Using structural MRI to identify bipolar disorders - 13 site machine learning study in 3020 individuals from the ENIGMA Bipolar Disorders Working Group.
Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47-67.00, ROC-AUC = 71.49%, 95% CI = 69.39-73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70-60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen's Kappa = 0.83, 95% CI = 0.829-0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.


Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter.
Disruption of the BRCA1 tumor suppressor can be caused not only by inherited mutations in familial cancers but also by BRCA1 gene silencing in sporadic cancers. Hypoxia, a key feature of the tumor microenvironment, has been shown to downregulate BRCA1 at the transcriptional level via repressive E2F4/p130 complexes. Here we showed that hypoxia also drives epigenetic modification of the BRCA1 promoter, with decreased H3K4 methylation as a key repressive modification produced by the lysine-specific histone demethylase LSD1. We also observed increased H3K9 methylation coupled with decreased H3K9 acetylation. Similar modifications were seen in the RAD51 promoter, which is also downregulated by hypoxia, whereas exactly opposite changes were seen in the promoter of the hypoxia-inducible gene VEGF. In cells containing the BRCA1 promoter driving a selectable HPRT gene, long-term silencing of the promoter was observed following exposure to hypoxic stress. Clones with silenced BRCA1 promoters were detected at frequencies of 2% or more following hypoxia, but at less than 6 × 10(-5) without hypoxia. The silenced clones showed decreased H3K4 methylation and decreased H3K9 acetylation in the BRCA1 promoters, consistent with the acute effects of hypoxic stress. Hypoxia-induced BRCA1 promoter silencing persisted in subsequent normoxic conditions but could be reversed by treatment with a histone deacetylase (HDAC) inhibitor but not with a DNA methylation inhibitor. Interestingly, treatment of cells with inhibitors of poly(ADP-ribose) polymerase (PARP) can cause short-term repression of BRCA1 expression, but such treatment does not produce H3K4 or H3K9 histone modification or BRCA1 promoter silencing. These results suggest that hypoxia is a driving force for long-term silencing of BRCA1, thereby promoting genome instability and tumor progression.


Activation of invariant NKT cells enhances the innate immune response and improves the disease course in influenza A virus infection.
Invariant NKT (iNKT) cells have an indubitable role in antiviral immunity, although the mechanisms by which these cells exert their functions are not fully elucidated. With the emerging importance of high-pathogenicity influenza A virus infections in humans, we questioned whether iNKT cells contribute to immune defence against influenza A virus and whether activation of these cells influences outcome. We show that activation of iNKT cells with alpha-galactosylceramide (alpha-GC) during influenza virus infection transiently enhanced early innate immune response without affecting T cell immunity, and reduced early viral titres in lungs of C57BL/6 mice. This is accompanied by a better disease course with improved weight loss profile. Temporal changes in iNKT cells in the liver, blood and lungs suggest activation and migration of iNKT cells from the liver to the lungs in mice that were administered alpha-GC. Improvement in viral titres appears dependent on activation of iNKT cells via the intraperitoneal route since intranasal administration of alpha-GC did not have the same effect. We conclude that activation of iNKT cells enhances early innate immune response in the lungs and contribute to antiviral immunity and improved disease course in influenza A virus infection.


Filling of carbon nanotubes and nanofibres.
The reliable production of carbon nanotubes and nanofibres is a relatively new development, and due to their unique structure, there has been much interest in filling their hollow interiors. In this review, we provide an overview of the most common approaches for filling these carbon nanostructures. We highlight that filled carbon nanostructures are an emerging material for biomedical applications.


Control of erythroid differentiation: asynchronous expression of the anion transporter and the peripheral components of the membrane skeleton in AEV- and S13-transformed cells.
Chicken erythroblasts transformed with avian erythroblastosis virus or S13 virus provide suitable model systems with which to analyze the maturation of immature erythroblasts into erythrocytes. The transformed cells are blocked in differentiation at around the colony-forming unit-erythroid stage of development but can be induced to differentiate in vitro. Analysis of the expression and assembly of components of the membrane skeleton indicates that these cells simultaneously synthesize alpha-spectrin, beta-spectrin, ankyrin, and protein 4.1 at levels that are comparable to those of mature erythroblasts. However, they do not express any detectable amounts of anion transporter. The peripheral membrane skeleton components assemble transiently and are subsequently rapidly catabolized, resulting in 20-40-fold lower steady-state levels than are found in maturing erythrocytes. Upon spontaneous or chemically induced terminal differentiation of these cells expression of the anion transporter is initiated with a concommitant increase in the steady-state levels of the peripheral membrane-skeletal components. These results suggest that during erythropoiesis, expression of the peripheral components of the membrane skeleton is initiated earlier than that of the anion transporter. Furthermore, they point a key role for the anion transporter in conferring long-term stability to the assembled erythroid membrane skeleton during terminal differentiation.


Identification and characterization of a novel class of c-Jun N-terminal kinase inhibitors.
In efforts to identify novel small molecules with anti-inflammatory properties, we discovered a unique series of tetracyclic indenoquinoxaline derivatives that inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 activation. Compound IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) was found to be a potent, noncytotoxic inhibitor of pro-inflammatory cytokine [interleukin (IL)-1α, IL-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, interferon-γ, and granulocyte-macrophage colony-stimulating factor] and nitric oxide production by human and murine monocyte/macrophages. Three additional potent inhibitors of cytokine production were identified through further screening of IQ-1 analogs. The sodium salt of IQ-1 inhibited LPS-induced TNF-α and IL-6 production in MonoMac-6 cells with IC(50) values of 0.25 and 0.61 μM, respectively. Screening of 131 protein kinases revealed that derivative IQ-3 [11H-indeno[1,2-b]quinoxalin-11-one-O-(2-furoyl)oxime]was a specific inhibitor of the c-Jun N-terminal kinase (JNK) family, with preference for JNK3. This compound, as well as IQ-1 and three additional oxime indenoquinoxalines, were found to be high-affinity JNK inhibitors with nanomolar binding affinity and ability to inhibit c-Jun phosphorylation. Furthermore, docking studies showed that hydrogen bonding interactions of the active indenoquinoxalines with Asn152, Gln155, and Met149 of JNK3 played an important role in enzyme binding activity. Finally, we showed that the sodium salt of IQ-1 had favorable pharmacokinetics and inhibited the ovalbumin-induced CD4(+) T-cell immune response in a murine delayed-type hypersensitivity model in vivo. We conclude that compounds with an indenoquinoxaline nucleus can serve as specific small-molecule modulators for mechanistic studies of JNKs as well as a potential leads for the development of anti-inflammatory drugs.


Cost-utility of angiotensin-converting enzyme inhibitor-based treatment compared with thiazide diuretic-based treatment for hypertension in elderly Australians considering diabetes as comorbidity.
The objective of this study was to examine the cost-effectiveness of angiotensin-converting enzyme inhibitor (ACEI)-based treatment compared with thiazide diuretic-based treatment for hypertension in elderly Australians considering diabetes as an outcome along with cardiovascular outcomes from the Australian government's perspective.We used a cost-utility analysis to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained. Data on cardiovascular events and new onset of diabetes were used from the Second Australian National Blood Pressure Study, a randomized clinical trial comparing diuretic-based (hydrochlorothiazide) versus ACEI-based (enalapril) treatment in 6083 elderly (age ≥65 years) hypertensive patients over a median 4.1-year period. For this economic analysis, the total study population was stratified into 2 groups. Group A was restricted to participants diabetes free at baseline (n = 5642); group B was restricted to participants with preexisting diabetes mellitus (type 1 or type 2) at baseline (n = 441). Data on utility scores for different events were used from available published literatures; whereas, treatment and adverse event management costs were calculated from direct health care costs available from Australian government reimbursement data. Costs and QALYs were discounted at 5% per annum. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty around utilities and cost data.After a treatment period of 5 years, for group A, the ICER was Australian dollars (AUD) 27,698 (&OV0556; 18,004; AUD 1-&OV0556; 0.65) per QALY gained comparing ACEI-based treatment with diuretic-based treatment (sensitive to the utility value for new-onset diabetes). In group B, ACEI-based treatment was a dominant strategy (both more effective and cost-saving). On probabilistic sensitivity analysis, the ICERs per QALY gained were always below AUD 50,000 for group B; whereas for group A, the probability of being below AUD 50,000 was 85%.Although the dispensed price of diuretic-based treatment of hypertension in the elderly is lower, upon considering the potential enhanced likelihood of the development of diabetes in addition to the costs of treating cardiovascular disease, ACEI-based treatment may be a more cost-effective strategy in this population.


Accurate prediction of kinase-substrate networks using knowledge graphs.
Phosphorylation of specific substrates by protein kinases is a key control mechanism for vital cell-fate decisions and other cellular processes. However, discovering specific kinase-substrate relationships is time-consuming and often rather serendipitous. Computational predictions alleviate these challenges, but the current approaches suffer from limitations like restricted kinome coverage and inaccuracy. They also typically utilise only local features without reflecting broader interaction context. To address these limitations, we have developed an alternative predictive model. It uses statistical relational learning on top of phosphorylation networks interpreted as knowledge graphs, a simple yet robust model for representing networked knowledge. Compared to a representative selection of six existing systems, our model has the highest kinome coverage and produces biologically valid high-confidence predictions not possible with the other tools. Specifically, we have experimentally validated predictions of previously unknown phosphorylations by the LATS1, AKT1, PKA and MST2 kinases in human. Thus, our tool is useful for focusing phosphoproteomic experiments, and facilitates the discovery of new phosphorylation reactions. Our model can be accessed publicly via an easy-to-use web interface (LinkPhinder).


