Stitching the synapse: Cross-linking mass spectrometry into resolving synaptic protein interactions.
Synaptic transmission is the predominant form of communication in the brain. It requires functionally specialized molecular machineries constituted by thousands of interacting synaptic proteins. Here, we made use of recent advances in cross-linking mass spectrometry (XL-MS) in combination with biochemical and computational approaches to reveal the architecture and assembly of synaptic protein complexes from mouse brain hippocampus and cerebellum. We obtained 11,999 unique lysine-lysine cross-links, comprising connections within and between 2362 proteins. This extensive collection was the basis to identify novel protein partners, to model protein conformational dynamics, and to delineate within and between protein interactions of main synaptic constituents, such as Camk2, the AMPA-type glutamate receptor, and associated proteins. Using XL-MS, we generated a protein interaction resource that we made easily accessible via a web-based platform (http://xlink.cncr.nl) to provide new entries into exploration of all protein interactions identified.


Life cycle assessment of aquaculture systems-a review of methodologies.
As capture fishery production has reached its limits and global demand for aquatic products is still increasing, aquaculture has become the world's fastest growing animal production sector. In attempts to evaluate the environmental consequences of this rapid expansion, life cycle assessment (LCA) has become a frequently used method. The present review of current peer-reviewed literature focusing on LCA of aquaculture systems is intended to clarify the methodological choices made, identify possible data gaps, and provide recommendations for future development within this field of research. The results of this review will also serve as a start-up activity of the EU FP7 SEAT (Sustaining Ethical Aquaculture Trade) project, which aims to perform several LCA studies on aquaculture systems in Asia over the next few years. From a full analysis of methodology in LCA, six phases were identified to differ the most amongst ten peer-reviewed articles and two PhD theses (functional unit, system boundaries, data and data quality, allocation, impact assessment methods, interpretation methods). Each phase is discussed with regards to differences amongst the studies, current LCA literature followed by recommendations where appropriate. The conclusions and recommendations section reflects on aquaculture-specific scenarios as well as on some more general issues in LCA. Aquaculture LCAs often require large system boundaries, including fisheries, agriculture, and livestock production systems from around the globe. The reviewed studies offered limited coverage of production in developing countries, low-intensity farming practices, and non-finfish species, although most farmed aquatic products originate from a wide range of farming practices in Asia. Apart from different choices of functional unit, system boundaries and impact assessment methods, the studies also differed in their choice of allocation factors and data sourcing. Interpretation of results also differed amongst the studies, and a number of methodological choices were identified influencing the outcomes. Efforts should be made to increase transparency to allow the results to be reproduced, and to construct aquaculture related database(s). More extensive data reporting, including environmental flows, within the greater field of LCA could be achieved, without compromising the focus of studies, by providing supporting information to articles and/or reporting only ID numbers from background databases. More research is needed into aquaculture in Asia based on the latest progress made by the LCA community.


Rapid and predictable genome evolution across three hybrid ant populations.
Hybridization is frequent in the wild but it is unclear when admixture events lead to predictable outcomes and if so, at what timescale. We show that selection led to correlated sorting of genetic variation rapidly after admixture in 3 hybrid Formica aquilonia × F. polyctena ant populations. Removal of ancestry from the species with the lowest effective population size happened in all populations, consistent with purging of deleterious load. This process was modulated by recombination rate variation and the density of functional sites. Moreover, haplotypes with signatures of positive selection in either species were more likely to fix in hybrids. These mechanisms led to mosaic genomes with comparable ancestry proportions. Our work demonstrates predictable evolution over short timescales after admixture in nature.


Endotoxin-induced renal inflammatory response. Oncostatin M as a major mediator of suppressed renin expression.
The systemic response to endotoxin is characterized by hypotension and severe reductions in blood pressure, leading to cardiovascular collapse that can accompany septicemia. The renin/angiotensin system would normally be expected to respond to hypotensive challenge; however, inflammation appears to modify this response. This study identifies a strong acute phase response of the kidney that is characterized by enhanced expression of serum amyloid A, haptoglobin and tissue inhibitor for metalloproteinase-1 and a reduced expression of renin. Equivalent regulatory effects were observed for the immortalized As4.1 kidney cell line that models certain features of juxtaglomerular cells. Oncostatin M, a known endotoxin-responsive proinflammatory cytokine, proved to be an effective inhibitor of renin gene expression. Suppression by oncostatin M involves activated STAT5 and requires an inhibitory element in the renin promoter that functions separately from cell type-specific enhancer elements. The renal acute phase reaction, unlike the liver acute phase reaction, is more strongly dependent on locally produced inflammatory factors.


Arachnoiditis from myelography with iopamidol, metrizamide, and iocarmate compared in the animal model.
A new aqueous myelographic contrast media, iopamidol, was compared to iocarmate and metrizamide with respect to the risk of arachnoiditis. Macaque monkeys underwent myelography with one of the three contrast media. Twelve weeks later, the animals were restudied with myelography, then sacrificed for histologic studies of the arachnoid. Results suggest that iopamidol is safer than iocarmate and equivalent to metrizamide with respect to the risk of arachnoiditis.


Influence of inoculum-to-substrate ratio on biogas enhancement during biochar-assisted co-digestion of food waste and sludge.
High accumulation of volatile fatty acids (VFAs) is one of the major concerns during mesophilic anaerobic co-digestion of food waste (FW) and sewage sludge (SS). Therefore, improving the stability of the anaerobic digestion process could surpass quick acidification while accelerating methanogenesis. In this study, the suitability of biochar-assisted co-digestion was evaluated at different inoculum and substrate ratios (I/S ratios: 0.1, 0.3, 0.6, and 0.9). The maximum methane yield of 256.85 mL/gVSadd was observed at an I/S ratio of 0.6. The results indicated fast volatile solid removal (∼ 47.17% to 73%) and a critical role of biochar addition in alleviating the underlying inhibitions. Substantial changes in the microbial community composition including Methanosata, Methanobrevibacter, and Methanosarcina were also observed which predominated and stabilised the methanogenesis process at higher I/S ratios. These results emphasised that the anaerobic co-digestion of FW/sludge is a promising approach, wherein the biochar amendment at different I/S ratios should be well maintained to avoid inhibitions from excess microbial VFA acidification of organic waste feedstocks.


Buddhist concepts as implicitly reducing prejudice and increasing prosociality.
Does Buddhism really promote tolerance? Based on cross-cultural and cross-religious evidence, we hypothesized that Buddhist concepts, possibly differing from Christian concepts, activate not only prosociality but also tolerance. Subliminally priming Buddhist concepts, compared with neutral or Christian concepts, decreased explicit prejudice against ethnic, ideological, and moral outgroups among Western Buddhists who valued universalism (Experiment 1, N = 116). It also increased spontaneous prosociality, and decreased, among low authoritarians or high universalists, implicit religious and ethnic prejudice among Westerners of Christian background (Experiment 2, N = 128) and Taiwanese of Buddhist/Taoist background (Experiment 3, N = 122). Increased compassion and tolerance of contradiction occasionally mediated some of the effects. The general idea that religion promotes (ingroup) prosociality and outgroup prejudice, based on research in monotheistic contexts, lacks cross-cultural sensitivity; Buddhist concepts activate extended prosociality and tolerance of outgroups, at least among those with socio-cognitive and moral openness.


Regulation of hepatic growth.
The liver is a conditional renewal system, which in the adult organism undergoes minimal cell production and/or cell renewal. However, a reduction in liver cell mass, because of either actual cell loss or cell atrophy, evokes a rapid regenerative response tailored to replace the lost tissue. Synthesis of DNA begins as early as 15 h after a two-thirds hepatectomy, and the fact that all the remaining hepatocytes enter DNA synthesis within the next 48 h does indicate they are all potentially proliferative, and it is unlikely that a distinct stem cell compartment exists. The temporal sequelae of events can be best explained by the semisynchronous passage of cells from G0 into the proliferative cycle (see Fig. 2) where they undergo one or more rounds of cell division before decycling back into the proliferatively quiescent G0 state. The age of the animal and its nutritional and hormonal status are all important modifiers of the response, but none of them is critical to the regenerative process. Experiments involving the administration of sera or the transfer of blood between animals strongly favor the existence of humoral regulatory factors; the liver is apparently capable of producing both inhibitory and stimulatory molecules that act by negative and positive feedback mechanisms, respectively, to control tissue homeostasis, whereas other organs, notably the pancreas, are important sources of facilitatory molecules. A chemical mechanism of self inhibition is a very intellectually appealing hypothesis, but at present there is no consistent message as to the identity of the inhibitory molecule, although most studies suggest the target site for its action is the G1-S transition. Unless the whole field is one of multilateral analysis of an artifact, then endogenous growth inhibitors do exist, but the problem now is one of biochemical isolation and characterization. The field compares rather badly with the many success stories in recent years in which new hormones and peptides have been speedily isolated and purified. A reduction in liver size appears to be associated with a decrease in the concentration of an hepatic growth inhibitor and the production and/or unmasking of a stimulatory factor(s) that is also of hepatic origin. Once again, there is little information about the biochemical nature of the principle and much less on its mode of action. We all assume that such stimulators, and for that matter inhibitors as well, act on "restriction points" or "mitosis operons" and so on.(ABSTRACT TRUNCATED AT 400 WORDS)


The basic stages in the development of scientific medical information in the USSR.
The following is a brief historical survey of the origins and development of medical information service during the pre-revolutionary as well as during the Soviet times. Here are elucidated problems which are connected with the founding of a national health system of information service. Also, presented are data on the activity of the Vsesoiuznyĭ nauchno-issledovatel'skiĭ institut meditsinskoĭ i mediko-tekhnicheskoĭ informatsii Ministerstva zdravookhraneniia U.S.S.R.-tr. All-union scientific-research institute of medical and medico-technical information (VNIIMI) of the U.S.S.R. Ministry of Public Health-and about the measures taken to create a highly efficient national (public) health information service.


