with the endonuclease expression vector. Thus, recombinational repair of chromosomal DSBs can occur at substantial levels in mammalian cells and it is not grossly affected in our assay by a deficiency of the Ku autoantigen. Rejoining of broken chromosome ends (end-joining) near the site of the DSB was also examined. In contrast to recombinational repair, end-joining was found to be severely impaired in the xrs-6 cells. Thus, the Ku protein appears to play a critical role in only one of the chromosomal DSB repair pathways.


Michaelmoelleria (Gesneriaceae), a new lithophilous dwelling genus and species with zigzag corolla tube from southern Vietnam.
Michaelmoelleria, a new genus from southern Vietnam is described with a single species, M. vietnamensis. The new genus is morphologically most similar to Deinostigma and Tribounia but it differs from the latter two by having four fertile stamens. Nuclear ribosomal internal transcribed spacer (ITS) region and plastid trnL-F intron spacer (trnL-F) DNA sequence data from the new genus and eighty-seven species representing 42 genera within tribe Didymocarpeae are used to resolve its generic placement. The molecular evidence reveals that it is most closely related to Cathayanthe rather than Deinostigma and Tribounia. The chromosome number is counted as 2n = 36 that further clarified its distinction comparing to the related genera within tribe Didymocarpeae. A global conservation assessment is also performed and classifies Michaelmoelleria vietnamensis as Critically Endangered (CR).


Surface-concentrated light and efficient carrier collection in microhole-patterned Si solar cells.
We investigate photovoltaic characteristics of crystalline Si solar cells with microhole-patterned surface. We compare patterned samples with different hole-widths and periods with a planar counterpart. From the finite-difference time-domain simulation, the patterned and planar samples are expected to have similar short circuit current density, J(sc) (difference: 1.2%). In contrast, the difference in the measured J(sc) is as large as 12.6%. The simulated optical field patterns reveal that the sample with more significantly concentrated light near the surface has higher quantum efficiency due to more efficient carrier collection. We report the highest efficiency of 15.6% among the hole-patterned solar cells.


Genome-wide RNA polymerase II profiles and RNA accumulation reveal kinetics of transcription and associated epigenetic changes during diurnal cycles.
Interactions of cell-autonomous circadian oscillators with diurnal cycles govern the temporal compartmentalization of cell physiology in mammals. To understand the transcriptional and epigenetic basis of diurnal rhythms in mouse liver genome-wide, we generated temporal DNA occupancy profiles by RNA polymerase II (Pol II) as well as profiles of the histone modifications H3K4me3 and H3K36me3. We used these data to quantify the relationships of phases and amplitudes between different marks. We found that rhythmic Pol II recruitment at promoters rather than rhythmic transition from paused to productive elongation underlies diurnal gene transcription, a conclusion further supported by modeling. Moreover, Pol II occupancy preceded mRNA accumulation by 3 hours, consistent with mRNA half-lives. Both methylation marks showed that the epigenetic landscape is highly dynamic and globally remodeled during the 24-hour cycle. While promoters of transcribed genes had tri-methylated H3K4 even at their trough activity times, tri-methylation levels reached their peak, on average, 1 hour after Pol II. Meanwhile, rhythms in tri-methylation of H3K36 lagged transcription by 3 hours. Finally, modeling profiles of Pol II occupancy and mRNA accumulation identified three classes of genes: one showing rhythmicity both in transcriptional and mRNA accumulation, a second class with rhythmic transcription but flat mRNA levels, and a third with constant transcription but rhythmic mRNAs. The latter class emphasizes widespread temporally gated posttranscriptional regulation in the mouse liver.


Dfam: a database of repetitive DNA based on profile hidden Markov models.
We present a database of repetitive DNA elements, called Dfam (http://dfam.janelia.org). Many genomes contain a large fraction of repetitive DNA, much of which is made up of remnants of transposable elements (TEs). Accurate annotation of TEs enables research into their biology and can shed light on the evolutionary processes that shape genomes. Identification and masking of TEs can also greatly simplify many downstream genome annotation and sequence analysis tasks. The commonly used TE annotation tools RepeatMasker and Censor depend on sequence homology search tools such as cross_match and BLAST variants, as well as Repbase, a collection of known TE families each represented by a single consensus sequence. Dfam contains entries corresponding to all Repbase TE entries for which instances have been found in the human genome. Each Dfam entry is represented by a profile hidden Markov model, built from alignments generated using RepeatMasker and Repbase. When used in conjunction with the hidden Markov model search tool nhmmer, Dfam produces a 2.9% increase in coverage over consensus sequence search methods on a large human benchmark, while maintaining low false discovery rates, and coverage of the full human genome is 54.5%. The website provides a collection of tools and data views to support improved TE curation and annotation efforts. Dfam is also available for download in flat file format or in the form of MySQL table dumps.


On-line species-unspecific isotope dilution analysis in the picomolar range reveals the time- and species-depending mercury uptake in human astrocytes.
In order to reveal the time-depending mercury species uptake by human astrocytes, a novel approach for total mercury analysis is presented, which uses an accelerated sample introduction system combined on-line with an inductively coupled plasma mass spectrometer equipped with a collision/reaction cell. Human astrocyte samples were incubated with inorganic mercury (HgCl2), methylmercury chloride (MeHgCl), and thimerosal. After 1-h incubation with Hg(2+), cellular concentrations of 3 μM were obtained, whereas for organic species, concentrations of 14-18 μM could be found. After 24 h, a cellular accumulation factor of 0.3 was observed for the cells incubated with Hg(2+), whereas the organic species both showed values of about 5. Due to the obtained steady-state signals, reliable results with relative standard deviations of well below 5 % and limits of detection in the concentration range of 1 ng L(-1) were obtained using external calibration and species-unspecific isotope dilution analysis approaches. The results were further validated using atomic fluorescence spectrometry.


Interpreting quantifier scope ambiguity: evidence of heuristic first, algorithmic second processing.
The present work suggests that sentence processing requires both heuristic and algorithmic processing streams, where the heuristic processing strategy precedes the algorithmic phase. This conclusion is based on three self-paced reading experiments in which the processing of two-sentence discourses was investigated, where context sentences exhibited quantifier scope ambiguity. Experiment 1 demonstrates that such sentences are processed in a shallow manner. Experiment 2 uses the same stimuli as Experiment 1 but adds questions to ensure deeper processing. Results indicate that reading times are consistent with a lexical-pragmatic interpretation of number associated with context sentences, but responses to questions are consistent with the algorithmic computation of quantifier scope. Experiment 3 shows the same pattern of results as Experiment 2, despite using stimuli with different lexical-pragmatic biases. These effects suggest that language processing can be superficial, and that deeper processing, which is sensitive to structure, only occurs if required. Implications for recent studies of quantifier scope ambiguity are discussed.


Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma.
Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management.


Effect of caffeine on LT, VT and HRVT.
Caffeine has many diverse physiological effects including central nervous system stimulation. Ventilatory threshold and a recently described heart rate variability threshold both have a relationship with autonomic control that could be altered by caffeine consumption. The purpose of this investigation was to determine the influence of caffeine on lactate, ventilatory, and heart rate variability thresholds during progressive exercise. Using a randomized placebo controlled, double-blind study design, 10 adults performed 2 graded maximal cycle ergometry tests with and without caffeine (5 mg·kg⁻¹). Respiratory gas exchange, blood lactate concentrations, and heart rate variability data were obtained at baseline and throughout exercise. At rest, caffeine (p<0.05) increased blood lactate, oxygen consumption, carbon dioxide production, and minute ventilation. For indices of heart rate variability at rest, caffeine increased (p<0.05) the coefficient of variation, while standard deviation, and mean successive difference displayed non-significant increases. During progressive exercise, minute ventilation volumes were higher in caffeine trials but no other parameters were significantly different compared to placebo tests. These data demonstrate the robustness of the lactate, ventilatory and heart rate variability thresholds when challenged by a physiological dose of caffeine.


Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-κB inhibitors in ovarian cancer therapy.
Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor growth. A combination of these agents results in a synergistic effect. Furthermore, mda-7/IL-24 induction by NSAIDs is essential for programmed cell death, since inhibition of mda-7/IL-24 by small interfering RNA abrogates apoptosis. mda-7/IL-24 activation leads to upregulation of growth arrest and DNA damage inducible (GADD) 45 α and γ and JNK activation. The NF-κB family of transcription factors has been implicated in ovarian cancer development. We previously established NF-κB/IκB signaling as an essential step for cell survival in cancer cells and hypothesized that targeting NF-κB could potentiate NSAID-mediated apoptosis induction in ovarian cancer cells. Indeed, combining NSAID treatment with NF-κB inhibitors led to enhanced apoptosis induction. Our results indicate that inhibition of NF-κB in combination with activation of mda-7/IL-24 expression may lead to a new combinatorial therapy for ovarian cancer.