Tetrathiafulvalene hetero radical cation dimerization in a redox-active [2]catenane.
The electronic properties of tetrathiafulvalene (TTF) can be tuned by attaching electron-donating or electron-withdrawing substituents. An electron-rich macrocyclic polyether containing two TTF units of different constitutions, namely 4,4'-bis(hydroxymethyl)tetrathiafulvalene (OTTFO) and 4,4'-bisthiotetrathiafulvalene (STTFS), has been synthesized. On two-electron oxidation, a hetero radical dimer is formed between OTTFO(•+) and STTFS(•+). The redox behavior of the macrocyclic polyether has been investigated by electrochemical techniques and UV-vis and electron paramagnetic resonance (EPR) spectroscopies. The [2]catenane in which the macrocyclic polyether is mechanically interlocked with the cyclobis(paraquat-p-phenylene) (CBPQT(4+)) ring has also been prepared using template-directed protocols. In the case of the [2]catenane, the formation of the TTF hetero radical dimer is prevented sterically by the CBPQT(4+) ring. After a one-electron oxidation, a 70:30 ratio of OTTFO(•+) to STTFS(•+) is present at equilibrium, and, as a result, two translational isomers of the [2]catenane associated with these electronically different isomeric states transpire. EPR titration spectroscopy and simulations reveal that the radical states of the two constitutionally different TTF units in the [2]catenane still experience long-range electronic intramolecular coupling interactions, despite the presence of the CBPQT(4+) ring, when one or both of them are oxidized to the radical cationic state. These findings in the case of both the free macrocyclic polyether and the [2]catenane have led to a deeper fundamental understanding of the mechanism of radical cation dimer formation between constitutionally different TTF units.


Bacteriophage-mediated toxin gene regulation in Clostridium difficile.
Clostridium difficile has been identified as the most important single identifiable cause of nosocomial antibiotic-associated diarrhea and colitis. Virulent strains of C. difficile produce two large protein toxins, toxin A and toxin B, which are involved in pathogenesis. In this study, we examined the effect of lysogeny by PhiCD119 on C. difficile toxin production. Transcriptional analysis demonstrated a decrease in the expression of pathogenicity locus (PaLoc) genes tcdA, tcdB, tcdR, tcdE, and tcdC in PhiCD119 lysogens. During this study we found that repR, a putative repressor gene of PhiCD119, was expressed in C. difficile lysogens and that its product, RepR, could downregulate tcdA::gusA and tcdR::gusA reporter fusions in Escherichia coli. We cloned and purified a recombinant RepR containing a C-terminal six-His tag and documented its binding to the upstream regions of tcdR in C. difficile PaLoc and in repR upstream region in PhiCD119 by gel shift assays. DNA footprinting experiments revealed similarities between the RepR binding sites in tcdR and repR upstream regions. These findings suggest that presence of a CD119-like temperate phage can influence toxin gene regulation in this nosocomially important pathogen.


Antibody response of two populations of common carp, Cyprinus carpio L., exposed to koi herpesvirus.
Common carp, Cyprinus carpio L., exposed to koi herpesvirus (KHV) may become persistently infected and populations containing such virus-infected individuals may transmit the virus to other fish when co-habited. Detection of virus-infected fish in a population is thus critical to surveillance and control programmes for KHV. A study was therefore designed to detect anti-KHV serum antibodies, with an enzyme-linked immunosorbent assay, in common carp following experimental exposures to KHV under varying environmental conditions. The study determined that a proportion of fish within a population experimentally exposed to KHV (at least 10-25%) develop high antibody titres (1/1600 or greater) to the virus, and this immunological response was detectable for several months (observed at the termination of the experiments at 65, 46 and 27 weeks post-exposure). Furthermore, this response was detected in one population of fish that did not succumb to a high level of mortality when maintained at water temperatures that were non-permissive for KHV. Elevating the water temperatures to permissive conditions for KHV resulted in recurrence of disease despite the presence of anti-virus antibodies, suggesting that serum antibodies alone are not protective under the conditions of our trials.


Expression of myogenic regulatory factors in chicken embryos during somite and limb development.
The expression of the myogenic regulatory factors (MRFs), Myf5, MyoD, myogenin (Mgn) and MRF4 have been analysed during the development of chicken embryo somites and limbs. In somites, Myf5 is expressed first in somites and paraxial mesoderm at HH stage 9 followed by MyoD at HH stage 12, and Mgn and MRF4 at HH stage 14. In older somites, Myf5 and MyoD are also expressed in the ventrally extending myotome prior to Mgn and MRF4 expression. In limb muscles a similar temporal sequence is observed with Myf5 expression detected first in forelimbs at HH stage 22, MyoD at HH stage 23, Mgn at HH stage 24 and MRF4 at HH stage 30. This report describes the precise time of onset of expression of each MRF in somites and limbs during chicken embryo development, and provides a detailed comparative timeline of MRF expression in different embryonic muscle groups.


The legacy of the Hwang case: research misconduct in biosciences.
This paper focuses on the infamous case of Hwang Woo Suk, the South-Korean national hero and once celebrated pioneer of stem cell research. After briefly discussing the evolution of his publication and research scandal in Science, I will attempt to outline the main reactions that emerged within scientific and bioethical discourses on the problem of research misconduct in contemporary biosciences. What were the ethical lapses in his research? What kind of research misconduct has been identified? How this kind of misconduct affects scientific integrity? How to avoid it? Focusing on these questions, the paper interprets the Hwang's case as a case study that might shed light on the worst aspects of highstakes global science. This case presents a group of problems that might endanger scientific integrity and public trust. Regulatory oversight, ethical requirements and institutional safeguards are often viewed by the scientific community as merely decelerating scientific progress and causing delays in the application of treatments. The Hwang's case represents how unimpeded progress works in contemporary science. Thus, the case might shed light on the often neglected benefits of "the social control of science".


Buffering capacity and membrane H+ conductance of neutrophilic and alkalophilic gram-positive bacteria.
Buffering capacity and membrane H+ conductance were examined in three gram-positive bacteria, Staphylococcus aureus, Bacillus subtilis, and Bacillus alcalophilus. An acid pulse technique was used to measure both parameters. The buffering capacity and membrane H+ conductance of B. alcalophilus are influenced by the pH of the medium and the culture conditions. Suspensions of B. alcalophilus cells from both H. A. medium and L-malate medium cultures grown at pH 10.5 exhibited higher values for these parameters than cells grown at pH 8.5. B. alcalophilus grown aerobically had a lower buffering capacity and a lower membrane conductance for protons than the neutrophilic bacteria S. aureus and B. subtilis. Fermenting cells exhibited significantly higher values for both variables than respiring cells.


Race-Ethnicity, Poverty, Urban Stressors, and Telomere Length in a Detroit Community-based Sample.
Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial-ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes.


Reduced ischemia-reoxygenation injury in rat intestine after luminal preservation with a tailored solution.
The intestine is extremely sensitive to ischemic preservation and reoxygenation injury. Current vascular perfusion and cold storage with University of Wisconsin (UW) solution neglect the intestinal lumen and the ongoing mucosal metabolism during hypothermia. This study was designed to test the effects of luminal preservation with an alternative preservation solution in addition to the common vascular flush with UW solution on graft viability after preservation and ex vivo reoxygenation. Rat intestine was preserved on ice for 6 hr in UW solution or Williams Medium E with additional buffering, impermeants, and a colloid (WMEplus) after being stapled or after flushing and filling the lumen with the respective preservation solution. Tissue slices were prepared from fresh and preserved intestines and were incubated with oxygen for 6 hr at 37°C to assess the viability after reoxygenation. Directly after preservation, histologic damage was mild and unaffected by preservation strategy. Contrary to luminal preservation, closed preservation resulted in significantly decreased ATP levels compared with control. Reoxygenation aggravated damage and revealed differences between the strategies. Luminal preservation better maintained the ATP levels and histologic integrity (vs. closed preservation) for both solutions. Histomorphologic integrity was superior after preservation with WMEplus (vs. UW solution). Expression of stress responsive genes was least up-regulated in the slices from tissue preserved luminally with WMEplus. In conclusion, preservation and reoxygenation injury can be attenuated by luminal preservation with WMEplus.


Alterations in the mechanical behavior of the human lumbar nucleus pulposus with degeneration and aging.
This study tested the hypothesis that changes in the morphology and composition of the nucleus pulposus with age and degeneration have associated changes in its mechanical properties. A torsional shear experiment was used to determine viscoelastic shear properties of cylindrical samples of human nucleus pulposus with large ranges of grades of morphological degeneration (normal to severely degenerated) and ages (range: 16-88 years; average: 57 +/- 21.5 years). Viscoelastic shear properties were determined from stress-relaxation and dynamic sinusoidal tests. A linear viscoelastic law with a variable-amplitude relaxation spectrum was used to model experimental behaviors of nucleus pulposus specimens. A statistically significant increase in the instantaneous and dynamic shear moduli was found with increasing age and grade of degeneration; the values for moduli ranged from 5.0 to 60 kPa. A significant decrease in tan delta was also detected; the values ranged from 0.43 to 0.33, indicating a decreased capacity for the nucleus pulposus to dissipate energy. The dynamic modulus and tan delta were also significantly affected by frequency. It was generally concluded that the nucleus pulposus undergoes a transition from "fluid-like" behavior to more "solid-like" behavior with aging and degeneration.


