Emerging immunosuppressive drugs in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are characterized by dysplastic morphologic features and ineffective hematopoiesis. Pathophysiological characteristics change over time making therapeutic development a major challenge. In early MDS, cytopenias arise or are exacerbated by humoral and cellular immune-mediators that suppress hematopoietic progenitor survival and alter the bone marrow microenvironment. In this review, current immunosuppressive regimens are described. To identify new therapies that may enhance immunosuppressive therapy (IST) response and identify pharmacodynamic biomarkers for patient selection, the inflammasome, cytokines, metabolic pathways and signaling events are described. Agents with the potential to induce early, durable hematologic remissions are needed and many new immunosuppressive agents are available for investigation. An immune-mediated mechanism is likely to contribute to MDS early after diagnosis. New approaches that interfere with inflammatory pathways in the bone marrow microenvironment may move closer toward sustained disease control in MDS.


Unprecedented early-summer heat stress and forecast of coral bleaching on the Great Barrier Reef, 2021-2022.
The Great Barrier Reef (GBR) is predicted to undergo its sixth mass coral bleaching event during the Southern Hemisphere summer of 2021-2022. Coral bleaching-level heat stress over the GBR is forecast to start earlier than any previous year in the satellite record (1985-present). The National Oceanic and Atmospheric Administration (NOAA) Coral Reef Watch (CRW) near real-time satellite-based heat stress products were used to investigate early-summer sea surface temperature (SST) and heat stress conditions on the GBR during late 2021. As of 14 December 2021, values of instantaneous heat stress (Coral Bleaching HotSpots) and accumulated heat stress over a 12-week running window (Degree Heating Weeks) on the GBR were unprecedented in the satellite record. Further, 89% of GBR satellite reef pixels for this date in 2021 had a positive seven-day SST trend of greater than 0.2 degrees Celsius/week. Background temperatures (the minimum temperature over the previous 29 days) were alarmingly high, with 87% of GBR reef pixels on 14 December 2021 being greater than the maximum SST over that same 29-day period for any year from 1985-2020. The GBR is starting the 2021-2022 summer season with more accumulated heat than ever before, which could have disastrous consequences for the health, recovery, and future of this critical reef system.


Advances in upper limb stroke rehabilitation: a technology push.
Strokes affect thousands of people worldwide leaving sufferers with severe disabilities affecting their daily activities. In recent years, new rehabilitation techniques have emerged such as constraint-induced therapy, biofeedback therapy and robot-aided therapy. In particular, robotic techniques allow precise recording of movements and application of forces to the affected limb, making it a valuable tool for motor rehabilitation. In addition, robot-aided therapy can utilise visual cues conveyed on a computer screen to convert repetitive movement practice into an engaging task such as a game. Visual cues can also be used to control the information sent to the patient about exercise performance and to potentially address psychosomatic variables influencing therapy. This paper overviews the current state-of-the-art on upper limb robot-mediated therapy with a focal point on the technical requirements of robotic therapy devices leading to the development of upper limb rehabilitation techniques that facilitate reach-to-touch, fine motor control, whole-arm movements and promote rehabilitation beyond hospital stay. The reviewed literature suggest that while there is evidence supporting the use of this technology to reduce functional impairment, besides the technological push, the challenge ahead lies on provision of effective assessment of outcome and modalities that have a stronger impact transferring functional gains into functional independence.


New ALS-Related Genes Expand the Spectrum Paradigm of Amyotrophic Lateral Sclerosis.
Amyotrophic Lateral Sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons. Clinical heterogeneity is a well-recognized feature of the disease as age of onset, site of onset and the duration of the disease can vary greatly among patients. A number of genes have been identified and associated to familial and sporadic forms of ALS but the majority of cases remains still unexplained. Recent breakthrough discoveries have demonstrated that clinical manifestations associated with ALS-related genes are not circumscribed to motor neurons involvement. In this view, ALS appears to be linked to different conditions over a continuum or spectrum in which overlapping phenotypes may be identified. In this review, we aim to examine the increasing number of spectra, including ALS/Frontotemporal Dementia and ALS/Myopathies spectra. Considering all these neurodegenerative disorders as different phenotypes of the same spectrum can help to identify common pathological pathways and consequently new therapeutic targets in these incurable diseases.


Cardiovascular and metabolic profile during intervention with urapidil in humans.
Increased sympathetic activity or vascular reactivity to norepinephrine or both may play a complementary role in the pathogenesis of essential hypertension. Therefore, blood pressure regulation and metabolic correlates of cardiovascular risk were evaluated in 19 normal subjects and in 13 subjects with essential hypertension receiving placebo and after 4 weeks of intervention with urapidil, an agent that was found experimentally to exert a combined central sympathetic and peripheral alpha-adrenergic receptor inhibition. In hypertensive patients, urapidil normalized the initially low norepinephrine pressor dose (+ 106%), mildly increased basal plasma norepinephrine levels (+36%), and markedly shifted the plasma norepinephrine concentration-blood pressure response curve (p less than 0.01). Blood pressure was decreased (p less than 0.001). In normal subjects, urapidil produced only mild increases in norepinephrine plasma levels (+22%) and norepinephrine pressor dose (+38%) and no change in blood pressure. Body weight, exchangeable sodium, and blood volume were unaltered or increased slightly. Heart rate; plasma epinephrine, renin, angiotensin II, basal aldosterone, and electrolyte levels; plasma clearances of norepinephrine and angiotensin II; pressor effects of angiotensin II; chronotropic responses to isoproterenol or a norepinephrine-induced rise in blood pressure; and urinary prostaglandin F2 alpha excretion, as well as serum lipoprotein fractions and glucose, insulin, and uric acid levels, were not significantly modified by urapidil. Prostaglandin E2 excretion tended to be increased. Aldosterone responsiveness to angiotensin II was increased by urapidil in normal (p less than 0.05) but not in hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Genetic Diversity and Population Structure of Busseola segeta Bowden (Lepidoptera; Noctuidae): A Case Study of Host Use Diversification in Guineo-Congolian Rainforest Relic Area, Kenya.
Habitat modification and fragmentation are considered as some of the factors that drive organism distribution and host use diversification. Indigenous African stem borer pests are thought to have diversified their host ranges to include maize [Zea mays L.] and sorghum [Sorghum bicolor (L.) Moench] in response to their increased availability through extensive cultivation. However, management efforts have been geared towards reducing pest populations in the cultivated fields with few attempts to understand possible evolution of "new" pest species. Recovery and growing persistence of Busseola segeta Bowden on maize (Zea mays L.) in Kakamega called for studies on the role of wild host plants on the invasion of crops by wild borer species. A two-year survey was carried out in a small agricultural landscape along the edge of Kakamega forest (Kenya) to assess host range and population genetic structure of B. segeta. The larvae of B. segeta were found on nine different plant species with the majority occurring on maize and sorghum. Of forty cytochrome b haplotypes identified, twenty-three occurred in both wild and cultivated habitats. The moths appear to fly long distances across the habitats with genetic analyses revealing weak differentiation between hosts in different habitats (FST = 0.016; p = 0.015). However, there was strong evidence of variation in genetic composition between growing seasons in the wild habitat (FST = 0.060; p < 0.001) with emergence or disappearance of haplotypes between habitats. Busseola segeta is an example of a phytophagous insect that utilizes plants with a human induced distribution range, maize, but does not show evidence of host race formation or reduction of gene flow among populations using different hosts. However, B. segeta is capable of becoming an important pest in the area and the current low densities may be attributed to the general low infestation levels and presence of a wide range of alternative hosts in the area.


British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update.
This British Association for Psychopharmacology guideline replaces the original version published in 2010, and contains updated information and recommendations. A consensus meeting was held in London in October 2017 attended by recognised experts and advocates in the field. They were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aiming to reach consensus where the evidence and/or clinical experience was considered adequate, or otherwise to flag the area as a direction for future research. A draft of the proceedings was circulated to all speakers for comments, which were incorporated into the final statement.


Pancreatic carcinoma surveillance in patients with familial melanoma.
To determine the optimal methods for pancreatic adenocarcinoma surveillance in high-risk patients with familial melanoma and cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. Case report with pedigree analysis and literature review, with an emphasis on guideline development for high-risk kindreds with familial pancreatic adenocarcinoma. A university-affiliated familial melanoma research clinic. Patients The proband was referred as a participant in a research clinic protocol and was found to carry a germline CDKN2A mutation and have a history of melanoma and pancreatic adenocarcinoma. A total of 179 family members were identified through the Utah Population Database and underwent evaluation for history of melanoma and pancreatic adenocarcinoma.Intervention/ Comprehensive family history and pedigree analysis performed by means of personal interview, medical record review, and use of cancer registry and population database records. Mutation status was confirmed by results of DNA sequence analysis. Tumor identity was confirmed with immunohistochemical markers. Estimated risk for pancreatic adenocarcinoma in a high-risk family with CDKN2A-positive melanoma. Guidelines for surveillance in these families were based on review of the literature. Sequence analysis confirmed a CDKN2A mutation, and immunohistochemical evaluation confirmed the diagnoses of metastatic melanoma and metastatic pancreatic adenocarcinoma. Pedigree analysis showed an observed-expected ratio of 8.9 to 12.6 for pancreatic adenocarcinoma and 16.4 to 20.8 for melanoma in this family. Guidelines used for surveillance of kindreds at high risk for pancreatic adenocarcinoma were applied to families with CDKN2A melanoma. Conclusion Patients with melanoma and a germline CDKN2A mutation should be considered for pancreatic adenocarcinoma surveillance that is based on the most recent published studies.