Molecular characterization of the murine Hif-1 alpha locus.
Hypoxia inducible factor 1 alpha (HIF-1 alpha) is a basic helix-loop-helix-PAS (bHLH-PAS) transcription factor that mediates certain cellular responses to low oxygen tension, iron chelators, Co2+, Ni2+, Mg2+, and low intracellular glucose concentration. Upon exposure to the above conditions, HIF-1 alpha is upregulated and heterodimerizes with the Ah receptor nuclear translocator (ARNT, also known as HIF-1 beta), the heterodimeric complex binds TACGTG-containing genomic enhancer elements, and activates transcription of target genes. As a first step in developing genetic models to study the biology related to cellular hypoxia, we have cloned the murine HIF-1 alpha cDNA, determined the tissue-specific expression of its mRNA, functionally analyzed its protein product, and characterized its promoter and its genomic structure. A comparison between the murine and human HIF-1 alpha protein sequence reveals 95%, 99%, and 83% identity in the bHLH, PAS, and variable domains, respectively. RNAse protection assays demonstrate that in adult mice, the mHIF-1 alpha mRNA is expressed at high levels in kidney, heart, brain, thymus, and placenta, with moderate expression in liver, spleen, testis, and lung and much lower expression in skeletal muscle testis. Northern blot analysis indicates that the mRNA of the murine HIF-1 alpha is transcribed in two forms, a major 4-kb species and a minor 5-kb species; both are present in all tissues examined. The Hif-1 alpha promoter is GC rich, does not have a TATA element near its transcriptional start site, and does not respond to hypoxia or Co2+. The mHIF-1 alpha structural gene is composed of 15 exons. The splice junction sites within the bHLH and the PAS domains of HIF-1 alpha gene are highly conserved with respect to a number of previously characterized members of the bHLH-PAS superfamily. However, unlike other bHLH-PAS genes, where the variable domain is encoded by 2 exons, the variable region of the mHIF-1 alpha gene is encoded by 7 exons. Furthermore, most of these splice junction sites in the variable region are conserved with that of HIF-2 alpha, a recently cloned hypoxia-responsive bHLH-PAS protein (also known as MOP2, EPAS1, and HLF). These data suggest that HIF-1 alpha, along with HIF-2 alpha, represents a new subclass of the bHLH-PAS superfamily.


Human αS1-casein induces IL-8 secretion by binding to the ecto-domain of the TLR4/MD2 receptor complex.
The milk protein αS1-casein was recently reported to induce secretion of proinflammatory cytokines via Toll-like receptor 4 (TLR4). In this study, αS1-casein was identified as binder of theTLR4 ecto domain. IL-8 secretion after stimulation of TLR4/MD2 (myeloid differentiation factor 2)/CD14 (cluster of differentiation 14)-transfected HEK293 cells (TLR4+) and Mono Mac 6 cells (MM6) with recombinant αS1-casein, or LPS as control was monitored. Binding of αS1-casein to TLR4 was quantified by microscale thermophoresis (MST). αS1-casein induced secretion of IL-8 in TLR4+ cells and in MM6 cells with a six-times higher final IL-8 concentration in supernatants. IL-8 secretion was inhibited by intracellular TLR4-domain antagonist TAK-242 with an IC50-value of 259.6 nM, by ecto-domain TLR4 antagonistic mianserin with 10-51 μM and by anti-CD14-IgA. The binding constants (KD) of αS1-casein to the TLR4, MD2, and CD14 were 2.8 μM, 0.3 μM and 2.7 μM, respectively. Finally, αS1-casein showed a higher affinity to TLR4/MD2 (KD: 2.2 μM) compared to LPS (KD: 8.2 μM). Human αS1-casein induced proinflammatory effects are dependent upon binding to the TLR4 ectodomain and the presence of CD14. αS1-casein displayed stronger TLR4 agonistic activity than LPS via a different mode of action. Breast milk protein αS1-casein is a proinflammatory cytokine.


Transmitter release is evoked with low probability predominately by calcium flux through single channel openings at the frog neuromuscular junction.
The quantitative relationship between presynaptic calcium influx and transmitter release critically depends on the spatial coupling of presynaptic calcium channels to synaptic vesicles. When there is a close association between calcium channels and synaptic vesicles, the flux through a single open calcium channel may be sufficient to trigger transmitter release. With increasing spatial distance, however, a larger number of open calcium channels might be required to contribute sufficient calcium ions to trigger vesicle fusion. Here we used a combination of pharmacological calcium channel block, high-resolution calcium imaging, postsynaptic recording, and 3D Monte Carlo reaction-diffusion simulations in the adult frog neuromuscular junction, to show that release of individual synaptic vesicles is predominately triggered by calcium ions entering the nerve terminal through the nearest open calcium channel. Furthermore, calcium ion flux through this channel has a low probability of triggering synaptic vesicle fusion (∼6%), even when multiple channels open in a single active zone. These mechanisms work to control the rare triggering of vesicle fusion in the frog neuromuscular junction from each of the tens of thousands of individual release sites at this large model synapse.


The impact of diagnosis on cervical and endometrial cancer patients and their spouses.
How information on diagnosis of endometrial and cervical cancer was given and its impact on women (n = 60) and their spouses (n = 47) were investigated by semistructured interviews and check-lists of psychological symptoms. In most cases the first information on diagnosis was given to the woman by telephone. Half of the women with endometrial cancer and four with cervical cancer solely obtained information by telephone. The least dissatisfied patients were those who received information on diagnosis by phone and simultaneously were offered a personal visit at their earliest convenience. Almost all spouses were given the news of the diagnosis exclusively by their ill partner. This way of being informed provoked anger and bitterness among the spouses. At initiation of treatment most women (93%) and men (81%) were classified as being in a psychological crisis, and a lack of coincidence concerning the different phases of crisis was observed in half of the couples. The study emphasizes the importance of directing attention both to the needs of patients/partners and to the needs of physicians when communicating a diagnosis of cancer.


All-optical nonlinearities in organics.
Recognition that organic solids possess some of the largest all-optical nonlinearities of all known materials has resulted in an interdisciplinary effort directed at both the basic understanding and exploitation of these effects. Parallel efforts on ionrganic semiconductors have already reached a mature stage whereby the origin of the effects, together with the prospects for device applications, are well known and appreciated. In this article, a unified picture of nonlinear optical phenomena in both classes of materials is presented. The specific implications for organic-based optical devices are discussed.


Control and detection of singlet-triplet mixing in a random nuclear field.
We observed mixing between two-electron singlet and triplet states in a double quantum dot, caused by interactions with nuclear spins in the host semiconductor. This mixing was suppressed when we applied a small magnetic field or increased the interdot tunnel coupling and thereby the singlet-triplet splitting. Electron transport involving transitions between triplets and singlets in turn polarized the nuclei, resulting in marked bistabilities. We extract from the fluctuating nuclear field a limitation on the time-averaged spin coherence time T2* of 25 nanoseconds. Control of the electron-nuclear interaction will therefore be crucial for the coherent manipulation of individual electron spins.


Temperature monitoring and lesion volume estimation during double-applicator laser-induced thermotherapy in ex vivo swine pancreas: a preliminary study.
Tissue temperature distribution plays a crucial role in the outcome of laser-induced thermotherapy (LITT), a technique employed for neoplasias removal. Since recent studies proposed LITT for pancreatic tumors treatment, assessment of temperature and of its effects around the laser applicator could be useful to define optimal laser settings. The aims of this work are temperature monitoring and measurement of ablated tissue volume in an ex vivo porcine pancreas undergoing double-applicator LITT. A three-dimensional numerical model is implemented to predict temperature rise and volumes of ablated tissue in treated pancreas. Experiments are performed to validate the model, with two modalities: (1) 12-fiber Bragg grating sensors are adopted to monitor the heating and cooling during LITT at several distances from the applicators tip, and (2) 1.5-T MR imaging is used to estimate the ablated volume. Experimental data agree with theoretical ones: at 2 mm from both applicators tips, the maximum temperature increase is approximately 60 °C downward from the tips, while it increases of about 40 °C and 30 °C, respectively, at the level and upward from the tips. This behavior occurs also at other distances, proving that the tissue downward from the tip is mostly heated. Furthermore, the estimated volume with MRI agrees with theoretical one (i.d., 0.91 ± 0.09 vs. 0.95 cm(3)). The encouraging results indicate that the model could be a suitable tool to choose the optimal laser settings, in order to control the volume of ablated tissue.


How bad faith lawsuits can be tailored to fit HMOs.
In January 1999, in the case of Goodrich v. Aetna, a California jury returned a record-breaking verdict of $120.5 million damages in favor of a widow as a result of Aetna's failure to act in good faith in the treatment of her terminally ill husband. The following article discusses the history and basis of this kind of lawsuit, major decisions specifically pertaining to HMOs, and the outlook for future liability in this area.


Heavy resistance training increases muscle size, strength and physical function in elderly male COPD-patients--a pilot study.
This study investigated the effects of heavy resistance training in elderly males with chronic obstructive pulmonary disease (COPD). 18 Home-dwelling male patients (age range: 65-80 years), with a mean forced expiratory volume in the first second (FEV1) of 46 +/- 3.4% of predicted value, were recruited. Baseline and post-training assessments included: Cross-sectional area (CSA) of quadriceps assessed by MRI, isometric and isokinetic knee extension strength, isometric trunk strength, leg extension power, normal and maximal gait-speed on a 30 m track, stair climbing time, number of chair stands in 30 s, lung function (FEV1) and self-reported health. Subjects were randomized to a resistance training group (RE, n = 9) or a control group conducting breathing exercises (CON, n = 9). RE performed heavy progressive resistance training twice a week for 12 weeks. 6 RE and 7 CON completed the study. In RE the following improved (P < 0.05): Quadriceps CSA: 4%, isometric knee extension strength: 14%, isokinetic knee extension strength at 60 degrees /s.: 18%, leg extension power: 19%, maximal gait speed: 14%, stair climbing time: 17%, isometric trunk flexion: 5% and self-reported health. In CON no changes were found. In conclusion, 12 weeks of heavy resistance training twice a week resulted in significant improvements in muscle size, knee extension strength, leg extension power, functional performance and self-reported health in elderly male COPD patients.