Calcium retention and increased vascular reactivity caused by a hypothalamic sodium transport inhibitor.
1. Using a previously established method of isolating an active-sodium-transport inhibitor (ASTI) from hypothalamic cell culture medium, the inhibitor was isolated and partially purified from sequential passages through Sephadex G-25 and h.p.l.c., and its effects on de-endothelialized rabbit aortic strips were investigated. 2. ASTI caused a cumulative concentration-dependent increase in tension which reversed slowly after wash, and the wash showed an identical effect on fresh strips. 3. Ouabain, used as a control, also caused a concentration-dependent increase in tension which reached a plateau at a concentration of 10 mmol/l. Both ouabain and ASTI caused a significant potentiation of the vasoconstrictor effect of noradrenaline at concentrations of 1 nmol/l-0.1 mmol/l. 4. Both ASTI and ouabain caused a significantly greater (P less than 0.01) calcium retention than control medium in aortic strips. 5. Incubation of ASTI with prolidase, chymotrypsin and carboxypeptidase A destroyed the vasoconstrictor effects as well as its inhibitory effects on sodium, potassium-dependent adenosine triphosphatase and sodium efflux from erythrocytes, but leucine aminopeptidase was ineffective. 6. These studies suggest that hypothalamic cells in culture release a peptidic inhibitor of active sodium transport which increases vascular reactivity, potentiates vasoconstrictor effects of noradrenaline and causes calcium retention.


Sulfuryl Fluoride Poisonings in Structural Fumigation, a Highly Regulated Industry-Potential Causes and Solutions.
Structural fumigations using sulfuryl fluoride for the extermination of dry-wood termites are conducted by the thousands in California and other warm-weather states. Sulfuryl fluoride is an odorless gas that targets the nervous system and can cause respiratory irritation, pulmonary edema, nausea, vomiting, seizures, and death. Structural voids or compartments such as wall sockets, crawl spaces, cabinets, or cells in air mattresses may create ongoing exposure after a structure has been certified as safe. The authors describe a case of potential sulfuryl fluoride exposure to a family following home fumigation. Despite regulation, sulfuryl fluoride poisonings from structural fumigations continue to occur. This article examines the physical characteristics of sulfuryl fluoride and the regulatory oversight of its application, in an effort to understand how and why these poisonings happen. Increasing aeration times of fumigated structures, overseeing monitoring efficacy, and using technology to capture clearance data could reduce sulfuryl fluoride exposure and illness.


Shared feed as a means of deer-to-deer transmission of Mycobacterium bovis.
To determine the ability of experimentally inoculated white-tailed deer (Odocoileus virginianus) to transmit Mycobacterium bovis to naïve deer through the sharing of feed, four deer were intratonsillarly inoculated with 4 x 10(5) colony-forming units of M. bovis. On a daily basis, feed not consumed by inoculated deer after approximately 8 hr was offered to four naïve deer maintained in a separate pen, where direct contact, aerosol transmission, or transmission through personnel were prevented. After 150 days, naïve deer were euthanized and examined. All naïve deer had lesions consistent with tuberculosis and M. bovis was isolated from various tissues. The most commonly affected tissues were lung, tracheobronchial lymph nodes, and mediastinal lymph nodes. This study demonstrates the potential for indirect transmission of M. bovis through the sharing of feed. Intentional or unintentional feeding of deer by wildlife or agricultural interests in regions where M. bovis infection is endemic should be avoided because both direct and indirect transmission through sharing of feed are enhanced.


Healing herbs and dangerous doctors: "fruit fever" and community conflicts with biomedical care in Northeast Thailand.
In Northeast Thailand, khai mak mai (fruit fever) is a local, ethnomedical category of illness identified by community members as untreatable by biomedical health providers. The illness is believed to be incompatible with several substances that may induce death, including fruit as well as two forms of medication associated with biomedical care: injections and intravenous solution. Consequently, fevers suspected of being khai mak mai are treated by herbalists while biomedical health services are avoided and feared. In this article, I examine local perceptions and treatment of khai mak mai. I also explore the context and consequences of concerns about the inadequacy of biomedical care, as well as the social meanings associated with the illness and the political-economic context that shapes both the meanings of, and everyday responses to, fevers suspected of being khai mak mai.


Post-Pneumonectomy ARDS and Ogilvie Syndrome - A Case Report.
The Acute Respiratory Distress Syndrome (ARDS) is a severe hypoxemic acute lung injury that may complicate lung resections. Reported mortality is very high, up to 50%. This report covers an ARDS case occurring post left pneumonectomy, with a favorable outcome, despite association with an acute colonic pseudo-obstruction syndrome (Ogilvie syndrome) that required abdominal surgery for decompression. A 60-year old Caucasian male, diagnosed with a stage IIIA left lung tumor underwent a left pneumonectomy. On the second postoperative day, the patient developed ARDS, requiring ventilatory support. Two days later, as the multiple organ dysfunction worsened, a bowel obstruction occurred. With an acute colonic pseudo-obstruction diagnosis, the decision was to perform laparotomy and a temporary cecostomy. A subsequent improvement in the respiratory parameters and vital functions resulted in weaning from ventilator 8 days after the onset of the ARDS and transfer to the surgery ward 14 days after pneumonectomy.


Elderly patients with CKD--dilemmas in dialysis therapy and vascular access.
The population of elderly patients with end-stage renal disease (ESRD) is growing rapidly worldwide. The high prevalence of comorbidities, limited life expectancy and complex quality of life issues associated with this population pose substantial challenges for clinicians in terms of clinical decision-making and providing optimal care. The first dilemma encountered in the management of an elderly patient with ESRD is deciding whether to initiate renal replacement therapy and, if so, selecting the most-suitable dialysis modality. Planning vascular access for haemodialysis is associated with additional challenges. Several clinical practice guidelines recommend an arteriovenous fistula, rather than a central venous catheter or arteriovenous graft, as the preferred access for maintenance haemodialysis therapy. However, whether this recommendation is applicable to elderly patients with ESRD and a limited life expectancy is unclear. Selection and planning of the most appropriate vascular access for an elderly patient with ESRD requires careful consideration of several factors and ultimately should lead to an improvement in the patient's quality of life.


NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer.
We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer. NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights. Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms. 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2-2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086-1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06-1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04-1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4. For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study.


Thyronamines are isozyme-specific substrates of deiodinases.
3-Iodothyronamine (3-T 1 AM) and thyronamine (T AM) are novel endogenous signaling molecules that exhibit great structural similarity to thyroid hormones but apparently antagonize classical thyroid hormone (T(3)) actions. Their proposed biosynthesis from thyroid hormones would require decarboxylation and more or less extensive deiodination. Deiodinases (Dio1, Dio2, and Dio3) catalyze the removal of iodine from their substrates. Because a role of deiodinases in thyronamine biosynthesis requires their ability to accept thyronamines as substrates, we investigated whether thyronamines are converted by deiodinases. Thyronamines were incubated with isozyme-specific deiodinase preparations. Deiodination products were analyzed using a newly established method applying liquid chromatography and tandem mass spectrometry (LC-MS/MS). Phenolic ring deiodinations of 3,3',5'-triiodothyronamine (rT3AM), 3',5'-diiodothyronamine (3',5'-T2AM), and 3,3'-diiodothyronamine (3,3'-T2AM) as well as tyrosyl ring deiodinations of 3,5,3'-triiodothyronamine (T3AM) and 3,5-diiodothyronamine (3,5-T2AM) were observed with Dio1. These reactions were completely inhibited by the Dio1-specific inhibitor 6n-propyl-2-thiouracil (PTU). Dio2 containing preparations also deiodinated rT(3)AM and 3',5'-T2AM at the phenolic rings but in a PTU-insensitive fashion. All thyronamines with tyrosyl ring iodine atoms were 5(3)-deiodinated by Dio3-containing preparations. In functional competition assays, the newly identified thyronamine substrates inhibited an established iodothyronine deiodination reaction. By contrast, thyronamines that had been excluded as deiodinase substrates in LC-MS/MS experiments failed to show any effect in the competition assays, thus verifying the former results. These data support a role for deiodinases in thyronamine biosynthesis and contribute to confining the biosynthetic pathways for 3-T 1 AM and T 0 AM.