Penicillin-binding component of Bacillus cereus.
(14)C-penicillin is irreversibly bound by Bacillus cereus 569. Incubation of penicillin-treated cells in a cell wall digestion medium results in solubilization of approximately 60% of the irreversibly bound lable. The extent of the solubilization is the same when cells are prepared by either a cold or 37 C treatment procedure. However, spheroplasts prepared by the cold treatment are leaky. When the resulting spheroplasts are incubated in supplemented medium, reduced rates and levels of penicillinase synthesis, relative to induced whole-cell controls, are observed. Spheroplasts from both cold and 37 C prepared cells exhibit this phenomena, although the spheroplasts from 37 C prepared cells synthesized approximately sixfold higher levels of penicillinase. The size distribution of the label solubilized during the preparation of spheroplasts was examined by using Bio Gel P-150 columns. Although no label appeared in the exclusion volume fractions when the cell wall digest of the 37 C treated cells was chromatographed, approximately 10% of the label from cold-treated cells did appear. These results suggest that the presence of irreversibly bound penicillin is required for the synthesis of induced levels of penicillinase and that the irreversibly bound penicillin can be solubilized as a labile complex with material which is excluded from BioGel P-150. It may be concluded that the penicillin-binding lipoprotein complex which has been previously observed is the penicillin-specific binding site. However, the location of this complex in relation to the cell membrane could not be determined.


Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care.
Benzodiazepines are extensively used in primary care, but their long-term use is associated with adverse health outcomes and dependence. To analyse the efficacy of two structured interventions in primary care to enable patients to discontinue long-term benzodiazepine use. A multicentre three-arm cluster randomised controlled trial was conducted, with randomisation at general practitioner level (trial registration ISRCTN13024375). A total of 532 patients taking benzodiazepines for at least 6 months participated. After all patients were included, general practitioners were randomly allocated (1:1:1) to usual care, a structured intervention with follow-up visits (SIF) or a structured intervention with written instructions (SIW). The primary end-point was the last month self-declared benzodiazepine discontinuation confirmed by prescription claims at 12 months. At 12 months, 76 of 168 (45%) patients in the SIW group and 86 of 191 (45%) in the SIF group had discontinued benzodiazepine use compared with 26 of 173 (15%) in the control group. After adjusting by cluster, the relative risks for benzodiazepine discontinuation were 3.01 (95% CI 2.03-4.46, P<0.0001) in the SIW and 3.00 (95% CI 2.04-4.40, P<0.0001) in the SIF group. The most frequently reported withdrawal symptoms were insomnia, anxiety and irritability. Both interventions led to significant reductions in long-term benzodiazepine use in patients without severe comorbidity. A structured intervention with a written individualised stepped-dose reduction is less time-consuming and as effective in primary care as a more complex intervention involving follow-up visits.


Looking on the bright side of serotonin transporter gene variation.
Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for depression in interaction with psychosocial adversity across the life span. However, genetically driven deficient serotonin transporter (5-HTT) function would not have been maintained throughout evolution if it only exerted negative effects without conveying any gain of function. Here, we review recent findings that humans and nonhuman primates carrying the s variant of the 5-HTTLPR outperform subjects carrying the long allele in an array of cognitive tasks and show increased social conformity. In addition, studies in 5-HTT knockout rodents are included that provide complementary insights in the beneficial effects of the 5-HTTLPR s-allele. We postulate that hypervigilance, mediated by hyperactivity in corticolimbic structures, may be the common denominator in the anxiety-related traits and (social) cognitive superiority of s-allele carriers and that environmental conditions determine whether a response will turn out to be negative (emotional) or positive (cognitive, in conformity with the social group). Taken together, these findings urge for a conceptual change in the current deficit-oriented connotation of the 5-HTTLPR variants. In fact, these factors may counterbalance or completely offset the negative consequences of the anxiety-related traits. This notion may not only explain the modest effect size of the 5-HTTLPR and inconsistent reports but may also lead to a more refined appreciation of allelic variation in 5-HTT function.


Genetic divergence between the Wistar-Kyoto rat and the spontaneously hypertensive rat.
A method of restriction fragment length polymorphism (RFLP) analysis was used to estimate the amount of genetic divergence between the spontaneously hypertensive rat (SHR) strain and the Wistar-Kyoto (WKY) strain. DNA from each strain was digested with eight restriction endonucleases and hybridized with six single copy gene sequences. The number of hybridization bands in each digestion was used to estimate the total number of bases analyzed and RFLPs were scored as single mutations. Divergence was then estimated by dividing the number of mutations by the number of bases analyzed. In a total of 808 bases analyzed in WKY rats, a minimum of 13 mutations were scored in SHR, which yields a nucleotide divergence of 1 change per 62 bp. This is an extremely high amount of divergence given the known origin of these two strains and is comparable to the maximum divergence possible between unrelated humans.


Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation.
Inflammation plays a role in the pathophysiology of depression. Sulforaphane (SFN), an isothiocyanate compound derived from broccoli, is a potent activator of the NF-E2-related factor-2 (Nrf2), which plays a role in inflammation. In this study, we examined whether the prevention effects of SFN in lipopolysaccharide (LPS) induced depression-like behavior in mice. Pretreatment with SFN significantly blocked an increase in the serum tumor necrosis factor-α (TNF-α) level and an increase in microglial activation of brain regions after a single administration of LPS (0.5 mg/kg). Furthermore, SFN significantly potentiated increased serum levels of IL-10 after LPS administration. In the tail-suspension test and forced swimming test, SFN significantly attenuated an increase of the immobility time after LPS administration. In addition, SFN significantly recovered to control levels for LPS-induced alterations in the proteins such as brain-derived neurotrophic factor, postsynaptic density protein 95 and AMPA receptor 1 (GluA1) and dendritic spine density in the brain regions. Finally, dietary intake of 0.1% glucoraphanin (a glucosinolate precursor of SFN) food during the juvenile and adolescence could prevent the onset of LPS-induced depression-like behaviors and dendritic spine changes in the brain regions at adulthood. In conclusion, these findings suggest that dietary intake of SFN-rich broccoli sprout has prophylactic effects on inflammation-related depressive symptoms. Therefore, supplementation of SFN-rich broccoli sprout could be prophylactic vegetable to prevent or minimize the relapse by inflammation in the remission state of depressed patients.


Minimal important differences and response shift in health-related quality of life; a longitudinal study in patients with multiple myeloma.
We previously reported that changes of 6-17 percent in the EORTC QLQ-C30 scores are regarded important by patients with multiple myeloma and thus may be considered as Minimal Important Differences (MIDs). However, patients' internal standard of measurement may have changed over time (response shift, RS). In the present work, we evaluated whether myeloma patients experience RS and if this could affect the MID-estimates. Between 2006 and 2008, 239 patients with multiple myeloma completed the EORTC QLQ-C30 at baseline (T1) and after three months (T2). At T2, patients were asked if they had noticed any change in the domains pain, fatigue, physical function and global quality of life. They were also asked to give a retrospective judgment of their baseline values on all the four domains. We found clear evidence of RS in myeloma patients. However, there were differences in both magnitude and direction between patients who stated that they improved and those who deteriorated. Deteriorating patients retrospectively reported better health-related quality of life at T1 for the domains pain, fatigue and physical function. In these patients, MIDs adjusted for RS were observed to increase up to 12 percentage points. In contrast, for patients stating that they improved, we only found evidence of statistically significant RS in the domain global quality of life. MIDs estimated from pre-test/post-test data appeared to be robust against RS in patients reporting improvement over 3-months. This could indicate that RS has a minimal impact on the results in patients who respond to treatment, and that RS may not have an important impact on interpretation of changes reported in clinical trials where an improvement occurs.Although the effect sizes of the RSs were small, RS in deteriorating patients may have an important impact on the interpretation of changes reported in clinical trials.


