Protecting Young Children From Tobacco Smoke Exposure: A Pilot Study of Project Zero Exposure.
Tobacco smoke exposure (TSE) harms children, who are often "captive smokers" in their own homes. Project Zero Exposure is a parent-oriented, theory-based intervention designed to reduce child TSE. This paper reports on findings from the pilot study, which was conducted in Israel from 2013 to 2014. The intervention consisted of motivational interviews, child biomarker and home air quality feedback, a Web site, a video, and self-help materials. The primary outcome was child TSE as measured by hair nicotine. Secondary outcome measures were air nicotine and particulate matter, parental reports of TSE, parental smoking behavior, and TSE child protection. A single-group pre- and posttest design was used. Twenty-six of the 29 recruited families completed the study. The intervention was feasible to implement and acceptable to participants. Among the 17 children with reliable hair samples at baseline and follow-up, log hair nicotine dropped significantly after the intervention (P = .04), hair nicotine levels decreased in 64.7% of children, and reductions to levels of nonexposed children were observed in 35.3% of children. The number of cigarettes smoked by parents (P = .001) and parent-reported child TSE declined (P = .01). Logistical issues arose with measurement of all objective measures, including air nicotine, which did not decline; home air particulate matter; and hair nicotine. A program based on motivational interviewing and demonstrating TSE and contamination to parents in a concrete and easily understandable way is a promising approach to protect children from TSE. Further research is needed to enhance current methods of measurement and assess promising interventions.


Dosimetry of a novel rotating gamma system for stereotactic radiosurgery.
This is the first report of the basic dosimetric properties of a new rotating gamma system: the RGS Vertex360™. Dosimetric properties were compared to those measured with traditional rotating gamma systems and with the Leksell Gamma Knife. The RGS Vertex360 is similar to the original rotating gamma system developed by OUR New Medical Technology Development Co., Ltd. (Shenzen, China), however, there are a few notable differences including the angular arrangement of the sources. Basic dosimetric properties of the RGS Vertex360 were measured including: absorbed dose rate, output factors, mechanical and radiation center accuracy and dose profiles. A significant discrepancy was observed for the 4 mm output measured from the RGS Vertex360 compared to those obtained from previous rotating gamma units: the 4 mm output from the RGS Vertex360 (0.807) was 32-38% higher than those measured from previous units. This is somewhat surprising considering the excellent agreement in 4 mm outputs from the RGS Vertex360, the corresponding outputs specified by the manufacturer of the original OUR unit and those measured for the Leksell Gamma Knife. The mechanical accuracy was similar to previous rotating gamma systems while the 50-90% penumbra was narrower. Dose profiles compared favorably with the Leksell Gamma Knife: in many instances the measured penumbra was narrower for the RGS Vertex360. Notwithstanding the 4 mm output factor, the dosimetric properties of the RGS Vertex360 compared favorably with those of previous rotating gamma systems. The 4 mm output discrepancy was attributed to suboptimal alignment of the primary and secondary collimators in previous studies. The dosimetric properties of the RGS Vertex360 and the Leksell Gamma Knife were similar and, taken together, the results suggest that the new rotating gamma system is well suited for stereotactic radiosurgery procedures.


Chronic cold exposure affects the antioxidant defense system in various rat tissues.
Chronic exposure to stress alters the normal body homeostasis and, hence, leads to the development of various human pathologies, which might involve alterations in the antioxidant defense system. We studied the effect of chronic cold exposure on oxidative stress and antioxidant defense system in various rat tissues. Male albino rats (Wistar strain), 2-3 months old, were exposed to 3 weeks of cold treatment. Antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) were measured in addition to the antioxidants, ascorbic acid (AsA) and glutathione (GSH), and the prooxidants, lipid peroxides (LPO) and xanthine oxidase (XOD), in brain, heart, kidney, liver and small intestine using standard protocols. Chronic cold exposure resulted in a significant increase in LPO in all the tissues studied while XOD was increased in the brain and intestine. Total SOD activity was significantly decreased in all the tissues, whereas CAT activity was significantly increased in the kidney and decreased in heart, liver and intestine in the animals exposed to cold. GPx activity was increased only in the brain and intestine of stressed rats. Chronic cold exposure resulted in significant decrease in GR activity in heart, liver and intestine. GST activity was increased (except heart) and GSH was significantly decreased in all the tissues in treated rats. AsA was increased in kidney and intestine but decreased in heart of stressed animals. The observed changes in the antioxidant defense system are tissue specific, but it is evident that chronic exposure to cold leads to oxidative stress by displacing the prooxidant-antioxidant balance of this defense system by increasing the prooxidants while depleting the antioxidant capacities.


Increasing film-focus distance (FFD) reduces radiation dose for x-ray examinations.
Increasing film-focus distance (FFD) from the traditional 100 cm has been shown to be an effective method of reducing dose whilst maintaining image quality. In particular, previous work increasing the FFD from 100 to 130 cm for lumbar spine examinations demonstrated an effective dose reduction of 44%. Objective. The current study continues on from this work by investigating the dose-reducing efficacy of this FFD change for pelvis X-ray examinations. Materials and methods. Dose measurements at 100 and 130 cm using thermoluminescent dosemeters were undertaken using an anthropomorphic phantom and patients. Image quality was assessed using CEC anatomical criteria and psychophysical tests. Results. The results showed that increasing the FFD results in a reduction in effective dose of 33%, with no change in image quality. The data provided in this and previous studies demonstrate the need for rapid implementation of this simple cost-effective procedure across imaging departments, leading to an important reduction in collective dose. Conclusion. The CEC recommendation of using 115 cm FFD for a number of procedures, although useful compared with 100 cm, undervalues by a factor between 2 and 3 the potential of this dose-reducing tool.


An oxidative enzyme boosting the enzymatic conversion of recalcitrant polysaccharides.
Efficient enzymatic conversion of crystalline polysaccharides is crucial for an economically and environmentally sustainable bioeconomy but remains unfavorably inefficient. We describe an enzyme that acts on the surface of crystalline chitin, where it introduces chain breaks and generates oxidized chain ends, thus promoting further degradation by chitinases. This enzymatic activity was discovered and further characterized by using mass spectrometry and chromatographic separation methods to detect oxidized products generated in the absence or presence of H(2)(18)O or (18)O(2). There are strong indications that similar enzymes exist that work on cellulose. Our findings not only demonstrate the existence of a hitherto unknown enzyme activity but also provide new avenues toward more efficient enzymatic conversion of biomass.


Incidence, correlates, and outcomes of acute, hospital-acquired anemia in patients with acute myocardial infarction.
Anemia is common among patients hospitalized with acute myocardial infarction and is associated with poor outcomes. Less is known about the incidence, correlates, and prognostic implications of acute, hospital-acquired anemia (HAA). We identified 2909 patients with acute myocardial infarction who had normal hemoglobin (Hgb) on admission in the multicenter TRIUMPH registry and defined HAA by criteria proposed by Beutler and Waalen. We used hierarchical Poisson regression to identify independent correlates of HAA and multivariable proportional hazards regression to identify the association of HAA with mortality and health status. At discharge, 1321 (45.4%) patients had HAA, of whom 348 (26.3%) developed moderate-severe HAA (Hgb <11 g/dL). The incidence of HAA varied significantly across hospitals (range, 33% to 69%; median rate ratio for HAA, 1.13; 95% confidence interval, 1.07 to 1.23, adjusting for patient characteristics). Although documented bleeding was more frequent with more severe HAA, fewer than half of the patients with moderate-severe HAA had any documented bleeding. Independent correlates of HAA included age, female sex, white race, chronic kidney disease, ST-segment elevation myocardial infarction, acute renal failure, use of glycoprotein IIb/IIIa inhibitors, in-hospital complications (cardiogenic shock, bleeding and bleeding severity), and length of stay. After adjustment for GRACE score and bleeding, patients with moderate-severe HAA had higher mortality rates (hazard ratio, 1.82; 95% confidence interval, 1.11 to 2.98 versus no HAA) and poorer health status at 1 year. HAA develops in nearly half of acute myocardial infarction hospitalizations among patients treated medically or with percutaneous coronary intervention, commonly in the absence of documented bleeding, and is associated with worse mortality and health status. Better understanding of how HAA can be prevented and whether its prevention can improve patient outcomes is needed.


Isolation of a cell-surface receptor for chick neural retina adherons.
Embryonic chick neural retina cells release glycoprotein complexes, termed adherons, into their culture medium. When absorbed onto the surface of petri dishes, neural retina adherons increase the initial rate of neural retina cell adhesion. In solution they increase the rate of cell-cell aggregation. Cell-cell and adheron-cell adhesions of cultured retina cells are selectively inhibited by heparan-sulfate glycosaminoglycan, but not by chondroitin sulfate or hyaluronic acid, suggesting that a heparan-sulfate proteoglycan may be involved in the adhesion process. We isolated a heparan-sulfate proteoglycan from the growth-conditioned medium of neural retina cells, and prepared an antiserum against it. Monovalent Fab' fragments of these antibodies completely inhibited cell-adheron adhesion, and partially blocked spontaneous cell-cell aggregation. An antigenically and structurally similar heparan-sulfate proteoglycan was isolated from the cell surface. This proteoglycan bound directly to adherons, and when absorbed to plastic, stimulated cell-substratum adhesion. These data suggest that a heparan-sulfate proteoglycan on the surface of chick neural retina cells acted as a receptor for adhesion-mediating glycoprotein complexes (adherons).


