[Reclink: an application for database linkage implementing the probabilistic record linkage method].
This paper presents a system for database linkage based on the probabilistic record linkage technique, developed in the C++ language with the Borland C++ Builder version 3.0 programming environment. The system was tested in the linkage of data sources of different sizes, evaluated both in terms of processing time and sensitivity for identifying true record pairs. Significantly less time was spent in record processing when the program was used, as compared to manual processing, especially in situations where larger databases were used. Manual and automatic processes had equivalent sensitivities in situations where we used databases with fewer records. However, as the number of records grew we noticed a clear reduction in the sensitivity of the manual process, but not in the automatic one. Although in its initial stage of development, the system performed well in terms of both processing speed and sensitivity. Although overall performance of algorithms was satisfactory, we intend to evaluate other routines in the attempt to improve the system's performance.


Cisplatin may induce frataxin expression.
Cisplatin is a widely used drug in cancer chemotherapy and resistance to cisplatin is a major limitation for its successful application. Intracellular inactivation of cisplatin and detoxification of reactive oxygen species (ROS) by glutathione (a crucial cellular antioxidant) is a mechanism for cisplatin resistance. During cDNA microarray analyses of differential gene expression between a cisplatin-resistant A2780CP70 human ovarian carcinoma cell line and its parental A2780 cell line, we discovered that frataxin gene expression was frequently overexpressed in the cisplatin-resistant variant. Decreased expression of frataxin protein is associated with Friedreich's ataxia (FRDA) which is a neurodegenerative disease involving ROS-mediated cellular damage. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols. To exploit potential involvement of frataxin gene in the development of resistance to cisplatin, we compared the levels of frataxin gene and protein in the cisplatin-resistant A2780CP70 ovarian carcinoma cell line and its parental A2780 cell line. We found that frataxin mRNA and protein expressions were elevated in the cisplatin-resistant cells. Our results suggest a potential role for cisplatin as an inducer of frataxin expression and implies that this gene may be a potential target for modulating the response to cisplatin. This is the first report showing an association between frataxin expression and cisplatin resistance.


The relationships of posttraumatic stress disorder and depression symptoms with health-related quality of life and the role of social support among Veterans.
The presence of posttraumatic stress disorder (PTSD) or depression symptoms is associated with poor quality of life. Social support buffers against developing symptoms of PTSD and depression and is associated with greater quality of life. We examined the relationships between PTSD and depression symptom severity with physical (PCS) and mental (MCS) health-related quality of life (HRQoL), and whether social support moderated these relationships. Randomly selected Veterans with at least one Primary Care or PTSD Clinical Team visit received a mailed survey including self-report measures of health and wellness. Among the 717 respondents, we examined the association between symptom severity and HRQoL using linear regression. We included interaction terms between symptom severity and social support to examine whether social support moderated these associations. Social support did not moderate the association between symptom severity and mental HRQoL. Higher PTSD and depression symptom severity were associated with lower MCS scores, whereas higher social support was associated with higher MCS scores. When examining physical HRQoL, social support moderated the association with PTSD and depression symptom severity. Among individuals with high social support, there was a negative association between symptom severity and PCS scores, whereas there was no association among those with low social support. Although there are contexts in which social support is helpful, in some cases it may interfere with HRQoL among those with mental health conditions. Thus, it is important to educate support providers about behaviors that enhance the benefits and minimize the costs of social support.


Analysis and quantification of vitamin D metabolites in serum by ultra-performance liquid chromatography coupled to tandem mass spectrometry and high-resolution mass spectrometry--a method comparison and validation.
The aim of the work was to develop and validate a method for the quantification of vitamin D metabolites in serum using ultra-high-pressure liquid chromatography coupled to mass spectrometry (LC/MS), and to validate a high-resolution mass spectrometry (LC/HRMS) approach against a tandem mass spectrometry (LC/MS/MS) approach using a large clinical sample set. A fast, accurate and reliable method for the quantification of the vitamin D metabolites, 25-hydroxyvitamin D2 (25OH-D2) and 25-hydroxyvitamin D3 (25OH-D3), in human serum was developed and validated. The C3 epimer of 25OH-D3 (3-epi-25OH-D3) was also separated from 25OH-D3. The samples were rapidly prepared via a protein precipitation step followed by solid-phase extraction (SPE) using an HLB μelution plate. Quantification was performed using both LC/MS/MS and LC/HRMS systems. Recovery, matrix effect, inter- and intra-day reproducibility were assessed. Lower limits of quantification (LLOQs) were determined for both 25OH-D2 and 25OH-D3 for the LC/MS/MS approach (6.2 and 3.4 µg/L, respectively) and the LC/HRMS approach (2.1 and 1.7 µg/L, respectively). A Passing & Bablok fit was determined between both approaches for 25OH-D3 on 662 clinical samples (1.11 + 1.06x). It was also shown that results can be affected by the inclusion of the isomer 3-epi-25OH-D3. Quantification of the relevant vitamin D metabolites was successfully developed and validated here. It was shown that LC/HRMS is an accurate, powerful and easy to use approach for quantification within clinical laboratories. Finally, the results here suggest that it is important to separate 3-epi-25OH-D3 from 25OH-D3.


The nucleotide sequence of chloroplast 5S ribosomal RNA from a fern, Dryopteris acuminata.
Dryopteris acuminata chloroplasts were found to contain three species of 5S rRNAs with different electrophoretic mobility. The large 5S rRNA species is composed of 122 nucleotides and its sequence is: pUAUUCUGGUGUCCCAGGCGUAGAGGAACCACAC-CGAUCCAUCUCGAACUUGGUGGUGAAACUCUGCCGCGGUAACCA AUACUCGGGGGGGGCCCU-GCGGAAAAAUAGCUCGAUGCCAGGAUAOH. This 5S rRNA shows high sequence homology with those from chloroplasts of flowering plants and from a blue-green alga, Anacystis nidulans.


Angiostatic steroids potentiated by sulfated cyclodextrins inhibit corneal neovascularization.
It is known that hydrocortisone can be converted to a potent angiogenesis inhibitor by coadministration with heparin or with a sulfated cyclodextrin. The activity of tetrahydrocortisol-S, a purely angiostatic corticosteroid, can be potentiated by beta-cyclodextrin tetradecasulfate as shown in this study. This drug "pair" and other pairs of corticosteroids and beta-cyclodextrin tetradecasulfate can be applied topically to inhibit corneal neovascularization. Endotoxin-induced corneal neovascularization in rabbits was treated with beta-cyclodextrin tetradecasulfate coadministered with either: hydrocortisone, tetrahydrocortisol-S, or 6-alpha-fluoro-17,21-dihydroxy-16-beta-methyl-pregna-4,9(11),diene,3, 20-dione. When optimal ratios of steroid and cyclodextrin were used, neovascularization was reduced to 13%, 26%, and 28% of untreated controls for the three steroids, respectively. Hydrocortisone-cyclodextrin drug pairs suppressed virtually all inflammatory cell infiltration (induced by endotoxin), whereas tetrahydrocortisol-cyclodextrin pairs only partially reduced inflammation. These results demonstrate that corneal neovascularization and corneal inflammation are separable processes and that the neovascularization may be treated specifically using angiostatic steroids without inflammatory activity.


Characterization of differentially methylated regions in 3 bovine imprinted genes: a model for studying human germ-cell and embryo development.
Correct imprinting is crucial for normal fetal and placental development in mammals. Experimental evidence in animal models and epidemiological studies in humans suggest that assisted reproductive technologies (ARTs) can interfere with imprinted gene regulation in gametogenesis and early embryogenesis. Bos taurus is an agriculturally important species in which ARTs are commonly employed. Because this species exhibits a similar preimplantation development and gestation length as humans, it is increasingly being used as a model for human germ-cell and embryo development. However, in contrast to humans and mice, there is relatively little information on bovine imprinted genes. Here, we characterized the bovine intergenic IGF2-H19 imprinting control region (ICR) spanning approximately 3 kb. We identified a 300-bp differentially methylated region (DMR) approximately 6 kb upstream of the H19 promoter, containing a CpG island with CTCF-binding site and high sequence similarity with the human intergenic ICR. Additional differentially methylated CpG islands lie -6 kb to -3 kb upstream of the promoter, however these are less conserved. Both classical bisulfite sequencing and bisulfite pyrosequencing demonstrated complete methylation of the IGF2-H19 ICR in sperm, complete demethylation in parthenogenetic embryos having only the female genome, and differential methylation in placental and somatic tissues. In addition, we established pyrosequencing assays for the previously reported bovine SNRPN and PEG3 DMRs. The observed methylation patterns were consistent with genomic imprinting in all analyzed tissues/cell types. The identified IGF2-H19 ICR and the developed quantitative methylation assays may prove useful for further studies on the relationship between ARTs and imprinting defects in the bovine model.


Poly(N-isopropylacrylamide) modified polydopamine as a temperature-responsive surface for cultivation and harvest of mesenchymal stem cells.
A thermo-responsive surface was fabricated by depositing poly(N-isopropylacrylamide) (PNIPAAm) onto polydopamine coated cell culture substrata through free radical polymerization for the purpose of culturing and harvesting human mesenchymal stem cells (hMSCs). Human MSCs were cultured onto the PNIPAAm-g-polydopamine coated surface and harvested by changing from physiological to ambient temperature. The produced PNIPAAm-g-polydopamine surface was characterized by atomic force microscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance, water contact angle measurement, differential scanning calorimetry, and cell culture studies. Our results revealed that hMSCs could be detached from the PNIPAAm-g-polydopamine surface within 60 min after switching the temperature from 37 °C to room temperature. The detached hMSCs were able to proliferate on the PNIPAAm-g-polydopamine coated surface for further growth and harvest.


Role of calcium in stabilizing the structure of hyalin, a major protein component of the sea urchin extraembryonic hyaline layer.
The interactions of NaCl and CaCl2 with the sea urchin embryo coat protein hyalin were investigated. Endogenous protein tryptophan fluorescence was enhanced by almost 45% in the presence of 200mM NaCl while 1mM CaCl2 reversed this effect and brought the intensity of fluorescence back close to that of the native protein. Half-maximal concentrations of 53 and 0.32mM were determined for NaCl and Ca+2, respectively. Hyalin conformation, as measured by circular dichroic spectroscopy, was altered by NaCl and CaCl2 in a fashion parallel to the effects of these salts on tryptophan fluorescence. Sodium chloride disrupted hyalin secondary structure while CaCl2 affected the return of hyalin to its native conformation. The interactions of NaCl and CaCl2 with hyalin were not modulated by MgCl2. These results suggest a role for CaCl2 in stabilizing hyalin against the disruptive effects of the high concentration of NaCl present in sea water.


