Evaluation of the regional nurse-supported hepatitis C shared care program in Western Australia: a mixed methods study.
Nurse-supported shared care services for patients living with hepatitis C have been implemented in some regional areas of Western Australia to provide access to local treatment and care services for patients and to improve currently low levels of treatment uptake. This study collected data from health professionals involved in managing the care of patients living with hepatitis C and from patients engaged in regional nurse-supported hepatitis C shared care services in Western Australia. Key informant qualitative interviews were conducted with health professionals in regions operating a nurse-supported shared care service and in regions without this service. Patients engaged in the shared care program at the time of the study were invited to complete a short questionnaire. Nurse-supported shared care services reduced patient transport costs to tertiary centres, accelerated access to treatment and delivered >98% compliance with treatment schedules. Patients engaged with regional hepatitis C shared care services expressed high levels of satisfaction and indicated that they would delay treatment if it was not available locally. Telehealth support from tertiary liver clinics and allied health services were available to health professionals engaged in regional shared care services and were used effectively. There was limited participation by general practitioners in regional hepatitis C shared care services and regional patients' access to treatment was influenced by the availability and capacity of health professionals. Uptake of treatment and engagement in the regional shared care program was limited for Aboriginal people and younger people although these groups had the highest rates of hepatitis C notifications in Western Australia. The patients consulted for this study preferred to access hepatitis C treatment and care locally rather than travel to tertiary liver clinics, up to 1500 kilometres away. The reasons for limited engagement in the shared care program by some groups with high rates of hepatitis C notifications requires further investigation. Health professionals identified several benefits of the shared care program including continuity of care for patients, shorter waiting times, longer appointment times and high levels of treatment compliance. Hepatitis nurses in regional areas can coordinate effective patient treatment and care when supported by treatment protocols and access to physicians and liver specialists, including through telehealth. Treatment and care options to suit individual preferences are required to avoid further stigmatising marginalised groups. The role of primary care in facilitating hepatitis C treatment uptake should be explored further including strategies for improving the participation of general practitioners in regional shared care services.


Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS.
The ready availability of unlimited quantities of neural stem cells derived from the human brain holds great interest for basic and applied neuroscience, including therapeutic cell replacement and gene transfer following transplantation. We report here the combination of epigenetic and genetic procedures for perpetuating human neural stem cell lines. Thus we tested various culture conditions and genes for those that optimally allow for the continuous, rapid expansion and passaging of human neural stem cells. Among them, v-myc (the p110 gag-myc fusion protein derived from the avian retroviral genome) seems to be the most effective gene; we have also identified a strict requirement for the presence of mitogens (FGF-2 and EGF) in the growth medium, in effect constituting a conditional perpetuality or immortalization. A monoclonal, nestin-positive, human neural stem cell line (HNSC.100) perpetuated in this way divides every 40 h and stops dividing upon mitogen removal, undergoing spontaneous morphological differentiation and upregulating markers of the three fundamental lineages in the CNS (neurons, astrocytes, and oligodendrocytes). HNSC.100 cells therefore retain basic features of epigenetically expanded human neural stem cells. Clonal analysis confirmed the stability, multipotency, and self-renewability of the cell line. Finally, HNSC.100 can be transfected and transduced using a variety of procedures and genes encoding proteins for marking purposes and of therapeutic interest (e.g., human tyrosine hydroxylase I).


The Heidelberg compact electron beam ion traps.
Electron beam ion traps (EBITs) are ideal tools for both production and study of highly charged ions (HCIs). In order to reduce their construction, maintenance, and operation costs, we have developed a novel, compact, room-temperature design, the Heidelberg Compact EBIT (HC-EBIT). Four already commissioned devices operate at the strongest fields (up to 0.86 T) reported for such EBITs using permanent magnets, run electron beam currents up to 80 mA, and energies up to 10 keV. They demonstrate HCI production, trapping, and extraction of pulsed Ar16+ bunches and continuous 100 pA ion beams of highly charged Xe up to charge state 29+, already with a 4 mA, 2 keV electron beam. Moreover, HC-EBITs offer large solid-angle ports and thus high photon count rates, e.g., in x-ray spectroscopy of dielectronic recombination in HCIs up to Fe24+, achieving an electron-energy resolving power of E/ΔE > 1500 at 5 keV. Besides traditional on-axis electron guns, we have also implemented a novel off-axis gun for laser, synchrotron, and free-electron laser applications, offering clear optical access along the trap axis. We report on its first operation at a synchrotron radiation facility demonstrating the resonant photoexcitation of highly charged oxygen.


Dynamic wait-listed designs for randomized trials: new designs for prevention of youth suicide.
The traditional wait-listed design, where half are randomly assigned to receive the intervention early and half are randomly assigned to receive it later, is often acceptable to communities who would not be comfortable with a no-treatment group. As such this traditional wait-listed design provides an excellent opportunity to evaluate short-term impact of an intervention. We introduce a new class of wait-listed designs for conducting randomized experiments where all subjects receive the intervention, and the timing of the intervention is randomly assigned. We use the term "dynamic wait-listed designs" to describe this new class. This paper examines a new class of statistical designs where random assignment to intervention condition occurs at multiple times in a trial. As an extension of a traditional wait-listed design, this dynamic design allows all subjects to receive the intervention at a random time. Motivated by our search for increased statistical power in an ongoing school-based trial that is testing a program of gatekeeper training to identify suicidal youth and refer them to treatment, this new design class is especially useful when the primary outcome is a count or rate of occurrence, such as suicidal behavior, whose rate can fluctuate over time due to uncontrolled factors. Statistical power is computed for various dynamic wait-listed designs under conditions where the underlying rate of occurrence is allowed to vary nonsystematically. We also present as an example a large ongoing trial to evaluate a gatekeeper training suicide prevention program in 32 schools which we initially began as a classic randomized wait-listed design. The primary outcome of interest in this study is the count of the number of children who are identified by the school system as having suicidal thoughts or behaviors who are then validated as being suicidal by mental health professionals in the community. A general result shows that dynamic wait-listed designs always have higher statistical power over a traditional wait-listed design. This power increase can be substantial. Efficiency gains of 33% are easy to obtain for situations where the intervention has a small effect and the variation in rate across time is quite high. When the rate variation for an outcome is very low or the intervention effect is large, efficiency gains approach 100%. A small increase in the number of times where random assignment occurs from 2 - for the standard wait-listed design, to say 4 can provide a large reduction in variance. Efficiency gains can also be high when converting standard wait-listed design to a dynamic one half-way into the study. As with all wait-listed designs, dynamic wait-listed designs can only be used to evaluate short-term impact. Since all subjects eventually receive the intervention, no comparison can be made after the end of the random assignment period. The statistical power benefits are primarily limited to outcomes that can be treated as count or time to event data. A dynamic design randomly assigns units - either individuals or groups - to start the intervention at varying times during the course of the study. This design is useful in testing interventions that screen for new or existing cases, as well as testing the scalability of interventions as they are disseminated or expanded system wide. They can improve on the traditional wait-listed design both in terms of statistical power and robustness in the presence of exogenous factors. This paper demonstrates that such designs yield smaller standard errors and can achieve higher statistical power than that of a standard wait-listed design. Just as important, dynamic designs can also help reduce the logistical challenges of implementing an intervention on a wide scale. When the intervention requires that significant training resources be allocated throughout the study, the dynamic wait-listed design is likely to increase the rate of training and lead to a higher level of program implementation.


Quantification of missing and overlapping data in multiple breath hold abdominal imaging.
Magnetic resonance imaging (MRI) of the abdomen is often performed in multiple breath holds which are designed to contiguously cover the region of interest. This technique may result in a failure to image all the appropriate area, and the extent of this failure is difficult to appreciate on a set of 2D slices. With reference to three patient cases, we present a method to quantify the extent of this problem and suggest a solution. First, we manually delineate the region of interest on a single breath hold fast spoiled gradient echo (FSPGR) sequence. Subsequently, we align images acquired in separate breath holds to this reference volume. A coloured 3D presentation makes the extent of unimaged and repeatedly imaged areas clearly visible to the clinician. The alignment also helps radiologists to accurately determine the location of individual slices. The described method can easily be automated and is ideally implemented at the scanner console, ensuring the availability of contiguously sampled datasets to radiologists with minimum user interaction from the radiographer. Such datasets enable the deployment of robust 3D analysis algorithms.


The role of HIV testing, counselling, and treatment in coping with HIV/AIDS in Uganda: a qualitative analysis.
HIV/AIDS has had a devastating impact at individual, household and community levels. This qualitative research investigates the role of HIV voluntary counselling and testing (VCT) and treatment in enabling HIV-positive Ugandans to cope with this disease. Twelve predetermined focus group discussions (FGDs) were conducted; six with men and six with women. Half of the men and women's groups were receiving antiretroviral therapy (ART) and half were not. An FGD was held with the health care providers administering ART. Testing for HIV was perceived as soliciting a death warrant. Participants affirmed that the incentive for testing was the possibility of accessing free ART. They described experiencing gender-variant stigma and depression on confirming their HIV status and commended the role of counselling in supporting them to adopt positive living. For those receiving ART, counselling reinforced treatment adherence. The findings also revealed gender differences in treatment adherence strategies. ART was described to reduce disease symptoms and restore physical health allowing them to resume their daily activities. Additionally, ART was preferred over traditional herbal treatment because it had clear dosages, expiry dates and was scientifically manufactured. Those that were not receiving ART bore myths and misconceptions about the effectiveness and side effects of ART, delaying the decision to seek treatment. Stigma and the attached concern of HIV/AIDS-related swift death, is a major barrier for VCT. Based on this study's findings, ensuring the provision of quality assured and gender conscious VCT and ART delivery services will enhance positive living and enforce compliance to ART programmes.