Serum vitamin D and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition (EPIC).
Results from the majority of studies show little association between circulating concentrations of vitamin D and prostate cancer risk, a finding that has not been demonstrated in a wider European population, however. The authors examined whether vitamin D concentrations were associated with prostate cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (1994-2000). Serum concentrations of 25-hydroxyvitamin D were measured in 652 prostate cancer cases matched to 752 controls from 7 European countries after a median follow-up time of 4.1 years. Conditional logistic regression models were used to calculate odds ratios for prostate cancer risk in relation to serum 25-hydroxyvitamin D after standardizing for month of blood collection and adjusting for covariates. No significant association was found between 25-hydroxyvitamin D and risk of prostate cancer (highest vs. lowest quintile: odds ratio = 1.28, 95% confidence interval: 0.88, 1.88; P for trend = 0.188). Subgroup analyses showed no significant heterogeneity by cancer stage or grade, age at diagnosis, body mass index, time from blood collection to diagnosis, or calcium intake. In summary, the results of this large nested case-control study provide no evidence in support of a protective effect of circulating concentrations of vitamin D on the risk of prostate cancer.


Late presentation to HIV care despite good access to health services: current epidemiological trends and how to do better.
In 2014, there were 36.9 million people worldwide living with human immunodeficiency virus (PLWH), of whom 17.1 million did not know they were infected. Whilst the number of new human immunodeficiency virus (HIV) infections has declined globally since 2000, there are still regions where new infection rates are rising, and diagnosing HIV early in the course of infection remains a challenge. Late presentation to care in HIV refers to individuals newly presenting for HIV care with a CD4 count below 350 cells/µl or with an acquired immune deficiency syndrome (AIDS)-defining event. Late presentation is associated with increased patient morbidity and mortality, healthcare costs and risk of onward transmission by individuals unaware of their status. Further, late presentation limits the effectiveness of all subsequent steps in the cascade of HIV care. Recent figures from 34 countries in Europe show that late presentation occurs in 38.3% to 49.8% of patients newly presenting for care, depending on region. In Switzerland, data from patients enrolled in the Swiss HIV Cohort Study put the rate of late presentation at 49.8% and show that patients outside established HIV risk groups are most likely to be late presenters. Provider-initiated testing needs to be improved to reach these groups, which include heterosexual men and women and older patients. The aim of this review is to describe the scale and implications of late presentation using cohort data from Switzerland and elsewhere in Europe, and to highlight initiatives to improve early HIV diagnosis. The importance of recognising indicator conditions and the potential for missed opportunities for HIV testing is illustrated in three clinical case studies.


Bacteriophage-mediated acquisition of antibiotic resistance by Staphylococcus aureus type 88.
Antibiotic-resistant Staphylococcus aureus strains of phage type 88, lysogenic for phage 188, when grown in mixed culture with a nonlysogenic novobiocin-resistant strain, acquired novobiocin resistance at a high rate from the nonlysogenic strain. With most strains of phage type 88, there was no detectable transfer of resistance from lysogenic to nonlysogenic cells. Lysogenization with phage 188 of phage-sensitive strains conferred on the lysogenized cells the ability to acquire chromosome and plasmid resistance markers. The acquisition of novobiocin resistance in liquid cultures depended on the aeration of the culture, cell density, and the presence of Ca2+. Pronase, and to a lesser degree other proteinases, increased the rate of acquisition of chromosome- and plasmid-determined resistance markers by cells lysogenic for phage 188.


Differentiation of Streptococcus uberis from Streptococcus parauberis by polymerase chain reaction and restriction fragment length polymorphism analysis of 16S ribosomal DNA.
Streptococcus uberis type II has been proposed recently as a separate species designated Streptococcus parauberis (A. M. Williams and M. D. Collins, J. Appl. Bacteriol. 68:485-490, 1990). Differentiation of S. parauberis from S. uberis has been possible only by DNA-DNA hybridization or 16S rRNA sequencing, since the biochemical and serological characteristics of the two species are indistinguishable. A simple and reliable technique was developed for differentiating S. parauberis (S. uberis type II [ATCC 13386]) from S. uberis (S. uberis type I [ATCC 9927, ATCC 13387, and ATCC 27958]) by restriction fragment length polymorphism (RFLP) analysis of 1.4-kb 16S ribosomal DNA (rDNA). Oligonucleotide primers complementary to 16S rRNA genes were used to amplify 16S ribosomal gene fragments from genomic DNA by polymerase chain reaction. The 1.4-kb 16S rDNA fragment was digested with ScaI, NspI, DdeI, and AvaII restriction endonucleases. Restriction fragments produced by all four restriction endonucleases were characteristic for each species. RFLP analysis of 16S rDNA from 24 "S. uberis" isolates obtained from mammary secretions of dairy cows indicated that all 24 isolates were indeed S. uberis.


Does idiopathic parkinsonism in Aberdeen follow intrauterine influenza?
A study is presented which fails to replicate a recent report that peak years of birth of patients later developing Parkinson's disease are related to the influenza pandemics of the period 1890-1930. The years of birth of a whole population cohort of 243 patients suffering from Parkinson's disease examined in Aberdeen in 1983 and reexamined in 1986/7 were compared with deaths due to influenza in the City of Aberdeen in the years 1900-1930. Although a significant peak of Parkinson births (compared with the age profile of the Aberdeen population in 1983) occurred in 1902, there appeared to be no systematic relationship between Parkinson births and influenza deaths. In addition, no season of birth effect could be detected in a comparison with 232 matched controls. The presence of peaks of birth years, for whatever aetiological reason, is of significance to epidemiological studies in that prevalence estimates may be influenced by the year of study relative to these mini-cohorts.


The Effects of Aerobic Exercise on Cognitive Function of Alzheimer's Disease Patients.
To evaluate the effect of moderate intensity of aerobic exercise on elderly people with mild Alzheimer's disease, we recruited fifty volunteers aged 50 years to 80 years with cognitive impairment. They were randomized into two groups: aerobic group (n=25) or control group (n=25). The aerobic group was treated with cycling training at 70% of maximal intensity for 40 min/d, 3 d/wk for 3 months. The control group was only treated with heath education. Both groups were received cognitive evaluation, laboratory examination before and after 3 months. The results showed that the Minimum Mental State Examination score, Quality of Life Alzheimer's Disease score and the plasma Apo-a1 level was significantly increased (P<0.05), the Alzheimer's Disease Assessment Scale-cognition score, Neuropsychiatric Inventory Questionnaire score was significantly decreased.(P<0.05) in aerobic group before and after 3 months in aerobic group. For the control group, there was no significant difference in scores of Alzheimer's Disease Assessment Scale-cognition, Neuropsychiatric Inventory Questionnaire, Quality of Life Alzheimer's Disease, Apo-a1 (P>0.05), while Minimum Mental State Examination scores decreased significantly after 3 months (P<0.05). In conclusion, moderate intensity of aerobic exercise can improve cognitive function in patients with mild Alzheimer's disease.


Perioperative Medical Management of Spine Surgery Patients With Osteoporosis.
Management of spine surgery patients with osteoporosis is challenging because of the difficulty of instrumenting and the potential complications, including nonunion and adjacent level fractures. Treatment of this patient population should involve a multidisciplinary approach including the spine surgeon, primary care physician, endocrinologist, and physical therapist. Indication for preoperative treatment before spinal fusion surgery is unclear. All patients should receive calcium and vitamin D. Hormone replacement therapy, including estrogen or selective estrogen receptor modulators, should be considered for elderly female patients with decreased bone mass. Bisphosphonates or intermittent parathyroid hormone are reserved for those with significant bone loss in the spine. Pretreatment with antiresorption medications affect bone remodeling, which is a vital part of graft incorporation and fusion. Although there have been numerous animal studies, there is limited clinical evidence. Accordingly, surgery should be delayed, if possible, to treat the osteoporosis before the intervention. Treatment may include bisphosphonates, as well as newer agents, such as recombinant parathyroid hormone. Further clinical data are needed to understand the relative advantages/disadvantage of antiresorptive vs anabolic agents, as well as the impact of administration of these medications before vs after fusion surgery. Future clinical studies will enable better understanding of the impact of current therapies on biomechanics and fusion outcomes in this unique and increasingly prevalent patient population.