Evaluation of marking efficiency of different alizarin red S concentrations on body fish structures in Oreochromis niloticus (Perciformes: Cichlidae) juveniles.
The use of alizarin red S (ARS) marked tilapias could provide valuable fisheries management information to evaluate fish stocking events and may facilitate aquaculture management practices. As a new technique in fishes, the aim of this study was to compare and evaluate the chemical marks produced in tilapia juveniles by ARS through two treatments: 1) 12 hours of immersion and 2) immersion after osmotic induction. This was analyzed at three concentrations: 50, 75 and 100mg/l, and in three structures: otoliths, fish scales and caudal fin rays of Oreochromis niloticus juveniles. After three culture months 80% of specimens were analyzed and significant differences (p<0.05) in mark intensity were detected between treatments for otoliths and fin rays, but not for fish scales. Significant differences between concentrations were found for the 12h immersion treatment, while no significant differences were detected with osmotic induction. Our results showed that marks appeared at all concentrations, and none of the concentrations produced weak marks. Osmotic induction had a greater mortality than the 12h immersion procedure. After eight culture months the rest of the specimens were analyzed and the mark permanence was observed in all cases. According to the present results we recommend the marking process of 12h immersion treatment at 100mg/L concentration.


An improved understanding of TNFL/TNFR interactions using structure-based classifications.
Tumor Necrosis Factor Ligand (TNFL)-Tumor Necrosis Factor Receptor (TNFR) interactions control key cellular processes; however, the molecular basis of the specificity of these interactions remains poorly understood. Using the T-RMSD (tree based on root mean square deviation), a newly developed structure-based sequence clustering method, we have re-analyzed the available structural data to re-interpret the interactions between TNFLs and TNFRs. This improves the classification of both TNFLs and TNFRs, such that the new groups defined here are in much stronger agreement with structural and functional features than existing schemes. Our clustering approach also identifies traces of a convergent evolutionary process for TNFLs and TNFRs, leading us to propose the co-evolution of TNFLs and the third cysteine rich domain (CRD) of large TNFRs.


Preclinical studies for adoptive immunotherapy in bone marrow transplantation. Generation of anti-CD3 activated cytotoxic T cells from normal donors and autologous bone marrow transplant candidates.
In order to obtain T cells for adoptive immunotherapy after autologous bone marrow transplantation (ABMT) for patients with resistant hematological malignancies, a culture system was developed for growing T cells and inducing non-MHC-restricted cytotoxicity using anti-CD3 monoclonal antibody (OKT3) activation. In this investigation, we show that (1) peripheral blood lymphocytes or bone marrow mononuclear cells (BMMNC) from normal donors and cancer patients can be activated with OKT3 and grown in interleukin-2; (2) normal BMMNC activated with OKT3/IL-2 exhibited non-MHC-restricted cytotoxicity and surface markers comparable to that exhibited by normal PBL activated with OKT3/IL-2; (3) both proliferation and cytotoxic functions were IL-2-dependent; (4) PBL activated with OKT3/IL-2 after cryogenic storage grew and killed comparable to PBL activated with OKT3/IL-2 prior to cryopreservation; (5) OKT3/IL-2-activated PBL and BMMNC obtained from 5 patients with non-Hodgkin's lymphomas (NHL) and 1 patient with acute myelogenous leukemia (AML) increased cell numbers 41-75-fold in 2 weeks of culture; 5 of 6 patients with NHL or AML had PBL and BMMNC that exhibited cytotoxic activity; and (6) contaminating leukemic cells did not overgrow in OKT3/IL-2-activated cultures and could no longer be detected on cytospin specimens after 3 weeks of culture. These data show that T cells in PBL or BMMNC from ABMT candidates can be activated with OKT3/IL-2 for adoptive immunotherapy in combination with ABMT.


Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct.
Intraductal papillary mucinous tumors (IPMTs) of the pancreas are rare tumors characterized by a malignant potential. Because of the progress of imaging procedures, smaller cystic pancreatic lesions are now detected and some of them correspond to IPMTs that involve ectatic pancreatic branch ducts but spare the main pancreatic duct. To investigate differences in morphology and clinical behavior of branch and main duct types of IPMT, a surgical series of 43 cases was studied. All pathologic specimens of IPMT, surgically resected in our institution between October 1987 and July 1998, were analyzed. In all cases, the entire pancreatic specimen was systematically examined. IPMT of the branch type was found in 13 (30%) patients, whereas IPMT of main pancreatic duct type that involved the main pancreatic duct and branch ducts was observed in 30 (70%) patients. Patients with IPMT of the branch type were younger (median age, 55 yrs vs 64 yrs), and all but one of the lesions were located in the head and neck of the pancreas (vs 17 of 30 patients with the main duct type). The size of the cysts ranged from 4 to 55 mm, and the major duct showed a mild dilation in most cases. In contrast to the main pancreatic duct type, which showed invasive carcinoma and in situ carcinoma in 11 (37%) of 30 patients and 6 (20%) of 30 patients, respectively, IPMT of the branch type showed significantly less aggressive histologic lesions with five (39%) patients with simple hyperplasia, six (46%) patients with atypical hyperplasia, and two (15%) patients with in situ carcinoma. No invasive carcinoma was observed in this group. IPMT of the branch type occurs in younger patients and is associated with less aggressive histologic features than is the main pancreatic duct type. Our findings raise the difficult issue of clinical management of IPMT of the branch type as a distinctive group.


Effect of Two Different Stunning Methods on the Quality Traits of Rabbit Meat.
The aim of the study was to assess the effect of two different stunning methods on the level of blood stress indicators (cortisol, insulin, glucose) and rabbit meat quality. The experiment was conducted on crossbreds of Hycole, Hyla, and Jordan rabbit strains: from mating Hyplus PS19 females with Hycole males (genotype I, n = 20) and Jordan × Hycole females with Hyla males (genotype II, n = 20). Prior to slaughter, the animals were weighed and divided into two groups according to the stunning method: 10 rabbits from each genetic group were stunned with an electric stunner, and the remaining 10 were stunned mechanically using a club. Genotype II was characterised by higher body weight at slaughter (p < 0.05), hot dressing percentage (p < 0.05), cold dressing percentage (p < 0.05), hot carcass weight (p < 0.05), and cold carcass weight (p < 0.05), compared to genotype I. The stunning method slightly influenced the meat lightness (p = 0.035). The meat of electrically stunned rabbits was characterised with higher drip loss (p < 0.0001) and lower plasticity (p = 0.043). Among the analysed traits of meat, only the drip loss (p = 0.014) and the percentage of extractable fat were affected by genotype (p = 0.044). Neither the stunning method nor the genotype affected rabbit meat texture characteristics. The study was undertaken because of the increasing importance of rabbit meat production as a developing sector of the meat industry and the need to improve the welfare of rabbits by selecting the most acceptable slaughter methods for these animals. To conclude, the analysed rabbit meat was characterised with good quality. There were only slight differences between genotypes and the stunning groups.


Who is healthy? Aspects to consider when including healthy volunteers in QST--based studies-a consensus statement by the EUROPAIN and NEUROPAIN consortia.
Clinical and human experimental pain studies often include so-called "healthy" controls in investigations of sensory abnormalities, using quantitative sensory testing (QST) as an outcome measure. However, the criteria for what is considered "healthy" vary among the different studies and between study centers and investigators, partly explaining the high variability of the results. Therefore, several aspects should be considered during inclusion of healthy volunteers in QST-based trials to have homogenous groups of healthy controls with less variability between human experimental studies, so that results are less likely to be false negative or false positive because of subject-related factors. The EUROPAIN and NEUROPAIN consortia aimed to define factors influencing the variability in selection of healthy subjects in QST-based studies before the start of both projects and to give recommendations how to minimize it based on the current literature and expertise of the participants. The present suggestions for inclusion criteria of healthy volunteers into QST-based trials describe a 2-level approach including standardized questionnaires enabling the collection of relevant information on sociodemographic data, medical history, current health status, coping strategies in dealing with pain, and the motivation of the volunteer to participate in the study. These suggestions are believed to help researchers interpret their results in comparison with others and improve the quality of clinical studies including healthy volunteers as controls or in human experimental pain studies. They aim to reduce any confounding factors. Furthermore, the acquired information will allow post hoc analyses of variance for different potential influencing factors.


Waiting Time for Specialist Consultation and Visit Requested in the Emergency Department; a Cross-Sectional Study.
Waiting time in the hospital directly affects the quality of healthcare providing centers. One of the waiting times in hospital is the time spent waiting for receiving various consultations and visits requested by emergency medicine specialists from specialist services. The present study was designed and performed to assess the waiting times for receiving specialist visits and consultations requested in the emergency department based on the corresponding service in a referral hospital in Isfahan, Iran. In the present cross-sectional study, patients presenting to emergency department of Dr. Shariati Hospital, Isfahan, Iran, from October 2017 to March 2018, who were in need of visit or consultation from other specialist services based on the opinion of the emergency medicine specialist, were studied. By attending the patients' bedside, the researcher filled out a checklist consisting of demographic data and waiting time of the patients and other probable related factors. Finally, raw data were entered to the computer and after correction of errors were statistically analyzed via SPSS software. Overall, 400 patients with the mean age of 53.3 ± 24.3 years were included in the study, 58.8% of which were male. Mean waiting time for receiving a visit or consultation among the studied patients was 242.0 ± 202.4 (min: 5 and max: 1200) minutes. Mean waiting time for a visit or consultation did not significantly correlate with the corresponding physician being resident or on-call. However, it showed a statistically significant correlation with triage level (p = 0.013), work shift (p = 0.000), type of service requested/the specialist service asked for a consultation or visit (p = 0.049), and the consultation or visit being emergent or non-emergent (p = 0.000). In addition, emergent visits or consultations by on-call physicians had been performed significantly faster than those by resident physicians; while non-emergent visits or consultations by resident physicians had been performed significantly faster than those by on-call physicians (p = 0.001). The results of the present study showed that patients with triage level 2, emergent visit of consultation and a visit or consultation request in the morning or evening shift wait a shorter time for receiving the visit or consultation. In addition, neurosurgery, nephrology, and pediatrics services had the shortest waiting times, while gastroenterology, gynecology, and infectious disease services had the longest waiting times for giving the visit or consultation requested from them.