Skeletal Anomalies in The Neandertal Family of El Sidrón (Spain) Support A Role of Inbreeding in Neandertal Extinction.
Neandertals disappeared from the fossil record around 40,000 bp, after a demographic history of small and isolated groups with high but variable levels of inbreeding, and episodes of interbreeding with other Paleolithic hominins. It is reasonable to expect that high levels of endogamy could be expressed in the skeleton of at least some Neandertal groups. Genetic studies indicate that the 13 individuals from the site of El Sidrón, Spain, dated around 49,000 bp, constituted a closely related kin group, making these Neandertals an appropriate case study for the observation of skeletal signs of inbreeding. We present the complete study of the 1674 identified skeletal specimens from El Sidrón. Altogether, 17 congenital anomalies were observed (narrowing of the internal nasal fossa, retained deciduous canine, clefts of the first cervical vertebra, unilateral hypoplasia of the second cervical vertebra, clefting of the twelfth thoracic vertebra, diminutive thoracic or lumbar rib, os centrale carpi and bipartite scaphoid, tripartite patella, left foot anomaly and cuboid-navicular coalition), with at least four individuals presenting congenital conditions (clefts of the first cervical vertebra). At 49,000 years ago, the Neandertals from El Sidrón, with genetic and skeletal evidence of inbreeding, could be representative of the beginning of the demographic collapse of this hominin phenotype.


Combining a variable-centered and a person-centered analytical approach to caregiving burden - a holistic approach.
Informal caregivers of persons with dementia often experience elevated levels of caregiving burden. However, existing studies tend to use a variable-centered approach to explore it. This study aims to understand the caregiving burden of informal caregivers of persons with dementia in Singapore through a combination of variable-centered and person-centered analytical approaches, and explore the correlates of identified factors and latent classes of caregiving burden. Zarit Burden Interview was used to gauge the caregiving burden of 282 primary informal caregivers of persons with dementia recruited through convenience sampling in Singapore. Factor analysis and latent class analysis were conducted to identify the latent factors and the latent classes of Zarit Burden Interview, followed by multiple linear regression and multinomial logistic regression to explore their significant correlates. The analyses suggested a 17-item 3-factor structure for Zarit burden interview and three mutually exclusive caregiving burden classes. Regression analyses found that caregiving related variables especially care recipients' memory and behaviour problems were correlated with both the factors and latent classes of caregiving burden. The combination of these two approaches suggests that caregivers experiencing higher burden on one domain are likely to experience higher burden on the other two domains. This further supports the point that more attention should be given to caregivers who experience an overall high burden. Future research could explore the generalizability of our findings among caregivers elsewhere and explore the type of support needed by caregivers, especially those experiencing high burden.


A new species of Branchinecta (Crustacea: Anostraca) from Uruguay.
Branchinecta uruguayensis, a new species of fairy shrimp, is described from a single seasonally astatic aquatic habitat in coastal Uruguay. This is the first record of an anostracan from the nation of Uruguay. Male B. uruguayensis n. sp. are separated from other Branchinecta species by the form of the second antennae. Branchinecta uruguayensis n. sp. share the distal antennomere lobiform projection with B. papillata Rogers, De los Rios, & Zúñiga, 2008 and B. achalensis César, 1985. Branchinecta uruguayensis n. sp. females are readily separated from all other Branchinecta by the presence of posteriolateral thoracic spines and lateral crenulations on the first abdomen segment margins. A key is provided to the Branchinectidae of South America.


Modifier genes and heart failure.
Recent progress in genomic applications have led to a better understanding of the relationship between genetic background and cardiovascular diseases such as heart failure. A considerable component of the variability in heart failure outcome is due to modifier genes, i.e. genes that are not involve in the genesis of a disease but modify the severity of the phenotypic expression once the disease has developed. The strategy most commonly used to identify modifier genes is based on association studies between the severity of the phenotype of the disease (morbidity and/or mortality) and the sequence variation(s) of selected candidate gene(s). This strategy has showed that several polymorphisms of the beta1 and beta2 adrenergic receptors genes and the angiotensin converting enzyme gene are correlated to the prognosis of patients with heart failure. Recently, we have applied an experimental strategy, known as genome mapping, for the identification of heart failure modifier genes. Genome mapping has previously been used with success to identify the genes involved in the development of both monogenic and multifactorial diseases. We have showed that the prognosis of heart failure mice, induced through overexpressing calsequestrin, is linked to 2 Quantitative Trait Loci (QTL) localized on chromosome 2 and 3. Using both strategies (candidate gene and genome mapping) should allow us to identify a number of modifier genes that may provide a more rational approach to identify patients at risk for disease and response to therapy.


Radiographically occult femoral and pelvic fractures are not mutually exclusive: a review of fractures detected by MRI following low-energy trauma.
The purpose of this study was to review the MRI examinations of a large group of low-energy trauma patients in whom pelvic MRI had detected radiographically occult fractures, in order to characterize prevailing fracture patterns and determine how often co-existing proximal femoral and pelvic fractures were observed. All patients having pelvic MRI over 5 years were identified. Word-search software selected 269 MRI reports containing the term 'fracture'. Further scrutiny identified 168 with diagnosis of fracture. MRI request and imaging record review identified 102 low-energy trauma cases that had MRI for clinical suspicion of fracture despite normal radiographs. Sixty-six cases were excluded for the following reasons: no expressed clinical suspicion of occult fracture; history suggesting high-energy trauma;skeletal co-morbidity hindering acute fracture identification;interval more than 2 weeks between radiographs and MRI. The 102 study MRI examinations, which employed a limited two-sequence protocol, were reviewed. Any fracture that had not been appreciated on radiographs was recorded and characterized as femoral, pelvic, or co-existing femoral and pelvic fractures. The 102 study cases had a median age of 82 years.The median interval between pelvic radiographs and MRI was 3 days. MRI showed undiagnosed femoral fracture in 48/102 cases (47.1%), sacral fracture in 41/102 (40.2%),and pubic fracture in 55/102 (53.9%). In 11/102 cases(10.8%), MRI showed undiagnosed fractures of both proximal femur and pelvic ring (seven sacral, six pubic bone, two other site fractures). In 10/11 cases with coexisting femoral and pelvic fractures, the femoral fracture was incomplete. Limited pelvic MRI found a high prevalence of radiographically occult femoral and pelvic fractures in low-energy trauma patients, with clinical suspicion of fracture despite normal radiographs. Co-existing occult femoral and pelvic ring fractures were commonly observed, and in such cases, the femoral fracture was likely to be incomplete and multiple pelvic fractures were typically present.


Adverse reproductive outcomes in women who subsequently develop rheumatoid arthritis.
The rates of adverse reproductive outcomes in 40 women with rheumatoid arthritis (RA) were compared with 67 of their unaffected female relatives. All women were aged between 35 and 65 years at the time of inquiry. Seven of the women with RA reported a perinatal death (six stillbirths, one early neonatal death) compared with one women in the unaffected group: estimated age adjusted relative risk (R) = 12.4, 95% confidence interval (95% CI) 1.6-91.1. The rate of spontaneous abortions was, however, not significantly different between the two groups (R = 1.2, 95% CI 0.5-2.9). All the perinatal deaths occurred before clinical disease onset in the women with RA. It is possible that in these two groups of women with a similar genetic background perinatal loss may be related, at least in part, to disease expression.


Targeted Casp8AP2 methylation increases drug resistance in mesenchymal stem cells and cancer cells.
Casp8AP2 contains a FLASH functional domain and is critical for the formation of death complex and the relay of death signal into the cells. Genetic defects in Casp8AP2 are associated with several diseases. A CpG island within the Casp8AP2 promoter is differentially regulated during somatic stem cell differentiation, and aberrant DNA methylation within the Casp8AP2 promoter has been reported in cancers. We hypothesized that abnormal DNA methylation of Casp8AP2 promoter might contribute to prolonged cellular survival or drug resistance in cancer. The epigenetic state within the Casp8AP2 promoter was then determined in different cancer cell lines and patient samples by methylation-specific PCR. Targeted Casp8AP2 methylation within normal and tumor cells was performed to see whether methylation promoted drug resistance. We found differential Casp8AP2 methylation among the normal and tumoral samples. Global demethylation in a platinum drug-resistant human gastric cancer cell line reversed Casp8AP2 methylation and diminished drug resistance. Targeted methylation of the Casp8AP2 promoter in somatic stem cells and cancer cells increased their resistance to drugs including platinum drugs. These data demonstrate that methylation within the Casp8AP2 promoter correlates with the development of drug resistance and might serve as a biomarker and treatment target for drug resistance in cancer cells.


Enhanced Release of Molecules upon Ultraviolet (UV) Light Irradiation from Photoresponsive Hydrogels Prepared from Bifunctional Azobenzene and Four-Arm Poly(ethylene glycol).
Advances in biosensors and drug delivery are dependent on hydrogels that respond to external stimuli. In this work, we describe the preparation and characterization of photoresponsive hydrogels prepared by cross-linking of di-NHS ester of azobenzoic acid and four-armed, amine-terminated poly(ethylene glycol). The porous structure and composition of the hydrogels were confirmed by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. The reversible photoisomerization of the azobenzene-containing hydrogel cross-linkers in the gels was confirmed by absorption spectroscopy. Specifically, the photoisomerization of the cross-linkers between their trans and cis configurations was observed by monitoring the absorbance of the hydrogels at the two characteristic peaks of azobenzene (π-π* at 330 nm and n-π* at 435 nm). The effect of photoisomerization on the hydrogel structure was investigated by microscopy. Ultraviolet (UV) irradiation-induced reduction in hydrogel size was observed, which may be a result of the inherently smaller footprint of the cis azobenzene conformation, as well as dipole-dipole interactions between the polar cis azobenzene and the polymer network. The UV-triggered reduction in hydrogel size was accompanied by enhanced release of the near-infrared fluorescent dye Alexa Fluor 750 (AF750). Enhanced release of AF750 was observed in samples irradiated with UV versus dark control. Together, these data demonstrate the potential of these systems as reversible photoresponsive biomaterials.