Secretagogue-induced enzyme release from the exocrine pancreas of rats following adaptation to a high protein diet.
The mechanisms of pancreatic adaptation to dietary changes and whether these changes are reflected in the serum are not fully understood. The present study investigates secretagogue-induced release of digestive enzymes from dispersed pancreatic acini as well as the concentrations of these enzymes in serum and pancreas after adaptation to a high protein diet. Adult rats were fed an 8.5% casein diet ad libitum. After 14 d the rats were divided into three groups and fed isoenergetic diets constituting 8.5, 24 or 40% protein for an additional 6 d. No significant differences in final body weight or pancreatic weight were observed among the groups of rats. Rats adapted to the 40% protein diet showed significantly higher trypsin and chymotrypsin activity in pancreatic homogenates than rats fed the 8.5% protein diet. These changes in pancreatic enzyme content were not reflected in serum. Pancreatic acini isolated from the 8.5% protein group showed a markedly reduced responsiveness to cholecystokinin (CCK-8), secretin- and carbachol-induced enzyme release in comparison to the other two dietary groups, although basal enzyme release was the same in all groups. These results indicate that the secretion of pancreatic enzymes following a physiological stimulus is affected by a low protein, high carbohydrate diet.


[Laparoscopic therapy of appendicovesical fistula -- two case reports].
Two cases of appendicovesical fistula are reported. One case was caused by Crohn's disease, the second case by a chronical appendicitis. The guiding symptoms in both cases were coprosuria and pneumaturia, with chronical infection of the urinary tract. No diagnostic imaging method was able to detect the fistula. The correct diagnosis was finally made by laparoscopy followed by laparoscopical appendicectomy and fistula closure. The clinical symptoms alone seem to be sufficient for indication to operate. Thus, an early laparoscopic operation significantly can shorten the length of disease.


Mode-locking evolution in ring fiber lasers with tunable repetition rate.
We have applied a simple approach to analyze behavior of the harmonically mode-locked fiber laser incorporating an adjustable Mach-Zehnder interferometer (MZI). Our model is able to describe key features of the laser outputs and explore limitations of physical mechanisms responsible for laser operation at different pulse repetition rates tuned over a whole GHz range. At low repetition rates the laser operates as a harmonically mode-locked soliton laser triggered by a fast saturable absorber. At high repetition rates the laser mode-locking occurs due to dissipative four-wave mixing seeded by MZI and gain spectrum filtering. However, the laser stability in this regime is rather low due to poor mode selectivity provided by MZI that is able to support the desired laser operation just near the lasing threshold. The use of a double MZI instead of a single MZI could improve the laser stability and extends the range of the laser tunability. The model predicts a gap between two repetitive rate ranges where pulse train generation is not supported.


Down syndrome and the genes of human chromosome 21: current knowledge and future potentials. Report on the Expert workshop on the biology of chromosome 21 genes: towards gene-phenotype correlations in Down syndrome. Washington D.C., September 28-October 1, 2007.
Down syndrome (DS), trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. With an incidence in some countries as high as one in approximately 700 live births, and a complex, extensive and variably severe phenotype, Down syndrome is a significant medical and social challenge. In recent years, there has been a rapid increase in information on the functions of the genes of human chromosome 21, as well as in techniques and resources for their analysis. A recent workshop brought together experts on the molecular biology of Down syndrome and chromosome 21 with interested researchers in other fields to discuss advances and potentials for generating gene-phenotype correlations. An additional goal of the workshop was to work towards identification of targets for therapeutics that will correct features of DS. A knowledge-based approach to therapeutics also requires the correlation of chromosome 21 gene function with phenotypic features.


An Adaptive Low-Rank Modeling-Based Active Learning Method for Medical Image Annotation.
Active learning is an effective solution to interactively select a limited number of informative examples and use them to train a learning algorithm that can achieve its optimal performance for specific tasks. It is suitable for medical image applications in which unlabeled data are abundant but manual annotation could be very time-consuming and expensive. However, designing an effective active learning strategy for informative example selection is a challenging task, due to the intrinsic presence of noise in medical images, the large number of images, and the variety of imaging modalities. In this study, a novel low-rank modeling-based multi-label active learning (LRMMAL) method is developed to address these challenges and select informative examples for training a classifier to achieve the optimal performance. The proposed method independently quantifies image noise and integrates it with other measures to guide a pool-based sampling process to determine the most informative examples for training a classifier. In addition, an automatic adaptive cross entropy-based parameter determination scheme is proposed for further optimizing the example sampling strategy. Experimental results on varied medical image datasets and comparisons with other state-of-the-art multi-label active learning methods illustrate the superior performance of the proposed method.


ESTIMATING WITHIN-HOUSEHOLD CONTACT NETWORKS FROM EGOCENTRIC DATA.
Acute respiratory diseases are transmitted over networks of social contacts. Large-scale simulation models are used to predict epidemic dynamics and evaluate the impact of various interventions, but the contact behavior in these models is based on simplistic and strong assumptions which are not informed by survey data. These assumptions are also used for estimating transmission measures such as the basic reproductive number and secondary attack rates. Development of methodology to infer contact networks from survey data could improve these models and estimation methods. We contribute to this area by developing a model of within-household social contacts and using it to analyze the Belgian POLYMOD data set, which contains detailed diaries of social contacts in a 24-hour period. We model dependency in contact behavior through a latent variable indicating which household members are at home. We estimate age-specific probabilities of being at home and age-specific probabilities of contact conditional on two members being at home. Our results differ from the standard random mixing assumption. In addition, we find that the probability that all members contact each other on a given day is fairly low: 0.49 for households with two 0-5 year olds and two 19-35 year olds, and 0.36 for households with two 12-18 year olds and two 36+ year olds. We find higher contact rates in households with 2-3 members, helping explain the higher influenza secondary attack rates found in households of this size.


Effect of Inflammatory Mediators Lipopolysaccharide and Lipoteichoic Acid on Iron Metabolism of Differentiated SH-SY5Y Cells Alters in the Presence of BV-2 Microglia.
Lipopolysaccharide (LPS) and lipoteichoic acid (LTA), the Gram-negative and the Gram-positive bacterial cell wall components are important mediators of neuroinflammation in sepsis. LPS and LTA are potent activators of microglial cells which induce the production of various pro-inflammatory cytokines. It has been demonstrated that disturbance of iron homeostasis of the brain is one of the underlying causes of neuronal cell death but the mechanisms contributing to this process are still questionable. In the present study, we established monocultures of differentiated SH-SY5Y cells and co-cultures of differentiated SH-SY5Y cells and BV-2 microglia as neuronal model systems to selectively examine the effect of inflammatory mediators LPS and LTA on iron homeostasis of SH-SY5Y cells both in mono- and co-cultures. We monitored the IL-6 and TNFα secretions of the treated cells and determined the mRNA and protein levels of iron importers (transferrin receptor-1 and divalent metal transporter-1), and iron storing genes (ferritin heavy chain and mitochondrial ferritin). Moreover, we examined the relation between hepcidin secretion and intracellular iron content. Our data revealed that LPS and LTA triggered distinct responses in SH-SY5Y cells by differently changing the expressions of iron uptake, as well as cytosolic and mitochondrial iron storage proteins. Moreover, they increased the total iron contents of the cells but at different rates. The presence of BV-2 microglial cells influenced the reactions of SH-SY5Y cells on both LPS and LTA treatments: iron uptake and iron storage, as well as the neuronal cytokine production have been modulated. Our results demonstrate that BV-2 cells alter the iron metabolism of SH-SY5Y cells, they contribute to the iron accumulation of SH-SY5Y cells by manipulating the effects of LTA and LPS proving that microglia are important regulators of neuronal iron metabolism at neuroinflammation.


Treatment of spastic diplegia in patients with cerebral palsy.
Appropriate treatment, which includes orthopaedic surgery, physical and occupational therapy, recreational therapy, orthotics, and utilization of assistive devices, will improve the functional outcomes of children with cerebral palsy. Medical modalities such as intramuscular injections of botulinum toxin, and constant intrathecal administration of Baclofen via an implanted pump may also be of benefit. There is a defined set of orthopaedic surgical procedures that can enhance function, and the challenge for the surgeon is to identify which combination of procedures is appropriate for each individual patient and at what point during development to implement them. Some surgeons prefer to wait until patients are older (8-10 years) and perform all of their surgical interventions in one sitting. We, however, favor a different approach wherein surgical procedures are done as indicated during childhood development to enhance function and allow further improvement of motor skills. We refer to this approach as 'Staged Multilevel Interventions in the Lower Extremity' or 'SMILE'. This paper will discuss the rationale for this approach and our recommendations regarding the indications and timing of surgical interventions, as well as techniques and outcomes as reported in the literature.


A Solanum lycopersicoides reference genome facilitates insights into tomato specialized metabolism and immunity.
Wild relatives of tomato are a valuable source of natural variation in tomato breeding, as many can be hybridized to the cultivated species (Solanum lycopersicum). Several, including Solanum lycopersicoides, have been crossed to S. lycopersicum for the development of ordered introgression lines (ILs), facilitating breeding for desirable traits. Despite the utility of these wild relatives and their associated ILs, few finished genome sequences have been produced to aid genetic and genomic studies. Here we report a chromosome-scale genome assembly for S. lycopersicoides LA2951, which contains 37 938 predicted protein-coding genes. With the aid of this genome assembly, we have precisely delimited the boundaries of the S. lycopersicoides introgressions in a set of S. lycopersicum cv. VF36 × LA2951 ILs. We demonstrate the usefulness of the LA2951 genome by identifying several quantitative trait loci for phenolics and carotenoids, including underlying candidate genes, and by investigating the genome organization and immunity-associated function of the clustered Pto gene family. In addition, syntenic analysis of R2R3MYB genes sheds light on the identity of the Aubergine locus underlying anthocyanin production. The genome sequence and IL map provide valuable resources for studying fruit nutrient/quality traits, pathogen resistance, and environmental stress tolerance. We present a new genome resource for the wild species S. lycopersicoides, which we use to shed light on the Aubergine locus responsible for anthocyanin production. We also provide IL boundary mappings, which facilitated identifying novel carotenoid quantitative trait loci of which one was likely driven by an uncharacterized lycopene β-cyclase whose function we demonstrate.