Sugar and chromosome stability: clastogenic effects of sugars in vitamin B6-deficient cells.
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency, caused either by mutations in the pyridoxal kinase-coding gene (dPdxk) or by vitamin B6 antagonists, results in chromosome aberrations (CABs). The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE) formation. Treatment of dPdxk mutant cells with α-lipoic acid (ALA) lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact cancer risk, as CABs are a well-known tumorigenic factor.


Are social organizational factors independently associated with a current bacterial sexually transmitted infection among urban adolescents and young adults?
This study explored the relationship between the social organization of neighborhoods including informal social control and social cohesion and a current bacterial sexually transmitted infection (STI) among adolescents and young adults in one U.S. urban setting. Data for the current study were collected from April 2004 to April 2007 in a cross-sectional household study. The target population included English-speaking, sexually-active persons between the ages of 15 and 24 years who resided in 486 neighborhoods. The study sample included 599 participants from 63 neighborhoods. A current bacterial STI was defined as diagnosis of a chlamydia and/or gonorrhea infection at the time of study participation. Participants reported on informal social control (i.e. scale comprised of 9 items) and social cohesion (i.e. scale comprised of 5 items) in their neighborhood. In a series of weighted multilevel logistic regression models stratified by gender, greater informal social control was significantly associated with a decreased odds of a current bacterial STI among females (AOR 0.53, 95% CI 0.34, 0.84) after controlling for individual social support and other factors. The association, while in a similar direction, was not significant for males (AOR 0.73, 95% CI 0.48, 1.12). Social cohesion was not significantly associated with a current bacterial STI among females (OR 0.85, 95% CI 0.61, 1.19) and separately, males (OR 0.98, 95% CI 0.67, 1.44). Greater individual social support was associated with an almost seven-fold increase in the odds of a bacterial STI among males (AOR 6.85, 95% CI 1.99, 23.53), a finding which is in contrast to our hypotheses. The findings suggest that neighborhood social organizational factors such as informal social control have an independent relationship with sexual health among U.S. urban youth. The causality of the relationship remains to be determined.


Photo-cross-linking and high-resolution mass spectrometry for assignment of RNA-binding sites in RNA-binding proteins.
RNA-protein complexes play pivotal roles in many central biological processes. Although methods based on high-throughput sequencing have advanced our ability to identify the specific RNAs bound by a particular protein, there is a need for precise and systematic ways to identify RNA interaction sites on proteins. We have developed an experimental and computational workflow combining photo-induced cross-linking, high-resolution mass spectrometry and automated analysis of the resulting mass spectra for the identification of cross-linked peptides, cross-linking sites and the cross-linked RNA oligonucleotide moieties of such RNA-binding proteins. The workflow can be applied to any RNA-protein complex of interest or to whole proteomes. We applied the approach to human and yeast mRNA-protein complexes in vitro and in vivo, demonstrating its powerful utility by identifying 257 cross-linking sites on 124 distinct RNA-binding proteins. The open-source software pipeline developed for this purpose, RNP(xl), is available as part of the OpenMS project.


Risk factors for resistance to "first-line" antimicrobials among urinary tract isolates of Escherichia coli in children.
There are increasing concerns regarding antimicrobial resistance in Canada. Data are limited on the prevalence, patterns of resistance and risk factors associated with resistant organisms, including coliforms, in children. This study was done to address these issues as they relate to urinary tract isolates of Escherichia coli in a tertiary care pediatric centre in Ottawa. A surveillance study was conducted from December 1992 to December 1994. Susceptibility testing of urinary tract isolates of E. coli was performed using a panel of antimicrobial agents. A case-control study was also conducted for subjects with isolates resistant to trimethoprim-sulfamethoxazole (T-S), this drug being used a representative "first-line" agent. A total of 1636 consecutive isolates were obtained from 967 subjects. Of the 1636 isolates, 736 (45.0%) were resistant to ampicillin, 514 (31.4%) were resistant to T-S, 363 (22.2%) were resistant to both ampicillin and T-S, and 27 (1.7%) were resistant to both ampicillin and gentamicin. In the case-control study 274 children with isolates resistant to T-S were matched with 274 children who had T-S-sensitive isolates obtained during the study period or the preceding or subsequent 6 months. Multivariate analyses indicated that subjects who had received antimicrobials for more than 4 weeks in the previous 6 months were about 23 times more likely to have isolates resistant to T-S than were subjects without this risk factor (odds ratio [OR] 23.4, 95% confidence interval [CI] 12.0-47.6). Children with genitourinary tract abnormalities were 2.4 times more likely to have resistant isolates than those without such abnormalities (95% CI 1.2-4.5). Compared with children who had no hospital admissions in the previous year, those with 1 admission in that period were more likely to have resistant isolates (OR 2.3, 95% CI 1.4-7.5), as were those with 2 or more admissions in that period (OR 3.2, 95% CI 1.1-4.8). Compared with children aged 2-6 years, children under 2 years of age were less likely to have resistant isolates (OR 0.3, 95% CI 0.2-0.8). Selective antimicrobial pressure and multiple admissions to hospital were among the risk factors associated with antimicrobial resistance. The finding of a low but definite level of resistance to both ampicillin and gentamicin is important for the selection of empiric therapy for sepsis in neonates. The role of inexpensive first-line agents in the outpatient treatment and prevention of urinary tract infections requires re-examination, particularly in children who have recently received antimicrobial therapy.


Immunogenicity and protectivity of Plasmodium falciparum EBA-175 peptide and its analog is associated with alpha-helical region shortening and displacement.
EBA-175 protein is used as a ligand in the binding of P. falciparum to red blood cells (RBCs). Evidence shows that the conserved peptide 1779 from this protein (with high red blood cell binding ability and known critical erythrocyte binding residues) plays an important role in the invasion process. This peptide is neither immunogenic nor protective; analogs having critical residues replaced by amino acids with similar volume or mass but different polarity were synthesized and inoculated into Aotus monkeys, and elicited different immunogenic and protective responses. Nuclear Magnetic Resonance (1H-NMR) studies revealed that peptide analog 21696 (non-immunogenic and non-protective) presents a large helical fragment, that the peptide 14012 (immunogenic and non-protective) helical fragment is smaller, while the peptide 22812 (immunogenic and protective) alpha-helix is shorter in a different region and possesses greater flexibility at its N-terminus. The presence of methionine residues could affect the structural stability of peptide 22812 and ultimately its immunological response. Our results suggest a new strategy for designing a new malaria multi-component subunit-based vaccine.


In vitro Characterization of Gut Microbiota-Derived Bacterial Strains With Neuroprotective Properties.
Neurodegenerative diseases are disabling, incurable, and progressive conditions characterized by neuronal loss and decreased cognitive function. Changes in gut microbiome composition have been linked to a number of neurodegenerative diseases, indicating a role for the gut-brain axis. Here, we show how specific gut-derived bacterial strains can modulate neuroinflammatory and neurodegenerative processes in vitro through the production of specific metabolites and discuss the potential therapeutic implications for neurodegenerative disorders. A panel of fifty gut bacterial strains was screened for their ability to reduce pro-inflammatory IL-6 secretion in U373 glioblastoma astrocytoma cells. Parabacteroides distasonis MRx0005 and Megasphaera massiliensis MRx0029 had the strongest capacity to reduce IL-6 secretion in vitro. Oxidative stress plays a crucial role in neuroinflammation and neurodegeneration, and both bacterial strains displayed intrinsic antioxidant capacity. While MRx0005 showed a general antioxidant activity on different brain cell lines, MRx0029 only protected differentiated SH-SY5Y neuroblastoma cells from chemically induced oxidative stress. MRx0029 also induced a mature phenotype in undifferentiated neuroblastoma cells through upregulation of microtubule-associated protein 2. Interestingly, short-chain fatty acid analysis revealed that MRx0005 mainly produced C1-C3 fatty acids, while MRx0029 produced C4-C6 fatty acids, specifically butyric, valeric and hexanoic acid. None of the short-chain fatty acids tested protected neuroblastoma cells from chemically induced oxidative stress. However, butyrate was able to reduce neuroinflammation in vitro, and the combination of butyrate and valerate induced neuronal maturation, albeit not to the same degree as the complex cell-free supernatant of MRx0029. This observation was confirmed by solvent extraction of cell-free supernatants, where only MRx0029 methanolic fractions containing butyrate and valerate showed an anti-inflammatory activity in U373 cells and retained the ability to differentiate neuroblastoma cells. In summary, our results suggest that the pleiotropic nature of live biotherapeutics, as opposed to isolated metabolites, could be a promising novel drug class in drug discovery for neurodegenerative disorders.