A series of multifunctional coordination polymers based on terpyridine and zinc halide: second-harmonic generation and two-photon absorption properties and intracellular imaging.
How can imaging be improved? Coordination polymers (CPs) show fascinating potential in optoelectronic optics but limited potential in bioimaging. Without doubt, it was very meaningful when CPs were first used in second-harmonic generation (SHG) imaging. Herein, through reasonable design and synthesis, a series of nonlinear optical CPs bearing very good one-photon excited fluorescence (OPEF), two-photon excited fluorescence (TPEF) and very strong SHG properties has been presented. Further study demonstrated that the nanoscale CPs show very strong SHG signals which have been applied in the three-dimensional imaging of thick block tissue with higher spatial resolution through simultaneous multichannel nonlinear optical (NLO) imaging technology. After simple encapsulation by polymeric micelles, the nanoscale CPs were successfully applied in SHG bio-imaging within the living cells. This finding throws light on the design of nanoscale NLO CPs and offers a simple avenue to develop novel effective exogenous SHG imaging agents.


Brominated flame retardants (BFRs) in air and dust from electronic waste storage facilities in Thailand.
This study reports concentrations of brominated flame retardants in dust samples (n=25) and in indoor (n=5) and outdoor air (n=10) (using PUF disk passive air samplers) from 5 electronic and electrical waste (e-waste) storage facilities in Thailand. Concentrations of Sigma(10)PBDEs (BDEs 17, 28, 47, 49, 66, 85, 99, 100, 153 and 154) in outdoor air in the vicinity of e-waste storage facilities ranged from 8 to 150 pg m(-3). Indoor air concentrations ranged from 46 to 350 pg m(-3), with highest concentrations found in a personal computer and printer waste storage room at an e-waste storage facility. These are lower than reported previously for electronic waste treatment facilities in China, Sweden, and the US. Concentrations of Sigma(21)PBDEs (Sigma(10)PBDEs+BDEs 181, 183, 184, 191, 196, 197, 203, 206, 207, 208 and 209), decabromodiphenylethane (DBDPE), decabromobiphenyl (BB-209) in dust were 320-290,000, 43-8700 and <20-2300 ng g(-1) respectively, with the highest concentrations of Sigma(21)PBDEs, BDE-209 and DBDPE in a room used to house discarded TVs, stereos and radios. PBDE concentrations in dust were slightly higher but within the range of those detected in workshop floor dust from an e-waste recycling centre in China. The highest concentration of BB-209 was detected in a room storing discarded personal computers and printers. Consistent with recent reports of elevated ratios of BDE-208:BDE-209 and BDE-183:BDE-209 in household electronics from South China, percentage ratios of BDE-208:BDE-209 (0.64-2.9%) and of BDE-208:BDE-183 (2.8-933%) in dust samples exceeded substantially those present in commercial deca-BDE and octa-BDE formulations. This suggests direct migration of BDE-208 and other nonabrominated BDEs from e-waste to the environment. Under realistic high-end scenarios of occupational exposure to BDE-99, workers in the facilities were exposed above a recently-published Health Based Limit Value for this congener. Reassuringly, estimated exposures to BDE-209 were below the USEPA's reference dose for this congener.


New assignment of the adenosine deaminase gene locus to chromosome 20q13 X 11 by study of a patient with interstitial deletion 20q.
A karyotype 46,XY,del(20)(q11 X 23q13 X 11) was found in a three year old boy with mental and growth retardation, low set ears, broad nasal bridge, and macrostomia. Adenosine deaminase (ADA) activity was reduced by about 50%, assigning the gene locus to the deleted segment. A review of the previously reported regional assignments suggests that the ADA gene is in the region of band 20q13 X 11.


Adverse effects of corticosteroids on the cardiovascular system.
To review the potential adverse effects of glucocorticoid therapy on the cardiovascular system and to provide insight into the mechanisms of these effects. Case reports and studies demonstrating adverse effects of glucocorticoid therapy on the cardiovascular system were examined from a MEDLINE search. Animal data and in vitro studies were identified to provide insight on the mechanisms of these effects. Undesirable effects identified were dyslipidemia, hypertension and left ventricular free wall rupture after myocardial infarction. Elevations of total plasma cholesterol, triglycerides, low density lipoprotein cholesterol and high density lipoprotein cholesterol are often reported. The elevation of various lipid subfractions is likely mediated by increased plasma insulin levels, impaired lipid catabolism and increased lipid production in the liver. Hypertension was shown to be more prevalent in patients treated with high doses of glucocorticoid. The mechanisms are complex, but final pathways include increased systemic vascular resistance, increased extracellular volume and increased cardiac contractility. Glucocorticoids were demonstrated to increase the incidence of left ventricular free wall rupture by delaying myocardial scar formation in the postmyocardial infarction period. The major adverse effects of glucocorticoids on the cardiovascular system include dyslipidemia and hypertension. These effects may predispose treated patients to coronary artery disease if high doses and prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in patients with other risk factors for cardiovascular disease, and attention should be paid to risk modification. Low dose and alternate day therapy may reduce the incidence of complications in corticosteroid therapy. The mechanisms of these adverse effects are complex and have not yet been fully explained.


Validation of XMALab software for marker-based XROMM.
Marker-based XROMM requires software tools for: (1) correcting fluoroscope distortion; (2) calibrating X-ray cameras; (3) tracking radio-opaque markers; and (4) calculating rigid body motion. In this paper we describe and validate XMALab, a new open-source software package for marker-based XROMM (C++ source and compiled versions on Bitbucket). Most marker-based XROMM studies to date have used XrayProject in MATLAB. XrayProject can produce results with excellent accuracy and precision, but it is somewhat cumbersome to use and requires a MATLAB license. We have designed XMALab to accelerate the XROMM process and to make it more accessible to new users. Features include the four XROMM steps (listed above) in one cohesive user interface, real-time plot windows for detecting errors, and integration with an online data management system, XMAPortal. Accuracy and precision of XMALab when tracking markers in a machined object are ±0.010 and ±0.043 mm, respectively. Mean precision for nine users tracking markers in a tutorial dataset of minipig feeding was ±0.062 mm in XMALab and ±0.14 mm in XrayProject. Reproducibility of 3D point locations across nine users was 10-fold greater in XMALab than in XrayProject, and six degree-of-freedom bone motions calculated with a joint coordinate system were 3- to 6-fold more reproducible in XMALab. XMALab is also suitable for tracking white or black markers in standard light videos with optional checkerboard calibration. We expect XMALab to increase both the quality and quantity of animal motion data available for comparative biomechanics research.


Severe hypophosphatemic osteomalacia secondary to fanconi syndrome due to adefovir: a case report.
Generalized proximal, type 2, renal tubular acidosis, also known as Fanconi syndrome, is a generalized dysfunction of the proximal renal tubule characterized by impaired reabsorption and increased urinary loss of phosphate and other solutes, such as uric acid, glucose, amino acids, and bicarbonate. Chronic hypophosphatemia is the second most common cause of osteomalacia after vitamin D deficiency in adult patients and can have a heterogeneous presentation, ranging from mild symptoms such as muscle weakness and skeletal pain to more severe presentation, such as disabling myopathy, severe bone and joint pain, difficulty walking, and even bone fractures. This report describes a case of severe hypophosphatemic osteomalacia with multiple fragility fractures induced by adefovir, which was worsened and confounded by a previous treatment with zoledronic acid and required prolonged intravenous potassium phosphate administration. We highlight the limited diagnostic value of dual X-ray absorptiometry and bone scintigraphy in this challenging diagnosis. Bone metabolism should always be assessed in patients treated with adefovir for early detection of osteomalacia due to Fanconi syndrome. Although rare, this condition may be life-threatening and mimic other bone metabolic disorders that are treated with drugs that may further impair phosphate balance.


The possible reason for serum 3,3'5'-(reverse) triiodothyronine increase in old people.
Healthy subjects aged 70-90 and 20-40 years were investigated for the level of reverse triiodothyronine (rT3). The mean level in 57 old subjects was higher and the triiodothyronine (T3) level lower than in 30 young persons. No negative correlation was observed. A serum T3 elevation caused by liothyronine administration (5-15 micrograms/day for two weeks) was not followed by a change of the mean rT3 level in 12 old subjects. After a single intramuscular thyrotropin (TSH) injection, the rT3 elevation lasted 24h longer in 19 old persons than in the 9 control ones, though the early rT3 response was similar in both groups. Propranolol administration (40 mg t.i.d. for a week) caused a similar rT3 elevation in old persons (n = 18) as in 12 young ones. From the indirect data it is concluded that the serum rT3 elevation in old age is a result of faster peripheral generation and not of increased production in the thyroid gland. The data do not indicate any change of rT3 metabolism. T4-T3 and T4-rT3 conversion are provoked by different enzymes. The elevation of rT3 might be a cause of the observed decrease in peripheral T3 generation in old subjects, acting by an inhibition of the T4-T3 conversion.


Membrane current responses of skate photoreceptors.
Light-evoked membrane currents were recorded with suction electrodes from the outer segments of individual photoreceptors enzymatically dissociated from the skate retina. The intensity-response relation of dark-adapted cells closely followed a Michaelis function for which a half-saturating response was elicited by a flash intensity that produced about 36 photoisomerizations. Dim-light responses, as well as the early rising phase of the responses to a wide range of flash intensities, could be described by a reaction scheme that involved a series of four first-order delay stages. The number of delay stages required to model the rising phase of the photocurrents did not change in light adaptation. However, background illumination that reduced sensitivity by 1.5 log units, or a bleaching exposure that resulted in a nearly equivalent desensitization, shortened significantly the time scale of the responses. In both instances there were two- to threefold increases in the rate constants of the transitional delays, and almost complete suppression of the tail current that characterized the response of the dark-adapted cell. These findings suggest that although light adaptation alters the gain and kinetics of the transduction mechanism, the nature of the intervening processes is the same in dark- and light-adapted photoreceptors. Moreover, the results show clearly that there is no need to postulate the existence of a second class of cone-like rods to account for the remarkable ability of skate photoreceptors to respond to incremental stimuli presented on "saturating" background fields or after exposure to an intense bleaching light.