Individualized total cavopulmonary connection technique for patients with asplenia syndrome.
Outcomes after univentricular repair for patients with asplenia syndrome remain unsatisfactory, not only because of clinical difficulties in patient selection, but also secondary to technical difficulties in the separation of the systemic and pulmonary circulations, particularly with the rerouting technique for the inferior systemic veins. Between February 1995 and May 2000, a total of 14 consecutive patients with asplenia syndrome underwent bidirectional cavopulmonary connection with obliteration of additional pulmonary blood flow, followed by a total cavopulmonary connection. The rerouting technique for inferior systemic venous blood flow was individualized to optimize laminar nonturbulent flow characteristics in the pathway, and to minimize prosthetic load and suture load on the atrial wall. The lateral tunnel or tube conduit technique was used in an extraatrial, intra-extraatrial, or intraatrial fashion. No fenestration was applied. No hospital mortality was observed. Systemic venous flow was evaluated using magnetic resonance angiography, revealing no signs of obstruction, turbulence, or stasis either in or near the reconstructed pathways, irrespective of the rerouting technique. Postoperative catheterization revealed favorable hemodynamics including an inferior vena cava pressure of 13 +/- 2 mm Hg and arterial oxygen saturation of 93.4% +/- 3.5% at room air. All patients have remained free of symptoms, although 1 patient died of acute septic complications 3.5 years after the procedure. The complexity of cardiac anomalies in asplenia syndrome warrants individualization of the total cavopulmonary connection technique used in reconstruction of the inferior systemic venous pathway. Optimizing flow characteristics in the pathway should be a priority. A staging approach allows suitable selection of candidates for univentricular repair.


Embryo migration following ART documented by 2D/3D ultrasound.
Embryos have traditionally been thought to implant at the exact site they are transferred during assisted reproductive technology (ART). The introduction of 2D/3D ultrasound has allowed for mapping of the transfer site using air bubbles as a surrogate marker of embryo location. This study's aim was to compare the location of embryo transfer (ET) on ultrasound to that of embryo implantation. We present four cases of ectopic pregnancy at four sites: tubal, cervical, interstitial and ovarian. We compare the site of implantation on 2D/3D ultrasound at six weeks of pregnancy to that of transfer as assessed on 2D/3D ultrasound. In all four cases, the embryo flash was visualised in the centre of the uterine cavity on ultrasound at ET. At six weeks of pregnancy, the uterine cavity was empty and an ectopic pregnancy was identified. The tubal and ovarian ectopics were managed surgically whilst the cervical and interstitial pregnancies were treated with systemic methotrexate. These cases demonstrate embryo implantation distal to the ultrasound-confirmed site of transfer. These cases provide visually compelling evidence of embryo migration following ET and lend support to the theory that ectopic pregnancy may occur as a result of embryo migration, rather than poor ET technique.


Epidemiology of the Critically Ill Child in the Resuscitation Bay.
Children account for approximately 33 million annual emergency department (ED) visits in the United States. The spectrum and frequency of children with a critical illness presenting to an ED has not been previously analyzed. The purpose of this study was to examine the range of critical illness presenting to a tertiary Children's Hospital ED. This study was a retrospective chart review of all pediatric patients requiring immediate care in the medical resuscitation bay during a 25-month period from August 2005 to September 2007. Data are from a single center, academic, tertiary care pediatric hospital. A log of all patients requiring immediate care is kept in the medical resuscitation bay. Patients recorded in the log for a period of 25 consecutive months were reviewed for type of critical illness, frequency of critical illness, mode of arrival, and outcome. Trauma patients were excluded. There were approximately 45,000 pediatric visits per year with a total of 87,766 patients seen during the study period. There were 249 pediatric patients who required care in the medical resuscitation bay during the reviewed period. Complete data were obtained from 242 subjects' charts. Patients requiring immediate care accounted for 0.28% of all the visits. This study documents the infrequent need for pediatric critical care in the ED of a nonacademic tertiary children's hospital in the United States and reinforces the need to provide protocols, mock codes, and simulation labs in preparation for critically ill children.


Medical examiner samples: a source for dengue surveillance.
Post-mortem medical examiner samples may be useful for sentinel surveillance of disorders usually detected by antibody determinations on specimens from ill patients or from surveys. We found anti-dengue IgM positivity in 3% (23/780) and anti-dengue IgG positivity in 77% (597/777) of sera obtained at the Puerto Rico medical examiner (Institute of Forensic Sciences) in December 2000, April 2001, and October 2001. This approach may be a useful alternative for estimating the population prevalence of serologic markers for dengue and other infectious diseases.


The effects of Sr-incorporated micro/nano rough titanium surface on rBMSC migration and osteogenic differentiation for rapid osteointegration.
Recruitment of endogenous bone marrow-derived mesenchymal stem cells (BMSCs) has been widely discussed as an alternative strategy for bone regeneration. Strontium (Sr) is known to direct the BMSCs' commitment to the bone lineage and encourage bone formation; however, the underlying mechanisms remain elusive. In this study, an Sr-incorporated micro/nano rough titanium surface (MNT-Sr) was fabricated by hydrothermal treatment in an attempt to facilitate BMSCs' recruitment and their osteogenic differentiation to enhance rapid osseointegration. Micro rough titanium (MT) was set as the control biomaterial. In vitro, MNT-Sr and its extracts promoted the migration and osteogenic differentiation of BMSCs. In animal studies, green fluorescent protein (GFP)-labeled BMSCs were intravenously injected into wild-type rats for tracing before tibial implantation surgery. The GFP+BMSC recruitment to the implantation site was successfully triggered by MNT-Sr implantation. A trend for increased bone area (BA%), bone-implant contact (BIC%) and removal torque values (RTVs) was observed for the MNT-Sr implant compared to that observed for MT at 2 weeks. Advanced mechanism analysis indicated that Sr2+ enhanced the SDF-1α/CXCR4 signaling pathway both in vitro and in vivo. Taken together, these findings suggest that MNT-Sr has promising therapeutic potential for future use in dental implants by homing endogenous stem cells to stimulate bone regeneration.


Structural cell-derived cytokines in allergic inflammation.
Based on observations of fluctuations in progenitors for inflammatory cells during allergic responses, we have proposed that a primary determinant of allergic inflammation involves microenvironmental influences on hemopoietic cell differentiation and phenotype; in addition, as a corollary of this, inflammatory cell burden is proposed as an important indicator of the severity and pattern of the inflammatory process in allergy. The studies outlined here focus on the effects of epithelial-cell- and fibroblast-derived cytokines on granulocytic and monocytic cell differentiation and activation in models involving allergic reactions in the upper and lower airways. Pure cultures of nasal or bronchial epithelial cells or fibroblasts are observed to give rise to cytokines important in inducing the differentiation of basophils, eosinophils, neutrophils and monocyte/macrophages. Gene expression, production and secretion of granulocyte/macrophage-colony-stimulating factor, interleukin-6 (IL-6) and IL-8 can be demonstrated in vitro and in vivo. Up-regulation of gene expression and production of these cytokines, which are important in inducing basophil, eosinophil and neutrophil/macrophage differentiation in several assays, is seen with IL-1 and the neuropeptide substance P; conversely, inhibition of cytokine production by structural cells is observed after pretreatment with corticosteroids in vitro, paralleling in vivo effects. Other modulatory effects also examined include: antiallergic compounds, which may affect posttranscriptional events in cytokine production, and heavy metal ions, which can also induce changes in gene expression. Structural-cell-derived extracellular matrices appear also to be important both in mast cell differentiation and in macrophage cytokine gene expression, both of which potentially feedback upon chronic allergic inflammatory processes, leading to their perpetuation.(ABSTRACT TRUNCATED AT 250 WORDS)


Predictive Analysis of Errors During Robot-Mediated Gamified Training.
This paper presents our approach to predicting future error-related events in a robot-mediated gamified physical training activity for stroke patients. The ability to predict future error under such conditions suggests the existence of distinguishable features and separated class characteristics between the casual gameplay state and error prune state in the data. Identifying such features provides valuable insight to creating individually tailored, adaptive games as well as possible ways to increase rehabilitation success by patients. Considering the time-series nature of sensory data created by motor actions of patients we employed a predictive analysis strategy on carefully engineered features of sequenced data. We split the data into fixed time windows and explored logistic regression models, decision trees, and recurrent neural networks to predict the likelihood of a patient making an error based on the features from the time window before the error. We achieved an 84.4% F1-score with a 0.76 ROC value in our best model for predicting motion accuracy related errors. Moreover, we computed the permutation importance of the features to explain which ones are more indicative of future errors.


Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors.
The mechanism by which COX inhibitors exert their analgesic effect is well established. However, data show no direct correlation between drug concentrations in plasma and the analgesic or adverse effects in chronic inflammatory conditions. This represents a major problem in the development of COX inhibitors, since it is difficult to predict the appropriate dosing regimen for the treatment of chronic inflammatory pain, based upon information from pre-clinical studies and eventually early clinical studies. The factors that determine response in inflammatory pain must be understood in order to make predictions about the time course of the analgesic effect. In this review the determinants of drug response and their variability will be discussed: physicochemical properties, pharmacokinetics (PK), pathophysiology and disease progression. From a mechanistic point of view, endogenous mediators of inflammation might be used as a biomarker for the analgesic effect and safety assessment. Such a biomarker can be an intermediate step between drug exposure and response. In addition, its concentration-effect relationship could be characterized by pharmacokinetic-pharmacodynamic (PK/PD) modelling. Indeed, recent investigations have shown that COX-2 inhibition, as determined by modelling of prostaglandin E2 (PGE2) levels in the whole blood assay in vitro can be used as a marker to predict drug effects (analgesia) in humans. A model-derived parameter, IC80, (total and unbound) was found to correlate directly with the analgesic plasma concentration of different COX inhibitors varying in enzyme selectivity. These findings indicate that PGE2 and thromboxane B2 inhibition can be used to predict and select efficacious doses in humans.


