Changing relations between proteins and osmolytes: a choice of nature.
Many studies aimed at advancing our understanding of the mechanisms of protein stabilization that support the survival of organisms under harsh environmental conditions are focused on deciphering the role of osmolytes as additives in the stabilization of protein. The exact interaction of an osmolyte with protein has been a matter of debate for a long time, but a clear unifying statement still cannot be provided regarding the actual behavior of the osmolyte. A literature survey reveals that there exist a large number of scholarly articles as well as elegant reviews that could aid a resolution of some problems of understanding systems comprising osmolytes and proteins. Additionally, there is no doubt from a vast literature survey that osmolytes display stabilizing behavior toward proteins. However, there are also a number of research articles available in the open literature that emphasize the destabilizing effects of osmolytes on protein stability and function. Therefore, a complete acquaintance of each osmolyte with respect to each protein is one of the most challenging tasks in the development of protein formulation and may be still needed in order to reliably administer the correct protein formulations through injection only. The lack of a comprehensive evaluation of a broad range of these osmolytes in protein systems stimulated our interest for the present perspective in this research field. To the best of our knowledge, this perspective delineates the most recent successful advances in the open literature and also on the basis of our research experience and should aid current researchers in the field of protein stabilization to develop new strategies.


Influence of ascorbic acid on iron absorption from an iron-fortified, chocolate-flavored milk drink in Jamaican children.
The influence of ascorbic acid on iron absorption from an iron-fortified, chocolate-flavored milk drink (6.3 mg total Fe per serving) was evaluated with a stable-isotope technique in 20 6-7-y-old Jamaican children. Each child received two test meals labeled with 5.6 mg 57Fe and 3.0 mg 58Fe as ferrous sulfate on 2 consecutive days. Three different doses of ascorbic acid (0, 25, and 50 mg per 25-g serving) were evaluated in two separate studies by using a crossover design. Iron isotope ratios were measured by negative thermal ionization mass spectrometry. In the first study, iron absorption was significantly greater (P < 0.0001) after the addition of 25 mg ascorbic acid: geometric mean iron absorption was 1.6% (range: 0.9-4.2%) and 5.1% (2.2-17.3%) for the test meals containing 0 and 25 mg ascorbic acid, respectively. In the second study, a significant difference (P < 0.05) in iron absorption was observed when the ascorbic acid content was increased from 25 to 50 mg: geometric mean iron absorption was 5.4% (range: 2.7-10.8%) compared with 7.7% (range: 4.7-16.5%), respectively. The chocolate drink contained relatively high amounts of polyphenolic compounds, phytic acid, and calcium, all well-known inhibitors of iron absorption. The low iron absorption without added ascorbic acid shows that chocolate milk is a poor vehicle for iron fortification unless sufficient amounts of an iron-absorption enhancer are added. Regular consumption of iron-fortified chocolate milk drinks containing added ascorbic acid could have a positive effect on iron nutrition in population groups vulnerable to iron deficiency.


Expression of biologically active heterodimeric bovine follicle-stimulating hormone in milk of transgenic mice.
Follicle-stimulating hormone (FSH; follitropin) is a pituitary glycoprotein composed of two post-translationally modified subunits, which must properly assemble to be biologically active. FSH has been difficult to purify and to obtain in quantities sufficient for detailed biochemical studies. We have targeted FSH expression to the mammary gland of transgenic mice by using cDNAs encoding the bovine alpha and FSH beta subunits and a modified rat beta-casein gene-based expression system. Lines of bigenic mice expressing both subunits have been generated either by coinjection of the subunit transgenes or by mating mice that acquired and expressed transgenes encoding an individual subunit. Up to 60 international units (15 micrograms) of biologically active FSH per ml was detected in the milk of the bigenic mice. These lines provide a model system for studying the post-transcriptional mechanisms that effect the expression and secretion of this heterodimeric hormone.


Competing on talent analytics.
Do investments in your employees actually affect workforce performance? Who are your top performers? How can you empower and motivate other employees to excel? Leading-edge companies such as Google, Best Buy, Procter & Gamble, and Sysco use sophisticated data-collection technology and analysis to answer these questions, leveraging a range of analytics to improve the way they attract and retain talent, connect their employee data to business performance, differentiate themselves from competitors, and more. The authors present the six key ways in which companies track, analyze, and use data about their people-ranging from a simple baseline of metrics to monitor the organization's overall health to custom modeling for predicting future head count depending on various "what if" scenarios. They go on to show that companies competing on talent analytics manage data and technology at an enterprise level, support what analytical leaders do, choose realistic targets for analysis, and hire analysts with strong interpersonal skills as well as broad expertise.


The proteomes of transcription factories containing RNA polymerases I, II or III.
Human nuclei contain three RNA polymerases (I, II and III) that transcribe different groups of genes; the active forms of all three are difficult to isolate because they are bound to the substructure. Here we describe a purification approach for isolating active RNA polymerase complexes from mammalian cells. After isolation, we analyzed their protein content by mass spectrometry. Each complex represents part of the core of a transcription factory. For example, the RNA polymerase II complex contains subunits unique to RNA polymerase II plus various transcription factors but shares a number of ribonucleoproteins with the other polymerase complexes; it is also rich in polymerase II transcripts. We also describe a native chromosome conformation capture method to confirm that the complexes remain attached to the same pairs of DNA templates found in vivo.


Less food for thought. Impact of attentional instructions on intrusive thoughts about snack foods.
Intrusive thoughts about food may play a role in unhealthy eating behaviours. Food-related thoughts that capture attention can lead to craving and further intrusive thoughts (Kavanagh, Andrade, & May, 2005). We tested whether diverting attention to mental images or bodily sensations would reduce the incidence of intrusive thoughts about snack foods. In two experiments, participants reported their thoughts in response to probes during three 10min periods. In the Baseline and Post-task period, participants were asked to let their mind wander. In the middle, Experimental, period, participants followed mind wandering (Control), thought diversion, or Thought Suppression instructions. Self-directed or Guided Imagery, Mindfulness-based Body Scanning, and Thought Suppression all reduced the proportion of thoughts about food, compared to Baseline. Following Body Scanning and Thought Suppression, food thoughts returned to Baseline frequencies Post-task, rather than rebounding. There were no effects of the interventions upon craving, although overall, craving and thought frequency were correlated. Thought control tasks may help people to ignore thoughts about food and thereby reduce their temptation to snack.


Global patterns and rates of habitat transitions across the eukaryotic tree of life.
The successful colonization of new habitats has played a fundamental role during the evolution of life. Salinity is one of the strongest barriers for organisms to cross, which has resulted in the evolution of distinct marine and non-marine (including both freshwater and soil) communities. Although microbes represent by far the vast majority of eukaryote diversity, the role of the salt barrier in shaping the diversity across the eukaryotic tree is poorly known. Traditional views suggest rare and ancient marine/non-marine transitions but this view is being challenged by the discovery of several recently transitioned lineages. Here, we investigate habitat evolution across the tree of eukaryotes using a unique set of taxon-rich phylogenies inferred from a combination of long-read and short-read environmental metabarcoding data spanning the ribosomal DNA operon. Our results show that, overall, marine and non-marine microbial communities are phylogenetically distinct but transitions have occurred in both directions in almost all major eukaryotic lineages, with hundreds of transition events detected. Some groups have experienced relatively high rates of transitions, most notably fungi for which crossing the salt barrier has probably been an important aspect of their successful diversification. At the deepest phylogenetic levels, ancestral habitat reconstruction analyses suggest that eukaryotes may have first evolved in non-marine habitats and that the two largest known eukaryotic assemblages (TSAR and Amorphea) arose in different habitats. Overall, our findings indicate that the salt barrier has played an important role during eukaryote evolution and provide a global perspective on habitat transitions in this domain of life.


Dielectrophoresis assisted concentration of micro-particles and their rapid quantitation based on optical means.
The detection and counting of micro particles having sizes comparable to biological entities can provide a tremendous impetus to rapid diagnostics and clinical applications. MEMS technology has already been used in capture and detection of such micron size entities in miniscule concentrations. For this purpose a concentration step is normally added prior to the detection process. A variety of methodologies are used for quantization of such micron size particles/entities including change in permittivity, medium impedance, magnetic permeability and other means. Although optical studies have been extensively performed prior to this, it has not been used for quantization of the micro particles. We have designed, developed and characterized a MEMS counter which captures micron size fluorescent beads using delectrophoresis (DEP) and monitors their accumulation in a 12 μm x 230 μm size channel and monitors this accumulation as growth of overall fluorescence. The field is generated by a set of finely placed interdigitated microelectrodes. As we apply an alternating voltage at 10 V(pp) for a range of different frequencies we are able to capture the flowing beads and concentrate them by several orders of magnitude. This is also followed by their quantification in terms of growing fluorescence signal. For quantitating the fluorescence values a CCD (charge couple device) module fitted over an inverted fluorescence microscope is used that visualizes the whole capture process and a Labview based image acquisition software simultaneously calculates the signal intensity over these frames and arranges it temporally. Our work will have tremendous utility in developing a rapid bacterial counting procedure and will be a valuable tool in microbiological laboratories.


Precise Haptic Device Co-Location for Visuo-Haptic Augmented Reality.
Visuo-haptic augmented reality systems enable users to see and touch digital information that is embedded in the real world. PHANToM haptic devices are often employed to provide haptic feedback. Precise co-location of computer-generated graphics and the haptic stylus is necessary to provide a realistic user experience. Previous work has focused on calibration procedures that compensate the non-linear position error caused by inaccuracies in the joint angle sensors. In this article we present a more complete procedure that additionally compensates for errors in the gimbal sensors and improves position calibration. The proposed procedure further includes software-based temporal alignment of sensor data and a method for the estimation of a reference for position calibration, resulting in increased robustness against haptic device initialization and external tracker noise. We designed our procedure to require minimal user input to maximize usability. We conducted an extensive evaluation with two different PHANToMs, two different optical trackers, and a mechanical tracker. Compared to state-of-the-art calibration procedures, our approach significantly improves the co-location of the haptic stylus. This results in higher fidelity visual and haptic augmentations, which are crucial for fine-motor tasks in areas such as medical training simulators, assembly planning tools, or rapid prototyping applications.