Cell wall beta-(1,6)-glucan of Saccharomyces cerevisiae: structural characterization and in situ synthesis.
Despite its essential role in the yeast cell wall, the exact composition of the beta-(1,6)-glucan component is not well characterized. While solubilizing the cell wall alkali-insoluble fraction from a wild type strain of Saccharomyces cerevisiae using a recombinant beta-(1,3)-glucanase followed by chromatographic characterization of the digest on an anion exchange column, we observed a soluble polymer that eluted at the end of the solvent gradient run. Further characterization indicated this soluble polymer to have a molecular mass of approximately 38 kDa and could be hydrolyzed only by beta-(1,6)-glucanase. Gas chromatography mass spectrometry and NMR ((1)H and (13)C) analyses confirmed it to be a beta-(1,6)-glucan polymer with, on average, branching at every fifth residue with one or two beta-(1,3)-linked glucose units in the side chain. This polymer peak was significantly reduced in the corresponding digests from mutants of the kre genes (kre9 and kre5) that are known to play a crucial role in the beta-(1,6)-glucan biosynthesis. In the current study, we have developed a biochemical assay wherein incubation of UDP-[(14)C]glucose with permeabilized S. cerevisiae yeasts resulted in the synthesis of a polymer chemically identical to the branched beta-(1,6)-glucan isolated from the cell wall. Using this assay, parameters essential for beta-(1,6)-glucan synthetic activity were defined.


Improving the quality of administration of the Surgical Safety Checklist: a mixed methods study in New Zealand hospitals.
While the WHO Surgical Safety Checklist (the Checklist) can improve patient outcomes, variable administration can erode benefits. We sought to understand and improve how operating room (OR) staff use the Checklist. Our specific aims were to: determine if OR staff can discriminate between good and poor quality of Checklist administration using a validated audit tool (WHOBARS); to determine reliability and accuracy of WHOBARS self-ratings; determine the influence of demographic variables on ratings and explore OR staff attitudes to Checklist administration. Mixed methods study using WHOBARS ratings of surgical cases by OR staff and two independent observers, thematic analysis of staff interviews. OR staff in three New Zealand hospitals. Reliability of WHOBARS for self-audit; staff attitudes to Checklist administration. Analysis of scores (243 participants, 2 observers, 59 cases) supported tool reliability, with 87% of WHOBARS score variance attributable to differences in Checklist administration between cases. Self-ratings were significantly higher than observer ratings, with some differences between professional groups but error variance from all raters was less than 10%. Key interview themes (33 interviewees) were: Team culture and embedding the Checklist, Information transfer and obstacles, Raising concerns and 'A tick-box exercise'. Interviewees felt the Checklist could promote teamwork and a safety culture, particularly enabling speaking up. Senior staff were of key importance in setting the appropriate tone. The WHOBARS tool could be useful for self-audit and quality improvement as OR staff can reliably discriminate between good and poor Checklist administration. OR staff self-ratings were lenient compared with external observers suggesting the value of external audit for benchmarking. Small differences between ratings from professional groups underpin the value of including all members of the team in scoring. We identified factors explaining staff perceptions of the Checklist that should inform quality improvement interventions.


Slow excitatory postsynaptic currents mediated by N-methyl-D-aspartate receptors on cultured mouse central neurones.
1. Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked between pairs of cultured neurones from either hippocampus or spinal cord were examined using the tight-seal whole-cell recording technique. 2. Using the selective N-methyl-D-aspartate (NMDA)-receptor antagonist, 2-amino-5-phosphonovaleric acid (APV), two components of the EPSP could be resolved in cultures from both brain regions. The APV-sensitive (slow) component had the same latency, but a much slower time-to-peak and longer duration than the APV-resistant (fast) component. Other NMDA antagonists such as ketamine also selectively blocked the slow component of the EPSP. 3. In Mg2+-free medium, the dual-component EPSP had a duration lasting up to 500 ms, greatly exceeding the membrane time constant of the postsynaptic neurone, suggesting that persistent activation of NMDA receptors was responsible for the long duration of the APV-sensitive component. 4. Under voltage clamp the excitatory postsynaptic currents (EPSCs) also showed fast and slow components, both of which had a reversal potential near 0 mV in physiological saline. The synaptic current could be fitted with a sum of two exponentials with a decay time constant for the slow EPSC near 80 ms. The slow current contributed approximately 50% of the total charge transfer during the EPSC. 5. In Mg2+-containing medium, the peak of the fast component was voltage insensitive, whereas the synaptic current measured at a latency of 10-50 ms was voltage dependent with a region of negative slope conductance at membrane potentials hyperpolarized to -30 mV. 6. Raising [Ca2+]o from 1 to 20 mM resulted in a shift of the reversal potential of the APV-sensitive component from near 0 mV to + 10 mV, but the reversal potential of the fast component remained near 0 mV. This suggests that conductances with different ionic permeability underlie the two components of the EPSC and that the slow component is highly permeable to Ca2+ as well as to monovalent cations. 7. Our results demonstrate that two functionally distinct excitatory amino acid receptor channels are simultaneously activated by transmitter release from a single presynaptic neurone. The conductance mechanism underlying the slow component of the EPSP displays the voltage dependence and Ca2+ permeability expected for NMDA-receptor channels. We suggest that the available conductance generating the slow EPSP may be sufficient, even at low firing rates, to influence excitability on both a short-term and more long-lasting basis.


Workplace discrimination and HIV/AIDS: the national EEOC ADA research project.
This article utilizes data from the Equal Employment Opportunity Commission's Integrated Mission System database to document the levels of employment discrimination involving individuals with HIV/AIDS. The researchers explore the theory that the nature of HIV/AIDS related employment discrimination is rooted in deeper stigmatization than discrimination against other disability groups. Researchers compare and contrast key demographic characteristics of Charging Parties and Respondents involved in HIV/AIDS related allegations of discrimination and their proportion of EEOC merit resolutions to those of persons with other physical, sensory, and neurological impairments. Findings indicate that, in contrast to the general disability group, HIV/AIDS was more likely to be male, ethnic minorities, between the ages of 25-44, in white collar jobs, in the South and West and to work for businesses with 15 to 100 employees. Additionally, the allegations in HIV/AIDS were more likely to receive merit resolution from the EEOC by a large difference of ten percent.


Environmental determinants of cholera outbreaks in inland Africa: a systematic review of main transmission foci and propagation routes.
Cholera is generally regarded as the prototypical waterborne and environmental disease. In Africa, available studies are scarce, and the relevance of this disease paradigm is questionable. Cholera outbreaks have been repeatedly reported far from the coasts: from 2009 through 2011, three-quarters of all cholera cases in Africa occurred in inland regions. Such outbreaks are either influenced by rainfall and subsequent floods or by drought- and water-induced stress. Their concurrence with global climatic events has also been observed. In lakes and rivers, aquatic reservoirs of Vibrio cholerae have been evocated. However, the role of these reservoirs in cholera epidemiology has not been established. Starting from inland cholera-endemic areas, epidemics burst and spread to various environments, including crowded slums and refugee camps. Human displacements constitute a major determinant of this spread. Further studies are urgently needed to better understand these complex dynamics, improve water and sanitation efforts, and eliminate cholera from Africa.


Museum Monsters and Victorious Viruses: Improving Public Understanding of Emerging Biomedical Research.
Although microbes directly impact everyone's health, most people have limited knowledge about them. In this article, we describe a museum and media public education campaign aimed at helping diverse audiences better understand emerging knowledge about microbes and infectious disease. Funded primarily by the Science Education Partnership (SEPA) program of the National Institutes of Health, this campaign involved crosscutting programs designed to extend impacts throughout a broad public audience.


First Report of Iris yellow spot virus Infection of Garlic and Egyptian Leek in Egypt.
Egyptian leek (Allium ampeloprasum), garlic (A. sativum), and onion (A. cepa) are key vegetables produced by small- and large-scale farmers in Egypt for national and international markets. Iris yellow spot virus (IYSV; family Bunyaviridae, genus Tospovirus) is an economically important viral pathogen of bulb and seed onion crops in many onion-growing areas of the world (1,3). During February and March of 2011, symptoms of spindle-shaped, straw-colored, irregular lesions with occasional green islands were observed on onion, garlic, and Egyptian leek cultivated on large and small farms in Dakahlia, Gharbia, Kalubia, Menofia, Qena, and Assiut governorates in Egypt. The presence of IYSV was confirmed by specific double antibody sandwich (DAS)-ELISA Flash Kits (Agdia Inc., Elkhart, IN) (2). A survey was carried out by collecting 100 plant samples (10 asymptomatic and 90 symptomatic) of each plant species from fields in the governorates of Dakahlia, Gharbia, Kalubia, Menofia, Qena, and Assiute and testing the plants using DAS-ELISA. For onion and garlic, 45% of the symptomatic samples and 0% of the asymptomatic plants tested positive. For leek, 34% of the symptomatic samples tested positive and 0% of the asymptomatic samples. ELISA-positive samples were tested using a reverse transcription (RT)-PCR assay with primers specific to the S RNA of IYSV (forward primer 5'-TAAAACAAACATTCAAACAA-3' and reverse primer 5'-CTCTTAAACACATTTAACAAGCAC-3') (2). Amplicons of approximately 1,100 bp were obtained from all symptomatic samples that were ELISA positive, but none of the asymptomatic plants nor the sterile water control sample produced PCR amplicons. The amplicons were cloned (at least three clones per plant species) using the TOPO TA Cloning Kit (Invitrogen, Grand Island, NY), and sequenced. The Egyptian onion IYSV isolate (GenBank No. JN541273) had the greatest nucleotide sequence identity (86%) with the corresponding S RNA region of IYSV isolates from India (GenBank Nos. EU310290, EU310284, and EU310276). The Egyptian garlic IYSV isolate (GenBank No. JN541275) showed the strongest identity (93%) with that of a Sri Lankan IYSV isolate (GenBank No. GU901211). The Egyptian leek IYSV isolate (GenBank No. JN541274) exhibited 91% sequence identity with that of the same Sri Lankan isolate (No. GU901211). To our knowledge, this is the first report of IYSV infecting garlic and Egyptian leek in Egypt. IYSV infection of onion was reported previously from the agricultural farm of the Faculty of Agriculture, Cairo University, Giza (4), but to our knowledge, this is the first report of natural infection by the virus in commercial onion production in Egypt. Further surveys and monitoring of IYSV incidence and distribution in the entire Egyptian governorate are under investigation. References: (1) D. H. Gent et al. Plant Dis. 88:446, 2004. (2) H. R. Pappu et al. Arch. Virol. 151:1015, 2006. (3) H. R. Pappu et al. Virus Res. 141:219, 2009. (4) A. Manal et al. Egypt. J. Virol. 3:49, 2006.