Optical coherence tomography assessment of retinal nerve fiber layer thickness changes after glaucoma surgery.
To assess changes in retinal nerve fiber layer (NFL) thickness in glaucoma patients after filtration surgery by using optical coherence tomography (OCT). Retrospective observational case series. Thirty-eight eyes of 31 glaucoma patients who underwent trabeculectomy or a combined procedure of cataract extraction and trabeculectomy were evaluated retrospectively. Eyes were imaged with OCT before surgery (1 week to 6 months before surgery; mean +/- standard deviation [SD], 71.3 +/- 61.2 days) and after surgery (6-12 months after surgery; 247.2 +/- 63.5 days) to measure peripapillary NFL thickness. Changes in mean and segmental NFL thickness with respect to age, postoperative change in intraocular pressure (IOP), preoperative visual field test global indices, and change in visual field global indices. A significant increase in the overall mean NFL thickness was present after surgery (P < 0.0001). Segmental analysis found a significant increase in NFL thickness in the nasal, superior, and temporal quadrants. IOP decreased after surgery from 22.0 +/- 6.4 mmHg to 11.4 +/- 4.7 mmHg (mean +/- SD). Twenty-eight (73.7%) of 38 eyes had an IOP reduction >30%. The mean NFL thickness increase (0.5- microm/mmHg decrease of IOP) was significantly correlated with the IOP reduction (r = -0.41; P = 0.03). No correlation was found between NFL thickness changes and age, preoperative visual field global indices, or change in visual field global indices. A significant increase of the mean NFL thickness, which was related to IOP reduction, was detected after glaucoma filtration surgery.


Quality and impact of problem-oriented drug information: a method to change clinical practice among physicians?
Problem-oriented drug information is characterised by health professionals actively seeking drug information through various sources. In this study our objective was to determine the quality and impact of problem-oriented drug information among physicians. Evaluation forms accompanying 163 written answers to physicians from a drug information centre were used to examine the quality and impact of problem-oriented drug information during the period December 1996 to June 1998. Physicians were asked whether the preliminary telephone answer was useful and, furthermore, whether the written answer was fast enough, relevant, adequately comprehensive and had valuable references. Physicians were also asked whether the answer had caused any change in their clinical practice. If yes, they were then asked to describe the actual changes. Of 163 evaluation forms, 117 (72%) were returned by physicians. Eighty-six physicians received a preliminary telephone answer and 83 (97%) stated that this was useful. Among the physicians, 92 (79%) found that the answer was fast enough, relevant, adequately comprehensive and with valuable references, while 19 (16%) found that the answer satisfied three of these four quality criteria. Seventy-one evaluation forms stated that the answer had caused a change in clinical practice. Sixty-eight (96%) of these contained a description of the change. Thirty-five evaluation forms that stated that the answers did not cause any change in clinical practice showed the same quality score as for the total group. Thus, 28 (80%) of these satisfied four and 5 (14%) satisfied three of the quality criteria. Improved routines for and control of ongoing pharmacotherapy was the most common change in clinical practice reported by physicians. The results show that, in general, physicians found problem-oriented drug information to be of high quality, and that it had an impact on their clinical practice. Problem-oriented drug information could be a method to change clinical practice among physicians.


Psychiatric comorbidity among children and adolescents with and without persistent attention-deficit hyperactivity disorder.
The aims of the present study were to examine the current psychiatric comorbidity among children and adolescents with and without persistent attention-deficit hyperactivity disorder (ADHD) as compared to school controls, and to determine the factors predicting psychiatric comorbidity. The sample included 296 patients (male, 85.5%), aged 11-17, who were diagnosed with DSM-IV ADHD at the mean age of 6.7 +/- 2.7 years and 185 school controls. The ADHD and other psychiatric diagnoses were made based on clinical assessments and confirmed by psychiatric interviews. The ADHD group was categorized into 186 patients (62.8%) with persistent ADHD and 110 (37.2%) without persistent ADHD. Compared to the controls, the two ADHD groups were more likely to have oppositional defiant disorder (ODD), conduct disorder (CD), tics, mood disorders, past and regular use of substances, substance use disorders and sleep disorders (odds ratios (ORs) = 1.8-25.3). Patients with persistent ADHD had higher risks for anxiety disorders, particularly specific phobia than the controls. Moreover, patients with persistent ADHD were more likely to have ODD than their partially remitted counterparts. Advanced analyses indicated that more severe baseline ADHD symptoms predicted ODD/CD at adolescence; longer methylphenidate treatment duration was associated with an increased risk for tics and ODD/CD at adolescence; and older age predicted higher risks for mood disorders and substance use disorders. Reduced ADHD symptoms at adolescence may not lead to decreased risks for psychiatric comorbidity, and identification of severe ADHD symptoms at childhood and age-specific comorbid patterns throughout the developmental stage is important to offset the long-term adverse psychiatric outcomes of ADHD.


Macroscopic and Mesoscopic Deterioration Behaviors of Concrete under the Coupling Effect of Chlorine Salt Erosion and Freezing-Thawing Cycle.
The aim of this study was to reveal the macroscopic and mesoscopic deterioration behaviors of concrete under the coupling effect of chlorine salt erosion and the freezing-thawing cycle. The rapid freezing-thawing test was carried out in a 5% chlorine salt environment. The macroscopic characteristics of concrete were analyzed by testing the mass, the relative dynamic modulus of elasticity, and the compressive strength of concrete under different freezing-thawing cycles. Using CT scanning technology and three-dimensional reconstruction technology, the pore structure, CT value, and surface deviation of concrete before and after freezing-thawing were analyzed. Based on the changes of solid volume, pore volume, and solid CT value of concrete, the calculation method of relative CT value was proposed, and the damage model was established with relative CT value as the damage variable. The results demonstrate that the mass loss rate decreases in the beginning and then increases in the process of chlorine salt erosion and freezing-thawing, and the smaller the concrete size, the greater the mass loss rate. The relative dynamic modulus of elasticity decreases gradually, slowly at the initial stage and then at a faster rate, and the compressive strength loss rate increases gradually. The pore quantity, porosity, and volume loss rate of concrete increase in a fluctuating manner, whereas the relative CT value decreases. The comprehensive analysis shows that the chlorine salt frost resistance of concrete is negatively related to the water-cement ratio when the freezing-thawing cycle is fixed. The damage model could better reflect the freezing-thawing damage degree of concrete with different water cement ratios, and the damage evolution process is well described by the Weibull function.


An augmented reality microscope with real-time artificial intelligence integration for cancer diagnosis.
The microscopic assessment of tissue samples is instrumental for the diagnosis and staging of cancer, and thus guides therapy. However, these assessments demonstrate considerable variability and many regions of the world lack access to trained pathologists. Though artificial intelligence (AI) promises to improve the access and quality of healthcare, the costs of image digitization in pathology and difficulties in deploying AI solutions remain as barriers to real-world use. Here we propose a cost-effective solution: the augmented reality microscope (ARM). The ARM overlays AI-based information onto the current view of the sample in real time, enabling seamless integration of AI into routine workflows. We demonstrate the utility of ARM in the detection of metastatic breast cancer and the identification of prostate cancer, with latency compatible with real-time use. We anticipate that the ARM will remove barriers towards the use of AI designed to improve the accuracy and efficiency of cancer diagnosis.


Rheumatoid arthritis at a time of passage.
To determine the relationship of what has been called pre-Columbian Old World rheumatoid arthritis (RA) to the RA identified in pre-Columbian North America. All published claims of pre-Columbian Old World RA were reviewed against the established North American standard for its recognition in archeologic sites. Those characteristics included polyarticular symmetrical marginal erosions [in the absence of subchondral erosions, peripheral joint fusion, or axial skeletal involvement (C1-2 excepted)], but requiring the presence of perilesional osteopenia on radiographic examination. T test and Fisher's exact test were used to assess the significance of the extent of joint distribution and the presence of subchondral erosions, peripheral joint fusion, and axial disease in the Old World cases that some have claimed represent RA. Old World reports of alleged RA often describe isolated bones or isolated "finds" without epidemiologic consideration. Subchondral erosions were present in 95%. The 2 cases without subchondral erosions had peripheral joint fusion and axial joint disease. Peripheral joint fusion and axial joint involvement were present in almost all cases. Perilesional sclerosis was actually quite prominent, as was other evidence of reactive new bone formation, but not perilesional osteopenia. As the pre-Columbian Old World erosive arthritis is clearly a different phenomenon from what has been documented in the New World, the issue appears to relate to criteria for naming RA. There clearly are 2 distinct groups that some classify under the broad banner of RA. As the Old World variety is indistinguishable from spondyloarthropathy, it is suggested that the Old World cases should be recategorized with spondyloarthropathy and that only the variety reported in archeologic sites in North America be classified as RA.


Bacillus cereus food poisoning: a provisional serotyping scheme.
A provisional serotyping scheme for Bacillus cereus has been developed. Eighteen selected cultures of B. cereus isolated from foods and clinical specimens were used to prepare agglutinating sera against the flagellar antigen. There were no significant cross-reactions between the sera. The sera were used to type 137 isolates of B. cereus from 34 British and Australian incidents of food poisoning associated with the consumption of cooked rice. The majority of the isolates from samples of food (56 of 84; 66-7%) and from clinical specimens (43 of 53; 81-1%) were of H-serotype 1. Types 1, 3 and 5 were isolated from foods, clinical specimens or both, obtained from 31 of the 34 episodes. Sixty-six isolates of B. cereus were obtained from 63 samples of uncooked long-grain rice. The majority of the isolates (38 of 66; 57-6%) were untypable and types 1, 3 and 5 made up only 5 of 66 (7-5%) of the total. The results support the theory that B. cereus may cause two distinct forms of foodborne illness. Strains from incidents of food poisoning characterised by a longer incubation period and with diarrhoea as the main symptom have provided serotypes 2, 6, 8, 9 and 10, whereas those causing the rice-associated emetic illness are usually serotypes 1, 3 or 5.