Functionalized HgTe nanoparticles promote laser-induced solid phase ionization/dissociation for comprehensive glycan sequencing.
Glycoconjugates are ubiquitously present and play a critical role in various biological processes. Due to their low stability and incredibly high degree of structural diversity, the structural characterization of glycan generally requires chemical derivatization and sophisticated instrumentation. Herein, we report a method for complicated glycan characterization in a single assay by employing 2,5-dihydroxybenzoic acid functionalized mercury telluride nanoparticles (HgTe@DHB NPs) as a dual ionization-dissociation element in matrix-assisted laser desorption/ionization mass spectrometry. Using a linear glycan, HgTe@DHB NPs promote laser-induced extensive and intense dissociation of the glycan, superior to HgTe microparticles and other inorganic nanoparticles (TiO2, ZnO, and Mn2O3 NPs). Abundant generation of diagnostic glycosidic (Y-, and B-type ions) and cross-ring cleavage (A-type ions) ions permits unambiguous determination of the composition, sequence, branching, and linkage of labile sialylated glycans. The general utility of this approach was demonstrated by the characterization of labile sialylated glycans and two sets of complicated isomeric glycans. This phenomenon was delineated further by investigating the NP's physico-chemical characteristics, revealing that their nanoscale-dependent thermodynamic properties, including UV absorption, photoelectron release dynamics and thermal energy, were the key to levitate temperature synergistically, thus inducing spontaneous glycan decomposition during the nanoparticle-assisted laser desorption-ionization process. Our results show that this "pseudo-MS/MS" obtained by HgTe@DHB can be beneficial for the analysis of biologically relevant and more complicated carbohydrates, without the need for chemical pre-derivatization and conventional tandem mass spectrometry.


Is clinical tolerance possible after allergen immunotherapy?
There is a growing evidence that allergen immunotherapy (AIT) can provide significant and long-lasting clinical benefit for a number of allergic individuals. However, it is less clear if AIT results in clinical tolerance, which is characterized by a persistent state of clinical non-reactivity to allergens after therapy is finished. Addressing this knowledge gap is particularly relevant for patients undergoing AIT for food allergies, as anything less than complete tolerance could have potentially devastating consequences. An increasing number of studies, in particular those involving oral immunotherapy, are attempting to assess tolerance induction following AIT. Clinical tolerance does appear to be achievable in a subset of patients undergoing AIT, but whether this is equivalent to the type of tolerance observed in nonallergic individuals remains unknown. Developing established criteria for assessing tolerance induction, as well as the use of consistent terminology when describing clinical tolerance, will be important for determining the disease-modifying potential of AIT.


Observing supernova 1987A with the refurbished Hubble Space Telescope.
Observations with the Hubble Space Telescope (HST), conducted since 1990, now offer an unprecedented glimpse into fast astrophysical shocks in the young remnant of supernova 1987A. Comparing observations taken in 2010 with the use of the refurbished instruments on HST with data taken in 2004, just before the Space Telescope Imaging Spectrograph failed, we find that the Lyα and Hα lines from shock emission continue to brighten, whereas their maximum velocities continue to decrease. We observe broad, blueshifted Lyα, which we attribute to resonant scattering of photons emitted from hot spots on the equatorial ring. We also detect N v λλ1239, 1243 angstrom line emission, but only to the red of Lyα. The profiles of the N v lines differ markedly from that of Hα, suggesting that the N4+ ions are scattered and accelerated by turbulent electromagnetic fields that isotropize the ions in the collisionless shock.


Identification of potential inhibitors against pathogenic missense mutations of PMM2 using a structure-based virtual screening approach.
The autosomal recessive phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is characterized by defective functioning of the PMM2 enzyme, which is necessary for the conversion of mannose-6-phosphate into mannose-1-phosphate. Here, a computational pipeline was drawn to identify the most significant mutations, and further, we used a virtual screening approach to identify a new lead compound to treat the identified significant mutations. We searched for missense mutation data related to PMM2-CDG in HGMD®, UniProt, and ClinVar. Our search yielded a total of 103 mutations, of which 91 are missense mutations. The D65Y, I132N, I132T, and F183S mutations were classified as deleterious, destabilizing, and altering the biophysical properties using the PredictSNP, iStable, and Align GVGD in silico prediction tools. Additionally, we applied a multistep protocol to screen for an alternative lead compound to the existing CID2876053 (1-(3-chlorophenyl)-3,3-bis(pyridine-2-yl)urea) with affinity to these identified significant mutants. Two compounds, CHEMBL1491007 (6-chloro-4-phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)-1H-quinolin-2-one) and CHEMBL3653029 (5-chloro-4-[6-[(3-fluorophenyl)methylamino]pyridin-2-yl]-N-(piperidin-4-ylmethyl)pyridin-2-amine), exhibited the highest binding affinity with the selected mutants and were chosen for further analysis. Through molecular docking, molecular dynamics simulation, and MMPBSA analysis, we found that the known compound, i.e. CID2876053, has stronger interaction with the D65Y mutant. The newly identified lead compound CHEMBL1491007 showed stronger interaction with the I132N and I132T mutants, whereas the most deleterious mutant, F183S, showed stronger interaction with CHEMBL3653029. This study is expected to aid in the field of precision medicine, and further to in vivo and in vitro analysis of these lead compounds might shed light on the treatment of PMM2-CDG. Communicated by Ramaswamy H. Sarma.


Solar-blind photoelectric detection systems for satellite applications.
The characteristics of open Magnetic Electron Multipliers (MEM) with continuous dynode and field strips are discussed in view of their use in satellite-borne detection systems. Special emphasis is placed on selection, thermal stabilization, calibration, and long-time performance of the extreme ultraviolet detectors Practical aspects of the design of satellite-borne detection systems, such as monitoring capabilities, immunity to charged particles, and electrical breakdown, are also described. Laboratory studies with fast electronics showed that the useful linear range of an MEM is restricted because of afterpulses. Most characteristics of MEM's reported in the literature appear to be due to the use of relatively slow electronics that do not resolve the afterpulses. Statistical studies of afterpulses are reported, and a tentative explanation for the generation of afterpulses is outlined.


Determination of three carcinogenic aromatic amines in urine of smokers and nonsmokers.
Aromatic amines (arylamines) such as o-toluidine, 2-aminonaphthalene, and 4-aminobiphenyl occur in the environment and are constituents of tobacco smoke. Human exposure to these aromatic amines has long been associated with an elevated risk of bladder cancer. A validated, specific, and sensitive method for measuring o-toluidine, 2-aminonaphthalene, and 4-aminobiphenyl in cigarette smokers and nonsmokers was developed. The method uses acid hydrolysis of the arylamine conjugates in urine, extraction with n-hexane, derivatization with pentafluoropropionic anhydride, and subsequent analysis with gas chromatography combined with mass spectrometry using negative ion chemical ionization. The limits of detection were 4 ng/L for o-toluidine and 1 ng/L for 2-aminonaphthalene and 4-aminobiphenyl. Smokers (N = 10) excreted significantly higher amounts of o-toluidine (204 versus 104 ng/24 h), 2-aminonaphthalene (20.8 versus 10.7 ng/24 h), and 4-aminobiphenyl (15.3 versus 9.6 ng/24 h) than nonsmokers (N = 10). Urinary arylamine excretion in smokers was associated with the extent of smoking as assessed by daily cigarette consumption, urinary excretion of nicotine equivalents (nicotine plus its five major metabolites), cotinine in saliva, and carbon monoxide in exhaled breath. All nonsmokers investigated had quantifiable amounts of o-toluidine, 2-aminonaphthalene, and 4-aminobiphenyl in their urine, confirming that other environmental sources of exposure to these compounds also occur. In conclusion, the analytical method is suitable for measuring short-term exposure to arylamines in urine of non-occupationally exposed smokers and nonsmokers.


Melanocortin regulation of histaminergic neurons via perifornical lateral hypothalamic melanocortin 4 receptors.
Histaminergic neurons of the tuberomammillary nucleus (TMN) are wake-promoting and contribute to the regulation of energy homeostasis. Evidence indicates that melanocortin 4 receptors (MC4R) are expressed within the TMN. However, whether the melanocortin system influences the activity and function of TMN neurons expressing histidine decarboxylase (HDC), the enzyme required for histamine synthesis, remains undefined. We utilized Hdc-Cre mice in combination with whole-cell patch-clamp electrophysiology and in vivo chemogenetic techniques to determine whether HDC neurons receive metabolically relevant information via the melanocortin system. We found that subsets of HDC-expressing neurons were excited by melanotan II (MTII), a non-selective melanocortin receptor agonist. Use of melanocortin receptor selective agonists (THIQ, [D-Trp8]-γ-MSH) and inhibitors of synaptic transmission (TTX, CNQX, AP5) indicated that the effect was mediated specifically by MC4Rs and involved a glutamatergic dependent presynaptic mechanism. MTII enhanced evoked excitatory post-synaptic currents (EPSCs) originating from electrical stimulation of the perifornical lateral hypothalamic area (PeFLH), supportive of melanocortin effects on the glutamatergic PeFLH projection to the TMN. Finally, in vivo chemogenetic inhibition of HDC neurons strikingly enhanced the anorexigenic effects of intracerebroventricular administration of MTII, suggesting that MC4R activation of histaminergic neurons may restrain the anorexigenic effects of melanocortin system activation. These experiments identify a functional interaction between the melanocortin and histaminergic systems and suggest that HDC neurons act naturally to restrain the anorexigenic effect of melanocortin system activation. These findings may have implications for the control of arousal and metabolic homeostasis, especially in the context of obesity, in which both processes are subjected to alterations.


Coarse-grained computations for a micellar system.
We establish, through coarse-grained computation, a connection between traditional, continuum numerical algorithms (initial value problems as well as fixed point algorithms), and atomistic simulations of the Larson model of micelle formation. The procedure hinges on the (expected) evolution of a few slow, coarse-grained mesoscopic observables of the Monte Carlo simulation, and on (computational) time scale separation between these and the remaining "slaved," fast variables. Short bursts of appropriately initialized atomistic simulation are used to estimate the (coarse grained, deterministic) local dynamics of the evolution of the observables. These estimates are then in turn used to accelerate the evolution to computational stationarity through traditional continuum algorithms (forward Euler integration, Newton-Raphson fixed point computation). This "equation-free" framework, bypassing the derivation of explicit, closed equations for the observables (e.g., equations of state), may provide a computational bridge between direct atomistic/stochastic simulation and the analysis of its macroscopic, system-level consequences.