Recognizing chromosomes in trouble: association of the spindle checkpoint protein Bub3p with altered kinetochores and a unique defective centromere.
Spindle checkpoint proteins monitor the interaction of the spindle apparatus with the kinetochores, halting anaphase even if the microtubule attachment of only a single chromosome is altered. In this study, we show that Bub3p of Saccharomyces cerevisiae, an evolutionarily conserved spindle checkpoint protein, exhibits distinct interactions with an altered or defective kinetochore(s). We show for the first time that green fluorescent protein-tagged S. cerevisiae Bub3p (Bub3-GFP) exhibits not only a diffuse nuclear localization pattern but also forms distinct nuclear foci in unperturbed growing and G(2)/M-arrested cells. As Bub3-GFP foci overlap only a subset of kinetochores, we tested a model in which alterations or defects in kinetochore or spindle integrity lead to the distinct enrichment of Bub3p at these structures. In support of our model, kinetochore-associated Bub3-GFP is enriched upon activation of the spindle checkpoint due to nocodazole-induced spindle disassembly, overexpression of the checkpoint kinase Mps1p, or the presence of a defective centromere (CEN). Most importantly, using a novel approach with the chromatin immunoprecipitation (ChIP) technique and genetically engineered defective CEN [CF/CEN6(Delta31)], we determined that Bub3-GFP can associate with a single defective kinetochore. Our studies represent the first comprehensive molecular analysis of spindle checkpoint protein function in the context of a wild-type or defective kinetochore(s) by use of live-cell imaging and the ChIP technique in S. cerevisiae.


Theoretical Investigations of the Chiral Transition of α-Amino Acid Confined in Various Sized Armchair Boron-Nitride Nanotubes.
We computationally study the chiral transition process of the α-Ala molecule under confined different sizes of armchair SWBNNTs to explore the confinement effect. We find that the influence of a confinement environment (in armchair SWBNNTs) on the α-Ala molecule would lead to different reaction pathways. Meanwhile, the preferred reaction pathway is also different in various sizes of armchair SWBNNTs, and their energy barriers for the rate-limiting step decrease rapidly with the decreasing of the diameters of the nanotubes. It is obvious that significant decrease of the chiral transition energy barrier occurs compared with the isolated α-Ala molecule chirality conversion mechanism, by ∼15.6 kcal mol-1, highlighting the improvement in the activity the enantiomers of α-Ala molecule. We concluded that the confinement environment has a significant impact at the nanoscale on the enantiomer transformation process of the chiral molecule.


Revealing hidden insect-fungus interactions; moderately specialized, modular and anti-nested detritivore networks.
Ecological networks are composed of interacting communities that influence ecosystem structure and function. Fungi are the driving force for ecosystem processes such as decomposition and carbon sequestration in terrestrial habitats, and are strongly influenced by interactions with invertebrates. Yet, interactions in detritivore communities have rarely been considered from a network perspective. In the present study, we analyse the interaction networks between three functional guilds of fungi and insects sampled from dead wood. Using DNA metabarcoding to identify fungi, we reveal a diversity of interactions differing in specificity in the detritivore networks, involving three guilds of fungi. Plant pathogenic fungi were relatively unspecialized in their interactions with insects inhabiting dead wood, while interactions between the insects and wood-decay fungi exhibited the highest degree of specialization, which was similar to estimates for animal-mediated seed dispersal networks in previous studies. The low degree of specialization for insect symbiont fungi was unexpected. In general, the pooled insect-fungus networks were significantly more specialized, more modular and less nested than randomized networks. Thus, the detritivore networks had an unusual anti-nested structure. Future studies might corroborate whether this is a common aspect of networks based on interactions with fungi, possibly owing to their often intense competition for substrate.


BMP2 expressing genetically engineered mesenchymal stem cells on composite fibrous scaffolds for enhanced bone regeneration in segmental defects.
The treatment of critical sized bone defect remains a significant challenge in orthopedics. The objective of the study is to evaluate the effect of the combination of bone morphogenetic protein 2 (BMP2) expressing genetically engineered mesenchymal stem cells (MSCs) [MSCs engineered using a multimam vector, pAceMam1, an emerging gene delivery vector] and an osteoconductive scaffold [silica coated nanohydroxyapatite-gelatin reinforced with fibers] in enhancing bone regeneration in critical sized segmental defects. The scaffold with transfected MSCs showed significantly higher viability, proliferation and osteogenic differentiation in vitro. Further, this group augmented union and new bone formation in critical sized rat femoral segmental defect at 12 weeks when compared to control groups (scaffold with MSCs and scaffold alone). These data demonstrated that the MSCs engineered for transient expression of BMP2 can improve the repair of segmental defects, which paves an avenue for using pAceMam1 as a vector for bone tissue regeneration.


Effectiveness of Integrated Palliative and Oncology Care for Patients With Acute Myeloid Leukemia: A Randomized Clinical Trial.
Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy experience substantial decline in their quality of life (QOL) and mood during their hospitalization for induction chemotherapy and often receive aggressive care at the end of life (EOL). However, the role of specialty palliative care for improving the QOL and care for this population is currently unknown. To assess the effect of integrated palliative and oncology care (IPC) on patient-reported and EOL outcomes in patients with AML. We conducted a multisite randomized clinical trial of IPC (n = 86) vs usual care (UC) (n = 74) for patients with AML undergoing intensive chemotherapy. Data were collected from January 2017 through July 2019 at 4 tertiary care academic hospitals in the United States. Patients assigned to IPC were seen by palliative care clinicians at least twice per week during their initial and subsequent hospitalizations. Patients completed the 44-item Functional Assessment of Cancer Therapy-Leukemia scale (score range, 0-176) to assess QOL; the 14-item Hospital Anxiety and Depression Scale (HADS), with subscales assessing symptoms of anxiety and depression (score range, 0-21); and the PTSD Checklist-Civilian version to assess posttraumatic stress disorder (PTSD) symptoms (score range, 17-85) at baseline and weeks 2, 4, 12, and 24. The primary end point was QOL at week 2. We used analysis of covariance adjusting and mixed linear effect models to evaluate patient-reported outcomes. We used Fisher exact test to compare patient-reported discussion of EOL care preferences and receipt of chemotherapy in the last 30 days of life. Of 235 eligible patients, 160 (68.1%) were enrolled; of the 160 participants, the median (range) age was 64.4 (19.7-80.1) years, and 64 (40.0%) were women. Compared with those receiving UC, IPC participants reported better QOL (adjusted mean score, 107.59 vs 116.45; P = .04), and lower depression (adjusted mean score, 7.20 vs 5.68; P = .02), anxiety (adjusted mean score, 5.94 vs 4.53; P = .02), and PTSD symptoms (adjusted mean score, 31.69 vs 27.79; P = .01) at week 2. Intervention effects were sustained to week 24 for QOL (β, 2.35; 95% CI, 0.02-4.68; P = .048), depression (β, -0.42; 95% CI, -0.82 to -0.02; P = .04), anxiety (β, -0.38; 95% CI, -0.75 to -0.01; P = .04), and PTSD symptoms (β, -1.43; 95% CI, -2.34 to -0.54; P = .002). Among patients who died, those receiving IPC were more likely than those receiving UC to report discussing EOL care preferences (21 of 28 [75.0%] vs 12 of 30 [40.0%]; P = .01) and less likely to receive chemotherapy near EOL (15 of 43 [34.9%] vs 27 of 41 [65.9%]; P = .01). In this randomized clinical trial of patients with AML, IPC led to substantial improvements in QOL, psychological distress, and EOL care. Palliative care should be considered a new standard of care for patients with AML. ClinicalTrials.gov Identifier: NCT02975869.


Thymoquinone protects cultured hippocampal and human induced pluripotent stem cells-derived neurons against α-synuclein-induced synapse damage.
The seeds of Nigella sativa are used worldwide to treat various diseases and ailments. Thymoquinone (TQ) that is present in the essential oil of these seeds mediates most of the plant's diverse therapeutic effects. The present study aimed to determine whether TQ protects against α-synuclein (αSN)-induced synaptic toxicity in rat hippocampal and human induced pluripotent stem cell (hiPSC)-derived neurons. Here, we report that αSN decreased the level of synaptophysin, a protein used as an indicator of synaptic density, in cultured hippocampal and hiPSC-derived neurons. However, simultaneous treatment with αSN and TQ protected neurons against αSN-induced synapse damage, as revealed by immunostaining. Moreover, administration of TQ efficiently induced protection in these cells against αSN-induced inhibition of synaptic vesicle recycling in hippocampal and hiPSC-derived neurons as well as against mutated P123H β-synuclein (βSN) in hippocampal neurons, as revealed by experiments using the fluorescent dye FM1-43. Using a multielectrode array, we further demonstrated that the treatment of hiPSC-derived neurons with αSN induced a reduction in spontaneous firing activity, and cotreatment with αSN and TQ partially reversed this loss. These results suggest that TQ protects cultured rat primary hippocampal and hiPSC-derived neurons against αSN-induced synaptic toxicity and could be a promising therapeutic agent for patients with Parkinson's disease and dementia with Lewy bodies.


Optimization of resolution and color reproduction by controlling luminance and contrast levels of a liquid-crystal display monitor.
The image quality of a color liquid-crystal display monitor is studied by changing the contrast and the luminance levels. The resolution is assessed with modulation transfer function area (MTFA) that is measured at nine different combinations of the luminance and contrast. At these combinations, we measure the chromaticity coordinates and luminance of red-green-blue channels as a function of the digital-analog convert value. We analyze the relations among MTFA value, constant-channel chromaticity, color gamut, and maximum luminance of a white pattern. From the results, the combination of levels is found that provides both high resolution and good color reproduction.


2019 Ejtm Special on Muscle Fascia.
For many years the fasciae have been considered by the anatomists only as a "white envelope for the muscles", that is generally removed in anatomical tables, to recognize muscle nerves and vessels. This is one of the reasons that different descriptions of the fasciae exist. On the other hand, in the last years the fasciae and their properties are becoming of central importance to clinicians practicing in various conventional and alternative therapies. The results from the worldwide research activities constitute a body of significant and important data, but this clinical interest is not supported by in-depth comprehension to how integrate the new knowledge about fasciae with the classical biomechanical models based on muscles, tendons and bones. To close this gap an Ejtm Special on "Muscle Fascia" will be published September 30, 2019, but the typescripts will be added to the Ejtm Early Release list as soon as all authors will approve their Epub papers. Deadline for original articles and reviews is June 1st, 2019, but the Editors hope that authors submit their typescripts much earlier.