Intraoperative frozen section analysis of sentinel lymph nodes in breast cancer patients: a meta-analysis and single-institution experience.
Accurate intraoperative pathologic examination of sentinel lymph nodes (SLNs) has been an important tool that can reduce the need for reoperations in patients with SLN-positive breast cancer. The objective of the current study was to determine the accuracy of intraoperative frozen section (IFS) of SLNs during breast cancer surgery. The authors retrospectively reviewed the records of 326 patients with breast cancer who underwent IF analysis of SLNs at a single institution. Then, they conducted a meta-analysis that included 47 published studies of IFS of SLNs in patients with breast cancer. Hematoxylin and eosin (H&E) staining revealed metastasis in SLNs in 99 patients (30.4%), including 61 patients with macrometastasis (MAM) (>2 mm) (the MAM group) and 38 patients with micrometastasis (Mi) or isolated tumor cell (ITC) deposits (the Mi/ITC group). The overall sensitivity of the institutional series was 60.6% (60 of 99 patients), and overall specificity was 100% (227 of 227 true negatives). The sensitivity of IFS was significantly lower in the Mi/ITC group (28.9%) than in the MAM group (80.3%; P < .0001). According to the meta-analysis of published studies and data from the author's institution (47 studies, for a total of 13,062 patients who underwent SLN dissection with IFS of SLNs), the mean sensitivity was 73%, and the mean specificity was 100%. The mean sensitivity was 94% for the MAM group and 40% for the Mi/ITC group. IFS of SLNs was more reliable for detecting MAM than for detecting Mi/ITC deposits. It lacked sufficient accuracy to rule out Mi/ITC deposits.


Impact of the Scottish Bowel Cancer Screening Programme on patient and tumour characteristics at a single centre.
The Scottish National Bowel Cancer Screening Programme aims to detect asymptomatic colorectal carcinomas and improve outcomes by identifying tumours at an earlier stage. We describe the characteristics of bowel cancers diagnosed through the screening programme since it was established in June 2007 by comparison with colorectal carcinomas from all other referral sources. All patients with colorectal cancer discussed by our regional colorectal multidisciplinary team (MDT) from June 2007 to August 2011 were included. Patient and tumour characteristics were collated prospectively from MDT records. The database was then reviewed retrospectively. During the study 209 916 (58%) of 364 759 invitations to participate in screening were accepted yielding 3895 (1.9%) positive results. The 255 (17%) screening-detected (SD) patients and 1232 (83%) other referrals (ORs) were discussed at the MDT within this period. Median age at diagnosis was 65.5 years for SD vs. 71.6 in OR (P < 0.001) with 64% vs. 53% male [SD vs. OR (P < 0.001)]. There were more left-sided tumours in SD (P = 0.005). Tumours were less advanced in SD group (P = 0.02) and more likely to undergo a laparoscopic resection (P = 0.003). Thirty (11.7%) of SD patients were dead at last follow-up compared with 458 (37.2%) of those from other sources (P < 0.001). This cohort from a centre with an established screening programme supports the effect of screening in detecting earlier stage. Those with screen-detected tumours were more likely to survive than patients from the OR group.


BRAF and NRAS mutations in melanoma and melanocytic nevi.
In this report, we investigated BRAF/NRAS mutations in samples from a case-control study of melanoma and a series of benign melanocytic nevi. We evaluated potential associations between BRAF mutations and histopathologic and pigmentary characteristics of melanoma. Mutations in BRAF and NRAS were detected by sequencing microdissected/laser-captured DNA from 18 in-situ melanomas, 64 primary melanomas, and 51 nevi. Nevi showed the highest frequency of BRAF mutations (82%). BRAF mutations were identified in 29% of invasive melanomas and in only 5.6% of in-situ melanomas. Mutations in NRAS were found in 5.2% of primary melanomas, 5.9% of nevi and no NRAS mutations were seen in in-situ melanomas. A majority of the BRAF mutations observed in primary invasive melanoma were seen in superficial spreading melanoma (15/17), and melanomas with BRAF mutations were also more likely to be found on a body site that was likely to be exposed to intermittent sun exposure compared with chronic or no sun exposure (P=0.02). Tumors with BRAF mutations were also significantly more likely to occur in association with a contiguous nevus (odds ratio 3.49, 95% confidence interval 1.06-11.46), although a contiguous nevus was not found in all melanomas with a BRAF mutation. Our data support the evidence that the mitogen-activated protein kinase pathway is upregulated in a large percentage of melanocytic lesions, but these mutations are not sufficient for malignant transformation. We suggest that BRAF mutations contribute to benign melanocytic hyperplasia, but are likely to contribute to invasive melanoma only in conjunction with other mutations.


The health and nutritional status of schoolchildren in Africa: evidence from school-based health programmes in Ghana and Tanzania. The Partnership for Child Development.
Surveys of the health of schoolchildren in Tanga Region, Tanzania and Volta Region, Ghana are reported. Two age groups of both sexes were studied: 8-9 and 12-13 years old. Children themselves tend to have a poor perception of their health status. This is confirmed by biomedical surveys. Evidence was common of chronic ill-health due to undernutrition, anaemia, parasitic infections and micronutrient deficiencies. The older age groups of both sexes were significantly more stunted (height-for-age z score < 2 below National Center for Health Statistics reference values) than the younger groups, indicating that linear growth continues to falter throughout the school-age years. Anaemia was common: 38% of children in Ghana and 75% of children in Tanzania had a haemoglobin level < 120 g/L. Younger children were more likely to be anaemic than older children, but no significant difference between the sexes was observed. Helminth infections which cause blood loss (Schistosoma haematobium and hookworms) were common and only 37% of children in Ghana and 14% in Tanzania had no evidence of worm infection. In Ghana, 71% of children had a low urinary iodine concentration; in Tanzania 38%. The burden of ill-health suggests that school health programmes in these countries which deliver anthelmintics and micronutrient supplements have the potential to improve the health, growth and educational achievements of schoolchildren.


Organoids: An invaluable tool in pharmacology.
Advances in stem cell cultures and human-induced pluripotent stem cells have inculcated interests in a rapidly evolving concept - "organoids." These are three-dimensional (3D) structures mimicking some of the phenomena of the real organs at anatomical, multicellular, and functional levels in vitro. Organoids have been proven to be better than two-dimensional cell culture in replicating the functionality, architectural, and geometrical features of tissues in vivo. Recent advancements have led to the generation of models for organ development and disease, finding applications in the drug discovery, screening of novel compounds, and personalized medicine. Since organoids follow the same natural pathway as the normal tissue or pathology, they can be used to study the expression of various genotypes and phenotypic variations across different species. In the light of these advancements, organoids are now being merged with bioengineering to come up with even better and reliable models to predict the disease progression and effectiveness of precision medicines, few of its important applications. This article discusses the various aspects of this emerging concept along with its uses, both in the present times and near future, with a special focus on pharmacological applications.


Signaling through sphingolipid microdomains of the plasma membrane: the concept of signaling platform.
Transmembrane signaling requires modular interactions between signaling proteins, phosphorylation or dephosphorylation of the interacting protein partners and temporary elaboration of supramolecular structures, to convey the molecular information from the cell surface to the nucleus. Such signaling complexes at the plasma membrane are instrumental in translating the extracellular cues into intracellular signals for gene activation. In the most straightforward case, ligand binding promotes homodimerization of the transmembrane receptor which facilitates modular interactions between the receptor's cytoplasmic domains and intracellular signaling and adaptor proteins. For example, most growth factor receptors contain a cytoplasmic protein tyrosine kinase (PTK) domain and ligand-mediated receptor dimerization leads to cross phosphorylation of tyrosines in the receptor's cytoplasmic domains, an event that initiates the signaling cascade. In other signaling pathways where the receptors have no intrinsic kinase activity, intracellular nonreceptor PTKs (i.e. Src family PTKs, JAKs) are recruited to the cytoplasmic domain of the engaged receptor. Execution of these initial phosphorylations and their translation into efficient cellular stimulation requires concomitant activation of diverse signaling pathways. Availability of stable, preassembled matrices at the plasma membrane would facilitate scaffolding of a large array of receptors, coreceptors, tyrosine kinases and other signaling and adapter proteins, as it is the case in signaling via the T cell antigen receptor. The concept of the signaling platform has gained usage to characterize the membrane structure where many different membrane-bound components need to be assembled in a coordinated manner to carry out signaling. The structural basis of the signaling platform lies in preferential assembly of certain classes of lipids into distinct physical and functional compartments within the plasma membrane. These membrane microdomains or rafts (Figure 1) serve as privileged sites where receptors and proximal signaling molecules optimally interact. In this review, we shall discuss first how signaling platforms are assembled and how receptors and their signaling machinery could be functionally linked in such structures. The second part of our review will deal with selected examples of raft-based signaling pathways in T lymphocytes and NK cells to illustrate the ways in which rafts may facilitate signaling.


Effects of hyperbaric gases on membrane nanostructure and function in neurons.
This mini-review summarizes current ideas of how hyperbaric gases (>1-10 atmospheres absolute) affect neuronal mechanisms of excitability through molecular interaction with membrane components. The dynamic nature of the lipid bilayer, its resident proteins, and the underlying cytoskeleton make each respective nanostructure a potential target for modulation by hyperbaric gases. Depending on the composition of the gas mixture, the relative concentrations of O(2) and inert gas, and total barometric pressure, the net effect of a particular gas on the cell membrane will be determined by the gas' 1) lipid solubility, 2) ability to oxidize lipids and proteins (O(2)), and 3) capacity, in the compressed state, to generate localized shear and strain forces between various nanostructures. A change in the properties of any one membrane component is anticipated to change conductance of membrane-spanning ion channels and thus neuronal function.