Hot photocarrier dynamics in organic solar cells.
Photocurrent in an organic solar cell is generated by a charge transfer reaction between electron donors and acceptors. Charge transfer is expected to proceed from thermalized states, but this picture has been challenged by recent studies that have investigated the role of hot excitons. Here we show a direct link between excess excitation energy and photocarrier mobility. Charge transfer from excited donor molecules generates hot photocarriers with excess energy coming from the offset between the lowest unoccupied molecular orbital of the donor and that of the acceptor. Hot photocarriers manifest themselves through a short-lived spike in terahertz photoconductivity that decays on a picosecond timescale as carriers thermalize. Different dynamics are observed when exciting the acceptor at its absorption edge to a thermalized state. Charge transfer in this case generates thermalized carriers described by terahertz photoconductivity dynamics consisting of an instrument-limited rise to a long-lived signal.


Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages.
Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.


Dopaminergic neurons reduced to silence by oxidative stress: an early step in the death cascade in Parkinson's disease?
Parkinson's disease (PD) is a common neurodegenerative disorder that is most often sporadic, but in some cases it can be inherited as a simple Mendelian trait. The most important pathological feature of the disease is the death of brainstem dopaminergic neurons in the substantia nigra, which leads to characteristic motor symptoms. The etiology of PD remains unknown, but mitochondrial dysfunction and oxidative stress may contribute actively to the underlying pathomechanism. New studies suggest that K(ATP) channel activation may represent a downstream effector of these two cellular anomalies.


Distributed optical-fiber sensing by four-photon mixing pulse walk-off.
We propose a distributed optical-fiber sensing scheme using four-photon mixing pulse walk-off. We use a copropagating system in which only a pump wave is launched into the fiber. We analyze the performance by including the effects of fiber birefringence, group-velocity dispersion, and self-phase modulation. A short system with high sensitivity and good resolution can be built. The useful operating length is limited by self-phase-modulation-induced pulse broadening.


A framework for identifying and selecting long term adaptation policy directions for deltas.
Deltas are precarious environments experiencing significant biophysical, and socio-economic changes with the ebb and flow of seasons (including with floods and drought), with infrastructural developments (such as dikes and polders), with the movement of people, and as a result of climate and environmental variability and change. Decisions are being taken about the future of deltas and about the provision of adaptation investment to enable people and the environment to respond to the changing climate and related changes. The paper presents a framework to identify options for, and trade-offs between, long term adaptation strategies in deltas. Using a three step process, we: (1) identify current policy-led adaptations actions in deltas by conducting literature searches on current observable adaptations, potential transformational adaptations and government policy; (2) develop narratives of future adaptation policy directions that take into account investment cost of adaptation and the extent to which significant policy change/political effort is required; and (3) explore trade-offs that occur within each policy direction using a subjective weighting process developed during a collaborative expert workshop. We conclude that the process of developing policy directions for adaptation can assist policy makers in scoping the spectrum of options that exist, while enabling them to consider their own willingness to make significant policy changes within the delta and to initiate transformative change.


Conformation-specific binding of p31(comet) antagonizes the function of Mad2 in the spindle checkpoint.
The spindle checkpoint ensures accurate chromosome segregation by delaying anaphase in response to misaligned sister chromatids during mitosis. Upon checkpoint activation, Mad2 binds directly to Cdc20 and inhibits the anaphase-promoting complex or cyclosome (APC/C). Cdc20 binding triggers a dramatic conformational change of Mad2. Consistent with an earlier report, we show herein that depletion of p31(comet) (formerly known as Cmt2) by RNA interference in HeLa cells causes a delay in mitotic exit following the removal of nocodazole. Purified recombinant p31(comet) protein antagonizes the ability of Mad2 to inhibit APC/C(Cdc20) in vitro and in Xenopus egg extracts. Interestingly, p31(comet) binds selectively to the Cdc20-bound conformation of Mad2. Binding of p31(comet) to Mad2 does not prevent the interaction between Mad2 and Cdc20 in vitro. During checkpoint inactivation in HeLa cells, p31(comet) forms a transient complex with APC/C(Cdc20)-bound Mad2. Purified p31(comet) enhances the activity of APC/C isolated from nocodazole-arrested HeLa cells without disrupting the Mad2-Cdc20 interaction. Therefore, our results suggest that p31(comet) counteracts the function of Mad2 and is required for the silencing of the spindle checkpoint.


γ-H2AX as a marker for dose deposition in the brain of wistar rats after synchrotron microbeam radiation.
Synchrotron radiation has shown high therapeutic potential in small animal models of malignant brain tumours. However, more studies are needed to understand the radiobiological effects caused by the delivery of high doses of spatially fractionated x-rays in tissue. The purpose of this study was to explore the use of the γ-H2AX antibody as a marker for dose deposition in the brain of rats after synchrotron microbeam radiation therapy (MRT). Normal and tumour-bearing Wistar rats were exposed to 35, 70 or 350 Gy of MRT to their right cerebral hemisphere. The brains were extracted either at 4 or 8 hours after irradiation and immediately placed in formalin. Sections of paraffin-embedded tissue were incubated with anti γ-H2AX primary antibody. While the presence of the C6 glioma does not seem to modulate the formation of γ-H2AX in normal tissue, the irradiation dose and the recovery versus time are the most important factors affecting the development of γ-H2AX foci. Our results also suggest that doses of 350 Gy can trigger the release of bystander signals that significantly amplify the DNA damage caused by radiation and that the γ-H2AX biomarker does not only represent DNA damage produced by radiation, but also damage caused by bystander effects. In conclusion, we suggest that the γ-H2AX foci should be used as biomarker for targeted and non-targeted DNA damage after synchrotron radiation rather than a tool to measure the actual physical doses.


Gene expression profiles during the activation of rat hepatic stellate cells evaluated by cDNA microarray.
Hepatic stellate cells (HSCs) are activated by producing potentially injurious connective tissue components during hepatic fibrosis, thereby exerting a pivotal action in the development of liver fibrogenesis. The aim of this study was to investigate differences in gene expression patterns during the activation of HSCs using complementary cDNA microarrays. HSCs were isolated from normal rat livers and cultured for 0 (3 h), 3, 5 and 7 d. RNA was extracted from cultured cells at each point. The target RNA was hybridized to gene-specific sequence probes immobilized on chips. The hybridization signal was assessed using a confocal laser scanner. Comparison of hybridization signals and patterns allows the identification of mRNAs that are expressed differentially. Statistical analysis was used to classify and cluster the genes according to their up- or downregulation. As a result, 33 upregulated early-stage and 36 upregulated late-stage gene candidates were identified. This time-based study revealed a number of newly discovered genes involved in fibrogenesis during the activation of HSCs.


Chromosomal abnormalities in liver cell dysplasia detected by comparative genomic hybridisation.
The pathogenetic relation between liver cell dysplasia and hepatocellular carcinoma (HCC) is poorly understood. The aim of this study was to determine whether there is a genetic link between liver cell dysplasia and HCC that could support the role of dysplasia as a tumour precursor lesion. Microdissection from paraffin wax embedded sections and degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) were combined to analyse chromosomal imbalances by comparative genomic hybridisation (CGH) in nine HCCs and nodules containing liver cell dysplasia and cirrhosis adjacent to the tumours. Seven cases of large cell changes (LCC) and three cases of small cell changes (SCC) were analysed. The genetic abnormalities detected in liver cell dysplasia were then compared with those present in the corresponding HCC. No abnormalities were detected in LCC and cirrhotic nodules, arguing against the preneoplasic nature of these cell foci. In contrast, a subset of chromosomal alterations present in HCCs was found in the adjacent SCC. These findings support the preneoplastic status of SCC in human hepatocarcinogenesis.


Genome-wide map of regulatory interactions in the human genome.
Increasing evidence suggests that interactions between regulatory genomic elements play an important role in regulating gene expression. We generated a genome-wide interaction map of regulatory elements in human cells (ENCODE tier 1 cells, K562, GM12878) using Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) experiments targeting six broadly distributed factors. Bound regions covered 80% of DNase I hypersensitive sites including 99.7% of TSS and 98% of enhancers. Correlating this map with ChIP-seq and RNA-seq data sets revealed cohesin, CTCF, and ZNF143 as key components of three-dimensional chromatin structure and revealed how the distal chromatin state affects gene transcription. Comparison of interactions between cell types revealed that enhancer-promoter interactions were highly cell-type-specific. Construction and comparison of distal and proximal regulatory networks revealed stark differences in structure and biological function. Proximal binding events are enriched at genes with housekeeping functions, while distal binding events interact with genes involved in dynamic biological processes including response to stimulus. This study reveals new mechanistic and functional insights into regulatory region organization in the nucleus.


Intraoperative Optical Coherence Tomography-Assisted 27-Gauge Vitrectomy in Eyes with Vitreoretinal Diseases.
To report intraoperative optical coherence tomography (iOCT)-assisted 27-gauge microincision vitrectomy surgery (MIVS) in eyes with vitreoretinal disease. A retrospective, interventional case series performed at a single center, including 6 eyes with retinal disease that underwent iOCT-assisted 27-gauge MIVS. The advantages of iOCT were most notable when it was used to evaluate, in real time, different macular areas: the pre-macula, in vitreomacular traction or epiretinal membrane; the intra-macula, in macular edema or macular hole; and the sub-macula, in macular detachment. Real-time imaging and the minimization of shadows cast on the underlying tissues by the 27-gauge instrumentation made it possible to quickly select the best procedure at each critical juncture of the surgery. No patients experienced any complications. Real-time iOCT imaging during 27-gauge MIVS provided excellent intraoperative visualization of retinal tissues without causing significant obstructions to the surgeon. The positive feedback from the system allowed the surgeon to better judge the necessity of additional surgical procedures.


Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study.
To evaluate the efficacy and safety of a combination analgesic tablet (37.5 mg tramadol/325 mg acetaminophen) for the treatment of fibromyalgia pain. This 91-day, multicenter, double-blind, randomized, placebo-controlled study compared tramadol/acetaminophen combination tablets with placebo. The primary outcome variable was cumulative time to discontinuation (Kaplan-Meier analysis). Secondary measures at the end of the study included pain, pain relief, total tender points, myalgia, health status, and Fibromyalgia Impact Questionnaire scores. Of the 315 subjects who were enrolled in the study, 313 (294 women [94%], mean [+/- SD] age, 50 +/- 10 years) completed at least one postrandomization efficacy assessment (tramadol/acetaminophen: n = 156; placebo: n = 157). Discontinuation of treatment for any reason was less common in those treated with tramadol/acetaminophen compared with placebo (48% vs. 62%, P = 0.004). Tramadol/acetaminophen-treated subjects also had significantly less pain at the end of the study (53 +/- 32 vs. 65 +/- 29 on a visual analog scale of 0 to 100, P <0.001), and better pain relief (1.7 +/- 1.4 vs. 0.8 +/- 1.3 on a scale of -1 to 4, P <0.001) and Fibromyalgia Impact Questionnaire scores (P = 0.008). Indexes of physical functioning, role-physical, body pain, health transition, and physical component summary all improved significantly in the tramadol/acetaminophen-treated subjects. Discontinuation due to adverse events occurred in 19% (n = 29) of tramadol/acetaminophen-treated subjects and 12% (n = 18) of placebo-treated subjects (P = 0.09). The mean dose of tramadol/acetaminophen was 4.0 +/- 1.8 tablets per day. A tramadol/acetaminophen combination tablet was effective for the treatment of fibromyalgia pain without any serious adverse effects.


Peripheral muscle strength and functional capacity in patients with moderate to severe asthma.
The adequate control of asthma includes the absence of nocturnal symptoms, minimal use of medication, normal or nearly normal lung function and no limitations to physical activity. The choice of a more sedentary lifestyle can lead to physical de-conditioning, thereby aggravating asthma symptoms and increasing the risk of obesity. This study aimed at performing a battery of function-related assessments in patients with asthma and comparing them to a healthy control group. A prospective, transversal and case-control study was designed. It was set up at Santa Casa de Misericórdia Hospital -Sao Paulo and Nove de Julho University on a population of outpatients. Subjects of the study were patients affected by moderate to severe asthma. A case-control study was carried out involving 20 patients with moderate to severe asthma and 15 healthy individuals (control group). All participants underwent body composition analysis (BMI and BIA) and a controlled walk test (Shuttle test), resistance muscle test (1RM) and answered a physical activity questionnaire (IPAQ). The group with asthma also answered a questionnaire addressing the clinical control of the illness (ACQ). In comparison to the control group (unpaired Student's t-test), the patients with asthma had a significantly higher BMI (31.09 ± 5.98 vs. 26.68 ± 7.56 kg/m(2)) and percentage of body fat (38.40 ± 6.75 vs. 33.28 ± 8.23%) as well as significantly lower values regarding distance traveled on the walk test (369 ± 110 vs. 494 ± 85 meters) and metabolic equivalents (3.74 ± 0.87 vs. 4.72 ± 0.60). A strong correlation was found between the distance completed and peripheral muscle strength (r: 0.57, p < 0.05) and METs (Metabolic equivalents - minutes/week) and peripheral muscle strength of 1RM (r: 0.61, p = 0.009). The individuals with asthma had lower functional capacity and levels of physical activity as well as a higher percentage of body fat compared to healthy individuals. This suggests that such patients have a reduced physical performance stemming from a sedentary lifestyle. Despite the existence of few studies reporting moderate to severe asthmatic patients and functional capacity assessment, it is clear that the assessment presented in the current study is a valid and accessible tool in clinical practice.


Randomized 36-month follow-up of posterior bulk-filled resin composite restorations.
The aim of this double blind, randomized controlled trial was to evaluate the 36-month clinical performance of the layering technique (incremental [IF] vs. bulk-fill [BF]) in posterior composite resin restorations bonded with self-etch (SE) and etch-and-rinse (ER) strategies. Posterior dental cavities of 72 participants (n = 236), with a cavity depth of at least 3 mm, were randomly divided into four groups. The restorations were bonded using either the Tetric N-Bond ER or Tetric N-Bond SE. The composite resin Tetric N-Ceram Bulk-Fill was placed either IF or using BF. Two experienced and calibrated examiners evaluated the restorations using FDI criteria in the baseline and after 12, 24 and 36-month. The statistical analyses were performed using the Wilcoxon Signed rank test (α = 0.05) RESULTS: After 36-month, 14, 21 and 33 restorations showed minor fractures, marginal desadaptation and color mismatch, respectively (p > 0.05). Thirty-three restorations showed some marginal discoloration after 36-month with significant difference between ER (3 for ER-IF; 3 for ER-BF) and SE (14 for SE-IF; 12 for SE-BF; p < 0.05). The BF technique showed excellent clinical performance, which was comparable during the 36-month of clinical evaluation with the 2-mm IF and it was not affected by the adhesive strategy. However, using the ER strategy reduces the risk of some marginal discoloration, irrespectively of the filling technique. The bulk-fill material showed excellent clinical behavior when compared to its use in an incremental filling technique, mainly when associated to etch-and-rinse adhesive material after 3 years of clinical evaluation.


Composition and properties of bovine milk: A study from dairy farms in northern Sweden; Part I. Effect of dairy farming system.
This study was part of a larger project that aimed to understand the causes for increasing variation in cheese ripening in a cheese-producing region in northern Sweden. The influence of different on-farm factors on raw milk composition and properties was investigated and is described in this paper, whereas the monthly variation in the milk quality traits during 1 yr is described in our companion paper. The dairy farming systems on a total of 42 dairy farms were characterized through a questionnaire and farm visits. Milk from farm tanks was sampled monthly over 1 yr and analyzed for quality attributes important for cheese making. On applying principal component analyses to evaluate the variation in on-farm factors, different types of farms were distinguished. Farms with loose housing and automatic milking system (AMS) or milking parlor had a higher number of lactating cows, and predominantly Swedish Holstein (SH) breed. Farms associated with tiestalls had a lower number of lactating cows and breeds other than SH. Applying principal component analyses to study the variation in composition and properties of tank milk samples from farms revealed a tendency for the formation of 2 clusters: milk from farms with AMS or a milking parlor, and milk from farms with tiestall milking. The interaction between the milking system, housing system, and breed probably contributed to this grouping. Other factors that were used in the characterization of the farming systems only showed a minor influence on raw milk quality. Despite the interaction, milk from tiestall farms with various cow breeds had higher concentrations (g/100 g of milk) of fat (4.74) and protein (3.63), and lower lactose concentrations (4.67) than milk from farms with predominantly SH cows and AMS (4.32, 3.47, and 4.74 g/100 g of milk, respectively) or a milking parlor (4.47, 3.54, and 4.79 g/100 g of milk, respectively). Higher somatic cell count (195 × 103/mL) and lower free fatty acid concentration (0.75 mmol/100 g of fat) were observed in milk from farms with AMS than in milk from tiestall systems (150 × 103/mL and 0.83 mmol/100 g of fat, respectively). Type of farm influenced milk gel strength, with milk from farms with predominantly SH cows showing the lowest gel strength (65.0 Pa), but not a longer rennet coagulation time. Effects of dairy farming system (e.g., dominant breed, milking system, housing, and herd size) on milk quality attributes indicate a need for further studies to evaluate the in-depth effects of farm-related factors on milk quality attributes.


Light Field Depth Estimation via Stitched Epipolar Plane Images.
Depth estimation is a fundamental problem in light field processing. Epipolar-plane image (EPI)-based methods often encounter challenges such as low accuracy in slope computation due to discretization errors and limited angular resolution. Besides, existing methods perform well in most regions but struggle to produce sharp edges in occluded regions and resolve ambiguities in texture-less regions. To address these issues, we propose the concept of stitched-EPI (SEPI) to enhance slope computation. SEPI achieves this by shifting and concatenating lines from different EPIs that correspond to the same 3D point. Moreover, we introduce the half-SEPI algorithm, which focuses exclusively on the non-occluded portion of lines to handle occlusion. Additionally, we present a depth propagation strategy aimed at improving depth estimation in texture-less regions. This strategy involves determining the depth of such regions by progressing from the edges towards the interior, prioritizing accurate regions over coarse regions. Through extensive experimental evaluations and ablation studies, we validate the effectiveness of our proposed method. The results demonstrate its superior ability to generate more accurate and robust depth maps across all regions compared to state-of-the-art methods. The source code will be publicly available at https://github.com/PingZhou-LF/Light-Field-Depth-Estimation-Based-on-Stitched-EPIs.