High-resolution specificity from DNA sequencing highlights alternative modes of Lac repressor binding.
Knowing the specificity of transcription factors is critical to understanding regulatory networks in cells. The lac repressor-operator system has been studied for many years, but not with high-throughput methods capable of determining specificity comprehensively. Details of its binding interaction and its selection of an asymmetric binding site have been controversial. We employed a new method to accurately determine relative binding affinities to thousands of sequences simultaneously, requiring only sequencing of bound and unbound fractions. An analysis of 2560 different DNA sequence variants, including both base changes and variations in operator length, provides a detailed view of lac repressor sequence specificity. We find that the protein can bind with nearly equal affinities to operators of three different lengths, but the sequence preference changes depending on the length, demonstrating alternative modes of interaction between the protein and DNA. The wild-type operator has an odd length, causing the two monomers to bind in alternative modes, making the asymmetric operator the preferred binding site. We tested two other members of the LacI/GalR protein family and find that neither can bind with high affinity to sites with alternative lengths or shows evidence of alternative binding modes. A further comparison with known and predicted motifs suggests that the lac repressor may be unique in this ability and that this may contribute to its selection.


The Development of Swedish Military Healthcare System: Part II-Re-evaluating the Military and Civilian Healthcare Systems in Crises Through a Dialogue and Study Among Practitioners.
Historical changes have transformed Sweden from being an offensive to a defensive and collaborative nation with national and international engagement, allowing it to finally achieve the ground for the civilian-military collaboration and the concept of a total defense healthcare. At the same time, with the decreasing number of international and interstate conflicts, and the military's involvement in national emergencies and humanitarian disaster relief, both the need and the role of the military healthcare system within the civilian society have been challenged. The recent impact of the COVID-19 in the USA and the necessity of military involvement have led health practitioners to anticipate and re-evaluate conditions that might exceed the civilian capacity of their own countries and the need to have collaboration with the military healthcare. This study investigated both these challenges and views from practitioners regarding the benefits of such collaboration and the manner in which it would be initiated. A primary study was conducted among responsive countries using a questionnaire created using the Nominal Group Technique. Relevant search subjects and keywords were extracted for a systematic review of the literature, according to the PRISMA model. The 14 countries responding to the questionnaire had either a well-developed military healthcare system or units created in collaboration with the civilian healthcare. The results from the questionnaire and the literature review indicated a need for transfer of military medical knowledge and resources in emergencies to the civilian health components, which in return, facilitated training opportunities for the military staff to maintain their skills and competencies. As the world witnesses a rapid change in the etiology of disasters and various crises, neither the military nor the civilian healthcare systems can address or manage the outcomes independently. There is an opportunity for both systems to develop future healthcare in collaboration. Rethinking education and training in war and conflict is indisputable. Collaborative educational initiatives in disaster medicine, public health and complex humanitarian emergencies, international humanitarian law, and the Geneva Convention, along with advanced training in competency-based skill sets, should be included in the undergraduate education of health professionals for the benefit of humanity.


Evaluation of an antigen-antibody "combination" enzyme linked immunosorbent assay for diagnosis of hepatitis C virus infections.
Development of "combination" assays detecting in parallel, within a single test, Hepatitis C Virus (HCV) antigens and antibodies, not only reduces the window period in HCV-infection but also costs. Reduction of costs is important for developing countries where money and personal resources are limited. We compared the Monolisa® HCV Antigen-Antibody Ultra (Bio-Rad Laboratories Limited, Marnes La Coquette, France) with the AXSYM HCV version 3.0 (Abbot Diagnostics, Germany)-the latter assay detecting only antibodies to HCV. Seventy three HCV-PCR positive and negative samples were tested. Although the two assays showed comparable results, two samples from a bone marrow transplant (BMT) patient of viral loads 7.8 × 105 and 8.9 × 106 IU/mL could not be detected by the Monolisa® HCV Antigen-Antibody Ultra assay. Failure to detect the two samples with viral loads considered above threshold of detection for antigen proteins suggested a lack of sensitivity by this assay to discover viral capsid protein in patient samples. Genotyping of these samples revealed genotype 1b, a HCV-subtype which is widespread and should thus be easily detected. We conclude that although this assay depicts high sensitivity and specificity in detecting antibodies to HCV, it seems not to add further benefit in our study population to detect HCV infections by enhanced sensitivity due the potential contingency to trace viral capsid antigens.


Vitamin E-Coated Polysulfone Membrane-Based Hemodiafiltration Attenuates Inflammation in a Rat Model of Lipopolysaccharide-Induced Systemic Inflammation.
Acute blood purification (ABP) therapy is used regularly in the clinical setting and reportedly alleviates organ failure associated with severe systemic inflammatory responses, leading to reduced mortality. The present study aimed to determine whether there is a difference in efficacy between polysulfone (PS) membranes, which are currently used regularly in the clinical setting, and vitamin E-coated polysulfone (VEPS) membranes, which are anticipated to exhibit the antioxidant and anti-inflammatory properties of vitamin E. Male Wistar rats (n=15/group) were intravenously administered 10 mg/kg of lipopolysaccharide (LPS) to establish a systemic inflammatory response model. Six hours after LPS administration, hemodiafiltration (HDF) was performed for 30 minutes using a PS or VEPS membrane under general anesthesia. Blood was collected at various time points, lung tissue was evaluated histologically, and 24-hour survival was assessed. The rats in the VEPS group tended to have a higher survival rate than those in the PS group when undergoing HDF, although the difference was not significant. With respect to lung tissue, the inflammatory response was suppressed to a greater extent in the VEPS group than the PS group. Serum interleukin (IL)-6 levels were reduced at an early stage, plasma antioxidant activity was increased, and oxidative stress was reduced in the VEPS group compared to the PS group. Relative to PS membrane-based HDF, the survival rate tended to improve and inflammation was subdued earlier due to the antioxidant activity and early attenuation of inflammation associated with VEPS membrane-based HDF.


A rapid method to estimate the concentration of citrate capped silver nanoparticles from UV-visible light spectra.
We present a generalized table of extinction coefficient data for silver nanoparticles from 8 to 100 nm. This table allows for easy and quick estimation of the concentration and size of modified and mono-dispersed silver nanoparticles from their optical spectra. We obtained data by determining the silver content of citrate-stabilised silver nanoparticles using sodium cyanide to dissolve the nanoparticles, and measuring solution conductivity with a pH meter and a cyanide-ion selective electrode. The quantification of the silver ion concentration enabled the calculation of extinction coefficients. Experimentally calculated extinction coefficients, in the current work, are in good agreement with collated literature values measured by different authors with non-standardized methodology and each for a limited range of particle size. They are also in good agreement with our theoretical calculations using Mie theory. Thus, we provide a highly standardized and comprehensive tabulated reference data-set.


TummyTrials: A Feasibility Study of Using Self-Experimentation to Detect Individualized Food Triggers.
Diagnostic self-tracking, the recording of personal information to diagnose or manage a health condition, is a common practice, especially for people with chronic conditions. Unfortunately, many who attempt diagnostic self-tracking have trouble accomplishing their goals. People often lack knowledge and skills needed to design and conduct scientifically rigorous experiments, and current tools provide little support. To address these shortcomings and explore opportunities for diagnostic self-tracking, we designed, developed, and evaluated a mobile app that applies a self-experimentation framework to support patients suffering from irritable bowel syndrome (IBS) in identifying their personal food triggers. TummyTrials aids a person in designing, executing, and analyzing self-experiments to evaluate whether a specific food triggers their symptoms. We examined the feasibility of this approach in a field study with 15 IBS patients, finding that participants could use the tool to reliably undergo a self-experiment. However, we also discovered an underlying tension between scientific validity and the lived experience of self-experimentation. We discuss challenges of applying clinical research methods in everyday life, motivating a need for the design of self-experimentation systems to balance rigor with the uncertainties of everyday life.


Magnesium, zinc, aluminium and gallium hydride complexes of the transition metals.
The preparation and applications of heterobimetallic complexes continue to occupy researchers in the fields of organometallic, main group, and coordination chemistry. This interest stems from the promise these complexes hold as precursors to materials, reagents in synthesis and as new catalysis. Here we survey and organise the state-of-the-art understanding of the TM-H-M linkage (M = Mg, Zn, Al, Ga). We discuss the structure and bonding in these complexes, their known reactivity, and their largely unrealised potential in catalysis.


Individual differences in attention influence perceptual decision making.
Sequential sampling decision-making models have been successful in accounting for reaction time (RT) and accuracy data in two-alternative forced choice tasks. These models have been used to describe the behavior of populations of participants, and explanatory structures have been proposed to account for between individual variability in model parameters. In this study we show that individual differences in behavior from a novel perceptual decision making task can be attributed to (1) differences in evidence accumulation rates, (2) differences in variability of evidence accumulation within trials, and (3) differences in non-decision times across individuals. Using electroencephalography (EEG), we demonstrate that these differences in cognitive variables, in turn, can be explained by attentional differences as measured by phase-locking of steady-state visual evoked potential (SSVEP) responses to the signal and noise components of the visual stimulus. Parameters of a cognitive model (a diffusion model) were obtained from accuracy and RT distributions and related to phase-locking indices (PLIs) of SSVEPs with a single step in a hierarchical Bayesian framework. Participants who were able to suppress the SSVEP response to visual noise in high frequency bands were able to accumulate correct evidence faster and had shorter non-decision times (preprocessing or motor response times), leading to more accurate responses and faster response times. We show that the combination of cognitive modeling and neural data in a hierarchical Bayesian framework relates physiological processes to the cognitive processes of participants, and that a model with a new (out-of-sample) participant's neural data can predict that participant's behavior more accurately than models without physiological data.