Synthesis and mass cytometric analysis of lanthanide-encoded polyelectrolyte microgels.
This article describes the synthesis and characterization of two series of functional polyelectrolyte copolymer microgels intended for bioassays based upon mass cytometry, a technique that detects metals by inductively coupled plasma mass spectrometry (ICP-MS). The microgels were loaded with Eu(III) ions, which were then converted in situ to EuF(3) nanoparticles (NPs). Both types of microgels are based upon copolymers of N-isopropylacrylamide (NIPAm) and methacrylic acid (MAA), poly(NIPAm/VCL/MAA) (VCL = N-vinylcaprolactam, V series), and poly(NIPAm/MAA/PEGMA) (PEGMA = poly(ethylene glycol)methacrylate, PG series). Very specific conditions (full neutralization of the MAA groups) were required to confine the EuF(3) NPs to the core of the microgels. We used mass cytometry to measure the number and the particle-to-particle variation of Eu ions per microgel. By controlling the amount of EuCl(3) added to the neutralized microgels. we could vary the atomic content of individual microgels from ca. 10(6) to 10(7) Eu atoms, either in the form of Eu(3+) ions or EuF(3) NPs. Leaching profiles of Eu ions from the hybrid microgels were measured by traditional ICP-MS.


Allele frequencies for candidate genes in atherosclerosis and diabetes among Trinidadian neonates.
Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations.


Relationship between retinal blood flow and arterial oxygen.
Vascular reactivity, the response of the vessels to a vasoactive stimulus such as hypoxia and hyperoxia, can be used to assess the vascular range of adjustment in which the vessels are able to compensate for changes in PO2. Previous studies in the retina have not accurately quantified retinal vascular responses and precisely targeted multiple PaO2 stimuli at the same time as controlling the level of carbon dioxide, thus precluding them from modelling the relationship between retinal blood flow and oxygen. The present study modelled the relationship between retinal blood flow and PaO2, showing them to be a combined linear and hyperbolic function. This model demonstrates that the resting tonus of the vessels is at the mid-point and that they have great vascular range of adjustment, compensating for decreases in oxygen above a PETCO2 of 32-37 mmHg but being limited below this threshold. Retinal blood flow (RBF) increases in response to a reduction in oxygen (hypoxia) but decreases in response to increased oxygen (hyperoxia). However, the relationship between blood flow and the arterial partial pressure of oxygen has not been quantified and modelled in the retina, particularly in the vascular reserve and resting tonus of the vessels. The present study aimed to determine the limitations of the retinal vasculature by modelling the relationship between RBF and oxygen. Retinal vascular responses were measured in 13 subjects for eight different blood gas conditions, with the end-tidal partial pressure of oxygen (PETCO2) ranging from 40-500 mmHg. Retinal vascular response measurements were repeated twice; using the Canon laser blood flowmeter (Canon Inc., Tokyo, Japan) during the first visit and using Doppler spectral domain optical coherence tomography during the second visit. We determined that the relationship between RBF and PaO2 can be modelled as a combination of hyperbolic and linear functions. We concluded that RBF compensated for decreases in arterial oxygen content for all stages of hypoxia used in the present study but can no longer compensate below a PETCO2 of 32-37 mmHg. These vessels have a great vascular range of adjustment, increasing diameter (8.5% arteriolar and 21% total venous area) with hypoxia (40 mmHg P ETC O2; P < 0.001) and decreasing diameter (6.9% arteriolar and 23% total venous area) with hyperoxia (500 mmHg PETCO2; P < 0.001) to the same extent. This indicates that the resting tonus is near the mid-point of the adjustment ranges at resting PaO2 where sensitivity is maximum.


Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - updated June 2014.
This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the prophylaxis of post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis. Main recommendations 1 ESGE recommends routine rectal administration of 100 mg of diclofenac or indomethacin immediately before or after ERCP in all patients without contraindication. In addition to this, in the case of high risk for post-ERCP pancreatitis (PEP), the placement of a 5-Fr prophylactic pancreatic stent should be strongly considered. Sublingually administered glyceryl trinitrate or 250 µg somatostatin given in bolus injection might be considered as an option in high risk cases if nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated and if prophylactic pancreatic stenting is not possible or successful. 2 ESGE recommends keeping the number of cannulation attempts as low as possible. 3 ESGE suggests restricting the use of a pancreatic guidewire as a backup technique for biliary cannulation to cases with repeated inadvertent cannulation of the pancreatic duct; if this method is used, deep biliary cannulation should be attempted using a guidewire rather than the contrast-assisted method and a prophylactic pancreatic stent should be placed. 4 ESGE suggests that needle-knife fistulotomy should be the preferred precut technique in patients with a bile duct dilated down to the papilla. Conventional precut and transpancreatic sphincterotomy present similar success and complication rates; if conventional precut is selected and pancreatic cannulation is easily obtained, ESGE suggests attempting to place a small-diameter (3-Fr or 5-Fr) pancreatic stent to guide the cut and leaving the pancreatic stent in place at the end of ERCP for a minimum of 12 - 24 hours. 4 ESGE does not recommend endoscopic papillary balloon dilation as an alternative to sphincterotomy in routine ERCP, but it may be advantageous in selected patients; if this technique is used, the duration of dilation should be longer than 1 minute.


Genome-wide association studies of Shigella spp. and Enteroinvasive Escherichia coli isolates demonstrate an absence of genetic markers for prediction of disease severity.
We investigated the association of symptoms and disease severity of shigellosis patients with genetic determinants of infecting Shigella and entero-invasive Escherichia coli (EIEC), because determinants that predict disease outcome per individual patient could be used to prioritize control measures. For this purpose, genome wide association studies (GWAS) were performed using presence or absence of single genes, combinations of genes, and k-mers. All genetic variants were derived from draft genome sequences of isolates from a multicenter cross-sectional study conducted in the Netherlands during 2016 and 2017. Clinical data of patients consisting of binary/dichotomous representation of symptoms and their calculated severity scores were also available from this study. To verify the suitability of the methods used, the genetic differences between the genera Shigella and Escherichia were used as control. The isolates obtained were representative of the population structure encountered in other Western European countries. No association was found between single genes or combinations of genes and separate symptoms or disease severity scores. Our benchmark characteristic, genus, resulted in eight associated genes and > 3,000,000 k-mers, indicating adequate performance of the algorithms used. To conclude, using several microbial GWAS methods, genetic variants in Shigella spp. and EIEC that can predict specific symptoms or a more severe course of disease were not identified, suggesting that disease severity of shigellosis is dependent on other factors than the genetic variation of the infecting bacteria. Specific genes or gene fragments of isolates from patients are unsuitable to predict outcomes and cannot be used for development, prioritization and optimization of guidelines for control measures of shigellosis or infections with EIEC.


Prognosis of patients with hepatocellular carcinoma. Validation and ranking of established staging-systems in a large western HCC-cohort.
HCC is diagnosed in approximately half a million people per year, worldwide. Staging is a more complex issue than in most other cancer entities and, mainly due to unique geographic characteristics of the disease, no universally accepted staging system exists to date. Focusing on survival rates we analyzed demographic, etiological, clinical, laboratory and tumor characteristics of HCC-patients in our institution and applied the common staging systems. Furthermore we aimed at identifying the most suitable of the current staging systems for predicting survival. Overall, 405 patients with HCC were identified from an electronic medical record database. The following seven staging systems were applied and ranked according to their ability to predict survival by using the Akaike information criterion (AIC) and the concordance-index (c-index): BCLC, CLIP, GETCH, JIS, Okuda, TNM and Child-Pugh. Separately, every single variable of each staging system was tested for prognostic meaning in uni- and multivariate analysis. Alcoholic cirrhosis (44.4%) was the leading etiological factor followed by viral hepatitis C (18.8%). Median survival was 18.1 months (95%-CI: 15.2-22.2). Ascites, bilirubin, alkaline phosphatase, AFP, number of tumor nodes and the BCLC tumor extension remained independent prognostic factors in multivariate analysis. Overall, all of the tested staging systems showed a reasonable discriminatory ability. CLIP (closely followed by JIS) was the top-ranked score in terms of prognostic capability with the best values of the AIC and c-index (AIC 2286, c-index 0.71), surpassing other established staging systems like BCLC (AIC 2343, c-index 0.66). The unidimensional scores TNM (AIC 2342, c-index 0.64) and Child-Pugh (AIC 2369, c-index 0.63) performed in an inferior fashion. Compared with six other staging systems, the CLIP-score was identified as the most suitable staging system for predicting prognosis in a large German cohort of predominantly non-surgical HCC-patients.