A framework of pediatric hospital discharge care informed by legislation, research, and practice.
To our knowledge, no widely used pediatric standards for hospital discharge care exist, despite nearly 10 000 pediatric discharges per day in the United States. This lack of standards undermines the quality of pediatric hospital discharge, hinders quality-improvement efforts, and adversely affects the health and well-being of children and their families after they leave the hospital. In this article, we first review guidance regarding the discharge process for adult patients, including federal law within the Social Security Act that outlines standards for hospital discharge; a variety of toolkits that aim to improve discharge care; and the research evidence that supports the discharge process. We then outline a framework within which to organize the diverse activities that constitute discharge care to be executed throughout the hospitalization of a child from admission to the actual discharge. In the framework, we describe processes to (1) initiate pediatric discharge care, (2) develop discharge care plans, (3) monitor discharge progress, and (4) finalize discharge. We contextualize these processes with a clinical case of a child undergoing hospital discharge. Use of this narrative review will help pediatric health care professionals (eg, nurses, social workers, and physicians) move forward to better understand what works and what does not during hospital discharge for children, while steadily improving their quality of care and health outcomes.


Sources of U.S. physician income: the contribution of government payments to the specialist-generalist income gap.
Physician income varies threefold among specialties. Lower incomes have produced shortages in primary care fields. To investigate the impact of government policy on generating income differentials among specialties. Cross-sectional analysis of the 2004 MEPS. For outpatient care, total payments made to 27 different types of specialists from five types of payers: Medicare, Medicaid, other government (the Veterans Administration and other state and local programs), private insurance, and out-of-pocket payments. For inpatient care, aggregate (i.e., all-specialty) inpatient physician reimbursement from the five payers. In 2004, physicians derived 78.6% of their practice income ($149,684 million, 95% CI, $140,784 million-$158,584 million) from outpatient sources and 21.4% of their income ($40,782 million, 95% CI, $36,839 million-$44,724 million) from inpatient sources. Government payers accounted for 32.7% of total physician income. Four specialties derived > 50% of their outpatient income from public sources, including both the lowest and highest paid specialties (geriatrics and hematology/oncology, respectively). Inter-specialty income differences result, in part, from government decisions.


Breakup of a multisoliton state of the linearly damped nonlinear Schrödinger equation.
We address the breakup (splitting) of multisoliton solutions of the nonlinear Schrödinger equation (NLSE), occurring due to linear loss. Two different approaches are used for the study of the splitting process. The first one is based on the direct numerical solution of the linearly damped NLSE and the subsequent analysis of the eigenvalue drift for the associated Zakharov-Shabat spectral problem. The second one involves the multisoliton adiabatic perturbation theory applied for studying the evolution of the solution parameters, with the linear loss taken as a small perturbation. We demonstrate that in the case of strong nonadiabatic loss the evolution of the Zakharov-Shabat eigenvalues can be quite nontrivial. We also demonstrate that the multisoliton breakup can be correctly described within the framework of the adiabatic perturbation theory and can take place even due to small linear loss. Eventually we elucidate the occurrence of the splitting and its dependence on the phase mismatch between the solitons forming a two-soliton bound state.


Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs.
To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs. 8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs. The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index. Growth hormone response was assessed by stimulation and suppression tests. Additionally, basal serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations and urine cortisol-to-creatinine concentration ratios were measured and dual energy x-ray absorptiometry was performed to evaluate body composition. Insulin sensitivity was lower in the hypothyroid group than in the euthyroid group, whereas acute insulin response to glucose was higher. Glucose effectiveness and disposition index were not different between groups. Basal serum GH and IGF-1 concentrations as well as abdominal fat content were high in hypothyroid dogs, but urine cortisol-to-creatinine concentration ratios were unchanged. Hypothyroidism appeared to negatively affect glucose homeostasis by inducing insulin resistance, but overall glucose tolerance was maintained by increased insulin secretion in hypothyroid dogs. Possible factors affecting insulin sensitivity are high serum GH and IGF-1 concentrations and an increase in abdominal fat. In dogs with diseases involving impaired insulin secretion such as diabetes mellitus, concurrent hypothyroidism can have important clinical implications.


Metastatic potential prediction by a visual grading system of cell motility: prospective validation in the Dunning R-3327 prostatic adenocarcinoma model.
A method for accurate prediction of prognosis in individual patients with prostatic carcinoma does not exist. The limitations of pathological grading systems may result from the failure of standard pathological examination of fixed dead tissue to accurately assess the biological and metastatic behavior of live tumor cells. Many of the sublines of the Dunning R-3327 rat prostatic adenocarcinoma are histologically similar yet differ in metastatic potential. Cells from the Dunning model were grown in culture and filmed by time-lapse videomicroscopy. These cells exhibited characteristic membrane ruffling, pseudopodal extension, and cellular translation that could be graded with 80% reproducibility. Individual cells from sublines with high metastatic potential were separated from cells from sublines of low metastatic potential in 96% of cases. We have applied our cell motility grading system to prospectively classify the metastatic potential of neoplastic cells. The mean motility grades of sublines of high and low metastatic potential differed significantly (Mann-Whitney-Wilcoxon, P less than 0.0005). Among seven sublines in which the grading system was developed, individual cells were correctly classified as high or low metastatic in 71% of cases by ruffling or pseudopodal extension, 73% of cases by translation, and 75% of cases by motility index, an average of the three parameters of motility. Among four newly tested sublines, cells from a low metastatic and high metastatic sublines were perfectly classified. Cells from two other low metastatic sublines were misclassified. When all 88 cells from the 11 sublines were classified, high metastatic cells were detected with 94% sensitivity and 50% specificity. The predictive value of a determination of low metastatic was 93%, whereas the predictive value of an assignment of high metastatic was 52%. The ability to detect and accurately classify most highly metastatic cells while rarely erring in a classification of low metastatic potential suggests that a grading system of cancer cell motility should be evaluated in human prostatic carcinoma. The motility of live prostatic carcinoma cells may predict patient prognosis better than standard pathological grading systems.


Results from Ghana's 2014 Report Card on Physical Activity for Children and Youth.
Limited evidence exists on indicators of physical activity (PA) and guidelines for children and youth in Ghana, despite the growing burden of physical inactivity, obesity, and related morbidity. A baseline description of PA indicators of Ghanaian children and youth is hereby presented in the 2014 Ghanaian Physical Activity Report Card. Data for the report card were obtained from a very limited available literature on PA among children and youth in Ghana. PA experts independently assigned grades to indicators based on available evidence, which were then harmonized and agreed to by group consensus. The report card is based on limited evidence. Thus, 2 indicators were not graded (Active Play, and Family and Peer Support). For sedentary behavior, a B grade was assigned based on evidence from the 2012 Ghana School Health Survey which indicated that 21% of children and youth were sedentary. Organized Sports was graded a C, while the remainder of indicators (Overall PA levels, Active Transportation, School, Community, and Government) were graded a D. About one-third of Ghanaian children and youth engage in inadequate PA. More research on PA behavior and enabling environments is needed to better grade the indicators of PA in the future and to inform policy and interventions in Ghana. Appropriate school physical education and after-school sports policies and programs are warranted.


The dose-response effect of medical exercise therapy on impairment in patients with unilateral longstanding subacromial pain.
The primary aim of this study was to investigate the effect of medical exercise therapy in shoulder impingement patients, along with possible correlations between impairment variables. A prospective unblended randomized clinical trial. Over four months, 61 participants were randomly assigned into a high-graded exercise therapy group (HD) (n=31) and into a low-graded exercise therapy group (LD) (n=30). Prognostic variables were similar between the groups at baseline. Five (8%) patients dropped out during the treatment period, and another four (6%) dropped out before followup. Pain was a composite score of a visual analogue scale (VAS). Isometric strength was measured during four resisted break tests on the shoulder. Function was measured by means of a functional assessment questionnaire (Shoulder Rating Questionnaire, SRQ). Both groups trained three times per week for twelve weeks, with tests pre- and posttraining and six months follow-up. The HD group achieved significantly (p < 0.05) better outcome effects than the LD group for pain, range of motion, isometric functional strength and function, but both groups increased function from pretest to posttest. In patients with uncomplicated subacromial pain syndrome, medical exercise therapy is an efficient treatment alternative, where high-grade doses should be emphasized. A major limitation is that the measurements were not undertaken by another person than the treating physiotherapists.


HLA-Mismatched Donors in Patients with Myelodysplastic Syndrome: An EBMT Registry Analysis.
Recently, haploidentical transplantation (haplo) using post-transplant cyclophosphamide (PTCy) has been reported to give very encouraging results in patients with hematological malignancies. Patients who have no HLA-matched donor currently have the choice between a mismatched unrelated donor, an unrelated cord blood (CB) donor, and a haploidentical related donor. The aim of our study is to compare the outcome of patients with myelodysplastic syndrome (MDS) who have been transplanted from a haploidentical donor using PTCy, an HLA-mismatched unrelated donor (marrow or peripheral blood stem cells), or an unrelated mismatched CB donor. A total of 833 MDS patients from the European Group for Blood and Marrow Transplantation (EBMT) registry, transplanted between 2011 and 2016, were identified. The potential benefit of haplo was compared with mismatched unrelated and CB donors in an adjusted and weighted model taking into account potential confounders and other prognostic variables. Haplo was at lower risk of acute graft-versus-host disease (GVHD) than mismatched unrelated donor (P = .010) but at similar risk than CB. Progression-free survival was better after haplo (versus mismatched unrelated, P = .056; versus CB, P = .003) and overall survival tended to be superior after haplo (versus mismatched unrelated, P = .082; versus CB, P = .002). Nonrelapse mortality was not significantly different between haplo and mismatched unrelated donors. Relapse risk was not influenced by the type of donor. In conclusion, patients with MDS from the EBMT registry receiving hematopoietic stem cell transplantation from a haplo donor have significantly better outcome than those receiving hematopoietic stem cell transplantation from a CB donor and at least similar or better outcome than with a mismatched unrelated donor. Prospective studies comparing the type of donors will be needed to confirm this assumption.