A Uniform System for the Annotation of Vertebrate microRNA Genes and the Evolution of the Human microRNAome.
Although microRNAs (miRNAs) are among the most intensively studied molecules of the past 20 years, determining what is and what is not a miRNA has not been straightforward. Here, we present a uniform system for the annotation and nomenclature of miRNA genes. We show that less than a third of the 1,881 human miRBase entries, and only approximately 16% of the 7,095 metazoan miRBase entries, are robustly supported as miRNA genes. Furthermore, we show that the human repertoire of miRNAs has been shaped by periods of intense miRNA innovation and that mature gene products show a very different tempo and mode of sequence evolution than star products. We establish a new open access database--MirGeneDB ( http://mirgenedb.org )--to catalog this set of miRNAs, which complements the efforts of miRBase but differs from it by annotating the mature versus star products and by imposing an evolutionary hierarchy upon this curated and consistently named repertoire.


A paracrine role for the epithelial progesterone receptor in mammary gland development.
Recently generated progesterone receptor (PR)-negative (PR-/-) mice provide an excellent model for dissecting the role of progesterone in the development of the mammary gland during puberty and pregnancy. However, the full extent of the mammary gland defect in these mice caused by the absence of the PR cannot be assessed, because PR-/- mice do not exhibit estrous cycles and fail to become pregnant. To circumvent this difficulty, we have transplanted PR-/- breasts into wild-type mice, and we have demonstrated that the development of the mammary gland in the absence of the PR is arrested at the stage of the simple ductal system found in the young virgin mouse. Mammary transplants lacking the PR in the stromal compartment give rise to normal alveolar growth, whereas transplants containing PR-/- epithelium conserve the abnormal phenotype. Chimeric epithelia in which PR-/- cells are in close vicinity to PR wild-type cells go through complete alveolar development to which the PR-/- cells contribute. Together, these results indicate that progesterone acts by a paracrine mechanism on a subset of mammary epithelial cells to allow for alveolar growth and that expression of the PR is not required in all the cells of the mammary epithelium in order for alveolar development to proceed normally.


Neuromorphic sensory systems.
Biology provides examples of efficient machines which greatly outperform conventional technology. Designers in neuromorphic engineering aim to construct electronic systems with the same efficient style of computation. This task requires a melding of novel engineering principles with knowledge gleaned from neuroscience. We discuss recent progress in realizing neuromorphic sensory systems which mimic the biological retina and cochlea, and subsequent sensor processing. The main trends are the increasing number of sensors and sensory systems that communicate through asynchronous digital signals analogous to neural spikes; the improved performance and usability of these sensors; and novel sensory processing methods which capitalize on the timing of spikes from these sensors. Experiments using these sensors can impact how we think the brain processes sensory information.


Longitudinal Telomere Erosion in Lymphocyte Subsets of Patients with Atherosclerotic Peripheral Arterial Disease (PAD).
Telomere attrition has been linked to accelerate vascular ageing and seems to predispose for vascular disease. Our aim was to study the telomere length dynamics over time and in subsets of leukocytes from 15 patients with peripheral arterial disease (PAD). The mean telomere length in subsets of leukocytes of patients with PAD was in the normal range of age-related telomere length values from healthy individuals. However, we found significant higher telomere attrition for T-cells from patients with PAD over a time period of six months when compared to the controls. The higher telomere loss in T-cells of patients with PAD most likely reflects a higher cell turnover of this leukocyte subset, which is involved in the process of chronic inflammatory disease underlying vascular disease. Further studies are needed to confirm these data and to assess how far this T-cell telomere attrition will correlate to the extent of the disease.


CD4 cell counts in adults with newly diagnosed HIV infection in Barbados.
To evaluate the absolute CD4 cell counts of all the newly diagnosed HIV-infected persons who presented at the Ladymeade Reference Unit (LRU), which serves as the national HIV/AIDS referral and treatment center for the country of Barbados. The study group was comprised of HIV-infected adults who had been diagnosed with HIV infection and referred to the LRU between January and December 2002. All the patients referred to the LRU had a CD4 cell count done at their first visit to the unit, as part of the routine workup to assess their disease status and need for antiretroviral therapy. Of the 106 newly diagnosed adults, 62 of them (58.5%) were males, who had a median age at presentation of 40 years; the other 44 of them (41.5%) were females, and their median age at presentation was 36 years. Nearly one-fifth (18.2%) of the females were aged 16-25 years, whereas only 8.1% of the males were in this age group. The majority (57.6%) of the study group were diagnosed because they presented with an HIV/AIDS-related illness. Overall, the median CD4 cell count at the time of diagnosis was 183/microL; 52 of 103 adults (50.5%) with a newly diagnosed HIV infection had a CD4 cell count that was < 200. Among males, the median CD4 cell count was 161/microL, and 32 (53.3%) of 60 males had CD4 cell counts < 200. In contrast, among females, the median CD4 cell count was 223, and 20 (46.5%) of 43 females had a CD4 cell count that was < 200/microL. However, this difference in the proportion of males and females with a CD4 cell count less than 200/microL was not statistically significant (P = 0.63). At the time of HIV diagnosis, over one-half of the adults had an initial CD4 cell count that was consistent with relatively advanced disease. Proportionally more women than men presented at a younger age, and proportionally more women than men presented in the early stages of the disease. These patterns indicate a clear need for enhanced educational efforts regarding the importance of HIV testing for at-risk individuals across Barbados. This testing could improve efforts to reduce transmission as well as the prognosis for patients who receive antiretroviral therapy.


Adapting a Clinical Data Repository to ICD-10-CM through the use of a Terminology Repository.
Clinical data repositories frequently contain patient diagnoses coded with the International Classification of Diseases, Ninth Revision (ICD-9-CM). These repositories now need to accommodate data coded with the Tenth Revision (ICD-10-CM). Database users wish to retrieve relevant data regardless of the system by which they are coded. We demonstrate how a terminology repository (the Research Entities Dictionary or RED) serves as an ontology relating terms of both ICD versions to each other to support seamless version-independent retrieval from the Biomedical Translational Research Information System (BTRIS) at the National Institutes of Health. We make use of the Center for Medicare and Medicaid Services' General Equivalence Mappings (GEMs) to reduce the modeling effort required to determine whether ICD-10-CM terms should be added to the RED as new concepts or as synonyms of existing concepts. A divide-and-conquer approach is used to develop integration heuristics that offer a satisfactory interim solution and facilitate additional refinement of the integration as time and resources allow.


e-Ana and e-Mia: A content analysis of pro-eating disorder Web sites.
The Internet offers Web sites that describe, endorse, and support eating disorders. We examined the features of pro-eating disorder Web sites and the messages to which users may be exposed. We conducted a systematic content analysis of 180 active Web sites, noting site logistics, site accessories, "thinspiration" material (images and prose intended to inspire weight loss), tips and tricks, recovery, themes, and perceived harm. Practically all (91%) of the Web sites were open to the public, and most (79%) had interactive features. A large majority (84%) offered pro-anorexia content, and 64% provided pro-bulimia content. Few sites focused on eating disorders as a lifestyle choice. Thinspiration material appeared on 85% of the sites, and 83% provided overt suggestions on how to engage in eating-disordered behaviors. Thirty-eight percent of the sites included recovery-oriented information or links. Common themes were success, control, perfection, and solidarity. Pro-eating disorder Web sites present graphic material to encourage, support, and motivate site users to continue their efforts with anorexia and bulimia. Continued monitoring will offer a valuable foundation to build a better understanding of the effects of these sites on their users.


Primary biliary cirrhosis and the nuclear pore complex.
Experimental models of autoimmune diseases have led to the conclusion that an immune response to nuclear antigens is a sentinel marker for loss of tolerance and potential tissue damage. Various proteins are targets of antinuclear antibodies in a variety of autoimmune diseases, ranging from systemic rheumatologic disorders to diseases affecting specific organs such as the liver. Autoantibodies against specific nuclear constituents have also been used as probes to understand the structure and the function of the targeted components and their relevance to disease pathogenesis. Approximately a quarter of patients with primary biliary cirrhosis (PBC) have antibodies targeting proteins of the nuclear pore complex (NPC), a multi-protein structure that mediates molecular transport across the nuclear envelope. Autoantibodies against the integral membrane glycoprotein gp210 and nucleoporin p62 appear to be highly specific for PBC, an autoimmune disease characterized by progressive destruction of intrahepatic biliary epithelial cells. This review discusses the diagnostic and clinical relevance of anti-NPC antibodies in PBC and the possibility that this autoimmune response may arise as a result of molecular mimicry.


Assessment of early cognitive impairment in patients with clinically isolated syndromes and multiple sclerosis.
Objective. The aim of our study was to investigate the frequency and pattern of cognitive impairment in patients with clinically isolated syndromes and definite diagnosis of multiple sclerosis within the last 2 years. Methods. We assessed the cognitive status of 46 patients aged 18-49 years with clinically isolated syndromes or definite diagnosis of multiple sclerosis who have onset of their symptoms within the last 2 years. Patients were matched with 40 healthy participants for age, sex, and educational level. Neuropsychological assessment was performed by stroop test, paced auditory serial addition test (PASAT), controlled oral word association test (COWAT), clock drawing test, trail making test (TMT), faces symbol test (FST). Hamilton Depression Scale and Modified Fatigue Impact Scale were used to quantify the severity of any depression and fatigue the subjects might suffer. Results. 19.6% of early MS/CIS group failed at 4 and more tests and had significant cognitive impairment focused on attention, executive functions, memory, and learning. No significant relationship was found between cognitive impairment and disability and fatigue scores. Discussion. Cognitive impairment can be present from the earliest stage of multiple sclerosis. It should be considered among the main manifestations of MS even in the earliest stages of the disease.