Down-regulation of miRNA 145 and up-regulation of miRNA 4516 may be associated with primary hypertension.
Complex mechanisms including genetic factors have been proposed in the pathogenesis of primary hypertension (HT). Micro RNAs (miRNAs) are single-stranded RNA molecules that are not converted into protein products. However, it has been established that genes regulate conversion into protein products. The primary aim of this study was to investigate the roles of miRNA 4516, miRNA 145, miRNA 24, and miRNA 181a in the pathogenesis of HT. The secondary aim was to investigate the relation between these miRNAs and renin, aldosterone, norepinephrine, renalase, and NOS. Fifty-two hypertensive and 51 control normotensive individuals under observation in the Cappadocia cohort were included in the study. miRNA 4516, miRNA 181a, miRNA 24, and miRNA 145 levels were measured using the ddPCR method. miRNA 4516 and norepinephrine levels were significantly higher in the HT group (P < .005 for both), while miRNA 145 levels were significantly lower (<.05). miRNA 4516 up-regulation (P < .05) and miRNA 145 down-regulation (P < .05) were identified as independent predictors of HT. Renalase exhibited negative correlation with miRNA 4516 and positive correlation with miRNA 145 in the patient and control group. In addition, negative correlation was present between miRNA 24 and NE and NOS and between miRNA 181a and NOS in the patient group. Our study identified, for the first time in the literature, miRNA 4516 up-regulation and miRNA 145 down-regulation as independent determinants of HT. Further studies performed in the light of our findings may lead to a better understanding of the pathogenesis and new therapeutic possibilities.


Computerized classification of intraductal breast lesions using histopathological images.
In the diagnosis of preinvasive breast cancer, some of the intraductal proliferations pose a special challenge. The continuum of intraductal breast lesions includes the usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS). The current standard of care is to perform percutaneous needle biopsies for diagnosis of palpable and image-detected breast abnormalities. UDH is considered benign and patients diagnosed UDH undergo routine follow-up, whereas ADH and DCIS are considered actionable and patients diagnosed with these two subtypes get additional surgical procedures. About 250,000 new cases of intraductal breast lesions are diagnosed every year. A conservative estimate would suggest that at least 50% of these patients are needlessly undergoing unnecessary surgeries. Thus, improvement in the diagnostic reproducibility and accuracy is critically important for effective clinical management of these patients. In this study, a prototype system for automatically classifying breast microscopic tissues to distinguish between UDH and actionable subtypes (ADH and DCIS) is introduced. This system automatically evaluates digitized slides of tissues for certain cytological criteria and classifies the tissues based on the quantitative features derived from the images. The system is trained using a total of 327 regions of interest (ROIs) collected across 62 patient cases and tested with a sequestered set of 149 ROIs collected across 33 patient cases. An overall accuracy of 87.9% is achieved on the entire test data. The test accuracy of 84.6% is obtained with borderline cases (26 of the 33 test cases) only, when compared against the diagnostic accuracies of nine pathologists on the same set (81.2% average), indicates that the system is highly competitive with the expert pathologists as a stand-alone diagnostic tool and has a great potential in improving diagnostic accuracy and reproducibility when used as a "second reader" in conjunction with the pathologists.


Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression.
Genes that modify oncogenesis may influence dormancy versus progression in cancer, thereby affecting clinical outcomes. The Bin1 gene encodes a nucleocytosolic adapter protein that interacts with and suppresses the cell transforming activity of Myc. Bin1 is often attenuated in breast cancer but its ability to negatively modify oncogenesis or progression in this context has not been gauged directly. In this study, we investigated the effects of mammary gland-specific deletion of Bin1 on initiation and progression of breast cancer in mice. Bin1 loss delayed the outgrowth and involution of the glandular ductal network during pregnancy but had no effect on tumor susceptibility. In contrast, in mice where tumors were initiated by the ras-activating carcinogen 7,12-dimethylbenz(a)anthracene, Bin1 loss strongly accentuated the formation of poorly differentiated tumors characterized by increased proliferation, survival, and motility. This effect was specific as Bin1 loss did not accentuate progression of tumors initiated by an overexpressed mouse mammary tumor virus-c-myc transgene, which on its own produced poorly differentiated and aggressive tumors. These findings suggest that Bin1 loss cooperates with ras activation to drive progression, establishing a role for Bin1 as a negative modifier of oncogenicity and progression in breast cancer.


Improving patient waiting times: a simulation study of an obesity care service.
Obesity care services are often faced with the need to adapt their resources to rising levels of demand. The main focus of this study was to help prioritise planned investments in new capacity allowing the service to improve patient experience and meet future anticipated demand. We developed computer models of patient flows in an obesity service in an Academic Health Science Centre that provides lifestyle, pharmacotherapy and surgery treatment options for the UK's National Health Service. Using these models we experiment with different scenarios to investigate the likely impact of alternative resource configurations on patient waiting times. Simulation results show that the timing and combination of adding extra resources (eg, surgeons and physicians) to the service are important. For example, increasing the capacity of the pharmacotherapy clinics equivalent to adding one physician reduced the relevant waiting list size and waiting times, but it then led to increased waiting times for surgical patients. Better service levels were achieved when the service operates with the resource capacity of two physicians and three surgeons. The results obtained from this study had an impact on the planning and organisation of the obesity service. Resource configuration combined with demand management (reduction in referral rates) along the care service can help improve patient waiting time targets for obesity services, such as the 18 week target of UK's National Health Service. The use of simulation models can help stakeholders understand the interconnectedness of the multiple microsystems (eg, clinics) comprising a complex clinical service for the same patient population, therefore, making stakeholders aware of the likely impact of resourcing decisions on the different microsystems.


Phenotypic characterization of a virulence-associated protein, VagH, of Yersinia pseudotuberculosis reveals a tight link between VagH and the type III secretion system.
Recently, a number of attenuated mutants of Yersinia pseudotuberculosis have been identified using a bioinformatics approach. One of the target genes identified in that study was vagH, which the authors now characterized further. VagH shows homology to HemK of Escherichia coli, possessing methyltransferase activity similar to that of HemK, and targeting release factors 1 and 2. Microarray studies comparing the wild-type and the vagH mutant revealed that the mRNA levels of only a few genes were altered in the mutant. By proteome analysis, expression of the virulence determinant YopD was found to be increased, indicating a possible connection between VagH and the virulence plasmid-encoded type III secretion system (T3SS). Further analysis showed that Yop expression and secretion were repressed in a vagH mutant. This phenotype could be suppressed by trans-complementation with the wild-type vagH gene or by deletion of the negative regulator yopD. Also, in a similar manner to a T3SS-negative mutant, the avirulent vagH mutant was rapidly cleared from Peyer's patches and could not reach the spleen after oral infection of mice. In a manner analogous to that of T3SS mutants, the vagH mutant could not block phagocytosis by macrophages. However, a vagH mutant showed no defects in the T3SS-independent ability to proliferate intracellularly and replicated to levels similar to those of the wild-type in macrophages. In conclusion, the vagH mutant exhibits a virulence phenotype similar to that of a T3SS-negative mutant, indicating a tight link between VagH and type III secretion in Y. pseudotuberculosis.


A randomized controlled bicenter trial of yoga for patients with colorectal cancer.
The aim of this trial was to evaluate the effects of yoga on health-related quality of life in patients with colorectal cancer. Patients with non-metastatic colorectal cancer were randomly assigned to a 10-week yoga intervention (90 min once weekly) or a waitlist control group. Primary outcome measure was disease-specific quality of life (Functional Assessment of Cancer Therapy - Colorectal [FACT-C]) at week 10. Secondary outcome measures included FACT-C subscales: spiritual well-being (FACT - Spirituality); fatigue (FACT - Fatigue); sleep disturbances (Pittsburgh Sleep Quality Inventory); depression and anxiety (Hospital Anxiety and Depression Scale); body awareness (Scale of Body Connection); and body-efficacy expectations (Body-Efficacy Expectations Scale). Outcomes were assessed at week 10 and week 22 after randomization. Fifty-four patients (mean age 68.3 ± 9.7 years) were randomized to yoga (n = 27; attrition rate 22.2%) and control group (n = 27; attrition rate 18.5%). Patients in the yoga group attended a mean of 5.3 ± 4.0 yoga classes. No significant group differences for the FACT-C total score were found. Group differences were found for emotional well-being at week 22 (∆ = 1.59; 95% CI = 0.27,2.90; p = 0.019), sleep disturbances at week 22 (∆ = -1.08; 95% CI = -2.13, -0.03; p = 0.043), anxiety at week 10 (∆ = -1.14; 95% CI = -2.20, -0.09; p = 0.043), and depression at week 10 (∆ = -1.34; 95% CI = -2.61, -0.8; p = 0.038). No serious adverse events occurred in the yoga group, while liver metastases were diagnosed in one patient in the control group. This randomized trial found no effects of yoga on health-related quality of life in patients with colorectal cancer. Given the high attrition rate and low intervention adherence, no definite conclusions can be drawn from this trial.


Nanoscale optoelectronic switches and logic devices.
The photoelectrochemical photocurrent switching (PEPS) effect, in the beginning regarded as a scientific curiosity, has become a field of extensive study for numerous research groups all over the world. This unique effect can be utilized for nanoscale switching and information processing, furthermore, is can serve as an interface between molecular information processing and macroscopic electronics. This review summarizes recent efforts in understanding photocurrent switching effects and their application for the construction of nanoscale switches and logic devices. Furthermore, some future prospects concerning the development of electronic/optoelectronic devices based on photoactive semiconducting hybrid materials are presented.


Blood pressure and heart rate response to posteriorly directed pressure applied to the cervical spine in young, pain-free individuals: a randomized, repeated-measures, double-blind, placebo-controlled study.
Randomized clinical trial. Objectives To compare the blood pressure (BP) and heart rate (HR) response of healthy volunteers to posteriorly directed (anterior-to-posterior [AP]) pressure applied to the cervical spine versus placebo. Manual therapists employ cervical spine AP mobilizations for various cervical-shoulder pain conditions. However, there is a paucity of literature describing the procedure, cardiovascular response, and safety profile. Thirty-nine (25 female) healthy participants (mean ± SD age, 24.7 ± 1.9 years) were randomly assigned to 1 of 2 groups. Group 1 received a placebo, consisting of light touch applied to the right C6 costal process. Group 2 received AP pressure at the same location. Blood pressure and HR were measured prior to, during, and after the application of AP pressure. One-way analysis of variance and paired-difference statistics were used for data analysis. There was no statistically significant difference between groups for mean systolic BP, mean diastolic BP, and mean HR (P >.05) for all time points. Within-group comparisons indicated statistically significant differences between baseline and post-AP pressure HR (-2.8 bpm; 95% confidence interval: -4.6, -1.1) and between baseline and post-AP pressure systolic BP (-2.4 mmHg; 95% confidence interval: -3.7, -1.0) in the AP group, and between baseline and postplacebo systolic BP (-2.6 mmHg; 95% confidence interval: -4.2, -1.0) in the placebo group. No participants reported any adverse reactions or side effects within 24 hours of testing. AP pressure caused a statistically significant physiologic response that resulted in a minor drop in HR (without causing asystole or vasodepression) after the procedure, whereas this cardiovascular change did not occur for those in the placebo group. Within both groups, there was a small but statistically significant reduction in systolic BP following the procedure.