Fertility Preferences of Women in a Province Center.
Fertility preferences and status are important parameters involved in reproductive health. The aim of the present study was to define some characteristics of the fertility preferences of women aged 15-49 years in our region. This cross-sectional study was conducted between 2013 and 2015. The study population consisted of 627 married women aged 15-49 years living in a city center. A questionnaire about socio-demographic characteristics, pregnancy and birth traits, and fertility preferences was applied. Chi-square, Mann-Whitney U, and Spearman correlation tests were analyzed using Statistical Package for Social Sciences (SPSS) version 20.00 (IBM, SPSS Corp.; Armonk, NY, USA) software for statistical analyses. A p<0.05 was considered statistically significant. The mean age of the women participating in the survey was 33.03±7.1 years. Median age at marriage was 20 years, mean age at first pregnancy was 21 years, and mean number of pregnancies was 3.07 years, with 14.6% having had more than five pregnancies and 34.6% having experienced previous miscarriages. The mean number of live births was 2.2, and 21.5% of women had waited 24 months between pregnancies. Additionally, 77.7% reported using family planning of any kind, with 62.1% using the modern method. Women's ages at first marriage varied significantly depending on education (p<0.001) and working status (p<0.001), whereas ages at first pregnancy varied significantly depending on educational status (p<0.001). The total number of pregnancies varied significantly depending on level of education, working status, and family income (p<0.001). Times between two pregnancies among women with histories of more than two pregnancies differed significantly depending on educational status (p<0.05). The most important factors in women's fertility preferences are education, work, and income. Increasing women's educational levels can lead to safe and healthy pregnancies and births.


Infants' conceptual representations of meaningful verbal and nonverbal sounds.
In adults, words are more effective than sounds at activating conceptual representations. We aimed to replicate these findings and extend them to infants. In a series of experiments using an eye tracker object recognition task, suitable for both adults and infants, participants heard either a word (e.g. cow) or an associated sound (e.g. mooing) followed by an image illustrating a target (e.g. cow) and a distracter (e.g. telephone). The results showed that adults reacted faster when the visual object matched the auditory stimulus and even faster in the word relative to the associated sound condition. Infants, however, did not show a similar pattern of eye-movements: only eighteen-month-olds, but not 9- or 12-month-olds, were equally fast at recognizing the target object in both conditions. Looking times, however, were longer for associated sounds, suggesting that processing sounds elicits greater allocation of attention. Our findings suggest that the advantage of words over associated sounds in activating conceptual representations emerges at a later stage during language development.


Wear of a dental composite in an artificial oral environment: A clinical correlation.
The study objective was to correlate wear between an in vitro method for simulating wear and in vivo wear of a posterior dental composite. Ten subjects (12 restorations) were selected from a five-year clinical study (University of North Carolina, School of Dentistry) that assessed wear of SureFil composite (Caulk, Dentsply). Subject casts were digitized and changes in volume and mean depth with time were calculated from the 3D digital models for contact and contact-free wear. SureFil composite disks were mounted in the University of Minnesota's Artificial Oral Environment, opposed by natural enamel, subjected to mandibular-like movements for 150 K, 300 K, 600 K, 1.2 M, and 1.5 M cycles, and loaded with peak forces of 13 N (n = 7) or 30 N (n = 3). Wear rates were calculated as the slope of the linear regressions fitting the wear data. Data were analyzed using one-way ANOVAs and post hoc t-tests where appropriate (p = 0.05). Clinical restorations included contact wear on seven restorations and contact-free wear on all restorations. Contact-free wear was less than contact wear (p < 0.01). SureFil clinical wear rates were 0.012 mm/year (mean depth) and 0.023 mm(3)/year (volume). Clinical restorations expanded slightly during the first year. Using a conversion rate of one year equals 3 × 10(5) cycles, there were no significant differences between the clinical and simulated data except depths at Year 5 and 13 N volume at Year 4. The 30 N simulation reproduced the clinical data if contact-free wear was taken into account. Good agreement between simulated and clinical wear implies that in vitro simulation can screen new composite formulations.


Allyl Isothiocyanate Inhibits the Proliferation of Renal Carcinoma Cell Line GRC-1 by Inducing an Imbalance Between Bcl2 and Bax.
BACKGROUND Because of the insensitivity of renal cell carcinoma (RCC) to both chemotherapy and radiotherapy, surgery remains the primary approach for anticancer treatment. However, patients who do not receive timely diagnoses may not be suitable for surgery, especially in the late phase of tumor development. Thus, the discovery of novel effective treatment is of great importance. Allyl isothiocyanate (AITC) can inhibit the proliferation and induce apoptosis in many cancer cells. In this paper, we report on an in vitro study to determine the effect of AITC on proliferation and apoptosis of RCC line GRC-1. MATERIAL AND METHODS CCK8 assay was used to detect cell proliferation under gradient concentrations of AITC. Flow cytometry was employed to evaluate cell apoptosis. Real-time fluorescent polymerase chain reaction quantified mRNA levels of Bax and Bcl-2 genes. Western blotting was further employed for protein expression assay. RESULTS AITC inhibited GRC-1 cell proliferation and induced cell apoptosis in a dose-dependent manner; it also elevated Bax while suppressing Bcl-2 gene expression at both mRNA and protein levels. In general, increasing concentration of AITC decreased Bcl-2/Bax ratio. CONCLUSIONS The inhibitory effect of AITC on GRC-1 cells is exerted via cell apoptosis, in which the imbalance of Bcl-2/Bax plays a significant role.


Transesophageal echocardiography in critically ill patients.
The feasibility, safety and clinical impact of transesophageal echocardiography were evaluated in 51 critically ill intensive care unit patients (28 men and 23 women; mean age 63 years) in whom transthoracic echocardiography was inadequate. At the time of transesophageal echocardiography, 30 patients (59%) were being mechanically ventilated. Transesophageal echocardiography was performed without significant complications in 49 patients (96%), and 2 patients with heart failure had worsening of hemodynamic and respiratory difficulties after insertion of the transesophageal probe. The most frequent indication, in 25 patients (49%), was unexplained hemodynamic instability. Other indications included evaluation of mitral regurgitation severity, prosthetic valvular dysfunction, endocarditis, aortic dissection and potential donor heart. In 30 patients (59%), transesophageal echocardiography identified cardiovascular problems that could not be clearly diagnosed by transthoracic echocardiography. In the remaining patients, transesophageal echocardiography permitted confident exclusion of suspected abnormalities because of its superior imaging qualities. Cardiac surgery was prompted by transesophageal echocardiographic findings in 12 patients (24%) and these findings were confirmed at operation in all. Therefore, transesophageal echocardiography can be safely performed and has a definite role in the diagnosis and expeditious management of critically ill cardiovascular patients.


How Conditions and Resources Connected to Digital Management Systems and Remote Work Are Associated with Sustainable Work.
The current state of work-life transformation will see more white-collar work being performed remotely using digital management systems. There is, however, a lack of research on factors and resources contributing to sustainable work when working remotely using digital management systems. The aim of this study was to study the conditions and resources connected to digital management systems and remote work, and their associations with sustainable work, in terms of process quality, trust, and sense of coherence, when working remotely during the COVID-19 pandemic. An analytical cross-sectional study was performed. Questionnaire data from white-collar employees (n = 484) in two private companies were analyzed with regression models, focusing on the importance of the conditions and resources connected to digital management systems and remote work, stratified by working from home or at the office. The results showed digital conditions and resources being associated with indicators of sustainable work. Furthermore, the results showed that social work relations were additional important explanatory factors for sustainable remote work. This study contributes to the development of a new post-pandemic work-life balance by concluding that sustainable remote work needs to be ensured by functional digital management systems and adequate leadership supporting the development of a positive team and learning climate.


Bone marrow stromal cells promote neurite extension in organotypic spinal cord slice: significance for cell transplantation therapy.
Recent reports have indicated that bone marrow stromal cells (BMSCs) have the potential to improve neurological function when transplanted into models of central nervous system (CNS) disorders, including traumatic spinal cord injury. In this study, the authors aimed to clarify the underlying mechanism through which BMSCs supported CNS regeneration in the spinal cord. The authors topically applied mouse BMSCs expressing green fluorescence protein (0.4-4 x 10(4) cells) on the organotypic spinal cord slice culture prepared from 6-day-old rat pups (n = 17). They were co-cultured for 3 weeks after the slice culture started, and the behavior of the applied BMSCs was serially observed using a fluorescence bioimaging technique. The authors completed a histological analysis at the end of the co-cultures and evaluated the profiles of the cultured BMSCs using microarray and immunocytochemistry techniques. The fluorescence bioimaging showed that the BMSCs survived and made a cluster on the slice during the experiments. They also induced a morphological change in the slice within 48 hours of co-culture. Immunohistochemistry analysis showed that the BMSCs promoted a marked neurite extension toward their cluster and some of the BMSCs expressed Tuj-1, an early neuronal marker. Analysis by microarray and immunocytochemistry revealed that BMSCs highly expressed the matrix metalloproteinases (MMPs), stromal cell-derived factor-1, and its specific receptor CXCR4. These findings suggest that the donor BMSCs can support CNS regeneration due to their acquisition of a suitable environment for differentiation and promotion of neurite extension via MMPs and chemokines.