Inhibition of PA endonuclease activity of influenza virus RNA polymerase by Kampo medicines.
To find a novel influenza inhibitor targeting the endonuclease activity of influenza A virus polymerase acidic protein (PA), which is essential for the acquisition of primers for viral mRNA transcription, seven Kampo extracts were tested in vitro for their ability to inhibit endonuclease activity of the recombinant PA protein that was expressed and purified from Escherichia coli. The Kampo medicines Kakkonto, Shosaikoto, Saikokeishito, Keishito, Maobushisaishinto, and Maoto, but not Chikujountanto, inhibited PA endonuclease activity in a dose-dependent manner. Our results indicate that Kampo medicines are good sources providing a structural lead for optimization of an influenza endonuclease inhibitor.


The effect of weight loss on lameness in obese dogs with osteoarthritis.
This paper describes the effect of weight loss on lameness in obese dogs with osteoarthritis (OA). Fourteen obese client-owned dogs with clinical and radiographic signs of OA participated in an open prospective clinical trial. After a screening visit and a visit for collection of baseline data, the dogs were fed a restricted-calorie diet over a study period of 16 weeks that incorporated six follow-up visits. At each visit, body weight and pelvic circumference were measured and severity of lameness was assessed using a numeric rating scale (NRS), a visual analogue scale (VAS) and kinetic gait analysis. This is the first study to assess both subjectively and objectively, the effect of weight loss alone on lameness in obese dogs with OA. The results indicate that body weight reduction causes a significant decrease in lameness from a weight loss of 6.10% onwards. Kinetic gait analysis supported the results from a body weight reduction of 8.85% onwards. These results confirm that weight loss should be presented as an important treatment modality to owners of obese dogs with OA and that noticeable improvement may be seen after modest weight loss in the region of 6.10 - 8.85% body weight.


Towards rule-based metabolic databases: a requirement analysis based on KEGG.
Knowledge of metabolic processes is collected in easily accessable online databases which are increasing rapidly in content and detail. Using these databases for the automatic construction of metabolic network models requires high accuracy and consistency. In this bipartite study we evaluate current accuracy and consistency problems using the KEGG database as a prominent example and propose design principles for dealing with such problems. In the first half, we present our computational approach for classifying inconsistencies and provide an overview of the classes of inconsistencies we identified. We detected inconsistencies both for database entries referring to substances and entries referring to reactions. In the second part, we present strategies to deal with the detected problem classes. We especially propose a rule-based database approach which allows for the inclusion of parameterised molecular species and parameterised reactions. Detailed case-studies and a comparison of explicit networks from KEGG with their anticipated rule-based representation underline the applicability and scalability of this approach.


Environmental tobacco smoke exposure and health effects in children: results from the 1991 National Health Interview Survey.
To determine the effect of environmental tobacco smoke exposure on the health of children in the United States. Cross-sectional study of children who participated in the 1991 National Health Interview Survey. 17448 children residing in the United States. Rates of respiratory illnesses and all illnesses, and the morbidity due to these illnesses, in children exposed to environmental tobacco smoke in the home daily compared with those in children not exposed in the home. Our analyses controlled for age, socioeconomic status, race, family size, sex, season, and region of the country. Children who were exposed to environmental tobacco smoke had a higher incidence of acute respiratory illnesses (relative risk (RR) = 1.10, 95% confidence interval (CI) 0.95 to 1.26) and all chronic respiratory diseases (RR = 1.28, 95% CI 0.99 to 1.65) than children who were not exposed, although both CIs included unity, and chance cannot be ruled out as being responsible for these findings. Children who were exposed to environmental tobacco smoke had, on average, 1.87 more days of restricted activity (95% CI 0.20 to 3.54), 1.06 more days of bed confinement (95% CI 0.20 to 1.92), and 1.45 more days of school absence (95% CI 0.40 to 2.50) per year than children who were not exposed. Environmental tobacco smoke exposure in the home, which is completely preventable, is an important predictor of increased morbidity in children.


Comparison of the calcaneal pitch angle and modified projection area per length squared method for medial longitudinal arch evaluation of the foot.
To compare the calcaneal pitch angle (CPA) values measured on direct lateral radiographs of feet, and the modified projection area per length squared (PAL), which was calculated as a new method for the evaluation of the medial longitudinal arch (MLA) of the foot. Direct lateral radiographs of patients who had weightbearing feet radiographies for any reason except trauma were retrospectively obtained from the archives. Direct lateral radiographs of the feet were printed and a transparent sheet was placed on it. A straight line was drawn between the most plantar process of the calcaneus and the head of the first metatarsal bone for the calculation of the PAL of the MLA. Two semilunar arcs were drawn upon this straight line. PAL1 and PAL2 were estimated using a point-counting technique. The CPA, lateral talo-calcaneal angles (LTCA), and talo-first metatarsal angles (TFMA) were measured. The correlations between PAL1, PAL2 of right and left feet and CPA, LTCA, and TFMA were explored. Fifty patients (27 females, 23 males) with a mean age of 40.12 (4-78) years were evaluated. Significant correlations were detected between PAL1, PAL2 and CPA, and TFMA for both right and left feet (p<0.05). A significant correlation was detected between the modified PAL method as a new technique and the standard CPA method for MLA evaluation. The PAL method is suggested as a simple and practical method for MLA evaluation.


Resequencing Reveals Different Domestication Rate for BADH1 and BADH2 in Rice (Oryza sativa).
BADH1 and BADH2 are two homologous genes, encoding betaine aldehyde dehydrogenase in rice. In the present study, we scanned BADHs sequences of 295 rice cultivars, and 10 wild rice accessions to determine the polymorphisms, gene functions and domestication of these two genes. A total of 16 alleles for BADH1 and 10 alleles for BADH2 were detected in transcribed region of cultivars and wild species. Association study showed that BADH1 has significant correlation with salt tolerance in rice during germination stage, the SNP (T/A) in exon 4 is highly correlated with salt tolerance index (STI) (P<10(-4)). While, BADH2 was only responsible for rice fragrance, of which two BADH2 alleles (8 bp deletion in exon 7 and C/T SNP in exon 13) explain 97% of aroma variation in our germplasm. Theses indicate that there are no overlapping functions between the two homologous genes. In addition, a large LD block was detected in BADH2 region, however, there was no large LD blocks in a 4-Mb region of BADH1. We found that BADH2 region only showed significant bias in Tajima's D value from the balance. Extended haplotype homozygosity study revealed fragrant accessions had a large LD block that extended around the mutation site (8 bp deletion in exon 7) of BADH2, while both of the BADH1 alleles (T/A in exon 4) did not show large extended LD block. All these results suggested that BADH2 was domesticated during rice evolution, while BADH1 was not selected by human beings.


The anti-inflammatory and antioxidant effects of melatonin on LPS-stimulated bovine mammary epithelial cells.
Mastitis is the most prevalent disease in dairy cattle worldwide and not only causes huge economic losses in the dairy industry but also threatens public health. To evaluate the therapeutic potential of melatonin in mastitis, we examined the ability of melatonin to protect bovine mammary epithelial cells (bMECs) from the harmful effects of lipopolysaccharide (LPS). We found that melatonin inhibited the LPS-binding protein-CD14-TLR4 signaling pathway in bMECs, which had opposing effects on pro-inflammatory and anti-inflammatory mediators. Melatonin decreased LPS-induced expression of pro-inflammatory cytokines, chemokines, and positive acute-phase proteins (APPs), including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, granulocyte-monocyte colony-stimulating factor, chemokine CC motif ligand (CCL)2, CCL5, serum amyloid A, haptoglobin, C-reactive protein, ceruloplasmin, and α-1 antitrypsin, and increased expression of the anti-inflammatory cytokine IL-1Ra and the negative APP fibrinogen. In addition, melatonin increased dityrosine levels but suppressed nitrite levels by upregulating the expression of Nrf2 and heme oxygenase-1 in the Nrf2 antioxidant defense pathway. Finally, melatonin administration increased the viability of LPS-stimulated bMECs. These results suggest that melatonin protects bMECs from LPS-induced inflammatory and oxidant stress damage and provide evidence that melatonin might have therapeutic utility in mastitis.


A search for thresholds and other nonlinearities in the relationship between hexavalent chromium and lung cancer.
The exposure-response relationship for airborne hexavalent chromium exposure and lung cancer mortality is well described by a linear relative rate model. However, categorical analyses have been interpreted to suggest the presence of a threshold. This study investigates nonlinear features of the exposure response in a cohort of 2,357 chemical workers with 122 lung cancer deaths. In Poisson regression, a simple model representing a two-step carcinogenesis process was evaluated. In a one-stage context, fractional polynomials were investigated. Cumulative exposure dose metrics were examined corresponding to cumulative exposure thresholds, exposure intensity (concentration) thresholds, dose-rate effects, and declining burden of accumulated effect on future risk. A simple two-stage model of carcinogenesis provided no improvement in fit. The best-fitting one-stage models used simple cumulative exposure with no threshold for exposure intensity and had sufficient power to rule out thresholds as large as 30 microg/m3 CrO3 (16 microg/m3 as Cr+6) (one-sided 95% confidence limit, likelihood ratio test). Slightly better-fitting models were observed with cumulative exposure thresholds of 0.03 and 0.5 mg-yr/m3 (as CrO3) with and without an exposure-race interaction term, respectively. With the best model, cumulative exposure thresholds as large as 0.4 mg-yr/m3 CrO3 were excluded (two-sided upper 95% confidence limit, likelihood ratio test). A small departure from dose-rate linearity was observed, corresponding to (intensity)0.8 but was not statistically significant. Models in which risk-inducing damage burdens declined over time, based on half-lives ranging from 0.1 to 40 years, fit less well than assuming a constant burden. A half-life of 8 years or less was excluded (one-sided 95% confidence limit). Examination of nonlinear features of the hexavalent chromium-lung cancer exposure response in a population used in a recent risk assessment supports using the traditional (lagged) cumulative exposure paradigm: no intensity (concentration) threshold, linearity in intensity, and constant increment in risk following exposure.