Multiple cerebellar zones are involved in the control of individual muscles: a retrograde transneuronal tracing study with rabies virus in the rat.
To identify cerebellar regions that are involved in the control of limb muscles, rabies virus was injected into the tibialis anterior (TA), the gastrocnemius (GC) or, for comparison, into the flexor digitorum (FD) muscles of the rat. Progression of retrograde transneuronal infection at supraspinal levels was assessed after variable time spans and was divided into three groups. Initially, infected neurons were observed in the reticular formation, lateral vestibular nucleus, red nucleus and motor cortex (group 1). Group 2 was characterized by labelling within the cerebellar nuclei as well as of two vermal strips of Purkinje cells (PCs). Double-labelling with zebrin enabled identification of these strips as the lateral part of the A1- and B-zone. For TA both zones were ipsilateral, whereas for GC the A1 strip predominated contralaterally. Group 3 infections showed additional labelling of multiple, in part bilateral, identifiable strips of PCs in vermis, paravermis and hemisphere. FD injections resulted in less robust labelling of vermal strips and more pronounced labelling within paravermal and hemispheral zonal regions. Only sporadic labelling in corresponding regions of the inferior olive and no labelling of cortical interneurons or granule cells was observed. Prolonged infection was seen to result in degeneration of PCs and possibly of motoneurons. We conclude that vermal, paravermal as well as hemispheral zones of the cerebellar cortex converge upon motoneurons that innervate a particular muscle. In addition, individual zones may control motorpools of different muscles and thus contribute to muscle synergies.


Using computer simulation to reduce access time for outpatient departments.
To develop general applicable models for analysing the capacity needed in appointment-based hospital facilities. A fairly simple analytical queuing model was used to obtain rapid global insight into the capacity needed to meet the norm of seeing 95% of all new patients within 2 weeks. For more detailed analysis, a simulation model was developed that could handle daily variations in demand and capacity schedules. The capacity needed to eliminate backlogs and the capacity needed to keep access time within 2 weeks was calculated. Both models were applied to two outpatient departments (neurology and gynaecology) at the Academic Medical Center in Amsterdam, the Netherlands. Model results for neurology were implemented. For neurology, to eliminate the 6-week backlog, 26 extra consultations per week were needed over 2 months. A permanent increase of 2-weekly consultations was required to keep access time within 2 weeks. Evaluation after implementation showed the improvements the model had predicted. The gynaecology department had sufficient capacity. With the simulation, it was calculated that the same service level could be achieved with 14% less capacity. Thus the models supported decisions made for departments with shortages of capacity as well as those for departments with adequate capacity. The analytical model provided quick insight into the extra capacity needed for the neurology department. The added value of the simulation model was the possibility of taking into account variations in demand for different weekdays and a realistic schedule for doctors' consultations. General applicability of the models was shown by applying both models to the gynaecology department.


Sex differences in the longitudinal associations between body composition and bone stiffness index in European children and adolescents.
Fat mass (FM) and fat free mass (FFM) may influence bone health differentially. However, existing evidences on associations between FM, FFM and bone health are inconsistent and vary according to sex and maturity. The present study aims to evaluate longitudinal associations between FM, FFM and bone stiffness index (SI) among European children and adolescents with 6 years follow-up. A sample of 2468 children from the IDEFICS/I.Family was included, with repeated measurements of SI using calcaneal quantitative ultrasound, body composition using skinfold thickness, sedentary behaviors and physical activity using self-administrated questionnaires. Regression coefficients (β) and 99%-confidence intervals (99% CI) were calculated by sex-specified generalized linear mixed effects models to analyze the longitudinal associations between FM and FFM z-scores (zFM and zFFM) and SI percentiles, and to explore the possible interactions between zFM, zFFM and maturity. Baseline zFFM was observed to predict the change in SI percentiles in both boys (β = 4.57, 99% CI: 1.36, 7.78) and girls (β = 3.42, 99% CI: 0.05, 6.79) after 2 years. Moreover, baseline zFFM (β = 8.72, 99% CI: 3.18, 14.27 in boys and β = 5.89, 99% CI: 0.34, 11.44 in girls) and the change in zFFM (β = 6.58, 99% CI: 0.83, 12.34 in boys and β = 4.81, 99% CI: -0.41, 10.02 in girls) were positively associated with the change in SI percentiles after 6 years. In contrast, a negative association was observed between the change in zFM and SI percentiles in boys after 6 years (β = -3.70, 99% CI: -6.99, -0.42). Besides, an interaction was observed between the change in zFM and menarche on the change in SI percentiles in girls at 6 years follow-up (p = .009), suggesting a negative association before menarche while a positive association after menarche. Our findings support the existing evidences for a positive relationship between FFM and SI during growth. Furthermore, long-term FM gain was inversely associated with SI in boys, whereas opposing associations were observed across menarche in girls.


Household responses to pandemic (H1N1) 2009-related school closures, Perth, Western Australia.
School closure is often purported to reduce influenza transmission, but little is known about its effect on families. We surveyed families affected by pandemic (H1N1) 2009-related school closures in Perth, Western Australia, Australia. Surveys were returned for 233 (58%) of 402 students. School closure was deemed appropriate by 110 parents (47%); however, 91 (45%) parents of 202 asymptomatic students reported taking >or=1 day off work to care for their child, and 71 (35%) had to make childcare arrangements because of the class closures. During the week, 172 (74%) students participated in activities outside the home on >or=1 occasion, resulting in an average of 3.7 out-of-home activities for each student. In our survey, activities outside the home were commonly reported by students affected by school closure, the effect on families was substantial, and parental opinion regarding school closures as a means to mitigate the outbreak of pandemic (H1N1) 2009 was divided.


X-ray structure determination of a dimeric hemoglobin from Caudina arenicola.
The X-ray structure of a dimeric, cyanomet-liganded hemoglobin D-chain (Hb-D) from Caudina arenicola has been determined by the molecular-replacement method. The search model was a concatenated model of three hemoglobin structures superimposed on the backbone of monomeric, hemichrome hemoglobin C-chain (Hb-C) from the same organism. Hb-D crystallizes in space group P4(1)2(1)2 with cell constants a = b = 77.0 and c =61.5 A with one subunit in the asymmetric unit. The dimer twofold axis corresponds to a crystallographic twofold along one of the body diagonals of the unit cell. Rotation and translation searches as well as model refinement were carried out in X-PLOR with the final model having an R value of 0.19 using the data from 5.0 to 2.9 A resolution (R = 0.26 for 10.0 to 2.9 A resolution). The homodimeric structure of Caudina Hb-D features close heme-heme contacts with an Fe-Fe distance of 19.0 A. The subunit-subunit interface involves both the E and F helices from each subunit with the E helices oriented antiparallel at 50 degrees with respect to one another, similar to the quaternary structure observed for the homodimeric hemoglobin from Scapharca inaequivalvis.


Effect of Facilitation of Local Maternal-and-Newborn Stakeholder Groups on Neonatal Mortality: Cluster-Randomized Controlled Trial.
Facilitation of local women's groups may reportedly reduce neonatal mortality. It is not known whether facilitation of groups composed of local health care staff and politicians can improve perinatal outcomes. We hypothesised that facilitation of local stakeholder groups would reduce neonatal mortality (primary outcome) and improve maternal, delivery, and newborn care indicators (secondary outcomes) in Quang Ninh province, Vietnam. In a cluster-randomized design 44 communes were allocated to intervention and 46 to control. Laywomen facilitated monthly meetings during 3 years in groups composed of health care staff and key persons in the communes. A problem-solving approach was employed. Births and neonatal deaths were monitored, and interviews were performed in households of neonatal deaths and of randomly selected surviving infants. A latent period before effect is expected in this type of intervention, but this timeframe was not pre-specified. Neonatal mortality rate (NMR) from July 2008 to June 2011 was 16.5/1,000 (195 deaths per 11,818 live births) in the intervention communes and 18.4/1,000 (194 per 10,559 live births) in control communes (adjusted odds ratio [OR] 0.96 [95% CI 0.73-1.25]). There was a significant downward time trend of NMR in intervention communes (p = 0.003) but not in control communes (p = 0.184). No significant difference in NMR was observed during the first two years (July 2008 to June 2010) while the third year (July 2010 to June 2011) had significantly lower NMR in intervention arm: adjusted OR 0.51 (95% CI 0.30-0.89). Women in intervention communes more frequently attended antenatal care (adjusted OR 2.27 [95% CI 1.07-4.8]). A randomized facilitation intervention with local stakeholder groups composed of primary care staff and local politicians working for three years with a perinatal problem-solving approach resulted in increased attendance to antenatal care and reduced neonatal mortality after a latent period.


SU-E-T-201: Safety-Focused Customization of Treatment Plan Documentation.
Plan report documentation contains numerous details about the treatment plan, but critical information for patient safety is often presented without special emphasis. This can make it difficult to detect errors from treatment planning and data transfer during the initial chart review. The objective of this work is to improve safety measures in radiation therapy practice by customizing the treatment plan report to emphasize safety-critical information. Commands within the template file from a commercial planning system (Eclipse, Varian Medical Systems) that automatically generates the treatment plan report were reviewed and modified. Safety-critical plan parameters were identified from published risks known to be inherent in the treatment planning process. Risks having medium to high potential impact on patient safety included incorrect patient identifiers, erroneous use of the treatment prescription, and incorrect transfer of beam parameters or consideration of accessories. Specific examples of critical information in the treatment plan report that can be overlooked during a chart review included prescribed dose per fraction and number of fractions, wedge and open field monitor units, presence of beam accessories, and table shifts for patient setup. Critical information was streamlined and concentrated. Patient and plan identification, dose prescription details, and patient positioning couch shift instructions were placed on the first page. Plan information to verify the correct data transfer to the record and verify system was re-organized in an easy to review tabular format and placed in the second page of the customized printout. Placeholders were introduced to indicate both the presence and absence of beam modifiers. Font sizes and spacing were adjusted for clarity, and departmental standards and terminology were introduced to streamline data communication among staff members. Plan reporting documentation has been customized to concentrate and emphasize safety-critical information, which should allow for a more efficient, robust chart review process.