Maternal postnatal depressive symptoms and offspring emotional and behavioral development at age 7 years in a U.K. birth cohort: The role of paternal involvement.
There is considerable variability in developmental outcomes of children whose mothers experience depression. Few longitudinal studies have examined contributions of paternal involvement in the association between maternal postnatal depression (PND) and offspring development. We examined pathways from maternal PND at 8 weeks (Edinburgh Postnatal Depression Scale; total score) to offspring emotional and behavioral development at 7 years (Strengths and Difficulties Questionnaire; total score) through behavioral, affective, and cognitive dimensions of paternal involvement in a U.K.-based birth cohort (Avon Longitudinal Study of Parents and Children; n = 3,434). Analyses were adjusted for baseline confounders and paternal PND (Edinburgh Postnatal Depression Scale; total score) as an intermediate confounder. Maternal PND was strongly associated with offspring development, but this association was not mediated by the combination of all indirect pathways through various dimensions of paternal involvement. Only father-child conflict emerged as a risk factor for adverse offspring development and as a mediator in the association between maternal PND and offspring development (albeit the effect size was small). If found causal, interventions that reduce father-child conflict may reduce the risk of adverse development in offspring of mothers with PND. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Structural and functional phenotyping in the cone-specific photoreceptor function loss 1 (cpfl1) mouse mutant - a model of cone dystrophies.
We performed a comprehensive in vivo assessment of retinal morphology and function in cpfl1 (cone photoreceptor function loss 1) mice to better define the disease process in this model of cone dystrophies. Mice were examined using electroretinography (ERG), confocal scanning laser ophthalmoscopy (cSLO), and spectral domain optical coherence tomography (SD-OCT). Cross-breeding cpfl1 mutants with mice expressing green fluorescent protein (GFP) under control of red-green cone opsin promoter allowed for an in vivo timeline analysis of number and distribution of cone photoreceptors using the autofluorescence (AF) mode of the cSLO. Light-evoked responses of cone origin were practically absent in cpfl1 mice, whereas rod system function appeared normal. In vivo imaging revealed a progressive loss of cone photoreceptors with a major decline between PW4 and PW8, while retinal architecture and layering remained essentially intact. While the absence of substantial light-evoked cone responses in the cpfl1 mice is evident from early on, the course of physical cone degeneration is protracted and has a major drop between PW4 and PW8. However, these changes do not lead to significant alterations in retinal architecture, probably due to the relatively low number and wide dissemination of cone photoreceptor cells within the afoveate mouse retina.


Reduced serum levels of oestradiol and brain derived neurotrophic factor in both diabetic women and HFD-feeding female mice.
The estrogen levels in the pre and post menstrual phases interact with brain-derived neurotrophic factor in a complex manner, which influences the overall state of the body. To study the role of oestradiol and brain-derived neurotrophic factor in modulating obesity related type 2 diabetes and the interactions between two factors, we enrolled 15 diabetic premenopausal women and 15 diabetic postmenopausal women respectively, the same number of healthy pre and postmenopausal women were recruited as two control groups. The fasting blood glucose, insulin, lipids, estrogen, and brain-derived neurotrophic factor levels were measured through clinical tests. Additionally, we set up obese female mouse model to mimic human trial stated above, to verify the relationship between estrogen and brain-derived neurotrophic factor. Our findings revealed that there is a moderately positive correlation between brain-derived neurotrophic factor and oestradiol in females, and decreased brain-derived neurotrophic factor may worsen impaired insulin function. The results further confirmed that high fat diet-fed mice which exhibited impaired glucose tolerance, showed lower levels of oestradiol and decreased expression of brain-derived neurotrophic factor mRNA in the ventromedial hypothalamus. The level of brain-derived neurotrophic factor reduced on condition that the level of oestradiol is sufficiently low, such as women in postmenopausal period, which aggravates diabetes through feeding-related pathways. Increasing the level of brain-derived neurotrophic factor may help to alleviate the progression of the disease in postmenopausal women with diabetes.


Salivary gland proteins of the human malaria vector, Anopheles dirus B (Diptera: Culicidae).
Salivary gland proteins of the human malaria vector, Anopheles dirus B were determined and analyzed. The amount of salivary gland proteins in mosquitoes aged between 3--10 days was approximately 1.08 +/- 0.04 microg/female and 0.1 +/- 0.05 microg/male. The salivary glands of both sexes displayed the same morphological organization as that of other anopheline mosquitoes. In females, apyrase accumulated in the distal regions, whereas alpha-glucosidase was found in the proximal region of the lateral lobes. This differential distribution of the analyzed enzymes reflects specialization of different regions for sugar and blood feeding. SDS-PAGE analysis revealed that at least seven major proteins were found in the female salivary glands, of which each morphological region contained different major proteins. Similar electrophoretic protein profiles were detected comparing unfed and blood-fed mosquitoes, suggesting that there is no specific protein induced by blood. Two-dimensional polyacrylamide gel analysis showed the most abundant salivary gland protein, with a molecular mass of approximately 35 kilodaltons and an isoelectric point of approximately 4.0. These results provide basic information that would lead to further study on the role of salivary proteins of An. dirus B in disease transmission and hematophagy.


Antiosteoporotic activity and constituents of Podocarpium podocarpum.
Our study aimed to investigate the antiosteoporotic properties of the ethanol extract of Podocarpium podocarpum (DC.) Yang et Huang (PE) in ovariectomized (OVX) rats and to characterize the active constituents. As a result, PE significantly inhibited the increased urinary Ca excretion and activity of bone resorption markers including tartrate-resistant acid phosphatase (TRAP), deoxypyridinoline crosslinks and cathepsin K in OVX rats, whereas exhibited little effects on the body, uterus and vagina weight. Detailed micro-CT analysis showed that PE notably enhanced bone quality, with increased bone mineral content (BMC), bone volume fraction (BVF), connectivity density (CD), tissue mineral content (TMC), tissue mineral density (TMD) and trabecular number (Tb. N), and decreased trabecular separation (Tb. Sp), in OVX animal. Those findings implied that PE had notable antiosteoporotic effect, especially effective in preventing bone resorption, with little side-effects on reproductive tissue. Further chemical investigation led to the isolation of 17 flavonoids, most of which showed significantly stimulatory effect on osteoblastic proliferation, ALP activity and mineralized nodes formation as well as inhibitory effect on osteoclastic TRAP activity in osteoblastic and osteoclastic cells. Our results indicated that PE, with abundant flavonoids, had remarkable antiosteoporotic activity and therefore can be a promising candidate for the treatment of postmenopausal osteoporosis induced by estrogen deficiency through herbal remedy.


Melioidosis in the Western Indian Ocean and the Importance of Improving Diagnosis, Surveillance, and Molecular Typing.
Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an infectious disease of humans or animals, and the specific environmental conditions that are present in western Indian Ocean islands are particularly suitable for the establishment/survival of B. pseudomallei. Indeed, an increasing number of new cases have been reported in this region (Madagascar, Mauritius, Réunion (France), and Seychelles, except Comoros and Mayotte (France)), and are described in this review. Our review clearly points out that further studies are needed in order to investigate the real incidence and burden of melioidosis in the western Indian Ocean and especially Madagascar, since it is likely to be higher than currently reported. Thus, research and surveillance priorities were recommended (i) to improve awareness of melioidosis in the population and among clinicians; (ii) to improve diagnostics, in order to provide rapid and effective treatment; (iii) to implement a surveillance and reporting system in the western Indian Ocean; and (iv) to investigate the presence of B. pseudomallei in environmental samples, since we have demonstrated its presence in soil samples originating from the yard of a Madagascan case.


Motion of glossy objects does not promote separation of lighting and surface colour.
The surface properties of an object, such as texture, glossiness or colour, provide important cues to its identity. However, the actual visual stimulus received by the eye is determined by both the properties of the object and the illumination. We tested whether operational colour constancy for glossy objects (the ability to distinguish changes in spectral reflectance of the object, from changes in the spectrum of the illumination) was affected by rotational motion of either the object or the light source. The different chromatic and geometric properties of the specular and diffuse reflections provide the basis for this discrimination, and we systematically varied specularity to control the available information. Observers viewed animations of isolated objects undergoing either lighting or surface-based spectral transformations accompanied by motion. By varying the axis of rotation, and surface patterning or geometry, we manipulated: (i) motion-related information about the scene, (ii) relative motion between the surface patterning and the specular reflection of the lighting, and (iii) image disruption caused by this motion. Despite large individual differences in performance with static stimuli, motion manipulations neither improved nor degraded performance. As motion significantly disrupts frame-by-frame low-level image statistics, we infer that operational constancy depends on a high-level scene interpretation, which is maintained in all conditions.