Lung morphometry and collagen and elastin content: changes during normal development and after prenatal hormone exposure in sheep.
This study examined whether the improvement in lung function after prenatal hormone exposure coincided with changes in lung morphometry or in collagen and elastin content. Fetal lambs received a single intramuscular injection of betamethasone (0.5 mg/kg) plus L-thyroxine (T4) (15 micrograms/kg) or vehicle control 48 h before delivery at 121, 128, or 135 d gestational age (d 121, d 128, d 135, term = 150 d). T4 was administered in conjunction with betamethasone in an attempt to enhance the maturational response. The right-upper lobes were instillation fixed at 30 cm H2O by Karnovsky's fixative after a 40-min period of mechanical ventilation. A number of significant changes occurred between d 121 and d 135 in control animals: alveolar airspace volume increased by 270%; despite a 40% reduction in alveolar septal thickness, alveolar septal volume did not change appreciably, suggesting a "redistribution" of septal tissue into the formation of secondary alveolar septa, which doubled in number; and both parenchymal collagen and elastin volume increased significantly, whereas pleural collagen and elastin volume did not change. In contrast to the changes seen in control animals, exposure to betamethasone plus T4 led to alveolar septal thinning at each gestational age without an associated increase in secondary septal number, a 40% decrease in alveolar septal volume, and a proportionate reduction in parenchymal elastin at d 121. Although attenuation of alveolar septa coincides with redistribution of septal tissue into the formation of secondary septa during normal maturation, exposure to betamethasone plus T4 promotes thinning of alveolar septa in the absence of secondary septal formation, which results in a loss of alveolar septal tissue.


X-ray crystallographic analyses of complexes between bovine beta-trypsin and Schiff base copper(II) or iron(III) chelates.
To establish the structural basis underlying the activity of a novel series of metal-chelate trypsin inhibitors, the structures of p-amidinosalicylidene-l-alaninato(aqua)copper(II) (1a), m-amidinosalicylidene-l-alaninato(aqua)copper(II) (1b), bis(p-amidinosalicylidene-l-alaninato)iron(III) (2a), and bis(m-amidinosalicylidene-l-alaninato)iron(III) (2b) bound to bovine beta-trypsin were studied by X-ray crystallography. The amidinium group of the inhibitor donates hydrogen bonds to Asp189, Gly219 and Ser190, as seen before in trypsin-benzamidine complexes. The copper(II) ion of 1a is situated away from trypsin's catalytic triad residues, and is octahedrally coordinated by a Schiff base and three water molecules. In contrast, the copper(II) ion of 1b is situated close to the catalytic triad and adopts a square pyramidal coordination geometry. The iron(III) ion of 2a is octahedrally coordinated by two Schiff base ligands and, like the copper(II) ion of 1a, is situated away from the catalytic triad. The p-amidinophenyl ring of a second Schiff base ligand of 2a is directed toward a hydrophobic groove formed by Trp215 and Leu99. Finally, the iron(III) ion of 2b appears to be replaced by magnesium(II), which is octahedrally coordinated by a Schiff base, Gln192 and two water molecules. One of the Schiff base ligands seen in the trypsin-2a complex or in the unbound form of 2b is replaced by water molecules and Gln192. His57 and Ser195 form water-mediated interactions with the magnesium(II) ion of 2b, and Ser195 also forms a hydrogen bond with the phenolic oxygen atom of the Schiff base ligand. These structures reveal a novel mode of interaction between metal-chelate inhibitors and serine proteases, thus providing a structural basis for the development of more potent inhibitors against a variety of trypsin-like enzymes.


Low-coherence heterodyne interferometry using an achromatic frequency shifter based on a frequency-domain optical delay line.
In this paper a high-sensitivity low-coherence heterodyne interferometric system consisting of two polarizing Michelson interferometers arranged in tandem is presented. A compact frequency-domain optical delay line was placed in the first interferometer to produce a 4.4 kHz frequency shift for broadband near-infrared light. The frequency shift was wavelength independent because the scanning delay line had a zero-group-delay configuration. The fringe amplitude and phase of a low-coherence interference signal were detected using a lock-in amplifier. The experimental results show that the signal-to-noise ratio in the proposed technique is more than 30-fold higher than that of conventional low-coherence homodyne interferometry.


Early Trend of Imported COVID-19 Cases in South Korea.
This study aimed to observe the initial trend of imported COVID-19 cases in South Korea since the beginning of the outbreak. All imported cases were classified into 5 regions (China, Asia, Europe, Africa, and America) according to travel history and potential exposure to the COVID-19. The list of countries for which confirmed cases had a travel history (single visit, multiple visits) and presented, were used to estimate the potential "exposure countries" of confirmed cases. For better understanding of the overall imported cases, time differences (day) among 3 major steps (symptom onset, entry to South Korea, laboratory confirmation) were measured based on available data. From the first importation of a COVID-19 case on January 20th, a total of 171 imported cases have been officially reported in South Korea as of March 23rd 2020. The overall trend of importation has significantly changed during this period. Importation of confirmed cases were initially from China, and subsequently from other Asian countries. After that, importation from Europe rapidly increased, with importation from America also increasing. One hundred fifteen (81%) were confirmed within 7 days of symptom onset. One Hundred forty three (84.1%) imported cases were confirmed within a week after entry into South Korea. One hundred seven imported cases (75.9%) developed symptoms within 5 days before or after, entry to South Korea. Streamlined processes of detection, subsequent testing, isolation, and treatment by public health authority, was key in minimizing the risk of secondary transmission.


Impact of clinical and haemodynamic factors on coronary flow reserve and invasive coronary flow capacity in non-obstructed coronary arteries: a patient-level pooled analysis of the DEBATE and ILIAS studies.
Coronary flow reserve (CFR) is a physiological index for the assessment of myocardial flow impairment due to focal or microcirculatory coronary artery disease (CAD). Coronary flow capacity (CFC) is another flow-based concept in diagnosing ischaemic heart disease, based on hyperaemic average peak velocity (hAPV) and CFR. We evaluated clinical and haemodynamic factors which potentially influence CFR and CFC in non-obstructed coronary arteries. Intracoronary Doppler flow velocity measurements to obtain CFR and CFC were performed after inducing hyperaemia in 390 non-obstructed vessels of patients who were scheduled for elective percutaneous coronary intervention (PCI) of another vessel. Akaike's information criterion (AIC) revealed age, female gender, history of myocardial infarction, hypercholesterolaemia, diastolic blood pressure, oral nitrates and rate pressure product as independent predictors of CFR and CFC. After regression analysis, age and female gender were associated with lower CFR and age was associated with worse CFC in angiographically non-obstructed vessels. Age and female gender are associated with lower CFR, and age with worse CFC in an angiographically non-obstructed coronary artery. CFC seems to be less sensitive to variations in clinical and haemodynamic parameters than CFR and is therefore a promising tool in contemporary clinical decision making in the cardiac catheterisation laboratory.


Autobiography: Kinuko Suzuki, MD.
The following reminiscence by Kinuko Suzuki is the 9th autobiography in a series published in the Journal of Neuropathology and Experimental Neurology. These have been solicited from senior members of the neuropathology community who have been noted leaders and contributors to neuroscience and to the American Association of Neuropathologists (AANP) and have a historical perspective of the importance of neuropathology in diagnosis, education, and research. It is hoped that this series will entertain, enlighten, and present members of the AANP with a better sense of the legacy that we have inherited, as well as reintroduce our respected neuroscientists as humans having interesting lives filled with joys and sorrows and allowing them to present their lives in their own words.MNH, RAS.


Practical guidelines for the surgical treatment of gallbladder cancer.
At present, surgical treatment is the only curative option for gallbladder (GB) cancer. Many efforts therefore have been made to improve resectability and the survival rate. However, GB cancer has a low incidence, and no randomized, controlled trials have been conducted to establish the optimal treatment modalities. The present guidelines include recent recommendations based on current understanding and highlight controversial issues that require further research. For T1a GB cancer, the optimal treatment modality is simple cholecystectomy, which can be carried out as either a laparotomy or a laparoscopic surgery. For T1b GB cancer, either simple or an extended cholecystectomy is appropriate. An extended cholecystectomy is generally recommended for patients with GB cancer at stage T2 or above. In extended cholecystectomy, a wedge resection of the GB bed or a segmentectomy IVb/V can be performed and the optimal extent of lymph node dissection should include the cystic duct lymph node, the common bile duct lymph node, the lymph nodes around the hepatoduodenal ligament (the hepatic artery and portal vein lymph nodes), and the posterior superior pancreaticoduodenal lymph node. Depending on patient status and disease severity, surgeons may decide to perform palliative surgeries.


Assessment of the occurrence of menstrual disorders in female flight attendants - preliminary report and literature review.
The aim of the presented study was to determine the incidence of menstrual disorders and to evaluate the influence of the work period and the frequency of flying on the occurrence of these disorders in flight attendants flying within one time zone. The questionnaire-based survey covered 43 flight attendants which remained within one time zone. The statistical analysis was made by Statistica 10.0 (StatSoft Inc., USA). The study population of flight attendants revealed the occurrence of irregular menstrual cycles in 21%. Irregular menstruations were found to occur more frequently in women with length of work period exceeding 5 years and in women covering more than 14 routes a week though the differences were not statistically significant (p>0.05). Statistically significant correlation was found between years of work and incidence of thyroid diseases and cervical erosions. Only flight attendants working longer than 5 were found to be treated for thyroid diseases. Also in these women cervical erosions developed more frequently than in women with a shorter period of work (55.00% and 21.74%, respectively). Sleep disturbances in the form of insomnia were reported in 19 cases (44%). The study revealed that women with sleep disturbances complain on dysmenorrhea significantly more frequently (p=0.03). The specificity of the work of flight attendants contributes to a higher incidence of menstrual disorders, sleep disturbances and cervical erosions. These disorders seem to be largely related to the shift work.