Subtle solvation behaviour of a biofuel additive: the methanol complex with 2,5-dimethylfuran.
Methanol is shown to engage two nearly equivalent solvation sites in 2,5-dimethylfuran, the electron-rich π cloud and the electron-deficient oxygen site. The latter only wins by a slight margin, thanks to the methyl group undergoing secondary interactions with the ring. These secondary attractions reduce the hydrogen bond-induced OH frequency shift of the OH-O contact, whereas the π cloud allows for a combined action of both binding mechanisms in the OH-π arrangement. In total, the hydrophobic character of 2,5-dimethylfuran is well reflected in the weak pair interactions, as judged by the small solvation shifts. Methanol solvation of 2,3-benzofuran is revisited and shown to be more ambiguous than previously thought, involving competition between five- and six-ring π clouds and the oxygen site for the OH group. The six-ring π cloud is slightly preferred. FTIR spectroscopy in supersonic jets is in systematic agreement with dispersion-corrected harmonic B3LYP and also B2PLYP predictions for these competing furan docking sites. Deuteration of the OH group helps to identify the docking sites because of its attenuated zero-point energy weakening effect on localized hydrogen bonds. Extension to less methylated furans is proposed in the context of a future forecasting competition for the performance of quantum chemical methods for intermolecular interactions.


Effects of red raspberry polyphenols and metabolites on the biomarkers of inflammation and insulin resistance in type 2 diabetes: a pilot study.
Berry fruits are rich in polyphenolic compounds (PCs) and may promote health benefits. Anthocyanin (ACN) concentrations of red raspberry (RR) (Rubus idaeus) extracts were 887.6 ± 262.8 μg g-1, consisting mainly of cyanidin-3-sophoroside (C3S) equivalents. To test the efficacy of RR in diabetes treatment, seven patients with type 2 diabetes mellitus (T2DM) were given one oral RR serving (123 g per day) for two weeks. Blood samples were drawn at the baseline (BSL) and post-feeding (PF) periods for phenolic metabolite, inflammation and insulin resistance (IR) biomarker analysis. Two urolithin conjugates, urolithin A glucuronide (Uro-A glur) and urolithin A sulphate (Uro-A sulf) were identified in the PF period in 5 of the 7 patients in nanomolar concentrations (1.6 ± 0.7-63.2 ± 31.2 nM). ACN-derived metabolites such as protocatechuic acid (PCA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were at micromolar levels and were higher during the PF period for diabetics and the levels were as follows: BSL: PCA = 0.6 ± 0.4, DOPAC = 1.2 ± 0.5; PF: PCA = 0.6 ± 0.4, DOPAC = 1.1 ± 0.6. The results revealed significant reductions in high sensitivity C-reactive protein, hsCRP (p = 0.01) and there was a downward trend in IR measured by the homeostatic model assessment of insulin resistance (HOMA-IR, p = 0.0584) in T2DM patients. DOPAC (1-100 μM) failed to stimulate insulin secretion in pancreatic β-cells. The multiplex assay showed variations in the cytokine levels between patients, but differences were not significant. This study demonstrates a potential use of RR in the treatment of inflammation and possibly IR as well in patients with type 2 diabetes.


Scaleable two-component gelator from phthalic acid derivatives and primary alkyl amines: acid-base interaction in the cooperative assembly.
A series of phthalic acid derivatives (P) with a carbon-chain tail was designed and synthesized as single-component gelators. A combination of the single-component gelator P and a non-gelling additive n-alkylamine A through acid-base interaction brought about a series of novel phase-selective two-component gelators PA. The gelation capabilities of P and PA, and the structural, morphological, thermo-dynamic and rheological properties of the corresponding gels were investigated. A molecular dynamics simulation showed that the H-bonding network in PA formed between the NH of A and the carbonyl oxygen of P altered the assembly process of gelator P. Crude PA could be synthesized through a one-step process without any purification and could selectively gel the oil phase without a typical heating-cooling process. Moreover, such a crude PA and its gelation process could be amplified to the kilogram scale with high efficiency, which offers a practical economically viable solution to marine oil-spill recovery.


Synapsin I, a phosphoprotein associated with synaptic vesicles: possible role in regulation of neurotransmitter release.
The data presented here provide evidence that the study of neuronal phosphoproteins can lead to the identification of previously unknown proteins and that these proteins may play important roles in neuronal communication. Specifically, in the case of synapsin I, direct evidence has been obtained that this phosphoprotein is involved in regulating neurotransmitter release. A tentative explanation of the results obtained in the micro-injection studies is as follows: synapsin I, in the dephosphostate, is bound to the cytoplasmic surface of synaptic vesicles and inhibits the ability of the vesicle to interact with the plasma membrane; increases in intracellular calcium activate calmodulin kinase II which in turn phosphorylates synapsin I and the phosphorylated synapsin I dissociates from the synaptic vesicle thus removing a constraint on the release of neurotransmitter. Clearly, more studies need to be done to rigorously test this hypothesis. Nevertheless these studies of synapsin I suggest that the study of previously unknown phosphoproteins will lead to the elucidation of previously unknown regulatory processes in neurons.


Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies.
Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients.


Ligands have various potential effects on the degradation of pregnane X receptor by proteasome.
The degradations of several nuclear receptors are involved in the proteasome-mediated pathway. In our recent experiments, we found that mouse pregnane X receptor (PXR) interacted with suppressor for gal1 (SUG1), a component of the proteasome, in a progesterone-dependent manner, but that endocrine-disrupting chemicals (EDCs), phthalic acid and nonylphenol, which activated PXR-mediated transcription, did not enhance this interaction. PXR protein levels were markedly increased in the presence of proteasome inhibitors, suggesting that PXR may be degraded by proteasome. Furthermore, in the absence of ongoing protein synthesis, there is much slower degradation of PXR in the presence of phthalic acid compared with that in the presence of progesterone. The transient expression studies demonstrated that overexpression of wild-type SUG1 generated proteolytic PXR fragments, and these productions were blocked by a proteasome inhibitor. Functionally, expression of SUG1 inhibited PXR- and progesterone-mediated transcription. Moreover, in the presence of EDCs, SUG1 had no effect on the transcription. These findings indicate that the interaction between PXR and SUG1 may be involved in the proteasome-mediated degradation. Moreover, an EDC strongly blocks the degradation of PXR compared with progesterone, suggesting that EDCs may affect PXR-mediated transcription of target genes through up-regulation of the PXR protein level.


Signal, noise, and bias for a broadband, division-of-amplitude Stokes polarimeter.
We analyze estimation error as a function of spectral bandwidth for division-of-amplitude (DoAm) Stokes polarimeters. Our approach allows quantitative assessment of the competing effects of noise and deterministic error, or bias, as bandwidth is varied.We use the signal-to-rms error (SRR) as a metric. Rather than calculating the SRR of the estimated Stokes parameters themselves, we use the singular-value decomposition to calculate the SRRs of the coefficients of the measured data vector projected onto the measurement matrix left singular vectors.We argue that calculating the SRRs for left singular vector coefficients will allow development of reconstruction filters to minimize Stokes estimation error. For the example case of a source with constant polarization over a relatively wide band, we show that as the spectral filter bandwidth is increased to include wavelengths significantly different than the design wavelength, the SRRs of the estimated left singular vector coefficients will a.) increase monotonically if relatively few photo-detection events (PDEs) are recorded, b.) after a sharp peak close to the design wavelength, decrease monotonically if relatively many PDEs are recorded, and c.) have well-defined maxima for nominal PDE counts. Given some idea of the source brightness relative to detector noise, one can specify a spectral filter bandwidth minimizing the variance and bias effects and optimizing Stokes parameter estimation. Our approach also allows one to specify the bandwidth over which the response of "achromatic" optics must be reasonably invariant with wavelength for rms Stokes estimation error to remain below some desired maximum. Finally, we point out that our method can be generalized not only to other types of polarimeters, but also to any sensing scheme that can be represented by a linear system for limiting values of a certain parameter.


Co-creating a large-scale adolescent health survey integrated with access to digital health interventions.
This paper describes how we engaged with adolescents and health providers to integrate access to digital health interventions as part of a large-scale secondary school health and wellbeing survey in New Zealand. We conducted nine participatory, iterative co-design sessions involving 29 adolescents, and two workshops with young people (n = 11), digital and health service providers (n = 11) and researchers (n = 9) to gain insights into end-user perspectives on the concept and how best to integrate digital interventions in to the survey. Students' perceived integrating access to digital health interventions into a large-scale youth health survey as acceptable and highly beneficial. They did not want personalized/normative feedback, but thought that every student should be offered all the help options. Participants identified key principles: assurance of confidentiality, usability, participant choice and control, and language. They highlighted wording as important for ease and comfort, and emphasised the importance of user control. Participants expressed that it would be useful and acceptable for survey respondents to receive information about digital help options addressing a range of health and wellbeing topics. The methodology of adolescent-practitioner-researcher collaboration and partnership was central to this research and provided useful insights for the development and delivery of adolescent health surveys integrated with digital help options. The results from the ongoing study will provide useful data on the impact of digital health interventions integrated in large-scale surveys, as a novel methodology. Future research on engaging with adolescents once interventions are delivered will be useful to explore benefits over time.