Delayed impact of new volcanic ejecta on ground water quality.
We observed long-term changes in the concentrations of dissolved ions in ground water caused by leachate from new volcanic ejecta deposited on the ground surface of the volcanic Miyakejima Island, Japan. Water samples were collected from nine wells and two rain collectors over a period of more than 10 years, and samples of runoff water were collected periodically. The samples were analyzed for temperature, pH, alkalinity, Cl(-), and SO(4)(2-); some of the samples were also analyzed for delta(13)C. Because the leachate from the volcanic ejecta contained sulfate, we recorded an increase in SO(4)(2) (-) concentrations in the (unconfined) well water. The increase in SO(4)(2)(-) was initially detected between less than 1.4 and 5.2 years after the eruption, showing peak concentrations from 2.4 to 6.4 years after the eruption. This delayed response reflects the transit time of downward-moving SO(4)(2) (-) in the vadose zone, corresponding to an apparent movement rate of 0.4 to 7.2 cm/d. The rate relates to the mean recharge, represented as a fraction of local mean rainfall, and is calculated using the Cl(-) balance method. The magnitude of the recorded increases reflects the volume of volcanic mudflow on the ground surface within the basin. For the management of ground water after an eruption, it is therefore important to know the chemical properties of the volcanic ejecta and the spatial distribution of mudflow to estimate the magnitude of the effect of ejecta on ground water quality.


Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats.
Ototoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs). However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3'-iminodipropionitrile (IDPN). Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI) and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents) and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure.


Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD.
Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.


Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR.
Ketamine is a widely used general anesthetic and has been reported to demonstrate neurotoxicity and neuroprotection. Investigation into the regulatory mechanism of ketamine on influencing neural development is of importance for a better and safer way of relieving pain. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the critical neural associated gene expression, and flow cytometry to detect the neural differentiation effect. Hence, in the present study the underlying mechanism of ketamine (50 nM) on neural differentiation of the mouse embryonic stem cell (mESC) line 46C was investigated. The results demonstrated that a low dose of ketamine (50 nM) promoted the differentiation of mESCs to neural stem cells (NSCs) and activated mammalian target of rapamycin (mTOR) by upregulating the expression levels of phosphorylated (p)‑mTOR. Furthermore, inhibition of the mTOR signaling pathway by rapamycin or knockdown of mTOR suppressed neural differentiation. A rescue experiment further confirmed that downregulation of mTOR inhibited the promotion of neural differentiation induced by ketamine. Taken together, the present study indicated that a low level of ketamine upregulated p‑mTOR expression levels, promoting neural differentiation.


Muonium Addition Reactions and Kinetic Isotope Effects in the Gas Phase: k∞ Rate Constants for Mu + C2H2.
The kinetics of the addition reaction of muonium (Mu) to acetylene have been studied in the gas phase at N2 moderator pressures mainly from ∼800 to 1000 Torr and over the temperature range from 168 to 446 K, but also down to 200 Torr at 168 K and over a much higher range of pressures, from 10 to 44 bar at 295 K, demonstrating pressure-independent rate constants, kMu(T). Even at 200 Torr moderator pressure, the kinetics for Mu + C2H2 addition behave as if effectively in the high-pressure limit, giving k∞ = kMu due to depolarization of the muon spin in the MuC2H2 radical formed in the addition step. The rate constants kMu(T) exhibit modest Arrhenius curvature over the range of measured temperatures. Comparisons with data and with calculations for the corresponding H(D) + C2H2 addition reactions reveal a much faster rate for the Mu reaction at the lowest temperatures, by 2 orders of magnitude, in accord with the propensity of Mu to undergo quantum tunneling. Moreover, isotopic atom exchange, which contributes in a major way to the analogous D atom reaction, forming C2HD + H, is expected to be unimportant in the case of Mu addition, a consequence of the much higher zero-point energy and hence weaker C-Mu bond that would form, meaning that the present report of the Mu + C2H2 reaction is effectively the only experimental study of kinetic isotope effects in the high-pressure limit for H-atom addition to acetylene.


An Effective Approach to Improving Cadmium Telluride (111)A Surface by Molecular-Beam-Epitaxy Growth of Tellurium Monolayer.
The surface cleansing treatment of non-natural cleavage planes of semiconductors is usually performed in vacuum using ion sputtering and subsequent annealing. In this Research Article, we report on the evolution of surface atomic structure caused by different ways of surface treatment as monitored by in situ core-level photoemission measurements of Cd-4d and Te-4d atomic levels and reflection high-energy electron diffraction (RHEED). Sputtering of surface increases the density of the dangling bonds by 50%. This feature and the less than ideal ordering can be detrimental to device applications. An effective approach is employed to improve the quality of this surface. One monolayer (ML) of Te grown by the method of molecular beam epitaxy (MBE) on the target surface with heating at 300 °C effectively improves the surface quality as evidenced by the improved sharpness of RHEED pattern and a reduced diffuse background in the spectra measured by high-resolution ultraviolet photoemission spectroscopy (HRUPS). Calculations have been performed for various atomic geometries by employing first-principles geometry optimization. In conjunction with an analysis of the core level component intensities in terms the layer-attenuation model, we propose a "vacancy site" model of the modified 1 ML-Te/CdTe(111)A (2 × 2) surface.


Outcomes of a community-based weight management programme for morbidly obese populations.
Morbid obesity is an ongoing concern worldwide. There is a paucity of research reporting primary care outcomes focussed on complex and morbidly obese populations. The National Institute for Health and Care Excellence (NICE) recommends a specialist, multidisciplinary weight management team for the successful management of such populations. This is the first service evaluation reporting both primary (weight change) and secondary [body mass index (BMI), waist circumference, physical activity levels, fruit and vegetable intake, Rosenberg self-esteem score] outcomes in these patients. The present study comprised a prospective observational study of a cohort data set for patients (n = 288) attending their 3-month and 6-month (n = 115) assessment appointments at a specialist community weight management programme. Patients had a mean (SD) initial BMI of 45.5 (6.6) kg m- ²; 66% were females. Over 80% of patients attending the service lost some weight by 3 months. Average absolute weight loss was 4.11 (4.95) kg at 3 months and 6.30 (8.41) kg at 6 months, equating to 3.28% (3.82%) and 4.90% (6.26%), respectively, demonstrating a statistically significant weight change at both time points (P < 0.001). This meets NICE best practice guidelines for the commissioning of services leading to a minimum of 3% average weight loss, with at least 30% of patients losing at ≥5% of their initial weight. Waist measurement and BMI were reduced significantly at 3 months. Improvements were also seen in physical activity levels, fruit and vegetable consumption, and self-esteem levels (P < 0.001). This service was successful in aiding weight loss in morbidly obese populations. The findings of the present study support the view that weight-loss targets of 3% are realistic.


Local hemodynamics and intimal hyperplasia at the venous side of a porcine arteriovenous shunt.
Venous anastomotic intimal hyperplasia (IH) observed in the arteriovenous shunt (AVS) has been associated with disturbed hemodynamics. This study aims to correlate hemodynamics with wall histology and wall mechanics by examining the flow field in AVS with computational fluid dynamics using experimental data taken from in vivo experiments. Input data to the computational model were obtained in vivo one month after AVS creation; adjacent vessels were submitted to histological and mechanical examination. The 3-D shunt geometry was determined using biplane angiography. Ultrasound measurements of flow rates were performed with perivascular flow probes and pressures were recorded through intravascular catheters. These data were considered as boundary conditions for calculation of the unsteady flow field. Numerical findings are suggestive of strong Dean vortices toward both vein flow exits, verified by color Doppler. The high wall shear stresses (WSSs) and their gradients appear to be related to areas of IH and vessel wall stiffening, as evidenced in preliminary histological and mechanical studies of the venous wall. Additionally, suture line hyperplasia seems to be aggravated by the high WSS gradients noted at the transition line from graft to vein.


Performance of Three SARS-CoV-2 Immunoassays, Three Rapid Lateral Flow Tests, and a Novel Bead-Based Affinity Surrogate Test for the Detection of SARS-CoV-2 Antibodies in Human Serum.
For the control of immunity in COVID-19 survivors and vaccinated subjects, there is an urgent need for reliable and rapid serological assays. Based on samples from 63 COVID-19 survivors up to 7 months after symptom onset, and on 50 serum samples taken before the beginning of the pandemic, we compared the performances of three commercial immunoassays for the detection of SARS-CoV-2 IgA and IgG antibodies (Euroimmun SARS-COV-2 IgA/IgG, Mikrogen recomWell SARS-CoV-2 IgA/IgG, and Serion ELISA agile SARS-CoV-2 IgA/IgG) and three rapid lateral flow (immunochromatographic) tests (Abbott PanBio COVID-19 IgG/IgM, Nadal COVID-19 IgG/IgM, and Cleartest Corona 2019-nCOV IgG/IgM) with a 50% plaque-reduction neutralization test (PRNT50) representing the gold standard. Fifty-seven out of 63 PCR-confirmed COVID-19 patients (90%) showed neutralizing antibodies. The sensitivity of the seven assays ranged from 7.0% to 98.3%, and the specificity ranged from 86.0% to 100.0%. Only one commercial immunoassay showed a sensitivity and specificity of greater than 98%.