The relationship between humoral and cellular immunity to IA-2 in IDDM.
Autoantibodies to the neuroendocrine protein insulinoma-associated protein 2 (IA-2), a member of the tyrosine phosphatase family, have been observed in individuals with or at increased risk for IDDM. Because this disease is thought to result from a T-cell-mediated autoimmune destruction of the insulin-producing pancreatic beta-cells, we analyzed humoral and cellular immune reactivity to this autoantigen to further define its role in the pathogenesis of IDDM. Peripheral blood mononuclear cells (PBMC) from individuals with newly diagnosed IDDM or at varying levels of risk for the disease were stimulated in vitro with the entire 42-kDa internal domain of IA-2 (amino acids 603-979), a series of control antigens (glutathionine-S-transferase, tetanus toxoid, Candida albicans, mumps, bovine serum albumin), and a mitogen (phytohemagglutinin). The frequency and mean stimulation index of PBMC proliferation against IA-2 was significantly higher in newly diagnosed IDDM subjects (14 of 33 [42%]; 3.8+/-4.5 at 10 microg/ml) and autoantibody-positive relatives at increased risk for IDDM (6 of 9 [66%]; 3.9+/-3.2) compared with autoantibody-negative relatives (1 of 15 [7%]; 1.8+/-1.0) or healthy control subjects (1 of 12 [8%]; 1.5+/-1.0). The frequencies of cellular immune reactivities to all other antigens were remarkably similar between each subject group. Sera from 58% of the newly diagnosed IDDM patients tested were IA-2 autoantibody positive. Despite investigations suggesting an inverse association between humoral and cellular immune reactivities against islet-cell-associated autoantigens, no such relationship was observed (rs=0.18, P=0.39) with respect to IA-2. These studies support the autoantigenic nature of IA-2 in IDDM and suggest the inclusion of cellular immune responses as an adjunct marker for the disease.


Arrest and Prosecution of Animal Sex Abuse (Bestiality) Offenders in the United States, 1975-2015.
Bestiality is an uncomfortable topic about which there is limited scientific literature. Prevalence research has focused on self-reported acts, and no research has established the actual frequency and nature of deliberate sex acts with animals. This quantitative, descriptive study examined 456 arrests for bestiality-related incidents in the United States from 1975 to 2015 to explore patterns of offending, offender characteristics, and how cases were adjudicated. The results suggest that animal sex offending may be linked to other criminal behavior, and involves a spectrum of sexual acts, including coercive, violent, and non-violent penetration; solicitation for sex with animals; and deviant behavior including torture and necrophilia. Findings of concern were that 31.6% of animal sex offenders also sexually offended against children and adults; 52.9% had a prior or subsequent criminal record involving human sexual abuse, animal abuse, interpersonal violence, substances, or property offenses; and only 39.1% of arrests involving the direct sexual abuse of animals resulted in prosecution. The broad range of sexual assault patterns and varied legal outcomes suggest that bestiality is more pervasive and more serious than previously thought and point to a need for additional research to aid in detection, intervention, sentencing, treatment, and supervision methods.


Compartmentalized Microhelices Prepared via Electrohydrodynamic Cojetting.
Anisotropically compartmentalized microparticles have attracted increasing interest in areas ranging from sensing, drug delivery, and catalysis to microactuators. Herein, a facile method is reported for the preparation of helically decorated microbuilding blocks, using a modified electrohydrodynamic cojetting method. Bicompartmental microfibers are twisted in situ, during electrojetting, resulting in helical microfibers. Subsequent cryosectioning of aligned fiber bundles provides access to helically decorated microcylinders. The unique helical structure endows the microfibers/microcylinders with several novel functions such as translational motion in response to rotating magnetic fields. Finally, microspheres with helically patterned compartments are obtained after interfacially driven shape shifting of helically decorated microcylinders.


Synchronous, alternating, and phase-locked stridulation by a tropical katydid.
In the field the chirps of neighboring Mecopoda sp. (Orthoptera, Tettigoniidae, and Mecopodinae) males are normally synchronized, but between more distant individuals the chirps are either synchronous or regularly alternating. The phase response to single-stimulus chirps depends on both the phase and the intensity of the stimulus. Iteration of the Poincaré map of the phase response predicts a variety of phase-locked synchronization regimes, incuding period-doubling bifurcations, in close agreement with experimental observations. The versatile acoustic behavior of Mecopoda encompasses most of the phenomena found in other synchronizing insects and thus provides a general model of insect synchronization behavior.


[For an empirical approach to object relations].
In this article, the authors address the concept of object relations and its place within psychodynamic theories regarding personality and, more specifically, in Kernberg's conceptualization of personality disorders and organization. The authors attempt to demonstrate the relevance of an empirical approach to object relations by presenting some of the instruments that are most considered. The Object Relations Rating Scale (ORRS ; Diguer, 2001), a new assessment instrument that is different from the others in that it assesses the therapeutic interaction as a whole, and that it is coherent with Kernberg's model of intervention and considers the overall relational manifestations. Finally, the authors present satisfying metrological ratings of this new instrument.


Risk factor characteristics in carers who physically abuse or neglect their elderly dependants.
This study investigates the prevalence of, and differences in, risk factor characteristics in a sample of two select populations of carers, one of which physically abused their elderly dependants and one of which neglected them. Nineteen carers (nine who had physically abused and 10 who had neglected their elderly relatives), who were referred to clinical psychology by either their general practitioner or their psychiatrist, were invited to take part in this study. A detailed history of risk factors was obtained, including history of alcohol dependency, type and history of mental ill health, history of maltreatment earlier in life, who they were caring for, how long they had been a carer and whether they felt isolated as a carer. Subjects were then given five assessments to determine whether there were any differences between the two groups. These were the Conflict Tactic Scale, Strain Scale, Beck Depression Inventory, Beck Anxiety Inventory and Cost of Care Index. An examination of the risk factors suggests that heavy alcohol consumption and past childhood abuse by fathers were likely to lead to physical abuse. Significantly higher conflict and depression scores were also present in the physical abuse group, while the neglect group had significantly higher anxiety scores. It is suggested that these findings should be incorporated into an assessment of future risk of abuse or neglect by the carer.


Modelling the adverse effects associated with ecstasy use.
Ecstasy, the street name for 3,4-meththylenedioxymethamphetamine, has been associated with a range of psychiatric symptoms and impaired psychological health in both problem and recreational users. The purpose of the present paper is to determine how these impairments are related to the history of polydrug use, and the conditions under which individuals ingest ecstasy. Associations between the variables of interest were investigated utilizing negative binomial regression. Liverpool and Preston in the North West of England. A convenience sample of 159 recreational ecstasy/polydrug users (80 males, 79 females). The sample was composed primarily of undergraduates. The dependent variable was the number of reported ecstasy-related adverse effects. Independent variables included quantitative aspects of ecstasy and other drug use, and the various beliefs and behaviours associated with ecstasy use. The number of adverse effects was associated positively with life-time exposure to ecstasy and negatively with period of abstinence from the drug. Adverse effects were more common among those who consumed ecstasy and alcohol concurrently, but were unrelated to other aspects of polydrug use. They were unaffected by whether the user took precautions when using the drug, and only weakly related to prior beliefs concerning the effects of ecstasy. Greater life-time exposure to ecstasy and consuming the drug concurrently with alcohol increase the likelihood of experiencing adverse effects, including paranoia, poor general health, irritability, confusion and moodiness. Adverse effects decrease with the period of abstinence from the drug.


Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion.
Eight women with insulin-dependent diabetes mellitus (IDDM) with low creatinine clearance rate (CCR) and normal urinary albumin excretion (UAE) were compared with three other groups of diabetic women: 19 with normal creatinine clearance rate (CCR) and UAE, 7 with normal CCR and microalbuminuria, and 7 with low CCR and microalbuminuria. The four groups were similar in age, duration of diabetes, HbA1, incidence of urinary tract infection, prevalence of bladder neuropathy, and urinary urea nitrogen excretion rate. The prevalence of hypertension was similar among the groups, although mean arterial pressure was higher in the low CCR and microalbuminuria group. Renal area index was lower in the low CCR and normal UAE groups than in the other groups of diabetic patients, but was not different from normal. Morphometric measures of mesangial expansion and estimates of arteriolar hyalinosis and global glomerulosclerosis were increased to a similar degree in the low CCR and normal UAE, normal CCR and microalbuminuria, and low CCR and microalbuminuria groups compared with the group without abnormalities of renal function. Therefore, it is likely that diabetic glomerulopathy is, at least in part, responsible for the loss of glomerular filtration rate seen in the low CCR and normal UAE patients. Thus, the definition of incipient nephropathy may have to be expanded beyond the concept of microalbuminuria if longitudinal study of such patients reveals an increased risk of the subsequent development of overt nephropathy. Finally, screening for diabetic kidney disease among IDDM patients should include determination of glomerular filtration rate and measurement of UAE and blood pressure, especially among women.