Effect of Secukinumab on the Different GRAPPA-OMERACT Core Domains in Psoriatic Arthritis: A Pooled Analysis of 2049 Patients.
To compare the efficacy of secukinumab with that of placebo across the updated Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and Outcome Measures in Rheumatology (GRAPPA-OMERACT) individual psoriatic arthritis (PsA) core domains using pooled data from 4 phase III PsA studies and 1 phase III ankylosing spondylitis (AS) study. Data were pooled from 2049 patients with PsA participating in 4 on-label phase III PsA studies (FUTURE 2-5), and the efficacy of each GRAPPA-OMERACT PsA core domain (musculoskeletal disease activity, skin disease activity, pain, patient's global assessment, physical function, health-related quality of life, fatigue, and systemic inflammation) was assessed using multiple measures and definitions specific to each domain. The MEASURE 2 study, a phase III clinical trial in patients with AS, was used to assess improvement in spine symptoms at Week 16. Treatment with secukinumab demonstrated robust and consistent efficacy across all GRAPPA-OMERACT PsA core domains, with secukinumab 300 mg showing the greatest response rates across most PsA core domains compared with placebo at Week 16. Notably, among patients treated with secukinumab 300 mg, 34.3% and 19.5% achieved complete resolution of swollen and tender joint counts, respectively; 53.2% and 61.5% achieved complete resolution of enthesitis and dactylitis, respectively; and 33.2% achieved 100% improvement in Psoriasis Area and Severity Index (all p < 0.05 vs placebo); similar improvements were shown for all other core domains. This analysis suggests that secukinumab can benefit people with PsA across the clinical phenotypic spectrum commonly encountered in this disease.


Acculturation among immigrant nurses in Israel and the United States of America.
Former Soviet Union (FSU) nurses in Israel and Filipino registered nurses (RNs) in the United States of America (USA) play significant roles in the delivery of health-care services in their host countries. However, little is known about how they acculturate in a different culture. The purposes of this study were to determine the levels of and the difference in acculturation of FSU nurses in Israel and Filipino RNs in the USA. Acculturation was assessed using A Short Acculturation Scale for Filipino Americans and t-test was conducted to determine the difference in acculturation between these two groups of immigrant nurses. Results revealed that Filipino RNs have an acculturation level that leaned towards their host culture while FSU nurses have an acculturation level that was closer to their original culture than the Israeli culture and that there was a significant difference in acculturation between these two groups of immigrant nurses. Differences in acculturation between two predominant groups of immigrant nurses in Israel and the USA exist. Understanding the differences and the factors that affect their integration into their host cultures could be used to develop strategies to assist Filipino and FSU immigrant nurses achieve positive personal and work-related outcomes.


Potent Inhibitor of Drug-Resistant HIV-1 Strains Identified from the Medicinal Plant Justicia gendarussa.
Justicia gendarussa, a medicinal plant collected in Vietnam, was identified as a potent anti-HIV-1 active lead from the evaluation of over 4500 plant extracts. Bioassay-guided separation of the extracts of the stems and roots of this plant led to the isolation of an anti-HIV arylnaphthalene lignan (ANL) glycoside, patentiflorin A (1). Evaluation of the compound against both the M- and T-tropic HIV-1 isolates showed it to possess a significantly higher inhibition effect than the clinically used anti-HIV drug AZT. Patentiflorin A and two congeners were synthesized, de novo, as an efficient strategy for resupply as well as for further structural modification of the anti-HIV ANL glycosides in the search for drug leads. Subsequently, it was determined that the presence of a quinovopyranosyloxy group in the structure is likely essential to retain the high degree of anti-HIV activity of this type of compounds. Patentiflorin A was further investigated against the HIV-1 gene expression of the R/U5 and U5/gag transcripts, and the data showed that the compound acts as a potential inhibitor of HIV-1 reverse transcription. Importantly, the compound displayed potent inhibitory activity against drug-resistant HIV-1 isolates of both the nucleotide analogue (AZT) and non-nucleotide analogue (nevaripine). Thus, the ANL glycosides have the potential to be developed as novel anti-HIV drugs.


Introduction of a new NHS electric-powered indoor/outdoor chair (EPIOC) service: benefits, risks and implications for prescribers.
To determine problems associated with electric-powered indoor/outdoor wheelchairs (EPIOCs) and the benefits perceived by their users. Hospital-based cohort study of all patients referred over a 19-month period. Regional Wheelchair Service for North West London serving nine district wheelchair services. Of the 174 subjects referred, 10 withdrew their application or were found to be unsuitable at screening, 164 were assessed and 124 were prescribed chairs. One hundred and thirteen subjects were interviewed by telephone four months after provision of the chair. Demographic and diagnostic data; current chair usage; self-reported accidents and component faults were compared with those recorded in the unit records; new activities embarked on since delivery; and benefits reported for main carers. Seventeen 'mishaps' were reported by 15 users including tipping from chairs (6) and falls during transfers (3). Three probably reflected mechanical failure. Component failure was found in 39% of EPIOCs, mostly affecting control boxes (22), frames (10) and footrests (10). New activities were undertaken by 56 (50%) users, usually shopping and visits to friends/family. Eighty-five per cent of users felt that the chairs made life easier for their informal carers through increased independence, reducing transfers and reduced need for 'pushing'. The component failures and self-reported accidents (some potentially dangerous) have implications for the NHS, manufacturers, prescribers and users. EPIOCs enhance the independence of severely physically disabled individuals in the community and assist carers by lessening dependence and enhancing social interaction. This study demonstrated the need for follow-up of EPIOC users and chairs.


Maternal height, childhood growth and risk of hip fracture in later life: a longitudinal study.
Although measures to enhance bone mineralization during childhood and adolescence are widely incorporated into preventive programmes against osteoporotic fracture, there are no published data directly linking growth rates in childhood with the risk of later hip fracture. We addressed this issue in a unique Finnish cohort in whom birth and childhood growth data were linked to later hospital discharge records. This permitted follow-up of 3639 men and 3447 women who were born in Helsinki University Central Hospital between 1924 and 1933, who went to school in Helsinki and still lived in Finland in 1971. Body size at birth was recorded and an average of 10 measurements were obtained of height and weight throughout childhood. We identified 112 subjects (55 men and 57 women) who sustained a hip fracture during 165 404 person-years of follow-up. After adjustment for age and sex in a proportional hazards model, we identified two major determinants of hip fracture risk: tall maternal height (p < 0.001) and a low rate of childhood growth (height, p = 0.006; weight, p = 0.01). The hazard ratio for hip fracture was 2.1 (95% CI 1.2-3.5) among men and women born to mothers taller than 1.61 m, when compared with those whose mothers were shorter than 1.54 m. The ratio was 1.9 (95% CI 1.1-3.2) among those whose rate of childhood height gain was below the lowest quartile for the cohort, compared with those whose growth rate was above the highest quartile. The effects of maternal height and childhood growth rate were statistically independent of each other, and remained after adjusting for socioeconomic status. The patterns of childhood growth that predicted future hip fracture differed between boys and girls. In boys, there was a constant deficit in height and weight between ages 7 and 15 years among those later sustaining fractures; in girls, there was a progressively increasing deficit in weight but a delayed height gain among those later sustaining fractures. This epidemiologic study provides the first direct evidence that a low rate of childhood growth is a risk factor for later hip fracture. Whether reduced growth rate is a consequence of childhood lifestyle, genetic background or intrauterine hormonal programming, the data support measures to optimize childhood growth as part of preventive strategies against osteoporotic fracture in future generations.


The detection of substructures within proteoglycan molecules. Electron-microscopic immuno-localization with the use of Protein A-gold.
Proteoglycan monomers from pig laryngeal cartilage were examined by electron microscopy with benzyldimethylalkylammonium chloride as the spreading agent. The proteoglycans appeared as extended molecules with a beaded structure, representing the chondroitin sulphate chains collapsed around the protein core. Often a fine filamentous tail was present at one end. Substructures within proteoglycan molecules were localized by incubation with specific antibodies followed by Protein A-gold (diameter 4 nm). After the use of an anti-(binding region) serum the Protein A-gold (typically one to three particles) bound at the extreme end of the filamentous region. A small proportion of the labelled molecules (10-15%) showed the presence of gold particles at both ends. A monoclonal antibody specific for a keratan sulphate epitope (MZ15) localized a keratan sulphate-rich region at one end of the proteoglycan, but gold particles were not observed along the extended part of the protein core. This distribution was not changed by prior chondroitin AC lyase digestion of the proteoglycan. Localization with a different monoclonal antibody to keratan sulphate (5-D-4) caused a change in the spreading behaviour of a proportion (approx. 20%) of the proteoglycan monomers that lost their beaded structure and appeared with the chondroitin sulphate chains projecting from the protein core. In these molecules the Protein A-gold localized antibody (5-D-4) along the length of the protein core whereas in those molecules with a beaded appearance it labelled only at one end. Labelling with either of the monoclonal antibodies was specific, as it was inhibited by exogenously added keratan sulphate. The differential localization achieved may reflect structural differences within the proteoglycan population involving keratan sulphate and the protein core to which it is attached. The results showed that by this technique substructures within proteoglycan molecules can be identified by Protein A-gold labelling after the use of specific monoclonal or polyclonal antibodies.