Kinematic and dynamic gait compensations in a rat model of lumbar radiculopathy and the effects of tumor necrosis factor-alpha antagonism.
Tumor necrosis factor-α (TNFα) has received significant attention as a mediator of lumbar radiculopathy, with interest in TNF antagonism to treat radiculopathy. Prior studies have demonstrated that TNF antagonists can attenuate heightened nociception resulting from lumbar radiculopathy in the preclinical model. Less is known about the potential impact of TNF antagonism on gait compensations, despite being of clinical relevance. In this study, we expand on previous descriptions of gait compensations resulting from lumbar radiculopathy in the rat and describe the ability of local TNF antagonism to prevent the development of gait compensations, altered weight bearing, and heightened nociception. Eighteen male Sprague-Dawley rats were investigated for mechanical sensitivity, weight-bearing, and gait pre- and post-operatively. For surgery, tail nucleus pulposus (NP) tissue was collected and the right L5 dorsal root ganglion (DRG) was exposed (Day 0). In sham animals, NP tissue was discarded (n = 6); for experimental animals, autologous NP was placed on the DRG with or without 20 μg of soluble TNF receptor type II (sTNFRII, n = 6 per group). Spatiotemporal gait characteristics (open arena) and mechanical sensitivity (von Frey filaments) were assessed on post-operative Day 5; gait dynamics (force plate arena) and weight-bearing (incapacitance meter) were assessed on post-operative Day 6. High-speed gait characterization revealed animals with NP alone had a 5% decrease in stance time on their affected limbs on Day 5 (P ≤0.032). Ground reaction force analysis on Day 6 aligned with temporal changes observed on Day 5, with vertical impulse reduced in the affected limb of animals with NP alone (area under the vertical force-time curve, P <0.02). Concordant with gait, animals with NP alone also had some evidence of affected limb mechanical allodynia on Day 5 (P = 0.08) and reduced weight-bearing on the affected limb on Day 6 (P <0.05). Delivery of sTNFRII at the time of NP placement ameliorated signs of mechanical hypersensitivity, imbalanced weight distribution, and gait compensations (P <0.1). Our data indicate gait characterization has value for describing early limb dysfunctions in pre-clinical models of lumbar radiculopathy. Furthermore, TNF antagonism prevented the development of gait compensations subsequent to lumbar radiculopathy in our model.


Multi-omics analysis to identify susceptibility genes for colorectal cancer.
Most genetic variants for colorectal cancer (CRC) identified in genome-wide association studies (GWAS) are located in intergenic regions, implying pathogenic dysregulations of gene expression. However, comprehensive assessments of target genes in CRC remain to be explored. We conducted a multi-omics analysis using transcriptome and/or DNA methylation data from the Genotype-Tissue Expression, The Cancer Genome Atlas and the Colonomics projects. We identified 116 putative target genes for 45 GWAS-identified variants. Using summary-data-based Mendelian randomization approach (SMR), we demonstrated that the CRC susceptibility for 29 out of the 45 CRC variants may be mediated by cis-effects on gene regulation. At a cutoff of the Bonferroni-corrected PSMR < 0.05, we determined 66 putative susceptibility genes, including 39 genes that have not been previously reported. We further performed in vitro assays for two selected genes, DIP2B and SFMBT1, and provide functional evidence that they play a vital role in colorectal carcinogenesis via disrupting cell behavior, including migration, invasion and epithelial-mesenchymal transition. Our study reveals a large number of putative novel susceptibility genes and provides additional insight into the underlying mechanisms for CRC genetic risk loci.


Customizable 3D Printed Implants Containing Triamcinolone Acetonide: Development, Analysis, Modification, and Modeling of Drug Release.
Three-dimensional-printed customizable drug-loaded implants provide promising opportunities to improve the current therapy options. In this study, we present a modular implant in which shape, dosage, and drug release can be individualized independently of each other to patient characteristics to improve parenteral therapy with triamcinolone acetonide (TA) over three months. This study focused on the examination of release modification via fused deposition modeling and subsequent prediction. The filaments for printing consisted of TA, ethyl cellulose, hypromellose, and triethyl citrate. Two-compartment implants were successfully developed, consisting of a shape-adaptable shell and an embedded drug-loaded network. For the network, different strand widths and pore size combinations were printed and analyzed in long-term dissolution studies to evaluate their impact on the release performance. TA release varied between 8.58 ± 1.38 mg and 21.93 mg ± 1.31 mg over three months depending on the network structure and the resulting specific surface area. Two different approaches were employed to predict the TA release over time. Because of the varying release characteristics, applicability was limited, but successful in several cases. Using a simple Higuchi-based approach, good release predictions could be made for a release time of 90 days from the release data of the initial 15 days (RMSEP ≤ 3.15%), reducing the analytical effort and simplifying quality control. These findings are important to establish customizable implants and to optimize the therapy with TA for specific intra-articular diseases.


Ankle fracture syndesmosis fixation and management: the current practice of orthopedic surgeons.
There is a wide variety of treatments for disruption of the syndesmosis. There is also controversy as to which device should be used for fixation of the syndesmosis, how many devices should be used, how many cortices the screws should engage, and whether, when, and where the screws should be removed. We conducted a study to determine how orthopedic surgeons manage these injuries. In a survey, we asked orthopedic trauma and foot and ankle fellowship directors and members of the Orthopaedic Trauma Association and the American Orthopaedic Foot and Ankle Society how they routinely treated the syndesmotic injury component of Danis-Weber type C or Lauge-Hansen pronation-external rotation type IV ankle fractures. The overall response rate was 50% (77/153). Fifty-one percent of respondents routinely used 3.5-mm cortical screws, 24% routinely used 4.5-mm cortical screws, and 14% routinely used a suture fixation device. Forty-four percent of respondents routinely used 1 screw, 44% routinely used 2 screws, and the rest were undecided between 1 and 2 screws. Twenty-nine percent of respondents engaged 3 cortices with syndesmotic screws, and 67% engaged 4 cortices. Syndesmotic screws were routinely removed 65% of the time and left in place 35% of the time. Routine removal of syndesmotic screws was done in the operating room in 95% of cases; it was done at 3 months in 49% of cases, at 4 months in 37%, and at 6 months in 12%. The most common method for treating syndesmotic injuries was through use of 3.5-mm screws engaging 4 cortices routinely removed in the operating room at 3 months. Number of screws used to fix the syndesmosis, either 1 or 2, was evenly split.


Butyrfentanyl overdose resulting in diffuse alveolar hemorrhage.
Butyrfentanyl is a potent short-acting opioid and a fentanyl analog with uncertain clinical effects. A review of the literature reveals no human case reports of butyrfentanyl overdose. As the use of analog and synthetic drugs continues to increase, clinicians are often faced with tremendous uncertainty when they encounter patients exposed to these synthetic drugs. We describe, to our knowledge, the first case of a butyrfentanyl overdose that resulted in clinically significant hemoptysis, acute lung injury, hypoxic respiratory failure, and diffuse alveolar hemorrhage. Complicating this case was a false-positive urine drug screen for fentanyl. Clinicians who encounter fentanyl exposures should be aware they may in fact be dealing with butyrfentanyl. As little is known of butyrfentanyl and our patient suffered a significant pulmonary hemorrhage, those who encounter butyrfentanyl exposures should monitor for hemorrhagic complications.


The factor structure of the Hospital Anxiety and Depression Scale in individuals with traumatic brain injury.
There is a lack of validated scales for screening for anxiety and depression in individuals with traumatic brain injury (TBI). The purpose of this study was to examine the factor structure of the Hospital Anxiety and Depression Scale (HADS) in individuals with TBI. A total of 294 individuals with TBI (72.1% male; mean age 37.1 years, S.D. 17.5, median post-traumatic amnesia (PTA) duration 17 days) completed the HADS 1 year post-injury. A series of confirmatory factor analyses was conducted to examine the fit of a one-, two- and three-factor solution, with and without controlling for item wording effects (Multi-Trait Multi-Method approach). The one-, two- or three-factor model fit the data only when controlling for negative item wording. The results are in support of the validity of the original anxiety and depression subscales of the HADS and demonstrate the importance of evaluating item wording effects when examining the factor structure of a questionnaire. The results would also justify the use of the HADS as a single scale of emotional distress. However, even though the three-factor solution fit the data, alternative scales should be used if the purpose of the assessment is to measure stress symptoms separately from anxiety and depression.


Mechanical probes can predict tenderness of cooked beef longissimus using uncooked measurements.
Two experiments were conducted to determine the effectiveness of using mechanical probes and objective color measurement on beef LM to predict cooked tenderness. In Exp. 1, sharp needle (SN), sharp blade (SB), blunt needle (BN), blunt blade (BB), and plumb bob (PB) probes were used to measure uncooked LM (n = 29) at 2 d postmortem in both a perpendicular and parallel orientation to the long axis of the strip loin. Additionally, instrumental color measurements were measured on uncooked muscle at 2 d postmortem. Steaks for trained sensory panel (TSP) and Warner-Bratzler shear force (WBSF) measurements were aged 14 d postmortem before cooking. Probe measurements taken perpendicular to the long axis of the LM were not correlated (P = 0.22 to 0.82) to TSP tenderness. Probe measurements (BB, BN, SN, SB, and PB) taken parallel to the long axis were correlated to TSP tenderness (r = -0.57, -0.40, -0.77, -0.52, and -0.53, respectively). A regression equation using the SN probe to predict TSP tenderness had a R2 value of 0.74. The SB probe combined with L* accounted for 45% of the variation in TSP tenderness, whereas the PB probe combined with L* accounted for 56% of the variation in TSP tenderness. A second experiment (n = 24) was conducted using the SN, SB, and PB probes on uncooked sections at 2 d and on cooked steaks at 14 d postmortem. Probe measurements on cooked steaks were not correlated to TSP tenderness. New regression equations were calculated using the probe measurements on uncooked steaks from both experiments. Prediction equations formulated with L* values and either SN, SB, or PB probes accounted for 49, 50, and 47% of the variability in TSP tenderness scores, respectively. An equation using WBSF of cooked steaks to predict TSP tenderness had an R2 of 0.58. Of the steaks predicted to be tender (predicted tenderness > 5.0) by the equations using the SN, SB, and PB probes on uncooked steaks and WBSF on cooked steaks, 85, 88, 80, and 84%, respectively, were actually tender (TSP tenderness > 5.0). Mechanical probe measurements of uncooked steaks at 2 d postmortem can potentially classify strip loins into groups based on tenderness, as well as WBSF measurements, which are more costly and time consuming.