Visual analysis of transcriptome data in the context of anatomical structures and biological networks.
The complexity and temporal as well as spatial resolution of transcriptome datasets is constantly increasing due to extensive technological developments. Here we present methods for advanced visualization and intuitive exploration of transcriptomics data as necessary prerequisites in order to facilitate the gain of biological knowledge. Color-coding of structural images based on the expression level enables a fast visual data analysis in the background of the examined biological system. The network-based exploration of these visualizations allows for comparative analysis of genes with specific transcript patterns and supports the extraction of functional relationships even from large datasets. In order to illustrate the presented methods, the tool HIVE was applied for visualization and exploration of database-retrieved expression data for master regulators of Arabidopsis thaliana flower and seed development in the context of corresponding tissue-specific regulatory networks.


Regulation of angiogenesis by hypoxia: role of the HIF system.
The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.


Evolution of the IS6110-based restriction fragment length polymorphism pattern during the transmission of Mycobacterium tuberculosis.
Interpretation of the molecular epidemiological data of Mycobacterium tuberculosis is dependent on the validity of the assumptions that have been made. It is assumed that the IS6110 banding pattern is sufficiently stable to define epidemiological events representing ongoing transmission. However, molecular epidemiological data also support the observation that the IS6110 banding pattern may change over time. Factors affecting this rate may include the nature and duration of disease in a host and the opportunity to experience different host environments during the transmission cycle. To estimate the rate of IS6110 change occurring during the process of transmission, M. tuberculosis isolates from epidemiologically linked patients were genotypically characterized by restriction fragment length polymorphism (RFLP) analysis. The identification of IS6110 banding pattern changes during ongoing transmission suggested that a rate could be estimated. IS6110 change was significantly associated with strains with >5 IS6110 elements (P = 0.013) and was not observed in low-copy-number isolates. The minimum rate of appearance of variant strains was calculated to be 0.14 variant cases per source-case per year. This data suggest that clustering of isolates based on identical RFLP patterns is expected to underestimate transmission in patients infected with high-copy-number isolates. A model based on the rate of appearance of both variant and invariant strains demonstrates that the genotypically defined population structure may change by 18.6% during the study period of approximately 6.5 years. The implications for the use of RFLP data for epidemiologic study are discussed.


Fourier transform spectrometry with a near-infrared supercontinuum source.
Optical fiber based supercontinuum light sources combine the brightness of lasers with the broad bandwidth of incandescent lamps and thus are promising candidates for sources in spectroscopic applications requiring high brightness and broad bandwidth. Herein, near-infrared (IR) Fourier transform (FT) spectrometry with a supercontinuum (SC) light source is investigated. The efficient, collimated propagation of broad bandwidth SC light through an 18 m path length multipass cell is demonstrated. A normalized spectral difference is calculated for the SC spectrum on consecutive FT mirror scans and is found to vary by less than 0.5%, indicating excellent spectral stability. The rms noise on zero absorbance lines is obtained as a function of the number of mirror scans at 0.125, 2, and 16 cm(-1) resolution for both the SC and conventional tungsten lamp source. The SC source has approximately a factor of ten times more noise than the lamp under comparable conditions for each resolution and data acquisition time. This clearly indicates that spectral acquisition with the SC source is not detector noise limited. NIR-FT spectra of methane and methyl salicylate, acquired with both the SC and lamp source, are reported. These spectra illustrate the advantage the SC source has over the incandescent source in that it can efficiently traverse long path lengths, thus providing a sensitivity advantage. The spectra also demonstrate the disadvantage of the SC source with respect to the lamp in the increased level of amplitude noise. Prospects for the future use of SC sources in absorption spectroscopy, including possible noise mitigation strategies, are briefly discussed.


[Ambiguity in Eric Kandel's neuroscientific basis of psychiatry].
The philosophical principles underlying the work of Eric Kandel are investigated on the basis of his innovative paper entitled 'A new intellectual framework for psychiatry' (Kandel 1998). A careful analysis of the concepts involved reveals some ambiguity in Kandel's proposition in the mind-body debate. On the one hand Kandel uses formulations that are compatible with (classical) psychophysical identity theories; on the other hand he expresses views that actually have more in common with non-eliminative physicalism (or epiphenomenalism). In addition, he weakens his position by using misleading metaphors an analogies. This can lead to what is known as the 'mereological fallacy'. The final part of the article examines what this ambiguity tells us about Kandel's views on psychotherapy and the social justification for psychiatry. Kandel's approach can lead to a pointless narrowing down of the psychiatrist's normative role and to an over-restrictive attitude to psychotherapy.


Direct measurement of frequency and polarization dependences of cross-phase modulation in fibers from high-resolution optical spectra.
We present the results of an experiment for frequency and polarization dependence characterization of non-linear cross-phase-modulation (XPM) effects in optical fibers. The measurement technique is based on the direct analysis of high-resolution optical spectra of a signal wave that is phase modulated by an intensity-modulated pump wave. Measurement results provide experimental confirmation of the scalar character, over the whole resonant frequency range, of the electrostrictive contribution to the nonlinear refractive index. Also, the results confirm experimentally the relation describing the polarization dependence of the Kerr contribution to XPM in non-polarization-maintaining fibers.


New entrants' practice patterns in Medicare home health care after the prospective payment system revision in 2008.
Medicare home health care spending increased under the prospective payment system (PPS) that was introduced specifically to control the rising spending. To explain this unexpected spending rise, we focused on new home health agencies that entered the market under the PPS. The high profit margins under the PPS attracted many new agencies to the market partially due to home health care's unique feature of low entry costs. We examined whether new entrants were more likely to adopt the practice patterns leading to higher profit margins than incumbent agencies that had been operating in the market before the PPS. Using 2008 to 2010 Medicare Home Health Claims and Provider of Services File, we estimated regressions of agencies' practice patterns controlling for agency and patient characteristics. We found that new entrants were more likely than incumbents to adopt practice patterns leading to high profit margins. They were more likely to target the 14th and 20th therapy visit where marginal revenue is relatively greater than that of other number of visits. Under the payment system that compensates extra therapy visits but not for other types of visits, entrants were also more likely to provide therapy visits, but less likely to provide medical social service visits. Given the high entry rates of agencies under the PPS, distinct practice patterns among entrants explain the drastic home health spending increase under the PPS. Heterogeneity in agencies' practice patterns also suggests an opportunity to improve efficiency in the Medicare home health care market.


Accuracy of a computed tomography bronchial wall thickness to pulmonary artery diameter ratio for assessing bronchial wall thickening in dogs.
Computed tomography is increasingly being used in veterinary medicine to evaluate animals with pulmonary signs such as coughing, tachypnea, and exercise intolerance, however, a quantitative measure of bronchial wall thickening has yet to be validated in veterinary medicine. Canine chronic bronchitis is a disease that is characterized histologically by thickening of the bronchial walls. Thoracic CT images of 16 dogs with chronic bronchitis and 72 dogs presenting for conditions unrelated to cough were evaluated. A ratio comparing the bronchial wall thickness to the adjacent pulmonary artery diameter was obtained in the right and left cranial and caudal lung lobes. There was no significant difference in dogs with chronic bronchitis or unaffected dogs between the left and right hemithorax, patient weight, patient age, image slice thickness, or CT machine used. Dogs with chronic bronchitis were found to have a significantly greater ratio than unaffected dogs (P < 0.001). The ratios in the cranial lung lobes were found to be significantly greater than the caudal lung lobes in both chronic bronchitis and unaffected dogs (P < 0.001). A receiver operating characteristic curve of the ratios in the cranial lung lobes had an area under the curve of 0.912, indicating high accuracy in predicting for bronchial wall thickening. A ratio of ≥ 0.6 in the cranial lung lobes was found to have a sensitivity of 77% and specificity of 100% in predicting for the presence of chronic bronchitis, and we propose using this cut-off as supportive of bronchial wall thickening on CT.


Electric field-induced circulation and vacuolization regulate enzyme reactions in coacervate-based protocells.
Artificial protocells operating under non-equilibrium conditions offer a new approach to achieve dynamic features with life-like properties. Using coacervate micro-droplets comprising polylysine (PLL) and a short single-stranded oligonucleotide (ss-oligo) as a membrane-free protocell model, we demonstrate that circulation and vacuolization can occur simultaneously inside the droplet in the presence of an electric field. The circulation is driven by electrohydrodynamics and applies specifically to the major components of the protocell (PLL and ss-oligo). Significantly, under low electric fields (E = 10 V cm-1) the circulation regulates the movement of the vacuoles, while high levels of vacuolization produced at higher electric fields can deform or reshape the circulation. By taking advantage of the interplay between vacuolization and circulation, we achieve dynamic localization of an enzyme cascade reaction at specific droplet locations. In addition, the spatial distribution of the enzyme reaction is globalized throughout the droplet by tuning the coupling of the circulation and vacuolization processes. Overall, our work provides a new strategy to create non-equilibrium dynamic behaviors in molecularly crowded membrane-free synthetic protocells.