Immunonanoshells for targeted photothermal ablation in medulloblastoma and glioma: an in vitro evaluation using human cell lines.
We are developing a novel approach to specifically target malignant brain tumor cells for photothermal ablation using antibody-tagged, near infrared-absorbing gold-silica nanoshells, referred to as immunonanoshells. Once localized to tumor cells, these nanoshells are extremely efficient at absorbing near-infrared light and can generate sufficient heat to kill cancer cells upon exposure to laser light. In this study, we evaluated the efficacy of immunonanoshells in vitro against both medulloblastoma and high-grade glioma cell lines. We used an antibody against HER2 to target gold-silica nanoshells to medulloblastoma cells, since HER2 is frequently overexpressed in medulloblastoma. We show that treatment with HER2-targeted nanoshells, but not non-targeted nanoshells, followed by exposure to laser light, can induce cell death in the HER2-overexpressing medulloblastoma cell line Daoy.2, as well as the parental Daoy cell line, which expresses HER2 at a moderate level, but not in dermal fibroblasts that do not express HER2. In an analogous set of experiments, we conjugated gold-silica nanoshells to an antibody against interleukin-13 receptor-alpha 2 (IL13Ralpha2), an antigen that is frequently overexpressed in gliomas. We demonstrate that these immunonanoshells are capable of inducing cell death in two high-grade glioma cell lines that express IL13Ralpha2, U373 and U87, but not in A431 epidermoid carcinoma cells that do not express significant levels of IL13Ralpha2. We believe that the use of antibody-tagged gold-silica nanoshells to selectively target cancer cells presents a promising new strategy for the treatment of central nervous system tumors that will minimize the damage and resulting toxicity to the surrounding normal brain.


HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.
Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare autosomal dominant inherited peripheral neuropathy caused by mutations in the SPTLC1 and SPTLC2 subunits of serine palmitoyltransferase (SPT). The mutations induce a permanent shift in the substrate preference from L-serine to L-alanine, which results in the pathological formation of atypical and neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Here we compared the enzymatic properties of 11 SPTLC1 and six SPTLC2 mutants using a uniform isotope labelling approach. In total, eight SPT mutants (STPLC1p.C133W, p.C133Y, p.S331F, p.S331Y and SPTLC2p.A182P, p.G382V, p.S384F, p.I504F) were associated with increased 1-deoxySL synthesis. Despite earlier reports, canonical activity with l-serine was not reduced in any of the investigated SPT mutants. Three variants (SPTLC1p.S331F/Y and SPTLC2p.I505Y) showed an increased canonical activity and increased formation of C20 sphingoid bases. These three mutations are associated with an exceptionally severe HSAN1 phenotype, and increased C20 sphingosine levels were also confirmed in plasma of patients. A principal component analysis of the analysed sphingoid bases clustered the mutations into three separate entities. Each cluster was related to a distinct clinical outcome (no, mild and severe HSAN1 phenotype). A homology model based on the protein structure of the prokaryotic SPT recapitulated the same grouping on a structural level. Mutations associated with the mild form clustered around the active site, whereas mutations associated with the severe form were located on the surface of the protein. In conclusion, we showed that HSAN1 mutations in SPT have distinct biochemical properties, which allowed for the prediction of the clinical symptoms on the basis of the plasma sphingoid base profile.


Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma.
Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.


The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRL/MP-lpr/lpr mice.
MRL/MP-lpr/lpr (MRL/lpr) mice develop a spontaneous autoimmune disease. Serum from these mice contained significantly higher concentrations of nitrite/nitrate than serum from age-matched control MRL/MP-+/+ (MRL/+), BALB/c or CBA/6J mice. Spleen and peritoneal cells from MRL/lpr mice also produced significantly more nitric oxide (NO) than those from the control mice when cultured with interferon (IFN) gamma and lipopolysaccharide (LPS) in vitro. It is interesting to note that peritoneal cells from MRL/lpr mice also produced markedly higher concentrations of interleukin (IL) 12 than those from MRL/+ or BALB/c mice when cultured with same stimuli. It is striking that cells from MRL/lpr mice produced high concentrations of NO when cultured cells from MRL/+ or BALB/c mice. The enhanced NO synthesis induced by IFN-gamma/LPS was substantially inhibited by anti-IL-12 antibody. In addition, IL-12-induced NO production can also be markedly inhibited by anti-IFN-gamma antibody, but only weakly inhibited by anti-tumor necrosis factor alpha antibody. The effect of IL-12 on NO production was dependent on the presence of natural killer and possibly T cells. Serum from MRL/lpr mice contained significantly higher concentrations of IL-12 compared with those of MRL/+ or BALB/c control mice. Daily injection of recombinant IL-12 led to increased serum levels of IFN-gamma and NO metabolites, and accelerated glomerulonephritis in the young MRL/lpr mice (but not in the MRL/+ mice) compared with controls injected with phosphate-buffered saline alone. These data, together with previous finding that NO synthase inhibitors can ameliorate autoimmune disease in MRL/lpr mice, suggest that high capacity of such mice to produce IL-12 and their greater responsiveness to IL-12, leading to the production of high concentrations of NO, are important factors in this spontaneous model of autoimmune disease.


Viral mediated redirection of NEMO/IKKγ to autophagosomes curtails the inflammatory cascade.
The early host response to viral infections involves transient activation of pattern recognition receptors leading to an induction of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Subsequent activation of cytokine receptors in an autocrine and paracrine manner results in an inflammatory cascade. The precise mechanisms by which viruses avert an inflammatory cascade are incompletely understood. Nuclear factor (NF)-κB is a central regulator of the inflammatory signaling cascade that is controlled by inhibitor of NF-κB (IκB) proteins and the IκB kinase (IKK) complex. In this study we show that murine cytomegalovirus inhibits the inflammatory cascade by blocking Toll-like receptor (TLR) and IL-1 receptor-dependent NF-κB activation. Inhibition occurs through an interaction of the viral M45 protein with the NF-κB essential modulator (NEMO), the regulatory subunit of the IKK complex. M45 induces proteasome-independent degradation of NEMO by targeting NEMO to autophagosomes for subsequent degradation in lysosomes. We propose that the selective and irreversible degradation of a central regulatory protein by autophagy represents a new viral strategy to dampen the inflammatory response.


Epidemiology of human African trypanosomiasis.
Human African trypanosomiasis (HAT), or sleeping sickness, is caused by Trypanosoma brucei gambiense, which is a chronic form of the disease present in western and central Africa, and by Trypanosoma brucei rhodesiense, which is an acute disease located in eastern and southern Africa. The rhodesiense form is a zoonosis, with the occasional infection of humans, but in the gambiense form, the human being is regarded as the main reservoir that plays a key role in the transmission cycle of the disease. The gambiense form currently assumes that 98% of the cases are declared; the Democratic Republic of the Congo is the most affected country, with more than 75% of the gambiense cases declared. The epidemiology of the disease is mediated by the interaction of the parasite (trypanosome) with the vectors (tsetse flies), as well as with the human and animal hosts within a particular environment. Related to these interactions, the disease is confined in spatially limited areas called "foci", which are located in Sub-Saharan Africa, mainly in remote rural areas. The risk of contracting HAT is, therefore, determined by the possibility of contact of a human being with an infected tsetse fly. Epidemics of HAT were described at the beginning of the 20th century; intensive activities have been set up to confront the disease, and it was under control in the 1960s, with fewer than 5,000 cases reported in the whole continent. The disease resurged at the end of the 1990s, but renewed efforts from endemic countries, cooperation agencies, and nongovernmental organizations led by the World Health Organization succeeded to raise awareness and resources, while reinforcing national programs, reversing the trend of the cases reported, and bringing the disease under control again. In this context, sustainable elimination of the gambiense HAT, defined as the interruption of the transmission of the disease, was considered as a feasible target for 2030. Since rhodesiense HAT is a zoonosis, where the animal reservoir plays a key role, the interruption of the disease's transmission is not deemed feasible.


Effects of intracisternal glucose or insulin injections on glucose homeostasis in cat.
The injection of glucose (100 mg) into the cisterna magna of intact anesthetized cats elicited immediate glycosuria and natriuresis without significant changes in blood glucose concentration. Immunoreactive insulin (IRI) increased 140% in plasma, and Na+ concentration decreased in cerebrospinal fluid (CSF). After kidney denervation there was a significant decrease in glucose and Na+ concentrations in urine. Control injections with mannitol did not elicit changes in the studied parameters. Abdominal vagotomy abolished the rise in IRI levels and the decrease in Na+ concentration in CSF. Vagotomy or adrenalectomy also attenuated the glycosuria and the rise in urine Na+ concentration. The intracisternal injection of insulin (0.5 U/kg) caused first, a decrease in glucose concentration in CSF and afterwards a longer latency in plasma. Again, these responses were significantly attenuated when insulin was administered in vagotomized cats. These experiments indicate that the nervous system, through the vagi, adrenal glands, and kidneys, plays an important role in glucose homeostasis after increasing glucose or insulin levels in the CSF above physiologic concentrations. The results obtained with a denervated kidney confirm the participation of nervous system in the effector mechanism that brings the sugar and Na+ into the urine. Evidence is presented for an interrelationship between glucose and Na+ concentrations in blood, urine, and CSF.


The logic of identity and resemblance in culturally appropriate health care.
Greater diversity in the health care workforce is frequently proposed as a means of addressing health disparities between minority and majority populations in the USA by improving health care access and quality for minority groups. 'Culturally appropriate' health care programs that include ethnic resemblance between physician and patient are emerging as new technologies of knowledge and power in a wide range of health care settings. Based on participant-observation research and interviews with patients and health care providers at a federally funded New England clinic, this article uses theories of cultural identity supported by ethnographic examples to examine arguments in favor of patient-provider resemblance. While ethnic identity is often assumed to incorporate cultural expertise or competence, in practice, developing and maintaining such expertise is the result of repeated performances developed in part through didactic trainings described herein. Claims for the efficacy of patient-provider resemblance in addressing disparities in quality of care mobilize notions of specificity, difference and recognition that both depend on and construct racialized ethnic identities. Proposed as a means to expand access to health care, resemblance programs nonetheless perpetuate segregation in health care by relying on minority health care providers to care for the minority poor. Both patients and health care providers I interviewed perceived benefits associated with ethnic resemblance, yet also articulated critiques of the essentialized notions of identity that render ethnicity automatically efficacious. Following Laclau, I argue that an exclusive focus on physician-patient resemblance constructs ethnicity as 'mere particularity' and in so doing helps to obscure the relations of power and inequality that produce the very health disparities that resemblance is meant to solve.