Imaging of prolonged BOLD response in the somatosensory cortex of the rat.
Blood oxygenation level-dependent (BOLD) functional MRI is a widely employed methodology in experimental and clinical neuroscience, although its nature is not fully understood. To gain insights into BOLD mechanisms and take advantage of the new functional methods, it is of interest to investigate prolonged paradigms of activation suitable for long experimental protocols and to observe any long-term modifications induced by these functional challenges. While different types of sustained stimulation paradigm have been explored in human studies, the BOLD response is typically limited to a few minutes in animal models, due to fatigue, anesthesia effects and physiological instability. In the present study, the rat forepaw was electrically stimulated for 2 h, which resulted in a prolonged and localized cortical BOLD response over that period. The stimulation paradigm, including an inter-stimulus interval (ISI) of 10 s, that is 25% of the total time, was applied at constant or variable frequency over 2 h. The steady-state level of the BOLD response was reached after 15-20 min of stimulation and was maintained until the end of the stimulation. On average, no substantial loss in activated volume was observed at the end of the stimulation, but less variability in the fraction of remaining activated volume and higher steady-state BOLD amplitude were observed when stimulation frequency was varied between 2 and 3 Hz every 5 min. We conclude that the combination of ISI and variable stimulus frequency reproducibly results in robust, prolonged and localized BOLD activation.


MRI bone marrow oedema precedes lumbar bone stress injury diagnosis in junior elite cricket fast bowlers.
Lumbar bone stress injury ('bone stress injury') is common in junior fast bowlers. The repetitive loading of cricket fast bowling may cause bone marrow oedema (BMO), detectable on MRI, before the bowler suffers from symptomatic bone stress injury. We investigated the temporal relationship between BMO, bone stress injury, along with bowling workload correlates, in elite junior fast bowlers throughout a cricket season. 65 junior fast bowlers were prospectively monitored for one 8-month cricket season. For research purposes, participants had up to six MRI scans at set times in the season; findings were withheld from them and their clinicians. Standard practices for bowling workload monitoring and injury diagnosis were followed. 15 (23%) participants developed bone stress injury during the study. All 15 of these participants had BMO detected on at least one of the preceding MRI scans, including the scan immediately prior to diagnosis. The risk of BMO progressing to bone stress injury during the season was greatest for participants with BMO present 2 weeks prior to the national championship tournament (period of high load) (RR=18.9, OR=44.8). Both bone stress injury and BMO were associated with bowling a higher percentage of days in training and having a shorter bowling break during the season. The number of balls bowled and acute-to-chronic workload were not associated with imaging abnormalities or injury. The presence of BMO on MRI in asymptomatic junior cricket fast bowlers confers a very high risk for bone stress injury. The risk may be managed by MRI screening and monitoring bowling frequency.


Association between ratio indexes of body composition phenotypes and metabolic risk in Italian adults.
The ratio between fat mass (FM) and fat-free mass (FFM) has been used to discriminate individual differences in body composition and improve prediction of metabolic risk. Here, we evaluated whether the use of a visceral adipose tissue-to-fat-free mass index (VAT:FFMI) ratio was a better predictor of metabolic risk than a fat mass index to fat-free mass index (FMI:FFMI) ratio. This is a cross-sectional study including 3441 adult participants (age range 18-81; men/women: 977/2464). FM and FFM were measured by bioelectrical impedance analysis and VAT by ultrasonography. A continuous metabolic risk Z score and harmonised international criteria were used to define cumulative metabolic risk and metabolic syndrome (MetS), respectively. Multivariate logistic and linear regression models were used to test associations between body composition indexes and metabolic risk. In unadjusted models, VAT:FFMI was a better predictor of MetS (OR 8.03, 95%CI 6.69-9.65) compared to FMI:FFMI (OR 2.91, 95%CI 2.45-3.46). However, the strength of association of VAT:FFMI and FMI:FFMI became comparable when models were adjusted for age, gender, clinical and sociodemographic factors (OR 4.06, 95%CI 3.31-4.97; OR 4.25, 95%CI 3.42-5.27, respectively). A similar pattern was observed for the association of the two indexes with the metabolic risk Z score (VAT:FFMI: unadjusted b = 0.69 ± 0.03, adjusted b = 0.36 ± 0.03; FMI:FFMI: unadjusted b = 0.28 ± 0.028, adjusted b = 0.38 ± 0.02). Our results suggest that there is no real advantage in using either VAT:FFMI or FMI:FFMI ratios as a predictor of metabolic risk in adults. However, these results warrant confirmation in longitudinal studies.


Comparison of colorimetric assays with quantitative amino acid analysis for protein quantification of Generalized Modules for Membrane Antigens (GMMA).
Genetically induced outer membrane particles from Gram-negative bacteria, called Generalized Modules for Membrane Antigens (GMMA), are being investigated as vaccines. Rapid methods are required for estimating the protein content for in-process assays during production. Since GMMA are complex biological structures containing lipid and polysaccharide as well as protein, protein determinations are not necessarily straightforward. We compared protein quantification by Bradford, Lowry, and Non-Interfering assays using bovine serum albumin (BSA) as standard with quantitative amino acid (AA) analysis, the most accurate currently available method for protein quantification. The Lowry assay has the lowest inter- and intra-assay variation and gives the best linearity between protein amount and absorbance. In all three assays, the color yield (optical density per mass of protein) of GMMA was markedly different from that of BSA with a ratio of approximately 4 for the Bradford assay, and highly variable between different GMMA; and approximately 0.7 for the Lowry and Non-Interfering assays, highlighting the need for calibrating the standard used in the colorimetric assay against GMMA quantified by AA analysis. In terms of a combination of ease, reproducibility, and proportionality of protein measurement, and comparability between samples, the Lowry assay was superior to Bradford and Non-Interfering assays for GMMA quantification.


Notum deacylates Wnt proteins to suppress signalling activity.
Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase.


TOPAS: an innovative proton Monte Carlo platform for research and clinical applications.
While Monte Carlo particle transport has proven useful in many areas (treatment head design, dose calculation, shielding design, and imaging studies) and has been particularly important for proton therapy (due to the conformal dose distributions and a finite beam range in the patient), the available general purpose Monte Carlo codes in proton therapy have been overly complex for most clinical medical physicists. The learning process has large costs not only in time but also in reliability. To address this issue, we developed an innovative proton Monte Carlo platform and tested the tool in a variety of proton therapy applications. Our approach was to take one of the already-established general purpose Monte Carlo codes and wrap and extend it to create a specialized user-friendly tool for proton therapy. The resulting tool, TOol for PArticle Simulation (TOPAS), should make Monte Carlo simulation more readily available for research and clinical physicists. TOPAS can model a passive scattering or scanning beam treatment head, model a patient geometry based on computed tomography (CT) images, score dose, fluence, etc., save and restart a phase space, provides advanced graphics, and is fully four-dimensional (4D) to handle variations in beam delivery and patient geometry during treatment. A custom-designed TOPAS parameter control system was placed at the heart of the code to meet requirements for ease of use, reliability, and repeatability without sacrificing flexibility. We built and tested the TOPAS code. We have shown that the TOPAS parameter system provides easy yet flexible control over all key simulation areas such as geometry setup, particle source setup, scoring setup, etc. Through design consistency, we have insured that user experience gained in configuring one component, scorer or filter applies equally well to configuring any other component, scorer or filter. We have incorporated key lessons from safety management, proactively removing possible sources of user error such as line-ordering mistakes. We have modeled proton therapy treatment examples including the UCSF eye treatment head, the MGH stereotactic alignment in radiosurgery treatment head and the MGH gantry treatment heads in passive scattering and scanning modes, and we have demonstrated dose calculation based on patient-specific CT data. Initial validation results show agreement with measured data and demonstrate the capabilities of TOPAS in simulating beam delivery in 3D and 4D. We have demonstrated TOPAS accuracy and usability in a variety of proton therapy setups. As we are preparing to make this tool freely available for researchers in medical physics, we anticipate widespread use of this tool in the growing proton therapy community.


Cerebrovascular autoregulation in critically ill patients during continuous hemodialysis.
In chronic renal failure, intermittent hemodialysis decreases cerebral blood flow velocity (CBFV); however, in critically ill patients with acute renal failure, the effect of continuous venovenous hemodialysis (CVVHD) on CBFV and cerebrovascular autoregulation (AR) is unknown. Therefore, a study was undertaken to investigate the potential effect of CVVHD on CBFV and AR in patients with acute renal failure. This cohort study investigated 20 patients with acute renal failure who required CVVHD. In these patients, the CBFV and index of AR (Mx) were measured using transcranial Doppler before and during CVVHD. The median Mx values at baseline were 0.33 [interquartile range (IQR): 0.02-0.55], and during CVVHD, they were 0.20 [0.07-0.40]. The differences in Mx (CVVHD--baseline) was (median [IQR]) -0.015 [-0.19-0.05], 95% confidence interval (CI) -0.16 to 0.05. The Mx was > 0.3 in 11/20 patients at baseline measurement. Six of these patients recovered to Mx < 0.3 during CVVHD. The CBFV was (median [IQR]) 47 [36-59] cm · sec(-1) at baseline and 49 [36-66] cm · sec(-1) during CVVHD. The difference of CBFV was 0.0 [-4 - 2.7], 95% CI -2.5 to 4.2. Compared with patients with intermittent hemodialysis, CVVHD did not influence CBFV and AR in critically ill patients with acute renal failure, possibly due to lower extracorporeal blood flow, slower change of plasma osmolarity, and a lower fluid extraction rate. In a subgroup of patients with sepsis, the AR was impaired at baseline in more than half of the patients, and this was reversed during CVVHD. The trial was registered at ClinicalTrials.gov ID: NCT01376531.


A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.
Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations. Patients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model. A 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1) 70 kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1) h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl(-1) h. bringing expected exposures in children closer to those predicted for adults. The popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.