The contribution of molecular epidemiology to the understanding and control of viral diseases of salmonid aquaculture.
Molecular epidemiology is a science which utilizes molecular biology to define the distribution of disease in a population (descriptive epidemiology) and relies heavily on integration of traditional (or analytical) epidemiological approaches to identify the etiological determinants of this distribution. The study of viral pathogens of aquaculture has provided many exciting opportunities to apply such tools. This review considers the extent to which molecular epidemiological studies have contributed to better understanding and control of disease in aquaculture, drawing on examples of viral diseases of salmonid fish of commercial significance including viral haemorrhagic septicaemia virus (VHSV), salmonid alphavirus (SAV) and infectious salmon anaemia virus (ISAV). Significant outcomes of molecular epidemiological studies include:Improved taxonomic classification of viruses. A better understanding of the natural distribution of viruses. An improved understanding of the origins of viral pathogens in aquaculture. An improved understanding of the risks of translocation of pathogens outwith their natural host range. An increased ability to trace the source of new disease outbreaks. Development of a basis for ensuring development of appropriate diagnostic tools. An ability to classify isolates and thus target future research aimed at better understanding biological function. While molecular epidemiological studies have no doubt already made a significant contribution in these areas, the advent of new technologies such as pyrosequencing heralds a quantum leap in the ability to generate descriptive molecular sequence data. The ability of molecular epidemiology to fulfil its potential to translate complex disease pathways into relevant fish health policy is thus unlikely to be limited by the generation of descriptive molecular markers. More likely, full realisation of the potential to better explain viral transmission pathways will be dependent on the ability to assimilate and analyse knowledge from a range of more traditional information sources. The development of methods to systematically record and share such epidemiologically important information thus represents a major challenge for fish health professionals in making the best future use of molecular data in supporting fish health policy and disease control.


Chlamydia psittaci in birds of prey, Sweden.
Chlamydia psittaci is an intracellular bacterium primarily causing respiratory diseases in birds but may also be transmitted to other animals, including humans. The prevalence of the pathogen in wild birds in Sweden is largely unknown. DNA was extracted from cloacae swabs and screened for C. psittaci by using a 23S rRNA gene PCR assay. Partial 16S rRNA and ompA gene fragments were sequence determined and phylogenies were analysed by the neighbour-joining method. The C. psittaci prevalence was 1.3% in 319 Peregrine Falcons and White-tailed Sea Eagles, vulnerable top-predators in Sweden. 16S rRNA and ompA gene analysis showed that novel Chlamydia species, as well as novel C. psittaci strains, are to be found among wild birds.


Flood risk modelling based on tangible and intangible urban flood damage quantification.
The usual way to quantify flood damage is by application stage-damage functions. Urban flood incidents in flat areas mostly result in intangible damages like traffic disturbance and inconvenience for pedestrians caused by pools at building entrances, on sidewalks and parking spaces. Stage-damage functions are not well suited to quantify damage for these floods. This paper presents an alternative method to quantify flood damage that uses data from a municipal call centre. The data cover a period of 10 years and contain detailed information on consequences of urban flood incidents. Call data are linked to individual flood incidents and then assigned to specific damage classes. The results are used to draw risk curves for a range of flood incidents of increasing damage severity. Risk curves for aggregated groups of damage classes show that total flood risk related to traffic disturbance is larger than risk of damage to private properties, which in turn is larger than flood risk related to human health. Risk curves for detailed damage classes show how distinctions can be made between flood risks related to many types of occupational use in urban areas. This information can be used to support prioritisation of actions for flood risk reduction. Since call data directly convey how citizens are affected by urban flood incidents, they provide valuable information that complements flood risk analysis based on hydraulic models.


Mechanical performance of hybrid Ilizarov frames containing full-threaded Schanz screws.
Modification of circular Ilizarov frames is necessary to overcome the difficulties in pin positioning due to unfavorable anatomic site or local soft-tissue conditions. Hybrid frame configurations consisting of half pins or full-threaded schanz screws are widely used in clinical practice. This study compared the mechanical performance of hybrid frames and a standard system. One standard and five modified hybrid systems were tested under axial compression, four-point bending, and torsional forces. Systems modified with full-threaded schanz screws showed a higher stiffness than half pin modifications and exhibited a similar mechanical performance of a standard system.


Contrast gain control determines global form percept in tripole Glass patterns.
A Glass pattern consists of randomly distributed dot pairs, or dipoles, whose orientation is determined by a geometric transform that defines the global percept for this pattern. The perception of Glass patterns involves a local process to associate paired dots into dipoles and a global process to group the dipoles into a global structure. We used a variant of Glass patterns consisting of tripoles instead of dipoles to estimate the effect of luminance contrast on the global form percept. In each tripole, an anchor dot and two context dots formed the vertices of an equilateral triangle with the anchor dot pointing toward the center of the display. Grouping the anchor dot with one context dot would result in a global percept of a clockwise (CW) spiral and grouping with the other dot a counterclockwise (CCW) spiral. We manipulated the contrast of the context dots and measured the probability of a participant judging the patterns as a CW spiral. The CW spiral judging probability first increased then decreased with the contrast of the CW context dots, resulting in an inverted U shape. The peak also shifted to the right as the contrast of the competing CCW context dots increased. Our result cannot be explained by the existing models for Glass pattern perception. Instead, the data was well fit by a divisive inhibition model, in which the response of a global pattern is the excitation raised by a power and divided by the inhibition from all global patterns plus an additive constant.


TCR clonotypes: molecular determinants of T-cell efficacy against HIV.
Because of the enormous complexity and breadth of the overall HIV-specific CD8(+) T-cell response, invaluable information regarding important aspects of T-cell efficacy against HIV can be sourced from studies performed on individual clonotypes. Data gathered from ex vivo and in vitro analyses of T-cell responses and viral evolution bring us one step closer towards deciphering the correlates of protection against HIV. HIV-responsive CD8(+) T-cell populations are characterized by specific clonotypic immunodominance patterns and public TCRs. The TCR endows T-cells with two key features, important for the effective control of HIV: avidity and crossreactivity. While TCR avidity is a major determinant of CD8(+) T-cell functional efficacy against the virus, crossreactivity towards wildtype and mutant viral epitopes is crucial for adaptation to HIV evolution. The properties of CD4(+) T-cell responses in HIV controllers appear also to be shaped by high avidity public TCR clonotypes. The molecular nature of the TCR, together with the clonotypic composition of the HIV-specific T-cell response, emerge as major determinants of anti-viral efficacy.


Simulations show decreasing carbon stocks and potential for carbon emissions in Rocky Mountain forests over the next century.
Climate change has altered the environment in which forests grow, and climate change models predict more severe alterations to come. Forests have already responded to these changes, and the future temperature and precipitation scenarios are of foremost concern, especially in the mountainous western United States, where forests occur in the dry environments that interface with grasslands. The objective of this study was to understand the trade-offs between temperature and water controls on these forested sites in the context of available climate projections. Three temperature and precipitation scenarios from IPCC AR4 AOGCMs ranging in precipitation levels were input to the process model Biome-BGC for key forested sites in the northern U.S. Rocky Mountains. Despite the omission of natural and human-caused disturbances in our simulations, our results show consequential effects from these conservative future temperature and precipitation scenarios. According to these projections, if future precipitation and temperatures are similar to or drier than the dry scenario depicted here, high-elevation forests on both the drier and wetter sites, which have in the absence of disturbance accumulated carbon, will reduce their carbon accumulation. Under the marginally drier climate projections, most forests became carbon sources by the end of the simulation horizon (2089). Under all three scenarios, growing season lengthened, the number of days with snow on the ground decreased, peak snow occurred earlier, and water stress increased through the projection horizon (1950-2089) for all sites, which represent the temperature and precipitation spectrum of forests in this region. The quantity, form, and timing of precipitation ultimately drive the carbon accumulation trajectory of forests in this region.


Cost-effectiveness of oral cancer screening: results from a cluster randomized controlled trial in India.
To evaluate oral cancer screening by visual inspection. A cluster randomized controlled trial was initiated in Trivandrum district, Kerala, India. Of 13 population clusters, seven were randomly allocated to three rounds of screening between 1996 and 2004, while standard care was provided in six (control arm). An activity-based approach was employed to calculate costs associated with various components of the screening trial. Information on the resources used and on clinical events in each trial arm was derived from trial databases. Total costs for each cluster were estimated in 2004 United States dollars (US$). The incremental cost per life-year saved was calculated for all eligible individuals and for high-risk individuals (i.e. tobacco or alcohol users). The proportion of oral cancers detected at an early stage (i.e. stage I or II) was higher in the intervention arm than the control arm (42% versus 24%, respectively). The incremental cost per life-year saved was US$ 835 for all individuals eligible for screening and US$ 156 for high-risk individuals. Oral cancer screening by visual inspection was performed for under US$ 6 per person. The most cost-effective approach to oral cancer screening by visual inspection is to offer it to the high-risk population. Targeted screening of this group will ensure that screening can be offered at a reasonable cost in a limited-resource setting.