Accumulation of mutations over the entire mitochondrial genome of breast cancer cells obtained by tissue microdissection.
The occurrence of heteroplasmy and mixtures is technically challenging for the analysis of mitochondrial DNA. More than that, observed mutations need to be carefully interpreted in the light of the phylogeny as mitochondrial DNA is a uniparental marker reflecting human evolution. Earlier attempts to explain the role of mtDNA in cancerous tissues led to substantial confusion in medical genetics mainly due to the presentation of low sequence data quality and misinterpretation of mutations representing a particular haplogroup background rather than being cancer-specific. The focus of this study is to characterize the extent and level of mutations in breast cancer samples obtained by tissue microdissection by application of an evaluated full mtDNA genome sequencing protocol. We amplified and sequenced the complete mitochondrial genomes of microdissected breast cancer cells of 15 patients and compared the results to those obtained from paired non-cancerous breast tissue derived from the same patients. We observed differences in the heteroplasmic states of substitutions between cancerous and normal cells, one of which was affecting a position that has been previously reported in lung cancer and another one that has been identified in 16 epithelial ovarian tumors, possibly indicating functional relevance. In the coding region, we found full transitions in two cancerous mitochondrial genomes and 12 heteroplasmic substitutions as compared to the non-cancerous breast cells. We identified somatic mutations over the entire mtDNA of human breast cancer cells potentially impairing the mitochondrial OXPHOS system.


A nuclear localization signal can enhance both the nuclear transport and expression of 1 kb DNA.
Although the entry of DNA into the nucleus is a crucial step of non-viral gene delivery, fundamental features of this transport process have remained unexplored. This study analyzed the effect of linear double stranded DNA size on its passive diffusion, its active transport and its NLS-assisted transport. The size limit for passive diffusion was found to be between 200 and 310 bp. DNA of 310-1500 bp entered the nuclei of digitonin treated cells in the absence of cytosolic extract by an active transport process. Both the size limit and the intensity of DNA nuclear transport could be increased by the attachment of strong nuclear localization signals. Conjugation of a 900 bp expression cassette to nuclear localization signals increased both its nuclear entry and expression in microinjected, living cells.


Integrated Assessment of Circulating Cell-Free MicroRNA Signatures in Plasma of Patients with Melanoma Brain Metastasis.
Primary cutaneous melanoma frequently metastasizes to distant organs including the brain. Identification of cell-free microRNAs (cfmiRs) found in the blood can be used as potential body fluid biomarkers for detecting and monitoring patients with melanoma brain metastasis (MBM). In this pilot study, we initially aimed to identify cfmiRs in the blood of MBM patients. Normal donors plasma (healthy, n = 48) and pre-operative MBM patients' plasma samples (n = 36) were compared for differences in >2000 microRNAs (miRs) using a next generation sequencing (NGS) probe-based assay. A 74 cfmiR signature was identified in an initial cohort of MBM plasma samples and then verified in a second cohort of MBM plasma samples (n = 24). Of these, only 58 cfmiRs were also detected in MBM tissues (n = 24). CfmiR signatures were also found in patients who have lung and breast cancer brain metastasis (n = 13) and glioblastomas (n = 36) compared to MBM plasma samples. The 74 cfmiR signature and the latter cfmiR signatures were then compared. We found a 6 cfmiR signature that was commonly upregulated in MBM plasma samples in all of the comparisons, and a 29 cfmiR signature that distinguishes MBM patients from normal donors' samples. In addition, we assessed for cfmiRs in plasma (n = 20) and urine (n = 14) samples collected from metastatic melanoma patients receiving checkpoint inhibitor immunotherapy (CII). Pre- and post-treatment samples showed consistent changes in cfmiRs. Analysis of pre- and post-treatment plasma samples showed 8 differentially expressed (DE) cfmiRs that overlapped with the 35 cfmiR signature found in MBM patients. In paired pre-treatment plasma and urine samples receiving CII 8 cfmiRs overlapped. This study identified specific cfmiRs in MBM plasma samples that may potentially allow for assessment of melanoma patients developing MBM. The cfmiR signatures identified in both blood and urine may have potential utility to assess CII responses after further validation.


Excavation of a Vietnam-era aircraft crash site: use of cross-cultural understanding and dual forensic recovery methods.
The excavation of a 23 year-old aircraft crash site in the Socialist Republic of Vietnam and the transformational processes preceding its excavation in 1995-1996 are detailed. The history of the site involved an initial catastrophic event, with subsequent reclamation and disturbances. Ultimately, a recovery effort by a joint U.S. team from the Central Identification Laboratory, Hawaii (CILHI). Joint Task Force-Full Accounting (JTF-FA) and a Socialist Republic of Vietnam contingent yielded numerous human remains, personal effects, and life-support items from the crash site. This case study should be of interest to the increasing number of forensic anthropologists who carry out work in international contexts. The application of forensic anthropology in human rights abuse cases, for example in Rwanda, Argentina, and Bosnia, provide examples of such cross-cultural endeavors. Cultural factors act in the development of a site and should not be overlooked as significant taphonomic agents. The approach that an indigenous person takes to a crash site or mass grave may be quite different from our own approach, involving Western science. Holland, Anderson, and Mann (I) describe the postmortem alternation of exhumed and/or curated bone caused by indigenous South-east Asian peoples; the examples provided by these authors demonstrate how culture affects the treatment of what we would call "evidence." The international nature of an incident can add complicating "filters" to the reconstruction of events, since reclamation responses by indigenous people vary according to their interpretations of the scene. An investigating forensic anthropologist needs to understand the emic viewpoint (the insider's view), as cultural anthropologists do, when attempting to recover and reconstruct such an incident. In response to the cultural (and natural) taphonomic agents at work on such a site, the use of dual forensic recovery methods--simultaneously treating the investigation scene like an aircraft crash and a clandestine burial site--is advised. Employing a flexible set of methods will allow for maximal recovery of evidence.


Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer.
Connective tissue growth factor (CTGF) has been shown to be implicated in tumor development and progression. The aim of this study was to investigate the role of CTGF in progression of colorectal cancer (CRC). Immunohistochemical staining of specimens from 119 patients with CRC was performed. Liposome-mediated transfection was used to introduce a CTGF expression vector into CRC cell lines. Transfectants were tested in invasive ability and experimental hepatic metastasis in BALB/c mice. Furthermore, a FOPflash/TOPflash reporter assay was performed to investigate CTGF on the beta-catenin/T-cell factor signaling pathway. Patients with stage II and stage III CRC whose tumors displayed high CTGF expression had a significantly higher overall survival and a disease-free advantage over patients with CRC with low CTGF expression. Alterations in the CTGF level in CRC cell lines modulated their invasive ability with an inverse correlation. In addition, a reduction in the CTGF level of CT26 cells after stable transfection with antisense CTGF resulted in increased liver metastasis in BALB/c mice. The activity of the beta-catenin/T-cell factor signaling pathway and its downstream effector gene matrix metalloproteinase 7 in these CTGF-transfected cells was strongly attenuated. Blockage of matrix metalloproteinase 7 with its neutralizing antibodies inhibited increased invasiveness in antisense CTGF-transfected CT26 cells. Our results implicate CTGF as a key regulator of CRC invasion and metastasis, and it appears to be a useful and better prognosis factor for patients with stage II and stage III CRC.


Resistance and Vulnerability of Honeybee (Apis mellifera) Gut Bacteria to Commonly Used Pesticides.
Agricultural and apicultural practices expose honeybees to a range of pesticides that have the potential to negatively affect their physiology, neurobiology, and behavior. Accumulating evidence suggests that these effects extend to the honeybee gut microbiome, which serves important functions for honeybee health. Here we test the potential effects of the pesticides thiacloprid, acetamiprid, and oxalic acid on the gut microbiota of honeybees, first in direct in vitro inhibition assays and secondly in an in vivo caged bee experiment to test if exposure leads to gut microbiota community changes. We found that thiacloprid did not inhibit the honeybee core gut bacteria in vitro, nor did it affect overall community composition or richness in vivo. Acetamiprid did also not inhibit bacterial growth in vitro, but it did affect community structure within bees. The eight bacterial genera tested showed variable levels of susceptibility to oxalic acid in vitro. In vivo, treatment with this pesticide reduced amplicon sequence variant (ASV) richness and affected gut microbiome composition, with most marked impact on the common crop bacteria Lactobacillus kunkeei and the genus Bombella. We conducted network analyses which captured known associations between bacterial members and illustrated the sensitivity of the microbiome to environmental stressors. Our findings point to risks of honeybee exposure to oxalic acid, which has been deemed safe for use in treatment against Varroa mites in honeybee colonies, and we advocate for more extensive assessment of the long-term effects that it may have on honeybee health.


Dangerous Duplicity: The Dual Functions of Casein Kinase 1 in Parasite Biology and Host Subversion.
Casein Kinase 1 (CK1) family members are serine/threonine protein kinases that are involved in many biological processes and highly conserved in eukaryotes from protozoan to humans. Even though pathogens exploit host CK1 signaling pathways to survive, the role of CK1 in infectious diseases and host/pathogen interaction is less well characterized compared to other diseases, such as cancer or neurodegenerative diseases. Here we present the current knowledge on CK1 in protozoan parasites highlighting their essential role for parasite survival and their importance for host-pathogen interactions. We also discuss how the dual requirement of CK1 family members for parasite biological processes and host subversion could be exploited to identify novel antimicrobial interventions.


Organochlorine contaminant exposure and reproductive success of black-crowned night-herons (Nycticorax nycticorax) nesting in Baltimore harbor, Maryland.
The declining size of the Baltimore Harbor black-crowned night-heron (Nycticorax nycticorax) colony has been hypothesized to be linked to polychlorinated biphenyl (PCB) exposure. In 1998, a "sample egg" was collected from 65 black-crowned night-heron nests (each containing > or = three eggs) for contaminant analysis, and the remaining eggs in these 65 nests, plus four two-egg nests, were monitored for hatching and fledging success. Eggs were also collected from 12 nests at Holland Island, a reference site in southern Chesapeake Bay. Samples were analyzed for 26 organochlorine pesticides and metabolities and 145 PCB congeners. Pesticide and metabolite concentrations, including p,p'-DDE, were well below thresholds associated with adverse reproductive effects at both sites. Average concentration of total PCBs, 12 Ah receptor-active PCB congeners, and toxic equivalents in eggs from Baltimore Harbor were greater (up to 35-fold) than that observed in Holland Island samples. Overall nest success at the Baltimore Harbor heronry was estimated by the Mayfield method to be 0.74, and the mean number of young fledged/hen was 2.05, which is within published productivity estimates for maintaining a stable black-crowned night-heron population. Using logistic regression, no significant relationships were found between organochlorine contaminant concentrations in sample eggs and hatching, fledging, or overall reproductive success. Processes other than poor reproduction (e.g., low postfledging survival, emigration, habitat degradation) may be responsible for the declining size of the Baltimore Harbor colony.