The association between neighbourhood socio-economic status and the onset of chronic widespread pain: results from the EPIFUND study.
Cross-sectional studies have reported an inverse relationship between socio-economic status and the prevalence of chronic widespread pain (CWP). However, the extent to which this relationship is explained by psychological factors is unknown. The aim of this study was to examine the hypothesis that socio-economic status predicts the onset of CWP but that this relationship would be explained by psychological factors. Subjects from three diverse socio-economic areas were recruited into a population-based prospective survey of pain. Subjects completed a questionnaire at baseline that assessed pain status and psychological factors and occupation. Fifteen months later subjects completed a follow-up questionnaire which assessed pain status. A total of 3489 subjects were free of CWP at baseline and eligible for follow-up, of whom 2782 (79.7%) participated. Of those, 281 (10%) subjects were classified as having new CWP. Logistic regression analysis revealed that compared to subjects from the most affluent socio-economic area, those from the moderate and least affluent areas were respectively, 1.47 (95% CI: 1.08-2.01) and 1.35 (95% CI: 1.00-1.82) times more likely to have new CWP. However, in a stepwise multivariate logistic regression analysis, controlling for psychological factors, the relationship between new onset CWP and socio-economic status was no longer evident. This study has demonstrated that socio-economic status is related to new onset CWP, but the association is explained by psychological factors. Understanding the factors underlying the association between socio-economic status and pain should help to design intervention strategies which may reduce the burden of chronic pain in identified high risk population groups.


Cocktails of paste coatings for performance enhancement of CuInGaS(2) thin-film solar cells.
To fabricate low-cost and printable wide-bandgap CuInxGa1-xS2 (CIGS) thin-film solar cells, a method based on a precursor solution was developed. In particular, under this method, multiple coatings with two pastes with different properties (e.g., viscosity) because of the different binder materials added were applied. Paste A could form a thin, dense layer enabling a high-efficiency solar cell but required several coating and drying cycles for the desired film thickness. On the other hand, paste B could easily form one-micrometer-thick films by means of a one-time spin-coating process but the porous microstructure limited the solar cell performance. Three different configurations of the CIGS films (A + B, B + A, and A + B + A) were realized by multiple coatings with the two pastes to find the optimal stacking configuration for a combination of the advantages of each paste. Solar cell devices using these films showed a notable difference in their photovoltaic characteristics. The bottom dense layer increased the minority carrier diffusion length and enhanced the short-circuit current. The top dense layer could suppress interface recombination but exhibited a low optical absorption, thereby decreasing the photocurrent. As a result, the A + B configuration could be suggested as a desirable simple stacking structure. The solar cell with A + B coating showed a highly improved efficiency (4.66%) compared to the cell with a film prepared by paste B only (2.90%), achieved by simple insertion of a single thin (200 nm), dense layer between the Mo back contact and a thick porous CIGS layer.


Focal liver lesions: pattern-based classification scheme for enhancement at arterial phase CT.
To present our early experience with a classification scheme for categorizing focal liver lesions on the basis of the enhancement patterns that they exhibit in the arterial phase of computed tomography (CT) and to determine whether particular enhancement patterns suggest particular diagnoses. The authors reviewed arterial phase CT images in 100 consecutive patients with focal liver lesions, excluding simple cysts. The enhancement pattern of the dominant or representative lesion in each patient was classified into one of five categories-homogeneous, abnormal internal vessels or variegated, peripheral puddles, complete ring, or incomplete ring-by three radiologists blinded to the proved diagnosis. Lesions without enhancement were recorded separately. Agreement was reached by consensus in all cases. Standards of reference included findings at histologic examination, correlative imaging, or clinical and imaging follow-up. Ninety-two percent of the 100 lesions demonstrated arterial phase enhancement. Patterns associated with positive predictive values of 82% or greater and specificity of 80% or greater included abnormal internal vessels or variegated (hepatocellular carcinoma), peripheral puddles (hemangioma), and complete ring (metastasis). The appearance of hepatic lesions in the arterial phase of enhancement has potential use in the determination of specific diagnoses. The classification scheme used in this study may be a useful tool for the interpretation of arterial phase CT studies.


Binding-activated localization microscopy of DNA structures.
Many nucleic acid stains show a strong fluorescence enhancement upon binding to double-stranded DNA. Here we exploit this property to perform superresolution microscopy based on the localization of individual binding events. The dynamic labeling scheme and the optimization of fluorophore brightness yielded a resolution of ∼14 nm (fwhm) and a spatial sampling of 1/nm. We illustrate our approach with two different DNA-binding dyes and apply it to visualize the organization of the bacterial chromosome in fixed Escherichia coli cells. In general, the principle of binding-activated localization microscopy (BALM) can be extended to other dyes and targets such as protein structures.


Optimising subjective anterior eye grading precision.
To establish the optimum grading increment which ensured parity between practitioners while maximising clinical precision. Second year optometry students (n = 127, 19.5 ± 1.4 years, 55 % female) and qualified eye care practitioners (n = 61, 40.2 ± 14.8 years, 52 % female) had 30 s to grade each of bulbar, limbal and palpebral hyperaemia of the upper lid of 4 patients imaged live with a digital slit lamp under 16× magnification, diffuse illumination, with the image projected on a screen. The patients were presented in a randomised sequence 3 times in succession, during which the graders used the Efron printed grading scale once to the nearest 0.1 increment, once to nearest 0.5 increment and once to the nearest integer grade in a randomised order. Graders were masked to their previous responses. For most grading conditions less than 20 % of clinicians showed a ≤0.1 difference in grade from the mean. In contrast, more than 50 % of the student graders and 40 % of experienced graders showed a difference in grade from the mean within 0.5 for all conditions under measurement. Student precision in grading was better with both 0.1 and 0.5 grading increments than grading to the nearest unit, except for limbal hyperaemia where they performed more accurately with 0.5 unit increment grading. Limbal grading precision was not affected by grading step increment for experienced practitioners, but 0.1 and 0.5 grading increments were both better than the 1.0 grading increment for bulbar hyperaemia and the 0.1 grading increment was better than the 0.5 grading increment and both were better than the 1.0 grading increment for palpebral hyperaemia. Although narrower interval scales maximise the ability to detect smaller clinical changes, the grading increment should not exceed one standard deviation of the discrepancy between measurements. Therefore, 0.5 grading increments are recommended for subjective anterior eye physiology grading (limbal, bulbar and palpebral redness).


Pulp response and cytotoxicity evaluation of 2 dentin bonding agents.
This study evaluated the biocompatibility of two dentin bonding agents (Clearfil Liner Bond 2 and Scotchbond Multi-Purpose) applied in human dental pulps and cell cultures. In vivo: Twenty human third molars that were scheduled for extraction were used. After cavity preparation, pulp exposure was achieved with a carbide bur. Hemorrhage control was obtained with saline solution. In 16 teeth, adhesive pulp capping was performed and the cavities were sealed with resin composite. In the control group (n = 4), pulps were capped with Ca(OH)2 and the cavities were sealed with IRM. Teeth were extracted 30 or 90 days following treatment and prepared for histological examination and bacterial detection. In vitro: materials were applied in Petri dishes, where NIH-3T3 cells were plated. The cells were counted 2, 4, and 6 days after plating to obtain the growth curves and to determine cell viability. All data were submitted to statistical analysis. In vivo: Dentin bridge formation was seen in all teeth capped with Ca(OH)2, without an inflammatory response. Mild inflammatory responses and dentin bridge formation after 90 days were observed in 50% of specimens treated with Liner Bond 2. Pulps treated with Scotchbond Multi-Purpose presented mild to severe inflammatory response, and no mineralized tissue formation was detected. Bacteria were not disclosed in any specimen. In vitro: The cytotoxicity was similar between the two bonding agents, and both had statistically higher cytotoxic effects (P < 0.002) than Ca(OH)2. Ca(OH)2 produced pulp healing in all teeth and exhibited lower cytotoxic effects than both adhesive systems; however, pulp healing was also observed under Liner Bond 2.


Postnatal changes in the connective tissue in the region lateral to the eustachian tube: possible relationship to tube function.
In order to delineate the possible role of connective tissue (CT) in the region lateral to the eustachian tube (ET) between the ET lumen and the tensor veli palatini muscle (TVPM), we studied the postnatal changes in the CT in histologic sections of human ET. In fetuses and neonates, the lateral region was filled with mesenchyme. Loose collagenous CT appeared first at 2 weeks of age, and in subjects older than 4 years of age, the collagen formed dense, meshlike structures attaching to both the subepithelial CT layer of the ET and the tendonlike membrane of the TVPM. Along the long axis of the ET, those attachments were distributed mainly in the region at the posterior part of the cartilaginous portion of the ET. Attachments to the subepithelial CT layer of the ET were distributed mainly in the upper half of the region. The dense, meshlike collagenous CT might help the ET to be opened by drawing the lateral wall of the ET lumen through inferolateral movement of the tendonlike membrane of the TVPM when the TVPM contracts. It may work to open mainly the parts that include the narrowest portion of the ET, and also the upper aspect of the ET lumen. Incomplete development of this structure in infants may be one of the factors associated with dysfunction in ET opening.


Maternal mortality: an autopsy audit.
The process of audit standardizes protocols in departments and has long-term benefits. Maternal autopsies though routinely performed, deserve a special attention. This study was carried out to calculate the maternal mortality ratio (MMR) in a tertiary care hospital and to correlate final cause of death with the clinical diagnosis. An audit of maternal autopsies was carried out to evaluate current practices, identify fallacies and suggest corrective measures to rectify them. Eighty-nine autopsies of maternal deaths in the period 2003 to 2007 were studied in detail along with the clinical details. There were 158 maternal deaths and 13940 live births in this five-year period. Maternal mortality rate was found to be very high (1133/ 100000 live births) in our institution with a high number of complicated referral cases (68/89 cases, 76%). Of the 89 autopsies, acute fulminant viral hepatitis was the commonest cause of indirect maternal deaths (37 cases, 41.5%). This was followed by direct causes like pregnancy-induced hypertension (12 cases, 13.4%) and puerperal sepsis (10 cases, 11.2%). Certain fallacies were noted during the audit process. During the audit it was realized that in maternal mortality autopsies, special emphasis should be given to clinicopathologic correlation, microbiological studies, identification of thromboembolic phenomenon and adequate sectioning of relevant organs. We found difficulty in identification of placental bed in the uterus in postpartum autopsies. A systematic approach can help us for better understanding of the pathophysiology of diseases occurring in pregnancy.