The effect of a protocol of aggressive donor management: Implications for the national organ donor shortage.
The disparity between the number of people awaiting organ transplantation and the number of organs available has become a public health crisis. As many as 25% of potential donors are lost as a result of cardiovascular collapse (CVC) before organ harvest. A policy of aggressive donor management (ADM) may decrease the number of cadaveric donors lost as a result of CVC. Retrospective analysis of potential brain-dead donors evaluated from January 1995 to December 2003 at nine American College of Surgeons-verified Level I trauma centers covered by a regional organ procurement agency. One center (Los Angeles County + University of Southern California Medical Center [LAC]) had an ADM protocol in place instituted January 1999; the remaining eight centers with no ADM protocol were grouped as Center A. The incidence of CVC and organ donation demographics were compared between centers and within LAC before (LAC-Pre) and after (LAC-Post) adoption of ADM. ADM consists of early identification of potential organ donors, a dedicated team that provides medical management, and aggressive fluid resuscitation as well as hormone replacement therapy with solumedrol and thyroxin. The incidence of CVC was significantly higher in LAC-Pre (odds ratio [OR] 15.0, p < 0.001) and Center A (OR 5.8, p < 0.001) compared with LAC-Post. The number of organs harvested per potential donor for LAC-Post (2.4) was significantly higher than LAC-Pre (2.0, p = 0.02) and Center A (2.1, p < 0.01). An aggressive donor management protocol decreases the number of donors lost as a result of cardiovascular collapse and increases the number of harvested organs per potential donor.


A kinetic and electromyographic comparison of the standing cable press and bench press.
This study compared the standing cable press (SCP) and the traditional bench press (BP) to better understand the biomechanical limitations of pushing from a standing position together with the activation amplitudes of trunk and shoulder muscles. A static biomechanical model (4D Watbak) was used to assess the forces that can be pushed with 2 arms in a standing position. Then, 14 recreationally trained men performed 1 repetition maximum (1RM) BP and 1RM single-arm SP exercises while superficial electromyography (EMG) of various shoulder and torso muscles was measured. The 1RM BP performance resulted in an average load (74.2 +/- 17.6 kg) significantly higher than 1RM single-arm SP (26.0 +/- 4.4 kg). In addition, the model predicted that pushing forces from a standing position under ideal mechanical conditions are limited to 40.8% of the subject's body weight. For the 1RM BP, anterior deltoid and pectoralis major were more activated than most of the trunk muscles. In contrast, for the 1RM single-arm SP, the left internal oblique and left latissimus dorsi activities were similar to those of the anterior deltoid and pectoralis major. The EMG amplitudes of pectoralis major and the erector muscles were larger for 1RM BP. Conversely, the activation levels of left abdominal muscles and left latissimus dorsi were higher for 1RM right-arm SP. The BP emphasizes the activation of the shoulder and chest muscles and challenges the capability to develop great shoulder torques. The SCP performance also relies on the strength of shoulder and chest musculature; however, it is whole-body stability and equilibrium together with joint stability that present the major limitation in force generation. Our EMG findings show that SCP performance is limited by the activation and neuromuscular coordination of torso muscles, not maximal muscle activation of the chest and shoulder muscles. This has implications for the utility of these exercise approaches to achieve different training goals.


Globalization and human cooperation.
Globalization magnifies the problems that affect all people and that require large-scale human cooperation, for example, the overharvesting of natural resources and human-induced global warming. However, what does globalization imply for the cooperation needed to address such global social dilemmas? Two competing hypotheses are offered. One hypothesis is that globalization prompts reactionary movements that reinforce parochial distinctions among people. Large-scale cooperation then focuses on favoring one's own ethnic, racial, or language group. The alternative hypothesis suggests that globalization strengthens cosmopolitan attitudes by weakening the relevance of ethnicity, locality, or nationhood as sources of identification. In essence, globalization, the increasing interconnectedness of people worldwide, broadens the group boundaries within which individuals perceive they belong. We test these hypotheses by measuring globalization at both the country and individual levels and analyzing the relationship between globalization and individual cooperation with distal others in multilevel sequential cooperation experiments in which players can contribute to individual, local, and/or global accounts. Our samples were drawn from the general populations of the United States, Italy, Russia, Argentina, South Africa, and Iran. We find that as country and individual levels of globalization increase, so too does individual cooperation at the global level vis-à-vis the local level. In essence, "globalized" individuals draw broader group boundaries than others, eschewing parochial motivations in favor of cosmopolitan ones. Globalization may thus be fundamental in shaping contemporary large-scale cooperation and may be a positive force toward the provision of global public goods.


Impact of low blood culture usage on rates of antimicrobial resistance.
The magnitude of impact caused by low blood culture utilization on estimates of the proportions and incidence rates of antimicrobial-resistant (AMR) bacterial infections is largely unknown. We used routine electronic databases of microbiology, hospital admission and drug prescription at Sunpasitthiprasong Hospital, Ubon Ratchathani, Thailand, from 2011 to 2015, and bootstrap simulations. The proportions of Escherichia coli and Klebsiella pneumoniae bacteraemias caused by 3rd generation cephalosporin resistant isolates (3GCREC and 3GCRKP) were estimated to increase by 13 and 24 percentage points (from 44% to 57% and from 51% to 75%), respectively, if blood culture utilization rate was reduced from 82 to 26 blood culture specimens per 1,000 patient-days. Among patients with hospital-origin bloodstream infections, the proportion of 3GCREC and 3GCRKP whose first positive blood culture was taken within ±1 calendar day of the start of a parenteral antibiotic at the study hospital was substantially lower than those whose first positive blood culture was taken later into parenteral antibiotic treatment (30% versus 79%, p<0.001; and 37% versus 86%, p<0.001). Similar effects were observed for methicillin-resistant Staphylococcus aureus, carbapenem-resistant Acinetobacter spp. and carbapenem-resistant Pseudomonas aeruginosa. Impacts of low blood culture utilization rate on the estimated proportions and incidence rates of AMR infections could be high. We recommend that AMR surveillance reports should additionally include blood culture utilization rate and stratification by exposure to a parenteral antibiotic at the hospital.


Parental smoking and children's respiratory health: independent effects of prenatal and postnatal exposure.
Adverse effects have been reported of prenatal and/or postnatal passive exposure to smoking on children's health. Uncertainties remain about the relative importance of smoking at different periods in the child's life. We investigate this in a pooled analysis, on 53,879 children from 12 cross-sectional studies--components of the PATY study (Pollution And The Young). Effects were estimated, within each study, of three exposures: mother smoked during pregnancy, parental smoking in the first two years, current parental smoking. Outcomes were: wheeze, asthma, "woken by wheeze", bronchitis, nocturnal cough, morning cough, "sensitivity to inhaled allergens" and hay fever. Logistic regressions were used, controlling for individual risk factors and study area. Heterogeneity between study-specific results, and mean effects (allowing for heterogeneity) were estimated using meta-analytical tools. There was strong evidence linking parental smoking to wheeze, asthma, bronchitis and nocturnal cough, with mean odds ratios all around 1.15, with independent effects of prenatal and postnatal exposures for most associations. Adverse effects of both pre- and postnatal parental smoking on children's respiratory health were confirmed. Asthma was most strongly associated with maternal smoking during pregnancy, but postnatal exposure showed independent associations with a range of other respiratory symptoms. All tobacco smoke exposure has serious consequences for children's respiratory health and needs to be reduced urgently.


Angle-dependent strong-field ionization of halomethanes.
We study, experimentally and theoretically, the ionization probability of singly halogenated methane molecules, CH3Cl and CH3Br, in intense linearly polarized 800 nm laser pulses as a function of the angle between the molecular axis and the laser polarization. Experimentally, the molecules are exposed to two laser pulses with a relative time delay. The first, weaker pulse induces a nuclear rotational wave packet within the molecules, which are then ionized by the second, stronger pulse. The angle-dependent ionization yields are extracted from fits of the measured delay-dependent ionization signal to a superposition of moments of the rotational wave packet's angular distribution. Angle-dependent strong-field ionization (SFI) yields are also calculated using time-dependent density functional theory. Good agreement between measurements and theory is obtained. Interestingly, we find a marked difference between the angle-dependence of the ionization yields for these two halomethane species despite the similar structure of their highest occupied molecular orbitals. Calculations reveal that these differences are a result of multichannel (CH3Cl) vs single-channel (CH3Br) ionization and of increased hole localization on Br vs Cl. By adding calculations for CH3F, we can discern clear trends in the ionization dynamics with increasing halogen mass. These results are illustrative, as chemical functionalization and molecular alignment are likely to be important parameters for initiating and controlling charge migration dynamics via SFI.