Estimated impact of the 2020 economic downturn on under-5 mortality for 129 countries.
In low- and middle-income countries (LMICs), economic downturns can lead to increased child mortality by affecting dietary, environmental, and care-seeking factors. This study estimates the potential loss of life in children under five years old attributable to economic downturns in 2020. We used a multi-level, mixed effects model to estimate the relationship between gross domestic product (GDP) per capita and under-5 mortality rates (U5MRs) specific to each of 129 LMICs. Public data were retrieved from the World Bank World Development Indicators database and the United Nations World Populations Prospects estimates for the years 1990-2020. Country-specific regression coefficients on the relationship between child mortality and GDP were used to estimate the impact on U5MR of reductions in GDP per capita of 5%, 10%, and 15%. A 5% reduction in GDP per capita in 2020 was estimated to cause an additional 282,996 deaths in children under 5 in 2020. At 10% and 15%, recessions led to higher losses of under-5 lives, increasing to 585,802 and 911,026 additional deaths, respectively. Nearly half of all the potential under-5 lives lost in LMICs were estimated to occur in Sub-Saharan Africa. Because most of these deaths will likely be due to nutrition and environmental factors amenable to intervention, countries should ensure continued investments in food supplementation, growth monitoring, and comprehensive primary health care to mitigate potential burdens.


SAS-1 is a C2 domain protein critical for centriole integrity in C. elegans.
Centrioles are microtubule-based organelles important for the formation of cilia, flagella and centrosomes. Despite progress in understanding the underlying assembly mechanisms, how centriole integrity is ensured is incompletely understood, including in sperm cells, where such integrity is particularly critical. We identified C. elegans sas-1 in a genetic screen as a locus required for bipolar spindle assembly in the early embryo. Our analysis reveals that sperm-derived sas-1 mutant centrioles lose their integrity shortly after fertilization, and that a related defect occurs when maternal sas-1 function is lacking. We establish that sas-1 encodes a C2 domain containing protein that localizes to centrioles in C. elegans, and which can bind and stabilize microtubules when expressed in human cells. Moreover, we uncover that SAS-1 is related to C2CD3, a protein required for complete centriole formation in human cells and affected in a type of oral-facial-digital (OFD) syndrome.


Leukemia incidence among people exposed to chronic radiation from the contaminated Techa River, 1953-2005.
Beginning in 1950, people living on the banks of the Techa River received chronic low-dose-rate internal and external radiation exposures as a result of releases from the Mayak nuclear weapons plutonium production facility in the Southern Urals region of the Russian Federation. The Techa River cohort includes about 30,000 people who resided in riverside villages sometime between 1950 and 1960. Cumulative red bone marrow doses range up to 2 Gy with a mean of 0.3 Gy and a median of 0.2 Gy. Between 1953 and 2005, 93 first primary cases of leukemia, including 23 cases of chronic lymphatic leukemia (CLL), were ascertained among the cohort members. A significant linear dose-response relationship was seen for leukemias other than CLL (P < 0.001), but not for CLL. The estimated excess relative risk per Gy is 4.9 (95% confidence interval (CI): 1.6; 14.3) for leukemias other than CLL and less than 0 (95% upper bound 1.4) for CLL.


Accumbal Cholinergic Interneurons Differentially Influence Motivation Related to Satiety Signaling.
Satiety, rather than all or none, can instead be viewed as a cumulative decrease in the drive to eat that develops over the course of a meal. The nucleus accumbens (NAc) is known to play a critical role in this type of value reappraisal, but the underlying circuits that influence such processes are unclear. Although NAc cholinergic interneurons (CINs) comprise only a small proportion of NAc neurons, their local impact on reward-based processes provides a candidate cell population for investigating the neural underpinnings of satiety. The present research therefore aimed to determine the role of NAc-CINs in motivation for food reinforcers in relation to satiety signaling. Through bidirectional control of CIN activity in mice, we show that when motivated by food restriction, increasing CIN activity led to a reduction in palatable food consumption while reducing CIN excitability enhanced food intake. These activity-dependent changes developed only late in the session and were unlikely to be driven by the innate reinforcer strength, suggesting that CIN modulation was instead impacting the cumulative change in motivation underlying satiety signaling. We propose that on a circuit level, an overall increase in inhibitory tone onto NAc output neurons played a role in the behavioral results, as activating NAc-CINs led to an inhibition of medium spiny neurons that was dependent on nicotinic receptor activation. Our results reveal an important role for NAc-CINs in controlling motivation for food intake and additionally provide a circuit-level framework for investigating the endogenous cholinergic circuits that signal satiety.


Wnt signaling as a possible promoting factor of cell differentiation in pleomorphic adenomas.
There are well known that Wnt signaling was some roles of cell differentiation at the development tissues, especially the oral and maxillofacial regions of some developmental stages. Therefore, to determine Wnt signaling in the pleomorphic adenoma tissues, we examined. The expression of Wnt1 and β-catenin as well as the distribution of various cytoskeletal proteins CK7 and CK13 was examined in 30 cases of pleomorphic adenoma by immunohistochemistry. Wnt1 was detected in almost all tumor cells. The peripheral columnar cells in squamous metaplasia and small cuboidal cells in duct-like structures were strongly positive to Wnt1. Although β-catenin was clearly localized on the cell membrane of tumor cells, nuclear translocation was observed in small cuboidal cells and in some basaloid cells. The immunofluorescent staining pattern of Wnt1 and CK7 as well as Wnt1 and CK13 was consistent with IHC results. Thus, in pleomorphic adenoma, Wnt is involved in tumor cell differentiation of peripheral columnar cells forming solid nests and small peripheral columnar cells forming duct-like structures. Moreover, among the three currently known Wnt pathways, β-catenin is the suggested pathway working during cell differentiation. Furthermore, peripheral columnar cells in solid tumor nests and in squamous metaplasia are governed by another Wnt pathway other than β-catenin. Therefore, Wnt signaling through β-catenin pathway may be involved in the 'mixed' differentiation characteristic of pleomorphic adenoma although another pathway may also be possibly working in other parts of the tumor tissue.


Collagen IV-modified scaffolds improve islet survival and function and reduce time to euglycemia.
Islet transplantation on extracellular matrix (ECM) protein-modified biodegradable microporous poly(lactide-co-glycolide) scaffolds is a potential curative treatment for type 1 diabetes mellitus (T1DM). Collagen IV-modified scaffolds, relative to control scaffolds, significantly decreased the time required to restore euglycemia from 17 to 3 days. We investigated the processes by which collagen IV-modified scaffolds enhanced islet function and mediated early restoration of euglycemia post-transplantation. We characterized the effect of collagen IV-modified scaffolds on islet survival, metabolism, and insulin secretion in vitro and early- and intermediate-term islet mass and vascular density post-transplantation and correlated these with early restoration of euglycemia in a syngeneic mouse model. Control scaffolds maintained native islet morphologies and architectures as well as collagen IV-modified scaffolds in vivo. The islet size and vascular density increased, while β-cell proliferation decreased from day 16 to 113 post-transplantation. Collagen IV-modified scaffolds promoted islet cell viability and decreased early-stage apoptosis in islet cells in vitro-phenomena that coincided with enhanced islet metabolic function and glucose-stimulated insulin secretion. These findings suggest that collagen IV-modified scaffolds promote the early restoration of euglycemia post-transplantation by enhancing islet metabolism and glucose-stimulated insulin secretion. These studies of ECM proteins, in particular collagen IV, and islet function provide key insights for the engineering of a microenvironment that would serve as a platform for enhancing islet transplantation as a viable clinical therapy for T1DM.


Hierarchical Bayesian regularization of reconstructions for diffuse optical tomography using multiple priors.
Diffuse optical tomography (DOT) is a non-invasive brain imaging technique that uses low-levels of near-infrared light to measure optical absorption changes due to regional blood flow and blood oxygen saturation in the brain. By arranging light sources and detectors in a grid over the surface of the scalp, DOT studies attempt to spatially localize changes in oxy- and deoxy-hemoglobin in the brain that result from evoked brain activity during functional experiments. However, the reconstruction of accurate spatial images of hemoglobin changes from DOT data is an ill-posed linearized inverse problem, which requires model regularization to yield appropriate solutions. In this work, we describe and demonstrate the application of a parametric restricted maximum likelihood method (ReML) to incorporate multiple statistical priors into the recovery of optical images. This work is based on similar methods that have been applied to the inverse problem for magnetoencephalography (MEG). Herein, we discuss the adaptation of this model to DOT and demonstrate that this approach provides a means to objectively incorporate reconstruction constraints and demonstrate this approach through a series of simulated numerical examples.