Parents' lived experiences of parental needs for support at a burn centre.
Purpose: A burn injury to a child is a traumatic event and the parent's emotional reactions and coping strategies affect the child's adaptive outcome. It is therefore important that parents get the right support. The aim was to explore parents' lived experiences of their need for support when having a child admitted to a burn centre. Methods: Semi-structured face-to-face interviews were conducted with 22 parents of children age <12 years hospitalised with an accidental burn injury, 9 to 27 days after the burn accident, from April 2017 to July 2018. A Ricoeur-inspired textual analysis method was used. Results: Four themes emerged from the analysis and describe the parents' needs for support. The parents wanted to be taken care of as a whole family and feel safe in the hands of professionals. This, in turn, depended on being informed about the child's condition and treatment, but also on getting help in dealing with feelings of guilt. Not least, parents wanted opportunities to take care of their own fundamental needs in terms of hygiene, food, adequate rest and activities. Conclusion: As an overall understanding the healthcare providers should focus on the family as a whole in care and treatment.


Discrimination of fast click-series produced by tagged Risso's dolphins (Grampus griseus) for echolocation or communication.
Early studies that categorized odontocete pulsed sounds had few means of discriminating signals used for biosonar-based foraging from those used for communication. This capability to identify the function of sounds is important for understanding and interpreting behavior; it is also essential for monitoring and mitigating potential disturbance from human activities. Archival tags were placed on free-ranging Grampus griseus to quantify and discriminate between pulsed sounds used for echolocation-based foraging and those used for communication. Two types of rapid click-series pulsed sounds, buzzes and burst pulses, were identified as produced by the tagged dolphins and classified using a Gaussian mixture model based on their duration, association with jerk (i.e. rapid change of acceleration) and temporal association with click trains. Buzzes followed regular echolocation clicks and coincided with a strong jerk signal from accelerometers on the tag. They consisted of series averaging 359±210 clicks (mean±s.d.) with an increasing repetition rate and relatively low amplitude. Burst pulses consisted of relatively short click series averaging 45±54 clicks with decreasing repetition rate and longer inter-click interval that were less likely to be associated with regular echolocation and the jerk signal. These results suggest that the longer, relatively lower amplitude, jerk-associated buzzes are used in this species to capture prey, mostly during the bottom phase of foraging dives, as seen in other odontocetes. In contrast, the shorter, isolated burst pulses that are generally emitted by the dolphins while at or near the surface are used outside of a direct, known foraging context.


Prostheses option in revision total knee arthroplasty, from the bench to the bedside: (1) basic science and principles.
The number of primary and revision total knee arthroplasties (rTKAs) continues to increase annually. To date, most of the literature has focused on the surgical technique and outcome of revision prostheses. Thanks to the contributions of surgeons, engineers, and researchers, the design of prostheses has reached a prominent milestone. However, very limited discussion regarding the design, rationale and constitution of prostheses has been documented at present. An electronic search of four online databases (Embase, MEDLINE, PubMed, and Google Scholar) was conducted to identify eligible resources. Forty-four review articles were acquired by searching the terms 'prosthesis selection', 'prosthesis option', and 'prosthesis determination' in rTKA. Sixty-eight research articles investigating the factors affecting prosthesis options in rTKA were screened and integrated with the authors' perspective to reach a final recommendation. This article first discusses the pathological, individual, and other factors affecting prosthesis options in rTKA and further illustrates the classification, geometry, biomechanics, and constitution of the revision system from the authors' perspective. An evidence-based recommendation in the form of a matching algorithm was formulated. This review offers special value for decision-making regarding prosthesis options in rTKA. Particularly, it presents specific recommendations regarding unclear practical issues, such as the optimal level of constraint, individualized design, length, and fixation of extension stem, as well as the pros and cons of modularity.


PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.
Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.


Quantification of dissolved and particulate polyunsaturated aldehydes in the Adriatic sea.
Polyunsaturated aldehydes (PUA) are supposed to play critical roles in chemically-mediated plankton interactions. Laboratory studies suggest that they act as mediators of chemical defense and chemical communication. PUA are oxylipins containing an α,β,γ,δ-unsaturated aldehyde structure element and are mainly found in diatoms. We present here a detailed surface mapping of PUA during a spring bloom of the diatom Skeletonema marinoi in the Adriatic Sea. We monitored dissolved PUA, as well as particulate PUA, which are produced by phytoplankton after cell disintegration. Our survey revealed a patchy distribution of PUA and shows that at most stations S. marinoi is the major contributor to the overall PUA. Our data also suggest that lysis of a diatom bloom can contribute significantly to the dissolved PUA concentrations and that other producers, which are smaller in cell size compared to diatoms, have to be taken into account as well if the total PUA content of marine samples is considered. The analyses of samples collected in deeper water suggests that diatom contribution to PUA decreases with depth, while smaller-sized unidentified organisms take place as dominant contributors to the PUA concentrations.


Avipoxvirus infection in a collection of captive stone curlews (Burhinus oedicnemus).
A natural outbreak of avipoxvirus occurred in recently purchased stone curlews (Burhinus oedicnemus) at a breeding farm and subsequently spread to other stone curlews residing at the farm. The initial outbreak was characterized by mild vesicular skin lesions on the legs, which then developed crusts and bled. The overall morbidity rate was 100%, but none of the birds died, and all recovered without complication. Four gallinaceous species, also kept on the farm, did not develop lesions. Avipoxvirus was identified from the skin lesions by virus isolation, electron microscopy, and monoclonal antibody testing, as well as by polymerase chain reaction testing. Eight months after this outbreak, 7 male stone curlews developed large, round, crusty lesions on their legs. Although poxvirus virions were identified in the lesions, results of virus isolation were negative. These lesions possibly were the result of a recrudescence of the original infection in male birds that were stressed because they were housed together during the breeding season. This is the first clinical description of an avipoxvirus infection in stone curlews.


Psoriatic arthritis: epidemiology, clinical features, course, and outcome.
Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.


Recording high-dispersion spherical holographic gratings in a modified Rowland mounting by use of a multimode deformable mirror.
To reduce the uncorrected higher-order aberrations for holographic gratings requiring an extreme dispersion, we have modified the Rowland mounting by moving the recording laser sources away from the grating. Then, with a multimode deformable plane mirror to record the grating, the correction of all the aberrations up to the fourth order inclusive is found sufficient to obtain a high-quality image. Applied to the FUSE-LYMAN grating, with a groove density of as much as 5740 grooves/mm, for which a resolution of 30,000 was required, this new recording device produces a resolution from 139,000 to 222,000 over the spectral range.


The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin.
The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV-induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV-protective effects against DNA damage in UVB-tanned skin (but not in UVA-tanned skin) were significantly higher. UVA-induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up-regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB-exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV-induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis.


Risk factors for renal cell carcinoma in a Japanese population.
The incidence of renal cell carcinoma (RCC) is high in Western and Northern Europe and North America, and low in Asia. Although the incidence of RCC in Japan is lower than the rates in the other industrialized countries, there is no doubt that it is increasing. In this paper, we would like to introduce the summary of findings of JACC study, which evaluate the risk factors for RCC in a Japanese population. JACC study suggests nine risk factors (i.e., smoking, obesity, low physical activity, hypertension, diabetes mellitus, kidney diseases, beef, fondness for fatty food and black tea) and one preventive factor (i.e., starchy roots such as taro, sweet potato and potato) in a Japanese population. In Japan, however, drinking black tea may be a surrogate for westernized dietary habits while eating starchy roots may be a surrogate for traditional Japanese dietary habits. Further studies may be needed to evaluate risk factors for RCC because the number of cases is small in our studies.


Serum response factor regulates bone formation via IGF-1 and Runx2 signals.
Serum response factor (SRF) plays vital roles in numerous cellular processes; however, the physiological function of SRF in skeletal tissue remains unknown. In several organ systems, SRF regulates the expression of insulin-like growth factor-1 (IGF-1), which is crucial for normal development of mineralized skeleton and bone remodeling throughout life. Here, we show that conditional deletion of SRF in osteoblasts by osteocalcin-Cre generated viable mice with normal body size and body weight. Compared with normal siblings, osteoblast-specific SRF-deficient adult mice exhibited a marked decrease in bone mineral density and bone formation rate. Deletion of SRF in primary mouse calvarial osteoblasts reduced cell differentiation and mineralization in vitro. This was accompanied by a decrease in IGF-1 expression and secretion. Addition of IGF-1 in the culture media enhanced osteoblast differentiation in control cells and partially restored the mineralization defect of SRF-deficient cells, supporting an important role of SRF in regulating IGF-1 and IGF-1-mediated osteoblast differentiation. IGF-1-induced Akt activation was inhibited in SRF-deficient calvarial cells and enhanced in the SRF overexpressed cells. In addition, SRF deficiency decreased the transcriptional activity of Runx2, the key transcription factor for osteogenesis. Overexpression of SRF induced Runx2 transactivity in control cells and restored Runx2 transactivity in the SRF-deficient cells. Taken together, we conclude that SRF is important for IGF-1-induced osteoblast differentiation and mineralization via regulating IGF-1 expression and Runx2 transactivity.