The murine Hox-2 genes display dynamic dorsoventral patterns of expression during central nervous system development.
This report demonstrates that the genes in the murine Hox-2 cluster display spatially and temporally dynamic patterns of expression in the transverse plane of the developing CNS. All of the Hox-2 genes exhibit changing patterns of expression that reflect events during the ontogeny of the CNS. The observed expression correlates with the timing and location of the birth of major classes of neurons in the spinal cord. Therefore, it is suggested that the Hox-2 genes act to confer rostrocaudal positional information on each successive class of newly born neurons. This analysis has also revealed a striking dorsal restriction in the patterns of Hox-2 expression in the spinal cord between 12.5 and 14.5 days of gestation, which does not appear to correlate with any morphological structure. The cellular retinol binding protein (CRBP) shows a complementary ventral staining pattern, suggesting that a number of genes are dorsoventrally restricted during the development of the CNS. The expression of Hox-2 genes has also been compared with the Hox-3.1 gene, which exhibits a markedly different dorsoventral pattern of expression. This suggests that, while genes in the different murine Hox clusters may have similar A-P domains of expression, they are responding to different dorsoventral patterning signals in the developing spinal cord.


Clinical Outcomes and Return to Sport in Competitive Athletes Undergoing Arthroscopic Iliopsoas Fractional Lengthening Compared With a Matched Control Group Without Iliopsoas Fractional Lengthening.
To compare the minimum 2-year outcomes and return to sports in competitive athletes after arthroscopic iliopsoas fractional lengthening (IFL) and treatment for femoroacetabular impingement (FAI) to competitive athletes treated for FAI who did not undergo IFL. Data were prospectively collected and retrospectively reviewed between November 2009 and April 2014. Included patients were high school, collegiate, or professional athletes who underwent arthroscopic IFL, treatment for FAI, and preoperative modified Harris Hip Score, Non-Arthritic Athletic Hip Score, Hip Outcome Score-Sports Specific Subscale, and visual analog scale. Exclusion criteria were patients younger than 16 years, Tönnis grade >1, microfracture, abductor pathology, and previous hip conditions. A subgroup of athletes were matched to athletes who did not undergo IFL by age ± 5 years, sex, and body mass index ± 5. There were 75 athletes eligible for inclusion, 60 (80.0%) of whom had minimum 2-year follow-up. All patient-reported outcome (PRO) scores demonstrated significant improvements at latest follow-up (P < .001). Mean satisfaction was 7.9. No patients converted to arthroplasty. Painful snapping was resolved in 55 athletes (91.7%). Nine athletes (15.0%) had nonpainful snapping at follow-up. Thirty-nine (65%) returned to their sport. Forty (66.7%) maintained or improved their competitive abilities. There was one case (1.6%) of temporary postoperative numbness. There were no complaints of weakness in hip flexion. Forty-one IFL athletes were matched to 41 controls. No differences were detected in demographics, follow-up time, intraoperative findings, procedures, mean magnitudes of improvement, or return to sports. In competitive athletes, IFL during hip arthroscopy is safe and demonstrates favorable improvements in PROs and VAS, high satisfaction, and high rate of symptom resolution at a minimum of 2 years postoperatively. Most patients were able to return to sports and maintain or improve their competitive levels. These results were similar to a control group of athletes not requiring IFL. Level III, case-control study.


Protracted, Intermittent Outbreak of Salmonella Mbandaka Linked to a Restaurant - Michigan, 2008-2019.
In 2018, Michigan public health officials determined that a single restaurant in southwest Michigan was the source for a protracted, intermittent outbreak of Salmonella enterica serotype Mbandaka infections occurring since 2008. Isolates from 36 infected persons shared two highly related pulsed-field gel electrophoresis (PFGE) patterns and highly related whole genome sequencing (WGS) subtypes. The initial focus of the local public health investigation on food items rather than food sources (i.e., restaurants) through a questionnaire, difficulty in food history recollection among ill persons, and sporadic case identification over periods from months to years contributed to delayed source identification. The Kalamazoo County Health and Community Services Department (KHCSD) and the Michigan Department of Health and Human Services (MDHHS) collected clinical specimens, performed multiple rounds of environmental testing, and conducted multiple regulatory visits, and based on accumulated findings over 10 years, identified the restaurant source. A 2018 investigation by KCHCSD and MDHHS found that environmental samples and stool specimens from asymptomatic restaurant employees tested positive for the Salmonella Mbandaka outbreak strain. A complex association between the restaurant environment and employees resulted in patron illnesses. Environmental health interventions, facility renovation, asymptomatic employee exclusions, employee health monitoring, and recurrent facility environmental sampling measures were implemented. As a result of ongoing cases and environmental persistence of Salmonella Mbandaka, the restaurant closed permanently in 2018. Restaurant employee stool testing and environmental sampling for Salmonella early during the investigation of confirmed Salmonella cases linked to a restaurant enhances source identification. Exclusion or restriction of asymptomatic food workers with stool-positive nontyphoidal Salmonella should be considered part of restaurant outbreak mitigation.


Predictive value of the systemic immune inflammation (SII) index for stroke-associated pneumonia.
To investigate the predictive value of the systemic immune inflammation (SII) index on the occurrence of stroke-associated pneumonia (SAP) in patients with acute stroke. Data of patients with or without a previous history of pulmonary who visited the First Affiliated Hospital of Kunming Medical University within 24 h of the onset of stroke were collected between January 2017 and December 2019. Patient's demographic data, stroke type, past medical history, National Institutes of Health Stroke Scale score, Glasgow Coma score, and laboratory tests were collected. Logistic regression models and receiver-operating characteristic (ROC) curves were used to investigate the predictive value of SII for the development of SAP in patients with stroke. We included 395 patients with acute stroke, with a mean age of 63.89 ± 13.42 years, of whom 340 (86.1%) had ischemic stroke, and 55 (13.9%) had hemorrhagic stroke. Out of 395, 113 (28.6%) had SAP and 282 (71.4%) did not, and the SII level in the SAP group was higher than that of the non-SAP group (p < .05). Logistic regression analysis of patients with stroke showed that higher SII was a risk factor for SAP in patients with stroke (per 100 units, HR = 1.081, 95% CI: 1.035-1.130, p < .001), and tertile grouping of SII showed that the risk of SAP was 5.059 times higher in the SIIQ3 group than in the SIIQ1 group (95% CI: 2.061-12.418, p < .001). ROC curve analysis indicated that the SII index had predictive value for the occurrence of SAP in patients with stroke, with an area under the curve of 0.752 (95% CI: 0.698-0.806). When the cutoff value was 861.01, the SII predicted SAP in patients with stroke with a sensitivity of 61.9% and a specificity of 76.2%. Higher SII is an independent risk factor for the development of SAP in patients with stroke and has some predictive value for the development of SAP.


Sterile neutrophilic folliculitis with perifollicular vasculopathy: a distinctive cutaneous reaction pattern reflecting systemic disease.
The authors prospectively encountered skin biopsies from 20 patients which demonstrated a neutrophilic or suppurative and granulomatous folliculitis accompanied by a folliculocentric neutrophilic vascular reaction of Sweet's-like or leukocytoclastic vasculitis subtypes. While in each case the histomorphology raised diagnostic consideration of bacterial folliculitis, patients frequently expressed systemic complaints such as arthritis, fever, and malaise, and special stains for micro-organisms were negative. Among the clinical presentations were folliculitis, vasculitis, acneiform eruptions, vesiculopustular lesions, and erythema nodosum-like lesions, with the legs, arms, and upper back being the most commonly involved sites. Nineteen patients were found to have specific underlying systemic diseases, namely, inflammatory bowel disease, Reiter's disease, Behçet's disease, hepatitis B, connective tissue disease including mixed connective tissue disease and rheumatoid arthritis, scrofuloderma, and hematologic dyscrasias. The other patient had antecedent bacterial sinusitis in the setting of atopy. The folliculocentric nature of these lesions may reflect preferential processing of antigens through the hair follicle and/or homology between bacterial and follicular heat shock proteins in the susceptible host, namely, one who responds excessively to exogenous antigenic triggers. Folliculitis with folliculocentric vasculopathy may be a clue to underlying systemic disease and/or an extracutaneous infection. Certain light microscopic features in concert with the clinical presentation may distinguish such cases from conventional infectious folliculitis.


Fear, fight, familiarize: the experiences of people living with relapsing-remitting multiple sclerosis and taking oral medication.
Purpose: In addition to becoming familiar with the life changing event of having a chronic illness and exploring its meaning in daily life, people with relapsing-remitting Multiple Sclerosis (RRMS) are faced with important decisions about immunomodulating treatment. Biomedical research on the use of Disease Modifying Therapies (DMTs) mostly focuses on adherence, conceptualized and understood as a behavioral act leading to a desired outcome. Less attention has been paid to the meaning for a person with RRMS of starting and continuing the use of DMTs. Studies on the experiences of people with RRMS taking orally administered DMTs are lacking. The aim of this phenomenological study was to examine the experiences of people with RRMS taking oral medication. Methods: The study was guided by Interpretative Phenomenological Analysis (IPA) and Phenomenology of Practice. 25 persons with RRMS participated in in-depth interviews. Results: In general, participants of this study find themselves in alternating phases that vary by degree of experienced unfamiliarity or familiarity with concern to one's illness, one's changing body, and one's new life. The meaning of taking medication is closely related to these phases. Conclusions: Adherence serves a purpose in the lifeworlds of participants. Medication is the embodiment of this purpose. The pill has inherent meaning.