One-Year Prospective Study of Plasma Biomarkers From CNS in Patients With Mild Traumatic Brain Injury.
Objective: To investigate the longitudinal evolution of three blood biomarkers: neurofilament light (NFL), glial fibrillary acidic protein (GFAP) and tau, in out-patients and hospitalized patients with mild traumatic brain injury (mTBI) compared to controls, along with their associations-in patients-with clinical injury characteristics and demographic variables, and ability to discriminate patients with mTBI from controls. Methods: A longitudinal observation study including 207 patients with mTBI, 84 age and sex-matched community controls (CCs) and 52 trauma controls (TCs). Blood samples were collected at 5 timepoints: acute (<24 h), 72 h (24-72 h post-injury), 2 weeks, 3 and 12 months. Injury-related, clinical and demographic variables were obtained at inclusion and brain MRI within 72 h. Results: Plasma GFAP and tau were most elevated acutely and NFL at 2 weeks and 3 months. The group of patients with mTBI and concurrent other somatic injuries (mTBI+) had the highest elevation in all biomarkers across time points, and were more likely to be victims of traffic accidents and violence. All biomarkers were positively associated with traumatic intracranial findings on MRI obtained within 72 h. Glial fibrillary acidic protein and NFL levels were associated with Glasgow Coma Scale (GCS) score and presence of other somatic injuries. Acute GFAP concentrations showed the highest discriminability between patients and controls with an Area Under the Curve (AUC) of 0.92. Acute tau and 2-week NFL concentrations showed moderate discriminability (AUC = 0.70 and AUC = 0.75, respectively). Tau showed high discriminability between mTBI+ and TCs (AUC = 0.80). Conclusions: The association of plasma NFL with traumatic intracranial MRI findings, together with its later peak, could reflect ongoing secondary injury or repair mechanisms, allowing for a protracted diagnostic time window. Patients experiencing both mTBI and other injuries appear to be a subgroup with greater neural injury, differing from both the mTBI without other injuries and from both control groups. Acute GFAP concentrations showed the highest discriminability between patients and controls, were highly associated with intracranial traumatic injury, and showed the largest elevations compared to controls at the acute timepoint, suggesting it to be the most clinically useful plasma biomarker of primary CNS injury in mTBI.


Towards a molecular understanding of cation-anion interactions--probing the electronic structure of imidazolium ionic liquids by NMR spectroscopy, X-ray photoelectron spectroscopy and theoretical calculations.
Ten [C(8)C(1)Im](+) (1-methyl-3-octylimidazolium)-based ionic liquids with anions Cl(-), Br(-), I(-), [NO(3)](-), [BF(4)](-), [TfO](-), [PF(6)](-), [Tf(2)N](-), [Pf(2)N](-), and [FAP](-) (TfO=trifluoromethylsulfonate, Tf(2)N=bis(trifluoromethylsulfonyl)imide, Pf(2)N=bis(pentafluoroethylsulfonyl)imide, FAP=tris(pentafluoroethyl)trifluorophosphate) and two [C(8)C(1)C(1)Im](+) (1,2-dimethyl-3-octylimidazolium)-based ionic liquids with anions Br(-) and [Tf(2)N](-) were investigated by using X-ray photoelectron spectroscopy (XPS), NMR spectroscopy and theoretical calculations. While (1)H NMR spectroscopy is found to probe very specifically the strongest hydrogen-bond interaction between the hydrogen attached to the C(2) position and the anion, a comparative XPS study provides first direct experimental evidence for cation-anion charge-transfer phenomena in ionic liquids as a function of the ionic liquid's anion. These charge-transfer effects are found to be surprisingly similar for [C(8)C(1)Im](+) and [C(8)C(1)C(1)Im](+) salts of the same anion, which in combination with theoretical calculations leads to the conclusion that hydrogen bonding and charge transfer occur independently from each other, but are both more pronounced for small and more strongly coordinating anions, and are greatly reduced in the case of large and weakly coordinating anions.


Drinking-and-Driving-Related Cognitions Mediate the Relationship Between Alcohol Demand and Alcohol-Impaired Driving.
Elevated behavioral economic demand for alcohol has been shown to be associated with drinking and driving in college students. The present study sought to clarify the underlying mechanisms of this relationship by examining whether drinking-and-driving-related cognitions (e.g., attitudes, perceptions, and normative beliefs) mediate the association between alcohol demand and drinking and driving. A total of 134 young adult social drinkers completed an alcohol purchase task and measures of perceived dangerousness of drinking and driving, normative beliefs about drinking and driving, and perceived driving limit (i.e., perceived number of drinks one could consume and still drive safely). The frequency of drinking and driving in the past year was assessed via self-report. Individuals who reported drinking and driving exhibited greater alcohol demand (intensity, Omax, and elasticity) compared with those who did not engage in drinking and driving. Increased demand was also correlated with more favorable drinking-and-driving cognitions. Indirect effects tests revealed that perceived driving limit partially mediated the relationship between alcohol demand and drinking-and-driving behavior, even after accounting for drinking level, sex, and delay discounting. These findings provide further support for the utility of behavioral economic theory in understanding drinking-and-driving behavior. In particular, they provide evidence for one mechanism-drinking-and-driving-related cognitions-by which alcohol demand influences drinking and driving. Additional research using longitudinal and experimental designs is required to confirm this model and to identify other potential mediators.


Mapping of cortical activity in the first two decades of life: a high-density sleep electroencephalogram study.
Evidence that electroencephalography (EEG) slow-wave activity (SWA) (EEG spectral power in the 1-4.5 Hz band) during non-rapid eye movement sleep (NREM) reflects plastic changes is increasing (Tononi and Cirelli, 2006). Regional assessment of gray matter development from neuroimaging studies reveals a posteroanterior trajectory of cortical maturation in the first three decades of life (Shaw et al., 2008). Our aim was to test whether this regional cortical maturation is reflected in regional changes of sleep SWA. We evaluated all-night high-density EEG (128 channels) in 55 healthy human subjects (2.4-19.4 years) and assessed age-related changes in NREM sleep topography. As in adults, we observed frequency-specific topographical distributions of sleep EEG power in all subjects. However, from early childhood to late adolescence, the location on the scalp showing maximal SWA underwent a shift from posterior to anterior regions. This shift along the posteroanterior axis was only present in the SWA frequency range and remained stable across the night. Changes in the topography of SWA during sleep parallel neuroimaging study findings indicating cortical maturation starts early in posterior areas and spreads rostrally over the frontal cortex. Thus, SWA might reflect the underlying processes of cortical maturation. In the future, sleep SWA assessments may be used as a clinical tool to detect aberrations in cortical maturation.


Crystal phase competition by addition of a second metal cation in solid solution metal-organic frameworks.
Herein we report a synthetic study focused on the preparation of solid-solution metal-organic frameworks, MOFs, with the use of two kinds of linkers. In particular, we have explored the system composed by zinc, cobalt, 1,2,4-triazole and 4,4′-hexafluoroisopropylidenebisbenzoic acid (H2hfipbb). During this study, four new MOFs have been isolated, denoted TMPF-88 [M3(hfipbb)2(triazole)2(H2O)], TMPF-90 [M2(triazole)3(OCH2CH3)], TMPF-91 [M2(hfipbb)(triazole)2(H2O)] and TMPF-95 [M5(hfipbb)4(triazole)2(H2O)] (TMPF = transition metal polymeric framework, M = Zn, Co, or mixture of them). The study demonstrates that the addition of a second metal element during the MOF synthesis has a major effect in the formation of new phases, even at very high Zn/Co metal ratios. Furthermore, we show that during the MOF formation reaction, there is a competition among different crystal phases, where kinetically favoured phases of various compositions crystallize in short reaction times, precluding the formation of the pure solid-solution phases of other energetically more stable MOFs.


Effects of extracellular calcium and sodium on depolarization-induced automaticity in guinea pig papillary muscle.
Regenerative discharge of action potentials is induced in mammalian papillary muscles by passage of small depolarizing currents. In this paper, the effects of various extracellular calcium and sodium concentrations and of tetrodotoxin on this phenomenon were studied in guinea pig papillary muscles in a sucrose gap chamber. Phase 4 diastolic depolarization was found to be associated with an increase in membrane resistance. The slope of phase 4 depolarization was decreased by reductions in extracellular calcium or sodium concentration. The range of maximum diastolic potentials and the thresholds from which regenerative potentials arose were reduced, especially at the positive limit of potentials, by a reduction in either ion. It was concluded that both calcium and sodium influence diastolic depolarization and participate in the regenerative action potentials of depolarization-induced ventricular automaticity.


Severe maternal psychopathology and infant-mother attachment.
Eighty-two mother-infant dyads, comprising women with psychiatric disorder and individually matched controls, were followed up over the children's 1st year of life. The mothers with mental illness consisted of two subgroups: first, 25 severely mentally ill mothers who had been admitted to a psychiatric unit with their infants; and second, 16 mothers from a community sample meeting research diagnostic criteria for unipolar, nonpsychotic depression. With the exception of six dyads in the in-patient group, observations were made of the mother-infant interaction and the quality of the infant-mother attachment relationship at 12 months. The nature and course of the mothers' illness was also documented. Although few residual symptoms of maternal mental illness were detected at 1 year postpartum, interactional disturbances were evident among the case group dyads. A strong association was revealed between infant-mother attachment quality and maternal diagnosis; a manic episode of illness in the postpartum period was related to security in the attachment relationship, and psychotic or nonpsychotic depression was related to insecurity. Concurrent patterns of mother-infant interaction provided support for this finding.


School Board Policies on Prevention and Management of Anaphylaxis in İstanbul: Where Do We Stand?
Allergic diseases with a potential for anaphylaxis pose a critical public health issue in schools. This study was carried out to identify the current status of prevention and management of anaphylaxis in school children with the main goal of establishing such an action plan. Cross-sectional study. Schools were randomly selected from 11 different regions of Istanbul. A questionnaire was filled out by 2596 teachers/school principals from 232 public schools. A school safety committee was absent in 80% of elementary schools (ES) and 60.8% of preschools (PS). Although some form of health recording system was available in many schools, no such system was available in 24.5% of ESs and 10% of PSs. A specific inquiry for detecting children with food allergies was a routine practice in only 4% of ES and 10% of PS. Approximately 27% of teachers stated that monitoring children in school places was not possible at all times. Eighty four percent stated that no written anaphylaxis treatment protocol was available in their school and only around 2.3% in ES and 3.1% in PS stated that they would perform an epinephrine injection in the event of anaphylaxis. Our survey demonstrated critical gaps in the organization of schools for the management of children at risk of anaphylaxis. Data derived from this study would provide the initiative for legislators to review the current situation of school health policies along with the relevant authorities to establish school anaphylaxis guidelines.