A study of standardized extracts of Picrorhiza kurroa Royle ex Benth in experimental nonalcoholic fatty liver disease.
As a major organ of intermediary metabolism, the liver is exposed to a variety of metabolic insults due to diseases and xenobiotics viz., insulin resistance (IR) drugs, toxins, microbial products, etc. One of the consequences of these metabolic insults including obesity and type 2 diabetes mellitus is the development of non-alcoholic fatty liver disease (NAFLD). The recent alarming increase in the prevalence of NAFLD compels the need to develop an appropriate animal model of the disease so as to evolve effective interventions. In this study, we have developed, in the rat, a new model of NAFLD showing several key features akin to the disease in humans. Male Wistar rats were challenged with 30% high fat diet (HFD) - butter, for 2 weeks to induce NAFLD. A hydroalcoholic extract of Picrorhiza kurroa was administered to study the possible reversal of fatty changes in the liver. The extract was given in two doses viz., 200mg/kg and 400 mg/kg b.i.d., p.o. for a period of 4 weeks. There were three control groups (n = 6/group) - vehicle with a regular diet, vehicle with HFD, and HFD with silymarin - a known hepatoprotective.Histopathology showed that the P. kurroa extract brought about a reversal of the fatty infiltration of the liver (mg/g) and a lowering of the quantity of hepatic lipids (mg/g) compared to that in the HFD control group (38.33 ± 5.35 for 200mg/kg; 29.44 ± 8.49 for 400mg/kg of P. kurroa vs.130.07 ± 6.36mg/g of liver tissue in the HFD control group; P<0.001). Compared to the standard dose of the known hepatoprotective silymarin, P. kurroa reduced the lipid content (mg/g) of the liver more significantly at the dose of 400mg/kg (57.71 ± 12.45mg/kg vs. 29.44 ± 8.49 for the silymarin group vs. 400mg/kg of P. kurroa, P<0.001). In view of the increasing prevalence of metabolic syndrome and NAFLD, P. kurroa should be investigated by the reverse pharmacology path as a potential drug for the treatment of NAFLD, and essential safety studies and preformulation research for concentration of the putative actives should be carried out.


A review of powered-two-wheeler behaviour and safety.
Powered-two-wheelers (PTWs) constitute a very vulnerable type of road users. The notable increase in their share in traffic and the high risk of severe accident occurrence raise the need for further research. However, current research on PTW safety is not as extensive as for other road users (passenger cars, etc.). Consequently, the objective of this research is to provide a critical review of research on Power-Two-Wheeler behaviour and safety with regard to data collection, methods of analysis and contributory factors, and discuss the needs for further research. Both macroscopic analyses (accident frequency, accident rates and severity) and microscopic analyses (PTW rider behaviour, interaction with other motorised traffic) are examined and discussed in this paper. The research gaps and the needs for future research are identified, discussed and put in a broad framework. When the interactions between behaviour, accident frequency/rates and severity are co-considered and co-investigated with the various contributory factors (riders, other users, road and traffic environment, vehicles), the accident and injury causes as well as the related solutions are better identified.


Mitochondrial dysfunction and migraine: evidence and hypotheses.
The molecular basis of migraine is still not completely understood. An impairment of mitochondrial oxidative metabolism might play a role in the pathophysiology of this disease, by influencing neuronal information processing. Biochemical assays of platelets and muscle biopsies performed in migraine sufferers have shown a decreased activity of the respiratory chain enzymes. Studies with phosphorus magnetic resonance spectroscopy ((31)P-MRS) have demonstrated an impairment of the brain oxidative energy metabolism both during and between migraine attacks. However, molecular genetic studies have not detected specific mitochondrial DNA (mtDNA) mutations in patients with migraine, although other studies suggest that particular genetic markers (i.e. neutral polymorphisms or secondary mtDNA mutations) might be present in some migraine sufferers. Further studies are still needed to clarify if migraine is associated with unidentified mutations on the mtDNA or on nuclear genes that code mitochondrial proteins. In this paper, we review morphological, biochemical, imaging and genetic studies which bear on the hypothesis that migraine may be related to mitochondrial dysfunction at least in some individuals.


Cognitive and motor functioning in Parkinson disease: subjects with and without questionable dementia.
The nature of cognitive performance in subjects with Parkinson disease (PD) without dementia is controversial, perhaps because of failure to exclude subjects with unrecognized very mild dementia. To compare cognitive and motor functioning in well-characterized subjects with PD without overt dementia with healthy elderly control subjects. Subjects' conditions were evaluated clinically and psychometrically at entry into a longitudinal study of cognitive and motor performance in elderly subjects. Measures included a global dementia staging scale, the Washington University Clinical Dementia Rating; psychometric tests, including Logical Memory, Digit Span, Associate Learning, Information, Block Design, Digit Symbol, Trail-making A, Crossing-off, Boston Naming Test, and Word Fluency; and motor measures, including finger tapping, gait velocity, reaction time, and movement time. A university-based research facility. There were 3 groups of subjects: healthy elderly control subjects (n=43), subjects with PD without dementia (n=58), and subjects with PD with questionable dementia (n=22), each evaluated at time of entry. As expected, both PD groups were impaired on motor measures (gait velocity, finger tapping, and movement time) compared with the healthy elderly control group. Neither PD group showed slowing in reaction time. The subjects with PD with questionable dementia were more impaired on Logical Memory, Block Design, Digit Symbol, and Trailmaking A compared with the subjects with PD without dementia. Although free of clinically evident cognitive dysfunction (Clinical Dementia Rating score, 0), the PD group without dementia was impaired with respect to the healthy elderly control group on all measures from the psychometric assessment except Digit Span, Associate Learning, and Word Fluency. The PD group without dementia showed global cognitive impairments in comparison with the healthy elderly control group, possibly because the healthy elderly control subjects represented idealized aging. Although the deficits were of small magnitude, this finding suggests that PD may predispose to subclinical cognitive impairment. Longitudinal follow-up is required to determine whether subjects with PD destined to develop overt dementia can be distinguished from those who do not.


Effects on variable-interval performance in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately and in combination.
The objective of this investigation was to study the influence of the dose ratio between cannabidiol (CBD) and delta 9-tetrahydrocannabinol (delta 9-THC) on the effects of mixtures of the two cannabinoids on variable-interval (VI) schedule performance in rats. The effect on VI performance of a control solution, 10 mg/kg CBD, delta 9-THC (0.125, 0.5, 2 and 8 mg/kg) and a mixture of 10 mg/kg CBD + delta 9-THC (0.125, 0.5, 2 and 8 mg/kg) was investigated in 10 rats, with a different sequence of treatments for each animal. The results were expressed in terms of rate-dependency. The control solution, 10 mg/kg CBD, 0.125 mg/kg delta 9-THC, or 10 mg/kg CBD + delta 9-THC (0.125 mg/kg) did not cause rate-dependent effects. Delta 9-THC (0.5 and 2 mg/kg) produced rate-dependent effects. The dose of 8 mg/kg delta 9-THC almost suppressed responding. The combination of 10 mg/kg CBD + 0.5 mg/kg delta 9-THC did not cause rate-dependent effects but produced a response pattern similar to that obtained with 0.125 mg/kg delta 9-THC. At these doses CBD antagonized delta 9-THC. The combination of 10 mg/kg CBD + 2 mg/kg delta 9-THC caused rate-dependent effects. The rate-dependent regression line determined by this mixture was parallel to that produced by 2 mg/kg delta 9-THC. However, the lower intercept of the mixture with the y axis suggested potentiation of the depressant effects of delta 9-THC by CBD.(ABSTRACT TRUNCATED AT 250 WORDS)


Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53.
The cellular function of p53 is complex. It is well known that p53 plays a key role in cellular response to DNA damage. Moreover, p53 was implicated in cellular senescence, and it was demonstrated that p53 undergoes modification in senescent cells. However, it is not known how these modifications affect the ability of senescent cells to respond to DNA damage. To address this question, we studied the responses of cultured young and old normal diploid human fibroblasts to a variety of genotoxic stresses. Young fibroblasts were able to undergo p53-dependent and p53-independent apoptosis. In contrast, senescent fibroblasts were unable to undergo p53-dependent apoptosis, whereas p53-independent apoptosis was only slightly reduced. Interestingly, instead of undergoing p53-dependent apoptosis, senescent fibroblasts underwent necrosis. Furthermore, we found that old cells were unable to stabilize p53 in response to DNA damage. Exogenous expression or stabilization of p53 with proteasome inhibitors in old fibroblasts restored their ability to undergo apoptosis. Our results suggest that stabilization of p53 in response to DNA damage is impaired in old fibroblasts, resulting in induction of necrosis. The role of this phenomenon in normal aging and anticancer therapy is discussed.


[Malignant gliomas. Management and therapeutical results (author's transl)].
Decisions regarding surgical treatment of cerebral tumours depend on the nature and the operability. A tumour which is easily accessible without functional risk can be operated on immediately even if there is some doubt as to its precise nature. In the case of an anatomically ill defined tumour in an area of high functional risk, surgery should not be considered before undertaking stereotaxic investigation. This allows confirmation of (in 8% of cases) correction of the diagnosis and provides the surgeon with precise anatomical information enabling him to choose the most effective and least traumatic means. Therapeutic results are analysed in function of histological grade and reduction or otherwise of the tumour by surgery of interstitial radiotherapy. The interest and limitations of stereotaxic investigation are discussed and therapeutic results analysed. We conclude that : 1) convincing histological evidence is required before deciding on radiotherapy and chemotherapy ; 2) age and functional state are important factors in prognosis ; 3) tumoral reduction by surgery renders radiotherapy and chemotherapy more effective.


Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intrastriatal microdialysis.
Parkinson's disease (PD) patients express motor symptoms only after 60-80% striatal dopamine (DA) depletion. The presymptomatic phase of the disease may be sustained by biochemical modifications within the striatum. We used an appropriate specific 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model (Mounayar et al., 2007) to study the compensatory mechanisms operating in recovery from PD motor symptoms. We assessed the levels of DA and its metabolites (DOPAC, homovanillic acid), GABA, glutamate (Glu), serotonin (5-HT) and its metabolite (5HIAA) by repeated intracerebral microdialysis in awake animals before exposure to MPTP during full expression of the motor symptoms induced by MPTP and after recovery from these symptoms. Measurements were obtained from two functionally and anatomically different striatal areas: the associative-limbic territory and sensorimotor territory. Animals with motor symptoms displayed an extremely large decrease in levels of DA and its metabolites and an increase in Glu and GABA levels, as reported by other studies. However, we show here for the first time that serotonin levels increased in these animals. We found that increases in DA levels in the sensorimotor and/or associative-limbic territory and high levels of 5-HT and of its metabolite, 5HIAA, were associated with recovery from motor symptoms in this model. Determining whether similar changes in DA and 5-HT levels are involved in the compensatory mechanisms delaying the appearance of motor symptoms in the early stages of PD might make it possible to develop new treatment strategies for the disease.