An almost-parameter-free harmony search algorithm for groundwater pollution source identification.
The spatiotemporal characterization of unknown sources of groundwater pollution is frequently encountered in environmental problems. This study adopts a simulation-optimization approach that combines a contaminant transport simulation model with a heuristic harmony search algorithm to identify unknown pollution sources. In the proposed methodology, an almost-parameter-free harmony search algorithm is developed. The performance of this methodology is evaluated on an illustrative groundwater pollution source identification problem, and the identified results indicate that the proposed almost-parameter-free harmony search algorithm-based optimization model can give satisfactory estimations, even when the irregular geometry, erroneous monitoring data, and prior information shortage of potential locations are considered.


Experimental evaluation of additional short ranged repulsion in structural oscillation forces.
The paper addresses additional short ranged repulsion in structural oscillation forces between silica surfaces across a suspension of silica nanoparticles. Fit and prediction of the structural oscillation forces usually involve an exponentially decreasing harmonic as introduced by Israelachvili [Israelachvili, Intermolecular & surface forces, Academic Press, San Diego, USA, 1985]. Recently we demonstrated, for aqueous suspensions of silica nanoparticles at various concentrations, that this fit equation is insufficient to describe the structural oscillation forces in its whole range [Schön et al., Beilstein J. Nanotechnol., 2018, 9, 1095-1107]. An additional force acting on short separations leads to the fit parameters scattering widely as well as being dependent on each other and the starting point of the fit. An additional repulsive term was introduced to solve these problems. The additional repulsive force has also been observed by others, in ionic liquids and polyelectrolyte solutions at high ionic strength. It was attributed to the diffusive double layer forces. The rise of the additional repulsion with increasing particle concentration seems to conflict with this interpretation. In this work, colloidal probe atomic force microscopy is used in aqueous suspensions of silica nanoparticles to investigate other contributing factors such as the increasing hydrodynamic drag in the normal direction to the confining surface with increasing particle concentration. A kinetic component to the structural oscillation forces is observed. Furthermore, sodium chloride is used to adjust the ionic strength of two different concentrated silica nanoparticle suspensions. For these systems the additional decay length is compared to the Debye length in the range from low to high ionic strength. A master curve of the additional decay length over Debye length at different ionic strengths, approach speed and particle concentration is produced. It affirms the link between the two and the connection between the additional force and the diffusive double layer forces. The increasing trend for the additional repulsion with increasing particle concentration reveals a synergistic effect of diffusive double layer forces and structural oscillation forces at low to medium ionic strength, which cannot be observed at high ionic strength.


An Inductively Powered Scalable 32-Channel Wireless Neural Recording System-on-a-Chip for Neuroscience Applications.
We present an inductively powered 32-channel wireless integrated neural recording (WINeR) system-on-a-chip (SoC) to be ultimately used for one or more small freely behaving animals. The inductive powering is intended to relieve the animals from carrying bulky batteries used in other wireless systems, and enables long recording sessions. The WINeR system uses time-division multiplexing along with a novel power scheduling method that reduces the current in unused low-noise amplifiers (LNAs) to cut the total SoC power consumption. In addition, an on-chip high-efficiency active rectifier with optimized coils help improve the overall system power efficiency, which is controlled in a closed loop to supply stable power to the WINeR regardless of the coil displacements. The WINeR SoC has been implemented in a 0.5-μ m standard complementary metal-oxide semiconductor process, measuring 4.9×3.3 mm(2) and consuming 5.85 mW at ±1.5 V when 12 out of 32 LNAs are active at any time by power scheduling. Measured input-referred noise for the entire system, including the receiver located at 1.2 m, is 4.95 μVrms in the 1 Hz~10 kHz range when the system is inductively powered with 7-cm separation between aligned coils.


The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development.
The cytokines lymphotoxin (LT) alpha, beta and their receptor (LTbetaR) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNFalpha-was initially discovered due to its tumor necrotizing activity. LTbetaR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTbetaR comprises the noncanonical/canonical nuclear factor-kappaB (NF-kappaB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTbetaR signaling or Fcgamma-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTbetaR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTbetaR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.


Organ donation in Switzerland--an analysis of factors associated with consent rate.
Switzerland has a low post mortem organ donation rate. Here we examine variables that are associated with the consent of the deceased's next of kin (NOK) for organ donation, which is a prerequisite for donation in Switzerland. During one year, we registered information from NOK of all deceased patients in Swiss intensive care units, who were approached for consent to organ donation. We collected data on patient demographics, characteristics of NOK, factors related to the request process and to the clinical setting. We analyzed the association of collected predictors with consent rate using univariable logistic regression models; predictors with p-values <0.2 were selected for a multivariable logistic regression. Of 266 NOK approached for consent, consent was given in 137 (51.5%) cases. In multivariable analysis, we found associations of consent rates with Swiss nationality (OR 3.09, 95% CI: 1.46-6.54) and German language area (OR 0.31, 95% CI: 0.14-0.73). Consent rates tended to be higher if a parent was present during the request (OR 1.76, 95% CI: 0.93-3.33) and if the request was done before brain death was formally declared (OR 1.87, 95% CI: 0.90-3.87). Establishing an atmosphere of trust between the medical staff putting forward a request and the NOK, allowing sufficient time for the NOK to consider donation, and respecting personal values and cultural differences, could be of importance for increasing donation rates. Additional measures are needed to address the pronounced differences in consent rates between language regions.


Estimating the Bayesian loss function. A conjoint analysis approach.
Current health economic literature does not provide clear guidelines on how uncertainty around cost-effectiveness estimates should be incorporated into economic decision models. Bayesian analysis is a promising alternative to classical statistics for incorporating uncertainty in economic analysis. Estimating a loss function that relates outcomes to societal welfare is a key component of Bayesian decision analysis. Health economists commonly compute the loss function based on the quality-adjusted life-years associated with each outcome. However, if welfare economics is adopted as the theoretical foundation of the analysis, a loss function based in cost-benefit analysis (CBA) may be more appropriate. CBA has not found wide use in health economics due to practical issues associated with estimating such a loss function. In this paper, we present a method based in conjoint analysis for estimating the CBA loss function that can be applied in practice. We illustrate the use of the methodology using data from a pilot study.


Hydroxyapatite as a Nanomaterial for Advanced Tissue Engineering and Drug Therapy.
Hydroxyapatite (HAp) is a complicated ceramic material that varies between the way it appears in biological systems and how it is synthesized as various calcium phosphates. HAp varies in chemical composition of substituting atoms, crystallinity, grain size and electrical polarization. HAp can form solid to macro-, micro- and nanoporous structures. Also, particulate HAp can have highly porous structure. HAp can be used as coatings for metal implants in thicknesses from hundreds of microns down to hundreds of nanometers. Cotton wool-like HAp fibers can be electrospun compounded with polymers (or without) for tissue engineering (TE) scaffolds. This review describes the features of HAp that may be utilized further in developing novel applications. As a nanomaterial HAp has been applied for drug delivery. The adsorption of proteins and other compounds can be adjusted by modifying HAp composition, electrical polarization and wettability. Of special interest are the bisphosphonates that bind to HAp and thereby can be used to treat bone loss and also couple other drugs to the mineral. A new area for HAp constructs may appear in treating metallosis. HAp coating may function as a scavenger for the ions release from metal implants and thereby inhibit the adverse effects of the ion burden for the body. So far HAp is considered as safe biomaterial but nano HAp may insidiously possess adverse effects especially when ingested by cells and eliciting excess intracellular calcium. Thereby critical approach also for HAp biomaterials is of utmost importance.