A subgroup of pancreatic adenocarcinoma is sensitive to the 5-aza-dC DNA methyltransferase inhibitor.
Pancreatic Ductal Adenocarcinoma (PDAC) is a disease with a great heterogeneity in the response to treatments. To improve the responsiveness to treatments there are two different approaches, the first one consist to develop new and more efficient drugs that intent to cure all patients and the second one is to use already-approved drugs, alone or in combination, but selecting beforehand the most sensitive patients. In this work we explored the efficiency of the second possibility. We developed a collection of 17 PDAC samples collected by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery and preserved as xenografts and as primary cultures. This collection was characterized at molecular level by a transcriptomic analysis using an Affymetrix approach. In this paper we present data demonstrating that a subgroup of PDAC responds to low doses of 5-aza-dC. These tumors show a specific RNA expression profile that could serve as a marker, but there is no correlation with Dnmt1, Dnmt3A or Dnmt3B expression. Responder tumors corresponded to well-differentiated samples and longer survival patients. In conclusion, we present data obtained with the well-known drug 5-aza-dC as a proof of concept that a drug that seems to be inefficient in solid tumors in general could be applicable to a particular subgroup of patients with PDAC.


Spectroscopic evidence for altered chromophore--protein interactions in low-temperature photoproducts of the visual pigment responsible for congenital night blindness.
The replacement of Gly90 by Asp in human rhodopsin causes congenital night blindness. It has been suggested that the molecular origin for the trait is an altered electrostatic environment of the protonated retinal Schiff base chromophore. We have investigated the corresponding recombinant bovine rhodopsin mutant G90D, as well as the related mutants E113A and G90D/E113A, using spectroscopy at low temperature. This allows the assessment of chromophore-protein interactions under conditions where conformational changes are mainly restricted to the retinal-binding site. Each of the mutant pigments formed bathorhodopsin- and isorhodopsin-like intermediates, but the concomitant visible absorption changes reflected differences in the electrostatic environment of the protonated Schiff base in each pigment. Fourier transform infrared-difference spectroscopy revealed effects on the chromophore fingerprint and hydrogen-out-of-plane vibrational modes, which were indicative of the removal of an electrostatic perturbation near C12 of the retinal chromophore in all three mutants. A comparison of the UV-visible and infrared-difference spectra of the mutant pigments strongly suggests that Glu113 is stably protonated in G90D. The corresponding carbonyl-stretching mode is assigned to a band at 1727 cm-1. In contrast to the case in native bathorhodopsin, the all-trans-retinal chromophores in the primary photoproducts of the mutant pigments are essentially relaxed. The peptide carbonyl vibrational changes in mutants G90D and G90D/ E113A suggest that this is due to a more flexible retinal-binding site. Therefore, the steric strain exerted on the chromophore in native bathorhodopsin may be caused by electrostatic forces that specifically involve glutamate 113.


New approaches for exploring anatomical and functional connectivity in the human brain.
Information processing in the primate brain is based on the complementary principles of modular and distributed information processing. The former emphasizes the specialization of functions within different brain areas. The latter emphasizes the massively parallel nature of brain networks and the fact that function also emerges from the flow of information between brain areas. The localization of function to specific brain areas ("functional segregation") is the commonest approach to investigating function; however, an emerging, complementary approach ("functional integration") describes function in terms of the information flow across networks of areas. Here, we highlight recent advances in neuroimaging methodology that have made it possible to investigate the anatomical architecture of networks in the living human brain with diffusion tensor imaging (DTI). We also highlight recent thinking on the ways in which functional imaging can be used to characterize information transmission across networks in the human brain (functional and effective connectivity).


Near-infrared chemical imaging (NIR-CI) for counterfeit drug identification--a four-stage concept with a novel approach of data processing (Linear Image Signature).
A new stage concept was developed to reliably identify counterfeit tablets which are very similar to the genuine drug product. This concept combines single-point near-infrared spectroscopy (NIRS) and near-infrared chemical imaging (NIR-CI) with statistical variance analysis. The advantage of NIR-CI over NIRS is the potential to determine not only the amount, but also the spatial distribution of ingredients within a single tablet. Previously published NIR-CI studies used homogeneity as a key indicator for the identification of counterfeits. The state of the art approach for estimating homogeneity is to record the average and % standard deviation of predicted classification scores (i.e. concentrations) for a given component within a specimen. A disadvantage of this approach is the partial loss of spatial information. In view of this, we developed a new method using much more of the spatial information for the estimation of homogeneity. The method is based on (1) summation and unfolding of multidimensional predicted classification scores, which results in a Linear Image Signature (LIS) and (2) multivariate LIS data analysis (LIS-MVA). It could be demonstrated that this kind of NIR-CI data analysis represents an innovative approach for the identification of counterfeit tablets. Moreover, this procedure is applicable to determine the product variability, i.e. process signature of a given product thus being a valuable tool within the Quality by Design (QbD) approach of the ICH Q8 guideline.


Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients.
Invasive fungal infections, important causes of morbidity and mortality in critically ill patients, may be preventable with the prophylactic administration of antifungal agents. This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005), and EMBASE (1980 to week 36, 2005). We also handsearched reference lists, abstracts of conference proceedings and scientific meetings (1998 to 2004), and contacted authors of included studies and pharmaceutical manufacturers. We included randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen in non-neutropenic critically ill adult patients. Two authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We resolved differences by discussion. We synthesized data using the random effects model and expressed results as relative risk with 95% confidence intervals. We included 12 unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a nonabsorbable agent) involving 1606 randomized patients. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by about 25% (relative risk 0.76, 95% confidence interval 0.59 to 0.97) and invasive fungal infections by about 50% (relative risk 0.46, 95% confidence interval 0.31 to 0.68). We identified no significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or C. krusei, although the confidence intervals of the summary effect measures were wide. Adverse effects were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics. Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.


Does standard deviation matter? Using "standard deviation" to quantify security of multistage testing.
With the advent of web-based technology, online testing is becoming a mainstream mode in large-scale educational assessments. Most online tests are administered continuously in a testing window, which may post test security problems because examinees who take the test earlier may share information with those who take the test later. Researchers have proposed various statistical indices to assess the test security, and one most often used index is the average test-overlap rate, which was further generalized to the item pooling index (Chang & Zhang, 2002, 2003). These indices, however, are all defined as the means (that is, the expected proportion of common items among examinees) and they were originally proposed for computerized adaptive testing (CAT). Recently, multistage testing (MST) has become a popular alternative to CAT. The unique features of MST make it important to report not only the mean, but also the standard deviation (SD) of test overlap rate, as we advocate in this paper. The standard deviation of test overlap rate adds important information to the test security profile, because for the same mean, a large SD reflects that certain groups of examinees share more common items than other groups. In this study, we analytically derived the lower bounds of the SD under MST, with the results under CAT as a benchmark. It is shown that when the mean overlap rate is the same between MST and CAT, the SD of test overlap tends to be larger in MST. A simulation study was conducted to provide empirical evidence. We also compared the security of MST under the single-pool versus the multiple-pool designs; both analytical and simulation studies show that the non-overlapping multiple-pool design will slightly increase the security risk.


Delivering strong 1H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange.
Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this area's most compelling outcomes. Methods to optimize the low-cost parahydrogen-based approach signal amplification by reversible exchange with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2H labeling in both the agent and catalyst and achieve polarization lifetimes of ca 2 min with 50% polarization in the case of methyl-4,6-d2 -nicotinate. Because a 1.5-T hospital scanner has an effective 1H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this technique's generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine, and isonicotinamide analogs that feature as building blocks in biochemistry and many disease-treating drugs.


Somatic Embryogenesis in Peach-Palm (Bactris gasipaes) Using Different Explant Sources.
Peach palm (Bactris gasipaes Kunth) is a member of the family Arecaceae and is a multipurpose but underutilized species. Nowadays, fruit production for subsistence and local markets, and heart-of-palm production for local, national, and international markets are the most important uses of this plant. Conventional breeding programs in peach palm are long-term efforts due to the prolonged generation time, large plant size, difficulties with controlled pollination and other factors. Although it is a caespitose palm, its propagation is currently based on seeds, as off-shoots are difficult to root. Hence, tissue culture techniques are considered to be the most likely strategy for efficient clonal plantlet regeneration of this species. Among various techniques, somatic embryogenesis offers the advantages of potential automated large-scale production and putative genetic stability of the regenerated plantlets. The induction of somatic embryogenesis in peach palm can be achieved by using different explant sources including zygotic embryos, immature inflorescences and thin cell layers from the young leaves and shoot meristems. The choice of a particular explant depends on whether clonal propagation is desired or not, as well as on the plant conditions and availability of explants. Protocols to induce and express somatic embryogenesis from different peach palm explants, up to acclimatization of plantlets, are described in this chapter.


Overcoming barriers to exercise among parents: a social cognitive theory perspective.
Parents face numerous barriers to exercise and exhibit high levels of inactivity. Examining theory-based determinants of exercise among parents may inform interventions for this population. The purpose of this study was to test a social-cognitive model of parental exercise participation over a 12-month period. Mothers (n = 226) and fathers (n = 70) of children <16 completed measures of exercise, barriers self-efficacy, perceived barriers, and exercise planning at baseline and 1 year later. Panel analyses were used to test the hypothesized relationships. Barriers self-efficacy was related to exercise directly and indirectly through perceived barriers and prioritization/planning. Prioritization and planning also mediated the relationship between perceived barriers and exercise. These paths remained significant at 12 months. These results suggest efforts to increase exercise in parents should focus on improving confidence to overcome exercise barriers, reducing perceptions of barriers, and helping parents make specific plans for prioritizing and engaging in exercise.