Conformational flexibility of the ErbB2 ectodomain and trastuzumab antibody complex as revealed by molecular dynamics and principal component analysis.
Human epidermal growth factor receptor 2 (ErbB2) is a transmembrane oncoprotein that is over expressed in breast cancer. A successful therapeutic treatment is a monoclonal antibody called trastuzumab which interacts with the ErbB2 extracellular domain (ErbB2-ECD). A better understanding of the detailed structure of the receptor-antibody interaction is indeed of prime interest for the design of more effective anticancer therapies. In order to discuss the flexibility of the complex ErbB2-ECD/trastuzumab, we present, in this study, a multi-nanosecond molecular dynamics simulation (MD) together with an analysis of fluctuations, through a principal component analysis (PCA) of this system. Previous to this step and in order to validate the simulations, we have performed a detailed analysis of the variable antibody domain interactions with the extracellular domain IV of ErbB2. This structure has been statically elucidated by x-ray studies. Indeed, the simulation results are in excellent agreement with the available experimental information during the full trajectory. The PCA shows eigenvector fluctuations resulting in a hinge motion in which domain II and C(H) domains approach each other. This move is likely stabilized by the formation of H-bonds and salt bridge interactions between residues of the dimerization arm in the domain II and trastuzumab residues located in the C(H) domain. Finally, we discuss the flexibility of the MD/PCA model in relation with the static x-ray structure. A movement of the antibody toward the dimerization domain of the ErbB2 receptor is reported for the first time. This finding could have important consequences on the biological action of the monoclonal antibody.


The evolution of regeneration - where does that leave mammals?
This brief review considers the question of why some animals can regenerate and others cannot and elaborates the opposing views that have been expressed in the past on this topic, namely that regeneration is adaptive and has been gained or that it is a fundamental property of all organisms and has been lost. There is little empirical evidence to support either view, but some of the best comes from recent phylogenetic analyses of regenerative ability in Planarians which reveals that this property has been lost and gained several times in this group. In addition, a non-regenerating species has been induced to regenerate by altering only one signaling pathway. Extrapolating this to mammals it may be the case that there is more regenerative ability in mammals than has typically been thought to exist and that inducing regeneration in humans may not be as impossible as it may seem. The regenerative abilities of mammals is described and it turns out that there are several examples of classical epimorphic regeneration involving a blastema as exemplified by the regenerating Urodele limb that can be seen in mammals. Even the heart can regenerate in mammals which has long been considered to be a property unique to Urodeles and fish and several recent examples of regeneration have come from recent studies of the spiny mouse, Acomys, which are discussed here. It is suggested that a much more thorough phylogenetic analysis of mammalian regeneration would likely reveal some important insights into the evolution of regeneration.


Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children.
Convection-enhanced delivery (CED) for the treatment of malignant gliomas is a technique that can deliver chemotherapeutic agents directly into the tumor and the surrounding interstitium through sustained, low-grade positive-pressure infusion. This allows for high local concentrations of drug within the tumor while minimizing systemic levels that often lead to dose-limiting toxicity. Diffuse intrinsic pontine gliomas (DIPGs) are universally fatal childhood tumors for which there is currently no effective treatment. In this report the authors describe CED of the topoisomerase inhibitor topotecan for the treatment of DIPG in 2 children. As part of a pilot feasibility study, the authors treated 2 pediatric patients with DIPG. Stereotactic biopsy with frozen section confirmation of glial tumor was followed by placement of bilateral catheters for CED of topotecan during the same procedure. The first patient underwent CED 210 days after initial diagnosis, after radiation therapy and at the time of tumor recurrence, with a total dose of 0.403 mg in 6.04 ml over 100 hours. Her Karnofsky Performance Status (KPS) score was 60 before CED and 50 posttreatment. Serial MRI initially demonstrated a modest reduction in tumor size and edema, but the tumor progressed and the patient died 49 days after treatment. The second patient was treated 24 days after the initial diagnosis prior to radiation with a total dose of 0.284 mg in 5.30 ml over 100 hours. Her KPS score was 70 before CED and 50 posttreatment. Serial MRI similarly demonstrated an initial modest reduction in tumor size. The patient subsequently underwent fractionated radiation therapy, but the tumor progressed and she died 120 days after treatment. Topotecan delivered by prolonged CED into the brainstem in children with DIPG is technically feasible. In both patients, high infusion rates (> 0.12 ml/hr) and high infusion volumes (> 2.8 ml) resulted in new neurological deficits and reduction in the KPS score, but lower infusion rates (< 0.04 ml/hr) were well tolerated. While serial MRI showed moderate treatment effect, CED did not prolong survival in these 2 patients. More studies are needed to improve patient selection and determine the optimal flow rates for CED of chemotherapeutic agents into DIPG to maximize safety and efficacy. Clinical trial registration no.: NCT00324844.


Structural characterization of neurokinin-3 receptor selective peptide agonist scyliorhinin II bound to DPC micelles.
Scyliorhinin II, a cyclic Tachykinin peptide, is a potent NK3 receptor agonist. The pharmacology of NK3 receptor is least characterized out of the three tachykinin receptor subtypes cloned and characterized for Tachykinins. To understand the structural basis of peptide-receptor interaction, the three-dimensional structure of the Scyliorhinin II in aqueous and micellar environments has been studied by two-dimensional proton nuclear magnetic resonance (2D 1H-NMR spectroscopy) and distance geometry calculations. Proton NMR assignments have been carried out with the aid of correlation spectroscopy (gradient-COSY and TOCSY) and nuclear Overhauser effect spectroscopy (NOESY and ROESY) experiments. The inter proton distances and dihedral angle constraints obtained from the NMR data have been used in torsion angle dynamics algorithm for NMR applications (DYANA) to generate a family of structures, which have been refined using restrained energy minimization and dynamics. The results show that in an aqueous environment, Scyliorhinin II lacks a definite secondary structure. The structure is well-defined in presence of dodecyl phosphocholine micelles. The global fold of Scyliorhinin II bound to DPC micelles consists of a well-defined helix in the C-terminal region from residue 12-18 and a series of turns towards N-terminus. The structure is further stabilized by disulfide bond between Cys7 and Cys13. The conformational range of the peptide revealed by NMR and CD studies has been analyzed in terms of characteristic secondary features. Observed conformational features have been compared with those of Substance P, Neurokinin A and Neurokinin B, potent NK1, NK2, and NK3 agonists, respectively.


Internet gaming disorder in early adolescence: Associations with parental and adolescent mental health.
Internet gaming disorder (IGD) has been included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Currently, associations between IGD in early adolescence and mental health are largely unexplained. In the present study, the relation of IGD with adolescent and parental mental health was investigated for the first time. We surveyed 1095 family dyads (an adolescent aged 12-14 years and a related parent) with a standardized questionnaire for IGD as well as for adolescent and parental mental health. We conducted linear (dimensional approach) and logistic (categorical approach) regression analyses. Both with dimensional and categorical approaches, we observed statistically significant associations between IGD and male gender, a higher degree of adolescent antisocial behavior, anger control problems, emotional distress, self-esteem problems, hyperactivity/inattention and parental anxiety (linear regression model: corrected R2=0.41, logistic regression model: Nagelkerke's R2=0.41). IGD appears to be associated with internalizing and externalizing problems in adolescents. Moreover, the findings of the present study provide first evidence that not only adolescent but also parental mental health is relevant to IGD in early adolescence. Adolescent and parental mental health should be considered in prevention and intervention programs for IGD in adolescence.


Seasonality of gout in Korea: a multicenter study.
The object of this study was to evaluate the seasonality of gout in Korea. We retrospectively examined data from 330 patients seen at nine rheumatology clinics, treated with urate lowering therapy (ULT) more than one year after stopping prophylactic medication. Demographic data, clinical and laboratory features, and seasonality of gout onset and flares were collected. Season was classified in three-month intervals. The mean age was 52.2 yr and mean disease duration was 26.8 months. The male to female count was 318:12. The onset of acute gouty attacks was obtained in 256 patients. Gout developed most commonly in summer season (36.7%) (P<0.001) and in June (15.6%, P=0.002). During ULT, there were 147 (male 97.3%) gout flares. Although there was no statistically significant difference, gout flares were more common in summer (30.6%). Aggravating factors were identified in 57 flares: alcohol (72.0%) was most common. In the patients who attained target serum uric acid (<6 mg/dL) at the end of prophylaxis, gout flares were high in fall (35.8%) and September (17.0%). In Korea, the summer is most common season of gout onset and there is a tendency for gout flares to increase during ULT in summer/fall season.


Reliability of information-based integration of EEG and fMRI data: a simulation study.
Most studies involving simultaneous electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) data rely on the first-order, affine-linear correlation of EEG and fMRI features within the framework of the general linear model. An alternative is the use of information-based measures such as mutual information and entropy, which can also detect higher-order correlations present in the data. The estimate of information-theoretic quantities might be influenced by several parameters, such as the numerosity of the sample, the amount of correlation between variables, and the discretization (or binning) strategy of choice. While these issues have been investigated for invasive neurophysiological data and a number of bias-correction estimates have been developed, there has been no attempt to systematically examine the accuracy of information estimates for the multivariate distributions arising in the context of EEG-fMRI recordings. This is especially important given the differences between electrophysiological and EEG-fMRI recordings. In this study, we drew random samples from simulated bivariate and trivariate distributions, mimicking the statistical properties of EEG-fMRI data. We compared the estimated information shared by simulated random variables with its numerical value and found that the interaction between the binning strategy and the estimation method influences the accuracy of the estimate. Conditional on the simulation assumptions, we found that the equipopulated binning strategy yields the best and most consistent results across distributions and bias correction methods. We also found that within bias correction techniques, the asymptotically debiased (TPMC), the jackknife debiased (JD), and the best upper bound (BUB) approach give similar results, and those are consistent across distributions.