A Sense of Continuity in Mortality? Exploring Science-Oriented Finns' Views on Afterdeath.
Endorsement of science might entail a belief in "secular death", in which an individual faces annihilation as the bodily functions cease. In this article, we examine what science-oriented individuals think happens to humans after death. Does endorsement of science entail views on human annihilation or do people also express continuity beliefs? The open-ended responses of 387 Finns were analysed. The respondents were recruited online via organisations that promote science and research. The results suggest that while science-oriented Finns mainly endorsed annihilation and secular death, some also expressed (mostly nonreligious) views on continuation, e.g., in social bonds and nature. Secular forms of continuity were more likely mentioned by unbelievers, while theist respondents relied primarily on afterlife beliefs.


Functional brain imaging in apraxia.
An extensive literature describes structural lesions in apraxia, but few studies have used functional neuroimaging. We used positron emission tomography (PET) to characterize relative cerebral glucose metabolism in a 65-year-old, right-handed woman with progressive decline in ability to manipulate objects, write, and articulate speech. To characterize functional brain organization in apraxia. The patient underwent a neurological examination, neuropsychological testing, magnetic resonance imaging, and fludeoxyglucose F 18 PET. The patient's magnetic resonance image was coregistered to her PET image, which was compared with the PET images of 7 right-handed, healthy controls. Hemispheric regions of interest were normalized by calcrine cortex. Except for apraxia and mild grip weakness, results of the neurological examination were normal. There was ideomotor apraxia of both hands (command, imitation, and object) and buccofacial apraxia. The patient could recognize meaningful gestures performed by the examiner and discriminate between his accurate and awkward pantomime. The magnetic resonance image showed moderate generalized atrophy and mild ischemic changes. Positron emission tomographic scans showed abnormal fludeoxyglucose F 18 uptake in the posterior frontal, supplementary motor, and parietal regions, the left affected more than the right. Focal metabolic deficit was present in the angular gyrus, an area hypothesized to store conceptual knowledge of skilled movement. Greater parietal than frontal physiological dysfunction and preserved gesture recognition are not consistent with the theory that knowledge of limb praxis is stored in the dominant parietal cortex. Gesture comprehension may be more diffusely distributed.


A new paradigm for transcription factor TFIIB functionality.
Experimental and bioinformatic studies of transcription initiation by RNA polymerase II (RNAP2) have revealed a mechanism of RNAP2 transcription initiation less uniform across gene promoters than initially thought. However, the general transcription factor TFIIB is presumed to be universally required for RNAP2 transcription initiation. Based on bioinformatic analysis of data and effects of TFIIB knockdown in primary and transformed cell lines on cellular functionality and global gene expression, we report that TFIIB is dispensable for transcription of many human promoters, but is essential for herpes simplex virus-1 (HSV-1) gene transcription and replication. We report a novel cell cycle TFIIB regulation and localization of the acetylated TFIIB variant on the transcriptionally silent mitotic chromatids. Taken together, these results establish a new paradigm for TFIIB functionality in human gene expression, which when downregulated has potent anti-viral effects.


Focal symmetrical encephalomalacia in a goat.
Focal symmetrical encephalomalacia (FSE) is the most prominent lesion seen in the chronic form of enterotoxemia caused by Clostridium perfringens type D in sheep. However, this lesion has not been reported in goats. The current paper reports a case of FSE in a goat from the state of Paraíba in the Brazilian semiarid region. As reported by the farmer, 30, 4-48-month-old animals from a flock of 150 goats died after showing nervous signs, including blindness and recumbence, for periods varying between 1 and 14 days. The flock was grazing native pasture supplemented with wheat and corn bran. Additionally, lactating goats were supplemented with soybeans. A 4-month-old goat with nervous signs was examined clinically and then necropsied 3 days after the onset of clinical signs. Bilateral, focal, and symmetrical areas of brown discoloration were observed in the internal capsule and thalamus. Histologic lesions in these areas consisted of multifocal, bilateral malacia with a few neutrophils; endothelial cell swelling; perivascular edema; and hemorrhages. The etiology of these lesions was not determined. However, FSE is considered pathognomonic for C. perfringens type D enterotoxemia in sheep, and it is speculated that this microorganism was the etiologic agent in the present case. The flock had been vaccinated against type D enterotoxemia only once, approximately 3 months before the beginning of the outbreak. Insufficient immunity due to the incorrect vaccination protocol, low efficacy of the vaccine used, and a diet including large amounts of highly fermentable carbohydrates were suspected to be predisposing factors for this outbreak.


Cross-Sectional International Survey to Determine the Educational Interests of Spanish-Speaking Latin American Radiation Oncologists.
With the existing oncology disparities in Latin America, physician expertise has been cited as a possible contributor to inferior oncologic outcomes in some cancers. As two-dimensional radiotherapy rapidly evolved to intensity-modulated radiation therapy in Latin America, adequate contouring education is an actionable target to improving physician knowledge and clinical outcomes. Yet, topics of interest to Latin American radiation oncologists are underreported. We assessed Latin American interest in a virtual platform for case discussion and identified the educational topics of most interest to them. A Spanish-language online survey was designed by a team of Latin American educators. The questions assessed professional nationality, desire for an online educational platform for case presentation, career length, and topics of interest. Educational topics included head and neck (H&N), CNS, GI, lung, gynecologic, breast, and pediatric cancers, lymphoma, sarcoma, stereotactic body radiotherapy (SBRT), brachytherapy, and medical physics. One hundred thirty-three surveys were included for analysis. Overall, 127 respondents (98%) affirmed interest in participating in a virtual platform for case discussion and treatment advances. The most popular educational themes were H&N cancers (24%), SBRT (14%), and CNS cancers (13%). Of countries with > 10 respondents, the most popular educational topic remained H&N cancers for Argentina, Chile, and Mexico, but the most popular topic among Peruvian respondents was CNS cancer (27%). With international collaboration and a large sample size, we present the first survey results describing Latin American radiation oncology educational interests. Participants were overwhelmingly interested in a virtual platform, and most were specifically interested in H&N cancer education. These results can be used for focused didactic preparation in Latin America. Future efforts should expand on improving representation and outreach among Central American radiation oncologists.


Diagnostic laparoscopy: an update.
With new technical advances, wider availability, and the recent proliferation of less invasive surgery, the use of diagnostic laparoscopy has expanded far beyond its traditional role in the evaluation of chronic liver disease. Short of open laparotomy, diagnostic laparoscopy is the most accurate modality for staging of intra-abdominal malignancies, and is particularly well-suited for patients who otherwise would not require surgical palliation. In addition to avoiding unnecessary laparotomy in this group, diagnostic laparoscopy has proved valuable in the assessment of abdominal trauma, acute abdomen, and ischemic bowel disease. We briefly review here some of the new developments in the field of diagnostic laparoscopy.


[Hemodynamic features during coronary bypass surgery on the working heart].
Changes in hemodynamics and blood oxygen transport function were studied during coronary bypass surgery (CBS) on the working heart under anesthesia with propofol and fentanyl. In patients operated on the working heart, the course of the basic stage of an operation was characterized by a moderate reduction in cardiac index and stroke volume due to the cardiac changes and immobilization, which resulted in cardiac compression and venous return deterioration. These impairments did not lead to worse oxygen-transportfunction and they were completely eliminated in the rehabilitative period. Analyzing the results of studies of troponin-T and creatinine kinase-MB showed that the procedure of coronary bypass surgery without using EKK had a less damaging effect on the myocardium. Analyzing the course of an early postoperative period indicated that the use of perfusionless technology substantially reduced needs for inotropic support, the time of artificial ventilation, and the length of stay at an intensive care unit.


Efficient ArF laser production and detection of carbon atoms from simple hydrocarbons.
Excimer lasers are currently being utilized as a means of photofragmentation and fragment excitation for chemical detection purposes. In the case of small hydrocarbons, this phenomenon is generally not well characterized and is poorly understood. Experiments aimed at a better understanding of the interaction of simple carbon-containing molecules with the ArF (193-nm) excimer laser and at exploring the potential analytical applications of this process are described. Specifically, carbon atoms were generated by multiphoton photolysis of CO, CH(4), C(2)H(2), C(3)H(8), CH(3)OH, and CH(3)COCH(3) using the ArF laser. Their presence was detected by two sensitive methods, laser-induced fluorescence (LIF) and resonance ionization emission spectroscopy (RIES), both of which take advantage of the coincident overlap between the ArF laser and the(1)D(2) ? (1)P(1)(0) transition at 193.1 nm with emission detection at 247.9 nm. The RIES method detects single photons resulting from the photolytically produced carbon ion recombination and relaxation processes. An enhancement in the RIES signal was observed when a second tunable laser pulse operating at 247.9 nm followed the ArF laser pulse. Both methods not only offer sensitive detection of the photolytic precursor molecules but also require only relatively simple experimental apparatus. Detection levels for the precursor molelcule considerably lower than 10(11)/cc for LIF and 10(12)/cc for RIES can be estimated based on the observed rates of signal production.


Mechanisms of progression of chronic kidney disease.
Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. We will review possible mechanisms of progressive renal damage, including systemic and glomerular hypertension, various cytokines and growth factors, with special emphasis on the renin-angiotensin-aldosterone system (RAAS), podocyte loss, dyslipidemia and proteinuria. We will also discuss possible specific mechanisms of tubulointerstitial fibrosis that are not dependent on glomerulosclerosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number.


Human EEG recordings for 1,854 concepts presented in rapid serial visual presentation streams.
The neural basis of object recognition and semantic knowledge has been extensively studied but the high dimensionality of object space makes it challenging to develop overarching theories on how the brain organises object knowledge. To help understand how the brain allows us to recognise, categorise, and represent objects and object categories, there is a growing interest in using large-scale image databases for neuroimaging experiments. In the current paper, we present THINGS-EEG, a dataset containing human electroencephalography responses from 50 subjects to 1,854 object concepts and 22,248 images in the THINGS stimulus set, a manually curated and high-quality image database that was specifically designed for studying human vision. The THINGS-EEG dataset provides neuroimaging recordings to a systematic collection of objects and concepts and can therefore support a wide array of research to understand visual object processing in the human brain.