The complete swine olfactory subgenome: expansion of the olfactory gene repertoire in the pig genome.
Insects and animals can recognize surrounding environments by detecting thousands of chemical odorants. Olfaction is a complicated process that begins in the olfactory epithelium with the specific binding of volatile odorant molecules to dedicated olfactory receptors (ORs). OR proteins are encoded by the largest gene superfamily in the mammalian genome. We report here the whole genome analysis of the olfactory receptor genes of S. scrofa using conserved OR gene specific motifs and known OR protein sequences from diverse species. We identified 1,301 OR related sequences from the S. scrofa genome assembly, Sscrofa10.2, including 1,113 functional OR genes and 188 pseudogenes. OR genes were located in 46 different regions on 16 pig chromosomes. We classified the ORs into 17 families, three Class I and 14 Class II families, and further grouped them into 349 subfamilies. We also identified inter- and intra-chromosomal duplications of OR genes residing on 11 chromosomes. A significant number of pig OR genes (n = 212) showed less than 60% amino acid sequence similarity to known OR genes of other species. As the genome assembly Sscrofa10.2 covers 99.9% of the pig genome, our analysis represents an almost complete OR gene repertoire from an individual pig genome. We show that S. scrofa has one of the largest OR repertoires, suggesting an expansion of OR genes in the swine genome. A significant number of unique OR genes in the pig genome may suggest the presence of swine specific olfactory stimulation.


Mortality study of workers in 1,3-butadiene production units identified from a chemical workers cohort.
The International Agency for Research on Cancer has given the designations of "sufficient evidence" of carcinogenicity of 1,3-butadiene in experimental animals and "limited evidence" of carcinogenicity in humans. To investigate the carcinogenic effect in humans, we conducted a cohort mortality study among 364 men who were assigned to any of three 1,3-butadiene production units located within several chemical plants in the Kanawha Valley of West Virginia, including 277 men employed in a U.S. Rubber Reserve Plant which operated during World War II. The butadiene production units included in this study were selected from an index developed by the Union Carbide Corporation, which listed for each chemical production unit within their South Charleston, West Virginia and Institute, West Virginia, plants all products, by-products, and reactants. Departments included in the study were those where butadiene was a primary product and neither benzene nor ethylene oxide was present. A total of 185 deaths were observed; the standardized mortality ratio (SMR) for all causes of death was 91, reflecting lower mortality among the study population than the U.S. population. The study found a significantly elevated standardized mortality ratio (SMR) for lymphosarcoma and reticulosarcoma based on four observed cases (SMR = 577; 95% CI = 157-1480), which persisted in an analysis using county referent rates. An excess of lymphosarcoma and reticulosarcoma among all workers and among workers with routine exposure to 1,3-butadiene was also observed in the only other cohort of 1,3-butadiene production workers previously studied.(ABSTRACT TRUNCATED AT 250 WORDS)


Adaptive and self-averaging Thouless-Anderson-Palmer mean-field theory for probabilistic modeling.
We develop a generalization of the Thouless-Anderson-Palmer (TAP) mean-field approach of disorder physics, which makes the method applicable to the computation of approximate averages in probabilistic models for real data. In contrast to the conventional TAP approach, where the knowledge of the distribution of couplings between the random variables is required, our method adapts to the concrete set of couplings. We show the significance of the approach in two ways: Our approach reproduces replica symmetric results for a wide class of toy models (assuming a nonglassy phase) with given disorder distributions in the thermodynamic limit. On the other hand, simulations on a real data model demonstrate that the method achieves more accurate predictions as compared to conventional TAP approaches.


Protein ubiquitylation in pancreatic cancer.
Pancreatic cancer is one of the worst, as almost 100% of patients will die within 5 years after diagnosis. The tumors are characterized by an early, invasive, and metastatic phenotype, and extreme resistance to all known anticancer therapies. Therefore, there is an urgent need to develop new investigative strategies in order to identify new molecular targets and, possibly, new drugs to fight this disease efficiently. Whereas it has been known for more than 3 decades now, ubiquitylation is a post-translational modification of protein that only recently emerged as a major regulator of many biological functions, dependent and independent on the proteasome, whose failure is involved in many human diseases, including cancer. Indeed, despite its role in promoting protein degradation through the proteasome, ubiquitylation is now known to regulate diverse cellular processes, such as membrane protein endocytosis and intracellular trafficking, assembly of protein complexes, gene transcription, and activation or inactivation of enzymes. Taking into account that ubiquitylation machinery is a three-step process involving hundreds of proteins, which is countered by numerous ubiquitin hydrolases, and that the function of ubiquitylation relies on the recognition of the ubiquitin signals by hundreds of proteins containing a ubiquitin binding domain (including the proteasome), the number of possible therapeutic targets is exceptionally vast and will need to be explored carefully for each disease. In the case of pancreatic cancer, the study and the identification of specific alteration(s) in protein ubiquitylation may help to explain its severity and may furnish more specific targets for more efficient therapies.


Switching outpatients with bipolar or schizoaffective disorders and substance abuse from their current antipsychotic to aripiprazole.
Substance abuse is extremely common in patients with bipolar disorders, although minimal data are available on the treatment of this important clinical population. Aripiprazole is an atypical antipsychotic that is approved for the treatment of mania and that has a novel mechanism of action, acting as a dopamine-2 receptor partial agonist, thereby increasing dopamine release in some parts of the brain and decreasing dopa-mine release in other brain regions. Dopamine release is implicated in substance use, and both dopaminergic agonists and antagonists have been examined for the treatment of substance abuse. To our knowledge, dopa-mine receptor partial agonists have not been investigated for treatment of substance abuse in humans. Twenty antipsychotic-treated patients with bipolar or schizoaffective disorder and current substance abuse were switched to open-label aripipra-zole using an overlap and taper method. At baseline, diagnoses were confirmed using the Mini-International Neuropsychiatric Interview based on DSM-IV criteria. Psychiatric symptoms, side effects, and substance use and craving were assessed over 12 weeks. Psychiatric symptoms were assessed with the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS). Substance craving was assessed with visual analogue scales, and side effects were monitored using the Abnormal Involuntary Movement Scale, Simpson-Angus Scale, Barnes Akathisia Scale, and patient report. Study enrollment was from April 2003 to February 2004. Significant baseline-to-exit improvement in HAM-D (p = .002), YMRS (p = .021), and BPRS (p = .000) scores were observed without a significant change in antipsychotic-induced side effect scales. In 17 participants with current alcohol dependence, significant reductions in dollars spent on alcohol (p = .042) and alcohol craving (p = .003) were found. In 9 participants with cocaine-related disorders, significant reductions in cocaine craving (p = .014), but not use, were found. A change to aripiprazole was associated with symptomatic improvement. Limitations of the study include a small sample size, high attrition, and an open-label design. Controlled trials in dual-diagnosis patients are needed to confirm these findings.


[Study on the chemical constituents from Fructus Toosendan (III)].
To study the chemical constituents from Fructus Toosendan. Isolation and identification were carried out by using various chromatography techniques and spectral methods. Ten compounds were isolated and identified as n-Hentriacontane (I), Octacosyl alcohol (II), Stearic acid (III), Linoleic acid (IV), Isovanillin (V), Vanillin (VI), Vanillic acid (VII), Ohchinal (VIII), Succinic acid (IX) and Homoeriodictyol (X). Compounds V, VII, IX, X are isolated from this genus and compounds I, II, III are obtained from this plant for the first time.


Benzodiazepine--induced event amnesia following a stressful surgical procedure.
In a randomised, double-blind, parallel groups study, 40 patients undergoing surgical removal of impacted third molar teeth received either midazolam 15 mg orally followed at 35 min by intravenous saline or oral placebo followed by intravenous diazepam 10 mg (Diazemuls). Episodic (event) memory was assessed by showing patients photographs of dental and neutral objects both before and after sedation and by testing subsequent recognition at 1 week. Recall of actual surgical events was assessed by questionnaire. Both treatments induced significant amnesia for visual stimuli and for surgical events. However, the degree of amnesia was more profound for artificial stimuli and no relationship was found between the extent of amnesia for the two types of event. Drilling of bone was found to provoke the greatest cardiovascular stress response and a significant relationship was found between the degree of cardiovascular activation and subsequent memory for drilling. It is concluded that the extent of benzodiazepine-induced event-amnesia may be modified by cognitive factors and especially by the extent to which the event is cognitively encoded and elaborated.


Psychological profile of Turkish rock climbers: an examination of climbing experience and route difficulty.
The purpose of this study was to examine sensation seeking, physical self-perception, and intrinsic and extrinsic motives of rock climbers and to compare these psychological constructs with respect to their years of climbing experience and the difficulty of their climbing routes. 64 climbers (M age=29.1 yr., SD=6.4) voluntarily participated in this study. The Arnett Inventory of Sensation Seeking (AISS), Physical Self-Description Questionnaire (PSDQ), and Sport Motivation Scale (SMS) were administered to the rock climbers. Analysis indicated that the mean score of rock climbers on the Novelty subscale of the Sensation Seeking Scale was 33.9 (SD= 3.6) and mean value on the Intensity subscale was 29.2 (SD=5.2). The mean scores of rock climbers on the PSDQ ranged between 3.9 (SD= 1.0, Physical Activity) and 5.1 (SD= 1.1, Body Fat). Descriptive analysis indicated that the highest mean score of rock climbers on the SMS was obtained in Intrinsic motivation to Experience Stimulation (5.7, SD= 0.9). The independent sample t test showed no significant differences in sensation seeking, physical self-perception, and sport motivation with regard to years of climbing experience and route difficulty (p>.05). It may be concluded that sensation seeking in climbers is high, and they have internal motivational orientation and positive physical self-perception; their competence in climbing has no obvious relationship to these variables.