Spatiotemporal flow of information in the early visual pathway.
The spatial components of a visual scene are processed neurally in a sequence of coarse features followed by fine features. This coarse-to-fine temporal stream was initially considered to be a cortical function, but has recently been demonstrated in the dorsal lateral geniculate nucleus. The goal of this study was to test the hypothesis that coarse-to-fine processing is present at earlier stages of visual processing in the retinal ganglion cells that supply lateral geniculate nucleus (LGN) neurons. To compare coarse-to-fine processing in the cat's visual system, we measured the visual responses of connected neuronal pairs from the retina and LGN, and separate populations of cells from each region. We found that coarse-to-fine processing was clearly present at the ganglion cell layer of the retina. Interestingly, peak and high-spatial-frequency cutoff responses were higher in the LGN than in the retina, indicating that there was a progressive cascade of coarse-to-fine information from the retina to the LGN to the visual cortex. The analysis of early visual pathway receptive field characteristics showed that the physiological response interplay between the center and surround regions was consistent with coarse-to-fine features and may provide a primary role in the underlying mechanism. Taken together, the results from this study provided a framework for understanding the emergence and refinement of coarse-to-fine processing in the visual system.


The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer.
Neutrophil extracellular traps (NETs) are formed when neutrophils expel their DNA, histones and intracellular proteins into the extracellular space or circulation. NET formation is dependent on autophagy and is mediated by citrullination of histones to allow for the unwinding and subsequent expulsion of DNA. NETs have an important role in the pathogenesis of several sterile inflammatory diseases, including malignancy, therefore we investigated the role of NETs in the setting of pancreatic ductal adenocarcinoma (PDA). Neutrophils isolated from two distinct animal models of PDA had an increased propensity to form NETs following stimulation with platelet activating factor (PAF). Serum DNA, a marker of circulating NET formation, was elevated in tumor bearing animals as well as in patients with PDA. Citrullinated histone H3 expression, a marker of NET formation, was observed in pancreatic tumors obtained from murine models and patients with PDA. Inhibition of autophagy with chloroquine or genetic ablation of receptor for advanced glycation end products (RAGE) resulted in decreased propensity for NET formation, decreased serum DNA and decreased citrullinated histone H3 expression in the pancreatic tumor microenvironment. We conclude that NETs are upregulated in pancreatic cancer through RAGE-dependent/autophagy mediated pathways.


Metal-organic framework growth at functional interfaces: thin films and composites for diverse applications.
Porous metal-organic frameworks (MOFs) are highly ordered crystalline materials prepared by the self-assembly of metal ions with organic linkers to yield low density network structures of diverse topology. MOFs have attracted considerable attention over the last decade due to their facile preparation, tunable pore metrics and the ease of functionalisation of their internal surfaces, such that designer frameworks with exceptional properties for application in gas-storage, separation of small molecules, heterogeneous catalysis and drug delivery are becoming commonplace. For any material to find practical utility however, there is a need for processing and formulation into application-specific configurations. One way to do this is to prepare composite materials where the MOF is supported on a planar substrate or some other shaped body through interaction with functional groups at the support interface. This is a rapidly developing research area, and this review provides an overview of the diverse MOF composite materials prepared up to now, organised by interface type. The importance of the interface is explored within each section and while the overall emphasis is on applications of the composites, coatings and MOF-based devices, the most widely-used and successful synthetic strategies for composite formation are also presented. (183 references).


Identification of Dopaminergic Neurons That Can Both Establish Associative Memory and Acutely Terminate Its Behavioral Expression.
An adaptive transition from exploring the environment in search of vital resources to exploiting these resources once the search was successful is important to all animals. Here we study the neuronal circuitry that allows larval Drosophila melanogaster of either sex to negotiate this exploration-exploitation transition. We do so by combining Pavlovian conditioning with high-resolution behavioral tracking, optogenetic manipulation of individually identified neurons, and EM data-based analyses of synaptic organization. We find that optogenetic activation of the dopaminergic neuron DAN-i1 can both establish memory during training and acutely terminate learned search behavior in a subsequent recall test. Its activation leaves innate behavior unaffected, however. Specifically, DAN-i1 activation can establish associative memories of opposite valence after paired and unpaired training with odor, and its activation during the recall test can terminate the search behavior resulting from either of these memories. Our results further suggest that in its behavioral significance DAN-i1 activation resembles, but does not equal, sugar reward. Dendrogram analyses of all the synaptic connections between DAN-i1 and its two main targets, the Kenyon cells and the mushroom body output neuron MBON-i1, further suggest that the DAN-i1 signals during training and during the recall test could be delivered to the Kenyon cells and to MBON-i1, respectively, within previously unrecognized, locally confined branching structures. This would provide an elegant circuit motif to terminate search on its successful completion.SIGNIFICANCE STATEMENT In the struggle for survival, animals have to explore their environment in search of food. Once food is found, however, it is adaptive to prioritize exploiting it over continuing a search that would now be as pointless as searching for the glasses you are wearing. This exploration-exploitation trade-off is important for animals and humans, as well as for technical search devices. We investigate which of the only 10,000 neurons of a fruit fly larva can tip the balance in this trade-off, and identify a single dopamine neuron called DAN-i1 that can do so. Given the similarities in dopamine neuron function across the animal kingdom, this may reflect a general principle of how search is terminated once it is successful.


Smad-induced alterations of matrix metabolism by a myristoyl tetra peptide.
Regulation of extracellular matrix (ECM) components is essential for tissue homeostasis and function. We screened a small peptide that induces ECM protein synthesis for its usefulness in protecting keratinocytes. In this report, we demonstrate that myristoyl tetrapeptide Ala-Ala-Pro-Val (mAAPV) stimulates the expression of ECM proteins and inhibits the expression of metalloproteinases (MMPs) that degrade ECM proteins in Hs68 human fibroblast cells. In order to elucidate the underlying molecular mechanisms for the effects of mAAVP, we investigated the changes in gene expression in the presence of mAAPV using a cDNA microarray. Treatment with mAAPV resulted in decreased expression of MMP-related genes such as MMP1, MMP3, TIMP1 and TIMP3 and increased expression of collagen genes, including COL1A1, COL1A2, COL3A1, COL5A1 and COL6A3. The pattern of gene expression regulated by mAAPV was very similar to that of gene expression induced by transforming growth factor (TGF)-β, indicating that the TGF-β signaling pathway is crucial for simultaneous activation of several ECM-related genes by mAAPV. We examined whether the activation of SMAD, a downstream protein of TGF-β receptor, is involved in the signal transduction pathway induced by mAAPV. The results demonstrate that mAAVP directly activates SMAD2 and induces SMAD3 to bind to DNA. In conclusion, our results demonstrate that mAAPV both enhances the expression of collagen and inhibits its degradation via production of protease inhibitors that prevent enzymatic breakdown of the ECM. The results suggest that mAAPV would be a useful ECM-protecting agent.


Peptides of human thyroglobulin reactive with sera of patients with autoimmune thyroid disease.
Autoantibodies to thyroglobulin (Tg) are a prominent feature of the two autoimmune thyroid diseases, chronic lymphocytic (Hashimoto's) thyroiditis and Graves' disease. Similar autoantibodies are found in the serum of many normal individuals without evidence of thyroid disease. Previous studies have indicated that patients with autoimmune thyroid disease recognize epitopes of Tg which are not usually recognized by normal individuals. The goal of this investigation was to identify peptide fragments of Tg bearing these disease-associated epitopes. For this purpose, we utilized a panel of mAbs that bind to different epitopes of the Tg molecule. One of these mAbs (137C1) reacted with an epitope that was also recognized by the sera of patients with autoimmune thyroiditis. In the present study, we show that two peptides (15 and 23 kDa) that reacted with mAb 137C1 are located in different parts of the Tg molecule. Each peptide inhibited the binding of mAb 137C1 to the other peptide and to the intact Tg, indicating that the same epitope was represented on the two peptides. Loops and helices of the secondary structure of the two peptides might be involved in the conformational epitope recognized by mAb 137C1. A striking finding of this study is that two apparently unrelated fragments of the Tg molecule bind to the same mAb. These findings may have important ramifications with regard to epitope spread and the progression of the autoimmune response to disease.


Inflammatory biomarkers as independent prognosticators of 28-day mortality for COVID-19 patients admitted to general medicine or ICU wards: a retrospective cohort study.
Inflammatory biomarkers may be associated with disease severity and increased mortality in COVID-19 patients but have not been studied in North American populations. We sought to determine whether a set of commonly ordered inflammatory biomarkers can predict 28-day mortality. We analyzed a multi-centered (four) COVID-19 registry cohort from March 4th to December 7th, 2020. This cohort included COVID-19-positive patients admitted to medical wards or intensive care units. Patients presenting to the emergency department for COVID-19 symptoms and then subsequently discharged were also included. We performed Cox-regression analysis to measure whether commonly used biomarkers were associated with an increased 28-day mortality. Of 336 COVID-19-positive patients, 267 required hospital admission, and 69 were seen in the emergency room and discharged. The median age was 63 years (IQR 80-50) and the female-to-male ratio was 49:51. Derivation of internally validated cut-offs suggested that C-reactive protein ≥ 78.4 mg/L, neutrophil-to-lymphocyte ratio ≥ 6.1, lymphocyte-to-white blood cell ratio < 0.127, and a modified Glasgow prognostic score equal to 2 vs. 1 or 0 were associated with the highest increased risk of 28-day mortality. We provide early estimates of cut-off values for inflammatory biomarkers and indices measured at the time of admission that may be useful to clinicians for predicting 28-day mortality in North American COVID-19 patients.