Cohort profile: early school years follow-up of the Asking Questions about Alcohol in Pregnancy Longitudinal Study in Melbourne, Australia (AQUA at 6).
The Asking Questions about Alcohol in Pregnancy (AQUA) study, established in 2011, is a prebirth cohort of 1570 mother and child pairs designed to assess the effects of low to moderate prenatal alcohol exposure and sporadic binge drinking on long-term child development. Women attending general antenatal clinics in public hospitals in Melbourne, Australia, were recruited in their first trimester, followed up three times during pregnancy and at 12 and 24 months postpartum. The current follow-up of the 6-8-year-old children aims to strengthen our understanding of the relationship between these levels of prenatal alcohol exposure and neuropsychological functioning, facial dysmorphology, brain structure and function. Between June 2018 and April 2021, 802 of the 1342 eligible AQUA study families completed a parent-report questionnaire (60%). Restrictions associated with COVID-19 pandemic disrupted recruitment, but early school-age neuropsychological assessments were undertaken with 696 children (52%), and 482 (36%) craniofacial images were collected. A preplanned, exposure-representative subset of 146 children completed a brain MRI. An existing biobank was extended through collection of 427 (32%) child buccal swabs. Over half (59%) of mothers consumed some alcohol during pregnancy, with one in five reporting at least one binge-drinking episode prior to pregnancy recognition. Children's craniofacial shape was examined at 12 months of age, and low to moderate prenatal alcohol exposure was associated with subtle midface changes. At 2 years of age, formal developmental assessments showed no evidence that cognitive, language or motor outcome was associated with any of exposure level. We will investigate the relationship between prenatal alcohol exposure and specific aspects of neurodevelopment at 6-8 years, including craniofacial shape, brain structure and function. The contribution of genetics and epigenetics to individual variation in outcomes will be examined in conjunction with national and international collaborations.


"Wait--You're a conservative?" Political diversity and the dilemma of disclosure.
Many of the proposed recommendations for remedying the harmful effects of political homogeneity for psychology depend upon conservatives disclosing their political identity. Yet how likely is this, when disclosure is so harmful to the individual? Considering this issue as a social dilemma clarifies the pernicious nature of the problem, as well as suggesting how the dilemma can be resolved.


Effective Chemical Inactivation of Ebola Virus.
Reliable inactivation of specimens before removal from high-level biocontainment is crucial for safe operation. To evaluate efficacy of methods of chemical inactivation, we compared in vitro and in vivo approaches using Ebola virus as a surrogate pathogen. Consequently, we have established parameters and protocols leading to reliable and effective inactivation.


Nasal microbiota clusters associate with inflammatory response, viral load, and symptom severity in experimental rhinovirus challenge.
The role of nasal and fecal microbiota in viral respiratory infections has not been established. We collected nasal swabs and washes, and fecal samples in a clinical study assessing the effect of probiotic Bifidobacterium animalis subsp. lactis Bl-04 on experimental rhinovirus infection. The nasal and fecal microbiota were characterized by 16S rRNA gene sequencing. The resulting data were compared with nasal inflammatory marker concentrations, viral load, and clinical symptoms. By using unsupervised clustering, the nasal microbiota divided into six clusters. The clusters predominant of Staphylococcus, Corynebacterium/Alloiococcus, Moraxella, and Pseudomonadaceae/Mixed had characteristic inflammatory marker and viral load profiles in nasal washes. The nasal microbiota clusters of subjects before the infection associated with the severity of clinical cold symptoms during rhinovirus infection. Rhinovirus infection and probiotic intervention did not significantly alter the composition of nasal or fecal microbiota. Our results suggest that nasal microbiota may influence the virus load, host innate immune response, and clinical symptoms during rhinovirus infection, however, further studies are needed.


SIFT flow: dense correspondence across scenes and its applications.
While image alignment has been studied in different areas of computer vision for decades, aligning images depicting different scenes remains a challenging problem. Analogous to optical flow, where an image is aligned to its temporally adjacent frame, we propose SIFT flow, a method to align an image to its nearest neighbors in a large image corpus containing a variety of scenes. The SIFT flow algorithm consists of matching densely sampled, pixelwise SIFT features between two images while preserving spatial discontinuities. The SIFT features allow robust matching across different scene/object appearances, whereas the discontinuity-preserving spatial model allows matching of objects located at different parts of the scene. Experiments show that the proposed approach robustly aligns complex scene pairs containing significant spatial differences. Based on SIFT flow, we propose an alignment-based large database framework for image analysis and synthesis, where image information is transferred from the nearest neighbors to a query image according to the dense scene correspondence. This framework is demonstrated through concrete applications such as motion field prediction from a single image, motion synthesis via object transfer, satellite image registration, and face recognition.


Blessed be the Children: A Case-Control Study of Sexual Abusers in the Catholic Church.
Individuals working in churches and other youth-serving institutions have a unique level of access to children, yet the problem of sexual abuse in institutional settings has received scant research attention. To address this gap, we analyzed data from a large sample of clergy (N = 1,121) and applied a social-ecological model of offending to identify risk factors for sexual abuse perpetration. Using a case-control study design that compared clergy sexual abusers with three control groups of clergy, this study focuses specifically on individual-, relationship-, and community-level factors associated with a higher risk of abuse in professional populations. Findings revealed that clergy sexual abusers tended to have more truncated pre-seminary dating histories, and that their dating and sexual partners were more likely to have been male than female. Self-reported sexual abuse history was associated with a greater likelihood of sexual abuse perpetration among clergy. Clergy abusers tended to be more involved with youth and adolescents in their ministries; however, they were observed to relate less well to youth and adolescents than their clergy counterparts. Given widespread changes in our cultural understanding of abuse as well as more specific changes in the organizational approach to seminary education, these differences underscore the role that youth-serving institutions and society can have in the primary prevention of child sexual abuse.


Freezing temperatures as a limit to forest recruitment above tropical Andean treelines.
The elevation of altitudinal treelines is generally believed to occur where low mean temperatures during the growing season limit growth and prevent trees from establishing at higher elevations. Accordingly, treelines should move upslope with increasing global temperatures. Contrary to this prediction, tropical treelines have remained stable over the past several decades despite increasing mean temperatures. The observed stability of tropical treelines, coupled with the drastically different temperature profiles between temperate and tropical treelines, suggests that using mean measures of temperature to predict tropical treeline movements during climate change may be overly simplistic. We hypothesize that frost events at tropical treelines may slow climate driven treeline movement by preventing tree recruitment beyond the established forest canopy. To assess this hypothesis, we measured freezing resistance of four canopy-forming treeline species (Weinmannia fagaroides, Polylepis pauta, Clethra cuneata, and Gynoxys nitida) at two life stages (juvenile and adult) and during two seasons (warm-wet and cold-dry). Freezing resistances were then compared to microclimatic data to determine if freezing events in the grassland matrix above treeline are too harsh for these forest species. Freezing resistance varied among species and life stages from -5.7 degrees C for juveniles of P. pauta to -11.1 degrees C for juveniles of W. fagaroides. Over a four-year period, the lowest temperatures recorded at 10 cm above ground level in the grasslands above treeline and at treeline itself were -8.9 degrees C and -6.8 degrees C, respectively. Juveniles maintained freezing resistances similar to adults during the coldest parts of the year and ontogenetic differences in freezing resistance were only present during the warm season when temperatures did not represent a significant threat to active plant tissue. These findings support the hypothesis that rare extreme freezing events at and above tropical treelines can prevent recruitment outside of closed canopy forest for some tree species and may significantly slow treeline advancement despite warming mean temperatures. Predictions of treeline shifts under climate change should be reevaluated to include species-specific' climatic tolerances and measures of climatic variability.


Psychological burden of women with mild cervical intraepithelial neoplasia.
Forty women with diagnosis of CIN I attending our outpatient colposcopic clinic were evaluated regarding psychological distress and compliance to follow-up after they had been informed about their diagnosis. In our study 52.9% of the women (n=21) (group A) reported that they did not get sufficient information concerning diagnosis, while 47.1% of the women (n=19) received sufficient information (group B). Women with adequate information had less fear of having cancer than women with inadequate information (P=0.03). As expected these women had a statistically increased distress (P=0.004). In group A the patients reported that the follow-up period reinforced the anxiety compared to group B (P=0.04). The compliance for regular attendance of cervical cancer screening programs after treatment was significantly better in group B compared to group A (P=0.02). Our study indicates that adequate information for women about the diagnosis CIN I, reassurance and understanding from medical staff are vital for the success in the treatment of patients with mild dyskaryosis. The gynaecologist's counselling strategy plays a major role in these psychological effects.


A treatise on nursing knowledge development for the 21st century: beyond postmodernism.
This article explicates a framework for nursing knowledge development that incorporates both modernist and postmodernist philosophies. The framework derives from an "open philosophy" of science, which links science, philosophy, and practice in development of nursing knowledge. A neomodernist perspective is proposed that upholds modernist values for unified conceptualizations of nursing reality while recognizing the dynamic and value-laden nature of all levels of theory and metatheory. It is proposed that scientific inquiry extend beyond the postmodern critique to identify nursing metanarratives of nursing philosophy and nursing practice that serve as external correctives in the critique process. Philosophic positions related to the science, philosophy, and practice domains are put forth for continued dialogue about future directions for knowledge development in nursing.