Pathology of "toxic oils" and selected metals in the MRL/lpr mouse.
The Toxic Oil Syndrome epidemic that occurred in Spain in 1981 and affected nearly 20,000 people was caused by ingestion of oil mixtures that contained analine-denatured rapeseed oil. To date, an animal model in which to identify the actual etiologic agents(s) and to investigate the pathogenesis of the disease has not been discovered. In this study, the MRL/lpr was used to assess the histopathological response of 3 "toxic oils" and 3 metals. The oils tested were a denatured rapeseed oil collected from a family who were affected by the Toxic Oil Syndrome epidemic in Spain (CO756) plus two synthesized oils (RSD and RSA). Female mice, 7 weeks of age, received an undiluted (neat) or a 1:10 diluted dose of each oil; mercury (50 ppm), cadmium (100 ppm), or lead (50 ppm). Half of each group was killed after 5 weeks of exposure and the remaining mice after 10 weeks of exposure. Body and organ weights (liver, kidney, thymus, and spleen) were recorded and selected organs were collected for histopathology. Ten weeks after treatment, body weights (BW) of the cadmium and lead groups were significantly suppressed, and the body weight of the C0756-neat group was significantly increased compared to their respective controls. Kidney/BW were decreased in the RSA-neat and RSA 1:10 groups after 10 weeks of exposure, and the kidney/BW in the mercury and cadmium groups were increased. Spontaneous development (12 weeks of age) and progression (17 weeks of age) of histopathological lesions are described for selected organs examined in the naïve mice as are changes that resulted from exposure to the "toxic oils" and metals. C0756-neat, mercury, and lead suppressed progression of the glomerulonephritis that normally occurs in the MRL/lpr mouse. Also of interest were lesions that included mononuclear cuffing of hepatic bile ducts, progression of the granulomas that formed in the renal glomeruli, vessels in the lymphoid organs that contained tightly packed lymphocytes, and the presence of plasma cells in the thymus. All 3 oils stimulated early development of the lymphoproliferative syndrome characteristic of the MRL/lpr mouse as demonstrated by an increase in the thymus/BW and spleen/BW ratios after 5 weeks of treatment. These data contribute to our knowledge of spontaneous disease progression in the thymus, spleen, lymph nodes, and kidneys in the MRL/lpr mouse and the effects of 3 different "toxic oils" and metals on the development and progression of those lesions.


Comparison of four commercially available rapid enzyme immunoassays with cytotoxin assay for detection of Clostridium difficile toxin(s) from stool specimens.
Rapid (2.5- to 3.5-h) enzyme immunoassays (EIAs) for the detection of Clostridium difficile toxins have been developed. We report the results of simultaneous testing of 700 fresh stool specimens by the tissue culture cytotoxin assay and four EIAs (Bartels Prima System C. difficile Toxin A EIA, Cambridge Biotech Cytoclone A+B EIA, Meridian Diagnostics Premier C. difficile Toxin A EIA, and TechLab C. difficile Tox-A Test EIA). In cases of disagreement, culturing for toxigenic C. difficile was performed. A total of 61 (8.7%) specimens from 46 patients were positive for C. difficile toxin. The sensitivity of the cytotoxin assay was 87%, and that of culture was 93%. In comparison with the cytotoxin assay results, the sensitivity and specificity of the EIAs were as follows: Bartels, 87 and 96%; Cambridge, 89 and 99%; Meridian, 87 and 98%; and TechLab, 87 and 95%, respectively. In comparison with the cytotoxin assay plus toxigenic culture results, the sensitivity and specificity of the EIAs were as follows: Bartels, 84 and 97%; Cambridge, 85 and 99%; Meridian, 79 and 98%; and TechLab, 80 and 96%, respectively. The EIAs varied in positive predictive values (PPVs). A high PPV was seen with the Cambridge EIA (96%); lower PPVs were seen with the TechLab (64%), Bartels (72%), and Meridian (80%) EIAs because of high false-positive rates. The negative predictive values (98 to 99%) were excellent with all EIAs. Results were indeterminant with 0.3% of the samples by the Meridian EIA and 3% by all the other EIAs. Although the EIAs were less sensitive than the cytotoxin assay, they provide same-day results and may be useful in laboratories without tissue culture facilities.


The relationship between plasma steroid hormone concentrations and the reproductive cycle in the Northern Pacific rattlesnake, Crotalus oreganus.
We describe the reproductive cycle of Northern Pacific rattlesnakes (Crotalus oreganus) by quantifying steroid hormone concentrations and observing reproductive behaviors in free-ranging individuals. Additionally, we examined reproductive tissues from museum specimens. Plasma steroid hormone concentrations were quantified for both male and female snakes throughout the active season (March-October). We measured testosterone (T), 5alpha-dihydrotestosterone (DHT), and corticosterone (B) concentrations in both sexes and 17beta-estradiol (E2) and progesterone (P) in females only. We observed reproductive behaviors (e.g., consortship, courtship, and copulation) in the field and measured testis and follicle size in male and female snakes from museum collections to relate steroid hormone concentrations to the timing of reproductive events. Our study revealed that C. oreganus in central California exhibits a bimodal pattern of breeding, with most mating behavior occurring in the spring and some incidences of mating behavior observed in late summer/fall. Each breeding period corresponded with elevated androgen (T or DHT) levels in males. Testes were regressed in the spring when the majority of reproductive behavior was observed in this population, and they reached peak volume in August and September during spermatogenesis. Although we did not detect seasonal variation in female hormone concentrations, some females had high E2 in the spring and fall, coincident with mating and with increased follicle size (indicating vitellogenesis) in museum specimens. Females with high E2 concentrations also had high T and DHT concentrations. Corticosterone concentrations in males and females were not related either to time of year or to concentrations of any other hormones quantified. Progesterone concentrations in females also did not vary seasonally, but this likely reflected sampling bias as females tended to be underground, and thus unobtainable, in summer months when P would be expected to be elevated during gestation. In females, P was positively correlated with T and DHT, and E2 was positively correlated with T.


Modulation of tumor formation and intestinal cell migration by estrogens in the Apc(Min/+) mouse model of colorectal cancer.
Epidemiological studies suggest that post-menopausal hormone replacement therapy (HRT) reduces colorectal cancer (CRC) incidence. Phytoestrogens, including the soy isoflavone genistein and coumestrol, are used by many women as alternatives to HRT. Previous studies showed that ovariectomy induced a 77% increase in intestinal adenoma number in the C57BL/6J-Min/+ (Min/+) mouse, an animal model of adenomatous polyposis coli (APC)-associated CRC. Replacement of estradiol (E(2)) in ovariectomized Min/+ mice reduced tumor number to baseline and up-regulated the expression of estrogen receptor beta (ERbeta). We hypothesized that the phytoestrogens genistein and coumestrol would inhibit intestinal tumorigenesis in ovariectomized Min/+ mice. Min/+ and Apc(+/+) (WT) mice were ovariectomized and assigned to either a control diet or treatment with E(2), genistein or coumestrol. Treatment of ovariectomized Min/+ (Min/+ OX) mice with genistein resulted in a non-significant reduction in tumor number. Min/+ OX mice treated with coumestrol had significantly fewer tumors than untreated Min/+ OX controls and the same number of tumors as non-ovariectomized Min/+ mice. Bromodeoxyuridine migration assays also demonstrated that treatment with E(2) or coumestrol improved enterocyte migration rate. Immunoprecipitation and immunohistochemistry analyses showed that impaired association of the adherens junction proteins E-cadherin and beta-catenin in Min/+ mice was improved by treatment with either E(2) or coumestrol. Immunoblot analyses also showed that expression of ERbeta was elevated in enterocytes of Min/+ OX mice treated with E(2) or coumestrol as compared with those of untreated Min/+ OX mice. In conclusion, both coumestrol and E(2) prevent intestinal tumorigenesis and ameliorate enterocyte migration and intercellular adhesion in the Apc(Min/+) mouse model of CRC.


Surgical results of trabeculectomy and Ahmed valve implantation following a previous failed trabeculectomy in primary congenital glaucoma patients.
To compare the surgical results of trabeculectomy and Ahmed glaucoma valve implantation after a previous failed trabeculectomy. A retrospective comparative case series review was performed on 31 eye surgeries in 20 patients with primary congenital glaucoma who underwent trabeculectomy or Ahmed glaucoma valve implantation after a previous failed trabeculectomy with mitomycin C. The preoperative mean intraocular pressure was 25.5 mmHg in the trabeculectomy group and 26.9 mmHg in the Ahmed glaucoma valve implantation group (p = 0.73). The 48-month postoperative mean intraocular pressure was 19.6 mmHg in the trabeculectomy group and 20.2 mmHg in the Ahmed glaucoma valve implantation group (p = 0.95). The 12-month trabeculectomy success rate was 69%, compared with 64% for Ahmed glaucoma valve implantation, and the 48-month success rates were 42% and 36% for trabeculectomy and valve implantation, respectively. The success rates following the entire follow-up period were not significantly different between the two groups (p > 0.05 by log rank test). Postoperative complications occurred in 25% of the trabeculectomy-operated eyes and 9% of the Ahmed-implanted eyes (p = 0.38). There was no significant difference in surgical outcome between the trabeculectomy and Ahmed glaucoma valve implantation groups, neither of which had favorable results. However, the trabeculectomy group demonstrated a higher prevalence of adverse complications such as post-operative endophthalmitis.


Comparing apples and oranges--model-based assessment of different tsetse-transmitted trypanosomosis control strategies.
The current control strategies for tsetse-transmitted trypanosomosis in cattle (trypanocidal drugs, tsetse control and trypanotolerant cattle) are briefly reviewed and their adoption rates in different geographic regions of sub-Saharan Africa are presented. The impact of these control strategies and the potential use of vaccines, should they be developed, on trypanosomosis transmission were compared using a mathematical model. The relative trypanosomosis prevalence compared with no control was estimated across a range of control coverages (from none to complete control coverage) by varying the change in specific model parameters influenced by individual control measures. Based on this comparison, the relative rankings of the effect of control strategies on reducing disease prevalence were: vector control, vaccination, and drug use, in that order. In this model, trypanotolerance was assumed to decrease disease prevalence, but not to influence transmission. Differences in the predicted impact of control measures on the transmission of human sleeping sickness are discussed. Finally, the role of transmission model outputs as inputs for economic models to guide investment decisions for trypanosomosis control is emphasised.


Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts.
Management guidelines for pancreatic intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) are based on the assumption that mucinous cysts can be accurately distinguished from other pancreatic cystic lesions. Previous studies using surgical material have identified recurrent mutations in GNAS and KRAS in pancreatic mucinous neoplasms. Yet, the diagnostic utility of testing for both genes in pancreatic cyst fluid obtained by endoscopic ultrasound-fine-needle aspiration (EUS-FNA) remains unclear. GNAS and KRAS testing was performed on EUS-FNA pancreatic cyst fluid from 91 pancreatic cysts: 41 IPMNs, 9 IPMNs with adenocarcinoma, 16 MCNs, 10 cystic pancreatic neuroendocrine tumors (PanNET), 9 serous cystadenomas (SCA), 3 retention cysts, 2 pseudocysts, and 1 lymphoepithelial cyst. Mutations in GNAS were detected in 16 (39%) IPMNs and 2 (22%) IPMNs with adenocarcinoma. KRAS mutations were identified in 28 (68%) IPMNs, 7 (78%) IPMNs with adenocarcinoma, and 1 (6%) MCN. Mutations in either gene were present in 34 (83%) IPMNs, 8 (89%) IPMNs with adenocarcinoma, and 1 (6%) MCN. No mutations were found in cystic PanNETs, SCAs, retention cysts, pseudocysts, and a lymphoepithelial cyst. GNAS and KRAS mutations had 100% specificity [95% confidence interval (CI), 0.83-1.00] but 65% sensitivity (95% CI, 0.52-0.76) for mucinous differentiation. Among IPMNs, mutations in either gene had 98% specificity (95% CI, 0.86-1.00) and 84% sensitivity (95% CI, 0.70-0.92). The combination of GNAS and KRAS testing was highly specific and sensitive for IPMNs; however, the lack of sensitivity for MCNs highlights the need for additional markers to improve the detection of pancreatic mucinous neoplasms.


Correlation of melting temperature and cesium chloride buoyant density of bacterial deoxyribonucleic acid.
Samples of bacterial deoxyribonucleic acid from bacteria having guanine plus cytosine (GC) contents in the range of 27 to 72 moles per cent GC were analyzed by optical melting (T(m)) and equilibrium buoyant density methods. The relation between these properties is shown to be linear. The relative value of 1.99 moles per cent GC per degree C change in T(m) is calculated, and a reference method for the calculation of GC contents relative to a standard is derived.


Chronicling the philanthropic arm of neurological surgery: a review of the growth and development of the Neurosurgery Research & Education Foundation.
The Neurosurgery Research & Education Foundation (NREF), previously known as the Research Foundation of the American Association of Neurological Surgeons (AANS), was established in 1980 to encourage and facilitate innovation through financial support to young neurosurgeons in the process of honing their competencies in neurosciences and neurological surgery. This article provides a historical overview of NREF, its mission, and charitable contributions and the ever-expanding avenues for neurosurgeons, neurosurgical residents and fellows, and medical students to supplement clinical training and to further neurosurgical research advances. Data were collected from the historical archives of the AANS and NREF website. Available data included tabulated revenue, geographic and institutional records of funding, changes in funding for fellowships and awards, advertising methods, and sources of funding. Since 1984, NREF has invested more than $23 million into the future of neurosurgery. To date, NREF has provided more than 500 fellowship opportunities which have funded neurosurgeons' education and research efforts at all stages of training and practice. NREF is designed to serve as the vehicle through which the neurosurgical community fosters the continued excellence in the care of patients with neurosurgical diseases.


Puffed-up but shaky selves: State self-esteem level and variability in narcissists.
Different theoretical conceptualizations characterize grandiose narcissists by high, yet fragile self-esteem. Empirical evidence, however, has been inconsistent, particularly regarding the relationship between narcissism and self-esteem fragility (i.e., self-esteem variability). Here, we aim at unraveling this inconsistency by disentangling the effects of two theoretically distinct facets of narcissism (i.e., admiration and rivalry) on the two aspects of state self-esteem (i.e., level and variability). We report on data from a laboratory-based and two field-based studies (total N = 596) in realistic social contexts, capturing momentary, daily, and weekly fluctuations of state self-esteem. To estimate unbiased effects of narcissism on the level and variability of self-esteem within one model, we applied mixed-effects location scale models. Results of the three studies and their meta-analytical integration indicated that narcissism is positively linked to self-esteem level and variability. When distinguishing between admiration and rivalry, however, an important dissociation was identified: Admiration was related to high (and rather stable) levels of state self-esteem, whereas rivalry was related to (rather low and) fragile self-esteem. Analyses on underlying processes suggest that effects of rivalry on self-esteem variability are based on stronger decreases in self-esteem from one assessment to the next, particularly after a perceived lack of social inclusion. The revealed differentiated effects of admiration and rivalry explain why the analysis of narcissism as a unitary concept has led to the inconsistent past findings and provide deeper insights into the intrapersonal dynamics of grandiose narcissism governing state self-esteem. (PsycINFO Database Record


Tissue reaction after intrastromal corneal ring implantation in an experimental animal model.
To evaluate corneal wound healing in the hen animal model after additive surgery with an intracorneal ring segment (ICRS). We implanted one ICRS in each eye of 76 hens. In control group 1 (n = 22 hens), the stromal channel was prepared but no ICRS was inserted. In control group 2 (n = 2 hens), no surgery was performed. Animals were randomly separated into groups and euthanized after clinical follow-up of 4 and 12 hours, 1, 2, 3, and 7 days, and 1, 2, 3, 4, and 6 months. Corneas were stained with hematoxylin-eosin. Apoptosis was measured by terminal uridine nick end-labeling assays. Cell proliferation and myofibroblast-like differentiation were assayed by BrdU and α-smooth muscle actin immunofluorescence microscopy. Stromal matrix changes were documented by electron microscopy. Epithelial and stromal cell apoptosis around the ICRS-implanted and control group 1 eyes peaked at 12 hours, but continued for 72 hours. In ICRS-implanted eyes, epithelial and stromal proliferation was present at 12 and 24 hours, respectively, and peaked at 7 days and 72 hours, respectively. Some proliferation in the ICRS-implanted group continued through the 6-month follow-up, and myofibroblast-like cells differentiated one to three months after ICRS implantation. The segments rotated within the stroma as the limbal inferior angle approached the epithelium. Wound healing after ICRS implantation in hen corneas was similar to that of other corneal surgical wounds in stages. However, there were some specific features related to the small size of the epithelial wound and the device permanently implanted inside the cornea.


Calcifying dermatomyositis following antitetanus vaccination.
In the course of dermatomyositis, calcinosis is a complication frequently seen in children but rarely seen in adults. Calcinosis often induces poor functional prognosis, reducing mobility of the joints and muscles. Dermatomyositis developed in a 59-year-old woman, following an antitetanus vaccination; the dermatomyositis later became calcifying. To our knowledge, similar cases have not been reported.


Cost-effectiveness and safety of epidural steroids in the management of sciatica.
To investigate the clinical effectiveness of epidural steroid injections (ESIs) in the treatment of sciatica with an adequately powered study and to identify potential predictors of response to ESIs. Also, to investigate the safety and cost-effectiveness of lumbar ESIs in patients with sciatica. A pragmatic, prospective, multicentre, double-blind, randomised, placebo-controlled trial with 12-month follow-up was performed. Patients were stratified according to acute (<4 months since onset) versus chronic (4-18 months) presentation. All analyses were performed on an intention-to-treat basis with last observation carried forward used to impute missing data. Rheumatology, orthopaedic and pain clinics in four participating centres: three district hospitals and one teaching hospital in the south of England. Total of 228 patients listed for ESI with clinically diagnosed unilateral sciatica, aged between 18 and 70 years, who had a duration of symptoms between 4 weeks and 18 months. Patients received up to three injections of epidural steroid and local anaesthetic (active), or an injection of normal saline into the interspinous ligament (placebo). The primary outcome measure was the Oswestry Disability Questionnaire (ODQ); measures of pain relief and psychological and physical function were collected. Health economic data on return to work, analgesia use and other interventions were also measured. Quality-adjusted life-years (QALYs) were calculated using the SF-6D, calculated from the Short Form (SF-36). Costs per patient were derived from figures supplied by the centres' finance departments and a costings exercise performed as part of the study. A cost-utility analysis was performed using the SF-36 to calculate costs per QALY. ESI led to a transient benefit in ODQ and pain relief, compared with placebo at 3 weeks (p = 0.017, number needed to treat = 11.4). There was no benefit over placebo between weeks 6 and 52. Using incremental QALYs, this equates to and additional 2.2 days of full health. Acute sciatica seemed to respond no differently to chronic sciatica. There were no significant differences in any other indices, including objective tests of function, return to work or need for surgery at any time-points. There were no clinical predictors of response, although the trial lacked sufficient power to be confident of this. Adverse events were uncommon, with no difference between groups. Costs per QALY to providers under the trial protocol were 44,701 pounds sterling. Costs to the purchaser per QALY were 354,171 pounds sterling. If only one ESI was provided then costs per QALY fell to 25,745 pounds sterling to the provider and 167,145 pounds sterling to the purchaser. ESIs thus failed the QALY threshold recommended by the National Institute for Health and Clinical Excellence (NICE). Although ESIs appear relatively safe, it was found that they confer only transient benefit in symptoms and self-reported function in a small group of patients with sciatica at substantial costs. ESIs do not provide good value for money if NICE recommendations are followed. Additional research is suggested into the epidemiology of radicular pain, producing a register of all ESIs, possible subgroups who may benefit from ESIs, the use of radiological imaging, optimal early interventions, analgesic agents and nerve root injections, the use of cognitive behavioural therapy in rehabilitation, improved methods of assessment, a comparative cost-utility analysis between various treatment strategies, and methods to reduce the effect of scarring and inflammation.