Polar fluorenes and spirobifluorenes: fluorescence and fluorescence anisotropy spectra.
An extensive spectroscopic study is presented of two asymmetrically substituted fluorene dyes and of the related spiro dimers in both liquid and glassy solvents. Essential-state models are developed to accurately reproduce linear absorption and fluorescence spectra and their complex dependence on solvent polarity. The same models are exploited to quantitatively calculate fluorescence excitation and anisotropy spectra in rigid matrixes. Impressive red-edge effects observed for spiro dimers in glassy polar solvents are accurately reproduced and understood. Interchromophore interactions in the spiro dimers are very small, leading to marginal effects in absorption and fluorescence spectra, but they effectively promote energy transfer between the two chromophores, as best evidenced comparing anisotropy spectra of the substituted fluorenes and of corresponding spiro dimers dissolved in glassy solvent matrixes.


Chemotherapy in elderly patients with metastatic gastric cancer; a single Turkish cancer center experience.
To analyze the results of chemotherapy applied at the Bülent Ecevit University School of Medicine, Department of Medical Oncology, to elderly patients with metastatic gastric cancer (GC). The study retrospectively investigated hospital records including pathological reports, imaging records, chemotherapy regimens, response and toxicity profile. All patients received systemic chemotherapy for pathologically proven metastatic GC at the Bülent Ecevit University School of Medicine, Department of Medical Oncology. From 2005 to 2012, 23 metastatic GC patients older than 70 years were treated with systemic chemotherapy as a first-line therapy. As the first-line chemotherapy, 17 (74%) patients received polychemotherapy and the remaining six (26%) patients received monotherapy. Overall, 113 cycles were administered. The median progression free survival (PFS) for the first-line chemotherapy was 6 months (95% CI, 0-16) and the median overall survival (OS) was 14 months (95% CI, 3-30). Multivariate analysis revealed that decreased OS was significantly associated with poor Eastern Cooperative Oncology Group (ECOG) performance status (p=0.045), elevated carcinoembryonic antigen (CEA) levels at the diagnosis time (p = 0.040) and decreased number of chemotherapy cycles (p=0.019) with R-Sq (adj) = 41, 6%. One patient had a complete response with docetaxel, cisplatin and fluorouracil combined (DCF) regimen and had 12 months of disease free survival (DFS). This is the first study investigating the outcomes of chemotherapy in Turkish elderly metastatic GC patients. Docetaxel, cisplatin and fluorouracil combination were the most common regimen, which is a tolerable and effective choice in elderly patients who had good performance status.


Patterns of postpartum depot medroxyprogesterone administration among low-income mothers.
Depot medroxyprogesterone acetate (DMPA) is often administered immediately postpartum to reduce the risk of short-interval repeat or unintended pregnancies, but little is known about the actual patterns of postpartum DMPA use. This article examines the patterns of DMPA administered among low-income new mothers in an upstate New York State community. Mothers attending urban pediatric practices (births 2009-2011) completed a mailed survey approximately 5 months after delivery. Among 83 survey items were questions about breastfeeding and timing of DMPA receipt. Unintended pregnancy was reported by 48.8% of the subjects. Their deliveries occurred across four local hospitals. Among the 31.3% of subjects who received postpartum DMPA, 62.6% received it prior to hospital discharge. Those receiving in-hospital DMPA (n=127) were significantly more likely than other mothers to be black, older, urban dwelling, non-high school graduates, multiparous, and planning to formula feed. Administration patterns differed by hospital. This study of postpartum DMPA administration among a convenience sample of low-income mothers demonstrated rates of 26% overall, but there was between-hospital variability. Additional study may identify approaches to ensure timely administration to appropriate candidates.


Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats.
Methotrexate [(+) amethopterin, L-MTX] has two carboxyl groups in its structure and is eliminated mainly by excretion into urine and bile. To investigate the biliary excretion mechanism of L-MTX, we performed in vivo and in vitro studies using mutant rats, Eisai hyperbilirubinemic rats (EHBRs), whose canalicular multispecific organic anion transporter (cMOAT) is defective as a consequence of heredity. After i.v. administration of L-MTX to EHBRs, its plasma disappearance and biliary excretion was slower than in normal Sprague Dawley rat (SDR). ATP-dependence and overshoot phenomena were observed in the uptake of [3H]L-MTX by canalicular membrane vesicles (CMV) prepared from SDR, whereas no ATP-dependence was observed in CMV from EHBRs. The ATP-dependent uptake of L-MTX by SDR CMV exhibited saturable kinetics with a Km of 295 microM. L-MTX competitively inhibited the ATP-dependent uptake of [3H]2,4-dinitrophenyl-S-glutathione, a typical substrate for cMOAT, and the inhibition constant (Ki) of L-MTX was comparable with its own Km. These results suggest that L-MTX is excreted into bile by cMOAT. The inhibitory effects of L-MTX and its optical isomer, (-) amethopterin (D-MTX), on the uptake of [3H]L-MTX differed with Kis of 326 and 93 microM, respectively, indicating that the biologically inactive D form has a higher affinity for cMOAT than L-MTX.


Concomitant digoxin toxicity and warfarin interaction in a patient receiving clarithromycin.
To report a case of a clarithromycin-associated warfarin interaction and digoxin toxicity in a patient. A 72-year-old white woman with chronic atrial fibrillation receiving long-standing therapy with digoxin 0.25 mg/d and warfarin 22.5 mg/wk was prescribed clarithromycin 500 mg three times daily for eradication of Helicobacter pylori. The patient presented to the emergency department with gastrointestinal symptoms, weakness, dizziness, and visual changes 12 days after initiation of clarithromycin. Laboratory results revealed a serum digoxin concentration of 4.6 ng/mL (normal 1.0-2.6) and an international normalized ratio of 7.3 (2.0-3.0). Digoxin, warfarin, and clarithromycin were discontinued and the patient was admitted to the hospital for treatment to resolve the symptoms and to return laboratory values to a safe range. Reduced dosages of digoxin (0.125 mg/d) and warfarin (17.5 mg/wk) were restarted on day 7 of hospitalization. The patient was discharged on day 11 in good condition. Several reports of clarithromycin-induced drug interactions with digoxin and with warfarin have been published. Previously, case reports of macrolide-associated interactions mainly involved erythromycin, but more recently have implicated clarithromycin. The interaction between clarithromycin and warfarin is thought to occur from an inhibition of the cytochrome P450 drug metabolizing system. Clarithromycin is thought to cause digoxin toxicity by an alteration of the digoxin-metabolizing gut flora, thereby causing an increase in the digoxin concentration in susceptible individuals. Drug interactions can occur by different mechanisms in the same patient. Potential drug interactions can occur between commonly prescribed medications. It is important to monitor patients for symptoms and alterations in laboratory values to prevent not only serious complications, but also unnecessary hospitalizations.


Comparison of Blood-Based Shotgun and Targeted Metagenomic Sequencing for Microbiological Diagnosis of Infective Endocarditis.
Shotgun and targeted metagenomic sequencing have been shown in separate studies to be potentially useful for culture-free pathogen identification in blood and/or plasma of patients with infective endocarditis (IE). However, the 2 approaches have not been directly compared. The aim of this study was to compare shotgun metagenomic sequencing with targeted metagenomic sequencing (tMGS) for organism identification in blood or plasma of patients with IE. Patients with possible or definite IE were prospectively enrolled from October 2020 to July 2021. Shotgun metagenomic sequencing was performed with the Karius test, which uses microbial cell-free DNA (mcfDNA) sequencing to detect, identify, and quantitate DNA-based pathogens in plasma. tMGS was performed using a 16S ribosomal RNA (rRNA) polymerase chain reaction assay targeting the V1 to V3 regions of the 16S rRNA gene. Results were compared using the McNemar test of paired proportions. Samples from 34 patients were investigated. The Karius test was positive in 24/34 (71%), including 3/6 (50%) with blood culture-negative endocarditis (BCNE), which was not significantly different from the positivity rate of tMGS (P = .41). Results of the Karius test were concordant with tMGS in 75% of cases. The Karius test detected 2 cases of methicillin-resistant Staphylococcus aureus among the 7 S. aureus detections, in accordance with results of phenotypic susceptibility testing. The combination of blood cultures, the Karius test, and tMGS found a potential causative pathogen in 33/34 (97%), including 5/6 with BCNE. The Karius test and tMGS yielded comparable detection rates; however, beyond organism identification, the Karius test generated potentially useful antibiotic resistance data.


After-effects of cognitive control on pain.
The higher order processes involved in self-regulation are generally thought to depend on cognitive (attentional/executive) functions with limited resources. Experimental studies further show that exerting self-control in a first task results in decreased performance in other following self-control tasks, which may be interpreted as the consequence of either effective or perceived resource depletion outlasting the first task. Given that higher order cognitive/attentional processes are also considered to be involved in pain modulatory mechanisms, we tested the idea that pain could be influenced by prior mobilization of cognitive resources. The present study investigated the consequences of performing a cognitively demanding task on subsequent pain (ratings) and spinal nociceptive responses (nociceptive flexion reflex, NFR) elicited by noxious electrical stimulations in healthy volunteers. Participants received four noxious stimulations immediately after each of six successive blocks (2 min each) of a numerical Stroop task in a neutral condition (low cognitive demand) and six successive blocks in an interference condition (high cognitive demand). Results revealed that pain was rated higher following the condition requiring higher cognitive control. A similar effect was observed on the NFR. These findings suggest that pain regulation mechanisms including the descending pain modulatory system may be less efficient after the performance of tasks requiring high cognitive control resulting in stronger pain experience.


Moving Evidence to Action: A Strategy to Support the Implementation of Comprehensive Violence Prevention Efforts.
For public health agencies, the pragmatic need to bring together science and practice to affect public health outcomes manifests in the implementation of prevention strategies with the best available evidence. Knowledge translation makes scientific findings understandable to the knowledge user, often through synthesis of the best available evidence. Implementation science promotes the adoption and integration of evidence through prevention strategies implemented within various contexts. Working together, knowledge translation and implementation science can promote the uptake and advancement of scientific and practice-based evidence for strategies that will have the greatest impact across a variety of contexts. Violence Prevention in Practice (VPP) is an online resource designed to help practitioners select, adapt, implement, and evaluate multiple prevention strategies included in five technical packages developed by Centers for Disease Control's Division of Violence Prevention. A technical package translates the best available evidence into a core set of prevention strategies intended to be broadly implemented. VPP supports communities in using the technical package strategies in combination, drawing on key implementation science principles. In this article, we explain the process for developing VPP and provide a framework that can be used to develop similar guidance in other health promotion areas. The framework explains how both general components, such as selection and adaptation, come together with strategy-specific implementation guidance. Distinct from typical planning models, VPP is not designed as a linear stepwise process, and it allows practitioners to use one or more components alone, as well as helps practitioners link across components as needed.


An appraisal of the radiological features of pulmonary tuberculosis in Ilorin.
Pulmonary tuberculosis (PTB) remains a disease of serious socio-economic and public health importance in Nigeria. This study was carried out to appraise its radiological features with the aim of identifying any changes or new patterns. The chest radiographs of PTB patients examined in the radiology department, UITH, Ilorin over a 5-year period from January 1995 to December 1999 were studied. There were 423 patients including 47 children (0-14 years). Adults of working age (21-60 years) were more affected. There was a female preponderance. The most common radiological features were cavity formation, streaky opacities, reticulonodular opacities and nodular opacities. These features often occurred together in same patients and more usually bilaterally. However, where cavity formation was unilateral, it was more on the left side. In childhood disease, hilar lymphadenopathy, bronchopneumonia and pleural fluid collection were the most common. Cavity formation in children was equally frequent in the 0-5 years and the 6-10 years age groups. The chest radiograph remains an important tool in the diagnosis of PTB. The major radiological features remain the same but the patterns of sex distribution and cavity formation are probably changing. Key words: Pulmonary tuberculosis; radiological features.


Metastatic Melanoma of the Parotid Glands Bilaterally.
Melanoma is the most serious form of skin cancers and life-time risk of melanoma is increasing rapidly both in men and women. Melanoma in the parotid gland is seen rarely and it is more likely to be metastatic disease. We present here a rare case of metastatic malignant melanoma from the forehead skin to the parotid glands bilaterally.


Molecular Elucidation of Disease Biomarkers at the Interface of Chemistry and Biology.
Disease-related biomarkers are objectively measurable molecular signatures of physiological status that can serve as disease indicators or drug targets in clinical diagnosis and therapy, thus acting as a tool in support of personalized medicine. For example, the prostate-specific antigen (PSA) biomarker is now widely used to screen patients for prostate cancer. However, few such biomarkers are currently available, and the process of biomarker identification and validation is prolonged and complicated by inefficient methods of discovery and few reliable analytical platforms. Therefore, in this Perspective, we look at the advanced chemistry of aptamer molecules and their significant role as molecular probes in biomarker studies. As a special class of functional nucleic acids evolved from an iterative technology termed Systematic Evolution of Ligands by Exponential Enrichment (SELEX), these single-stranded oligonucleotides can recognize their respective targets with selectivity and affinity comparable to those of protein antibodies. Because of their fast turnaround time and exceptional chemical properties, aptamer probes can serve as novel molecular tools for biomarker investigations, particularly in assisting identification of new disease-related biomarkers. More importantly, aptamers are able to recognize biomarkers from complex biological environments such as blood serum and cell surfaces, which can provide direct evidence for further clinical applications. This Perspective highlights several major advancements of aptamer-based biomarker discovery strategies and their potential contribution to the practice of precision medicine.


Cardiotoxicity of trastuzumab in patients with HER2-positive gastric cancer.
Trastuzumab-induced cardiotoxicity (TIC) is the primary adverse event that limits the use of trastuzumab in HER2-positive breast cancer patients. However, the incidence and risk factors of TIC in HER2-positive gastric cancer are not known. Therefore, we evaluated the incidence and predictive factors of TIC in gastric cancer patients treated with trastuzumab in clinical practice. We reviewed cardiac dysfunction in HER2-positive gastric cancer patients between December 2005 and April 2015 in a prospectively-collected database that included prospective clinical trials at Yonsei Cancer Center, Republic of Korea. TIC was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10 percentage points from the baseline to a value less than 55%, as identified by a multiple-gated acquisition scan or an echocardiogram. Among the 115 patients, 70 patients (60.9%) received trastuzumab combined with chemotherapy, and 45 patients (39.1%) received chemotherapy alone as a first-line therapy. Symptomatic heart failure was not observed in either group, but a significant asymptomatic drop in LVEF was noted in five (7.1%) of the trastuzumab combined-group patients and in one (2.2%) chemotherapy-only group patient [hazard ratio (HR), 3.47; 95% confidence interval (CI), 0.40-29.8; P=0.257]. TIC was observed more frequently in elderly patients than in younger patients (HR, per age in year, 1.16; 95% CI, 1.02-1.31; P=0.019). Similar to prior observations in breast cancer, TIC in gastric cancer patients is not frequent or reversible. However, the asymptomatic drop in LVEF should be monitored continually in HER2-positive gastric cancer patients treated with trastuzumab, especially in elderly patients.


Upper extremity size differences in brachial plexus birth palsy.
The purpose of this investigation was to determine size differences between affected and unaffected upper extremities in patients with brachial plexus birth palsy (BPBP). Forty-eight patients with BPBP underwent measurements of the bilateral upper extremities. Average age at the time of evaluation was 47 months. In addition, patients or families were asked "How important is the difference in arm size and appearance to you?" Active motion was assessed using the modified Mallet classification, Toronto Test Score, and Hospital for Sick Children Active Movement Scale. Correlation between ratios of affected to unaffected limb lengths and girths and measures of active motion were assessed using Spearman's rank correlation coefficient. Upper arm, forearm, and hand lengths of the affected limbs were, on average, 95%, 94%, and 97% of the contralateral unaffected side, respectively. Upper arm girth, forearm girth, and hand width were, on average, 97%, 98%, and 95% of the contralateral side, respectively. All differences achieved statistical significance (p < 0.01). Furthermore, over 37% of patients or families reported that limb differences were "very" or "extremely important" to them. No statistically significant correlation between age and limb length discrepancy was noted. Furthermore, there were no correlations between upper limb discrepancies and measures of active motion in individual patients. Patients with BPBP and persistent neurological deficits may expect the affected upper extremity to be on average approximately 95% the length and girth of the contralateral limb. These differences do not correlate with patient age or clinical measurements of active movement.


β-NMR Investigation of the Depth-Dependent Magnetic Properties of an Antiferromagnetic Surface.
By measuring the prototypical antiferromagnet α-Fe_{2}O_{3}, we show that it is possible to determine the static spin orientation and dynamic spin correlations within nanometers from an antiferromagnetic surface using the nuclear spin polarization of implanted ^{8}Li^{+} ions detected with β-NMR. Remarkably, the first-order Morin spin reorientation in single crystal α-Fe_{2}O_{3} occurs at the same temperature at all depths between 1 and 100 nm from the (110) surface; however, the implanted nuclear spin experiences an increased 1/T_{1} relaxation rate at shallow depths revealing soft-surface magnons. The surface-localized dynamics decay towards the bulk with a characteristic length of ε=11±1 nm, closely matching the finite-size thresholds of hematite nanostructures.


Added value of soluble tumor necrosis factor-α receptor 1 as a biomarker of ESRD risk in patients with type 1 diabetes.
Recent studies have suggested that circulating levels of the tumor necrosis factor-α receptor 1 (sTNFαR1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified. Circulating levels of sTNFαR1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNFαR1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data. A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA1c, shorter duration of diabetes, and circulating levels of sTNFαR1. Notably, sTNFαR1 outperformed estimated glomerular filtration rate in terms of R(2). Circulating levels of the sTNFαR1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNFαR1 (as a -0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R(2), the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16-0.28; P < 0.0001) and 0.98 (0.78-1.23; P < 0.0001), respectively. The median increment in the risk score after including sTNFαR1 in the prediction model was 0.18 (0.12-0.30; P < 0.0001). Circulating levels of sTNFαR1 are independently associated with the cumulative incidence of ESRD. This association is both significant and biologically plausible and appears to provide added value as a biomarker, based on the absolute values of NRI and IDI.


Job satisfaction among a multigenerational nursing workforce.
To explore generational differences in job satisfaction. Effective retention strategies are required to mitigate the international nursing shortage. Job satisfaction, a strong and consistent predictor of retention, may differ across generations. Understanding job satisfaction generational differences may lead to increasing clarity about generation-specific retention approaches. The Ontario Nurse Survey collected data from 6541 Registered Nurses. Participants were categorized as Baby Boomer, Generation X or Generation Y based on birth year. Multivariate analysis of variance explored generational differences for overall and specific satisfaction components. In overall job satisfaction and five specific satisfaction components, Baby Boomers were significantly more satisfied than Generations X and Y. It is imperative to improve job satisfaction for younger generations of nurses. Strategies to improve job satisfaction for younger generations of nurses may include creating a shared governance framework where nurses are empowered to make decisions. Implementing shared governance, through nurse-led unit-based councils, may lead to greater job satisfaction, particularly for younger nurses. Opportunities to self schedule or job share may be other potential approaches to increase job satisfaction, especially for younger generations of nurses. Another potential strategy would be to aggressively provide and support education and career-development opportunities.


Screening for Protein-Protein Interaction Inhibitors Using a Bioluminescence Resonance Energy Transfer (BRET)-Based Assay in Yeast.
The bioluminescence resonance energy transfer (BRET) technology is a widely used live cell-based method for monitoring protein-protein interactions as well as conformational changes within proteins or molecular complexes. Considering the emergence of protein-protein interactions as a new promising class of therapeutic targets, we have adapted the BRET method in budding yeast. In this technical note, we describe the advantages of using this simple eukaryotic model rather than mammalian cells to perform high-throughput screening of chemical compound collections: genetic tractability, tolerance to solvent, rapidity, and no need of expensive robotic systems. Here, the HDM2/p53 interaction, related to cancer, is used to highlight the interest of this technology in yeast. Sharing the protocol of this BRET-based assay with the scientific community will extend its application to other protein-protein interactions, even though it is toxic for mammalian cells, in order to discover promising therapeutic candidates.